RU2791904C2 - Compounds and methods for targeted degradation of androgen receptor - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a bifunctional compound of ABM - L - CLM structure and its pharmaceutically acceptable salts, which contain at one end cereblon ligand, which binds to E3-ubiquitin ligase, and at the other end a fragment, which binds an androgen receptor, so that the androgen receptor is placed next to ubiquitin ligase to affect the degradation or inhibition of the androgen receptor, and also to a pharmaceutical composition for the treatment of prostate cancer based on them. In the general formula ABM - L - CLM, L is

where q is an integer from 1 to 8; each A^L is selected from CR^L1R^L2, O, NR^L3, C_3-11 cycloalkyl, azetidinyl, piperazinyl, piperidinyl; and R^L1, R^L2, and R^L3, each independently, is H, C_1-6 alkyl; CLM is a fragment binding cereblon E3-ubiquitin ligase, represented by a chemical structure:

where W is selected from CH₂ and C=O; each X is O; Z is O; G is H; each of Q₁, Q₂, Q₃, and Q₄ is C; A is H; n is an integer from 1 to 3; each R is independently -OR', -NR'R", -SR', piperazinyl, piperidinyl, -F, -Br, -I, -CF₃, -CN, -NO₂, -CO₂R', or -OCF₃, where one R is modified for covalent addition to PTM via a chemical linker fragment (L); R' and R" are independently selected from a bond, H, alkyl; and ABM contains a structure selected from a group consisting of:

and

,

where: W¹ is phenyl independently substituted with 1-3 of: H; halogen; CN; unbranched or branched C_1-6 alkyl optionally substituted with 1-3 substitutes selected from halogen and C_1-6 alkoxyl; each of Y³, Y⁴, Y⁵ is independently a bond, O, NR^Y2, CR^Y1R^Y2, or C=O; Q is 5- or 6-element alicyclic or aromatic ring with 0-2 heteroatoms, optionally substituted with 1 R^Q, each R^Q is independently: unbranched or branched C_1-6 alkyl; R^Y1 and R^Y2 are H; W² is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, or pyrazolyl, each optionally substituted with 1 R^W2; each R^W2 is halogen.

EFFECT: development of new bifunctional compounds, which function with the involvement of endogenous proteins to E3-ubiquitin ligase for degradation for the treatment of prostate cancer.

13 cl, 2 tbl, 7 dwg, 625 ex

Description

Link to related applications

[0001] This application claims priority under U.S. Provisional Application Serial No. 62/406888 filed October 11, 2016, U.S. Provisional Application Serial No. 62/528385 filed July 3, 2016, both of which are incorporated herein by reference in their entirety for all purposes.

Publicly funded research statement

[0002] The present invention was made with government support under grant number 1R44CA203199-01 from the National Cancer Institute. The government has certain rights to the present invention.

Inclusion by reference

[0003] U.S. Patent Application Serial No. 14/686640, filed April 14, 2015, published as U.S. Patent Application Publication Serial No. 2016/0058872; U.S. Patent Application Serial No. 14/792414, filed July 6, 2015, published as U.S. Patent Application Publication Serial No. 2015/0291562; U.S. Patent Application Serial No. 14/371956, filed July 11, 2014, published as U.S. Patent Application Publication Serial No. 2014/0356322; U.S. Patent Application Serial No. 15/074820, filed March 18, 2016, published as U.S. Patent Application Publication Serial No. 2016/0272639, are incorporated herein in their entirety. In addition, all references cited herein are incorporated herein by reference in their entirety.

The field of technology to which the present invention relates

[0004] The present disclosure relates to imide-based compounds, including bifunctional compounds containing it, and related uses. Bifunctional compounds are useful as modulators of targeted ubiquitination, especially for various polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds in accordance with the present disclosure. In some aspects, the bifunctional compounds comprise a Cereblon E3 ubiquitin ligase (CRBN) binding moiety that binds to the Cereblon E3 ubiquitin ligase, a target protein binding moiety that binds to the target protein (e.g., the androgen receptor), and optionally a linker moiety that connects the binding a cereblon fragment and a target protein-binding fragment. These compounds work in such a way that the target protein/polypeptide is placed in close proximity to the ubiquitin ligase to cause degradation (and inhibition) of that protein (eg, the androgen receptor).

Background of the Invention

[0005] Most small molecule drugs bind enzymes or receptors in narrow and well-defined pockets. On the other hand, protein-protein interactions are known to be difficult to target using small molecules due to their large contact surfaces and the shallow grooves or planar contact regions involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and therefore are more attractive therapeutic targets than conventional proteasome inhibitors due to their specificity for certain protein substrates. The development of E3 ligands has proven difficult, in part because they must disrupt protein-to-protein interactions. However, recent developments have made it possible to obtain specific ligands that bind to these ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds have been reported that target E3 ligases, but the field remains underdeveloped.

[0006] One E3 ligase with therapeutic potential is cereblon, a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, highlighting its physiological significance. Cereblon forms a complex with E3 ubiquitin ligase with DNA damage-binding protein 1 (DDB1), cullin-4A (CUL4A), and cullin regulator 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism that has not been fully elucidated, Cereblon ubiquitination of target proteins leads to an increase in fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes such as the formation of limbs and auditory vesicles. The end result is that this ubiquitin ligase complex is important for limb growth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA-damaged binding protein.

[0007] Thalidomide, which has been approved for a number of immunological indications, has also been approved for the treatment of certain neoplastic diseases, including multiple myeloma. In addition to multiple myeloma, thalidomide and some of its analogues are also currently being investigated for use in the treatment of a number of other cancers. Although the exact mechanism of thalidomide's antitumor activity is still being studied, it is known to inhibit angiogenesis. Recent literature discussing imide biology includes Lu et al. Science 343, 305 (2014), and Kronke et al. Science 343, 301 (2014).

[0008] It should be noted that thalidomide and its analogs, for example, pomolinamide and lenalinomide, are known to bind cereblon. These agents bind to Cereblon, altering the specificity of the complex, with induced ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors required for the growth of multiple myeloma. Indeed, higher expression of cereblon has been associated with increased efficacy of imide drugs in the treatment of multiple myeloma.

[0009] Androgen receptor (AR) refers to a family of nuclear hormone receptors that is activated by androgens such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58(4), 782-97; Vitam. Horm. 1999, 55:309- 52.). In the absence of androgens, AR binds to heat shock protein 90 (Hsp90) in the cytosol. When an androgen binds an AR, its conformation changes, releasing the AR from Hsp90 and opening the nuclear localization signal (NLS). The latter allows the AR to be translocated to the nucleus, where the AR acts as a transcription factor, promoting the expression of genes responsible for male sex characteristics (Endocr. Rev. 1987, 8(1): 1-28; Mol. Endocrinol. 2002, 16(10), 2181-7). AR deficiency leads to androgen insensitivity syndrome, formerly called testicular feminization.

[0010] Although AR is responsible for the development of male sexual characteristics, it is also a well-documented oncogene in some forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). A commonly measured target gene for AR activity is the secreted prostate specific antigen (PSA) protein. The current treatment regimen for prostate cancer involves inhibition of the androgen-AR axis in two ways. The first approach is based on androgen reduction, while the second strategy aims to suppress AR function (Nat. Rev. Drug Discovery, 2013, 12,823-824). Despite the development of effective targeted therapeutic agents, resistance develops in most patients and the disease progresses. An alternative approach to treating prostate cancer involves eliminating the AR protein. Since AR is an important driver of tumorigenesis in many forms of prostate cancer, its elimination should lead to a therapeutically favorable response.

[UN] There is a continuing need in the field for effective treatments for diseases, especially cancer, prostate cancer and Kennedy's disease. However, non-specific effects and the inability to target and modulate certain classes of proteins in general, such as transcription factors, still hinder the development of effective anti-cancer agents. As such, small molecule therapeutics that advantageously exploit or enhance Cereblon's substrate specificity and at the same time are "tunable" so that they can target a wide range of protein classes and modulate them with specificity would be very useful as a therapeutic agent.

Brief summary of the present invention

[0012] The present disclosure relates to bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligase for degradation, as well as methods of using them. In particular, the present disclosure relates to bifunctional or proteolysis-targeted chimeric (PROTAC) compounds that find use as modulators of targeted ubiquitination of a number of polypeptides and other proteins (such as the androgen receptor), which are then degraded and/or otherwise inhibited by bifunctional compounds, described in this document. An advantage of the compounds provided herein is that a wide range of pharmacological activities are possible, consistent with degradation/inhibition of target polypeptides of virtually any protein class or family. In addition, the present disclosure relates to methods of using an effective amount of the compounds described herein to treat or alleviate a disease state, including cancer, such as prostate cancer, and Kennedy's disease.

[0013] Thus, in one aspect, the present disclosure relates to the new imide-based compounds described herein.

[0014] In a further aspect, the present disclosure provides bifunctional or PROTAC compounds that contain an E3 ubiquitin ligase binding moiety (i.e., an E3 ubiquitin ligase ligand or "ULM" group) and a moiety that binds a target protein (i.e., a protein/polypeptide-targeting ligand or "RTM" group) such that the target protein/polypeptide is placed in close proximity to a ubiquitin ligase to effect degradation (and inhibition) of that protein. In a preferred embodiment, the ULM is a Cereblon E3 ubiquitin ligase binding fragment (i.e. "CLM"). For example, the structure of a bifunctional compound can be represented as PTM - CLM.

[0015] The respective positions of the PTM and CLM fragments, as well as their number, illustrated herein are presented by way of example only and are not intended to limit the connections in any way. The person skilled in the art will understand that the bifunctional compounds described herein can be synthesized so that the number and position of the corresponding functional fragments, if necessary, may vary.

[0016] In some embodiments, the difunctional compound may further comprise a chemical linker ("L"). In this example, the structure of the bifunctional compounds can be shown as PTM-L-CLM,

[0017] wherein PTM is a protein/polypeptide targeting fragment, L is a chemical linker fragment or bond that connects PTM and CLM, and CLM is a cereblon E3 ubiquitin ligase binding fragment.

[0018] In some preferred embodiments, the E3 ubiquitin ligase is cereblon. In this regard, according to some additional options for the implementation of the CLM bifunctional compound contains chemical components, such as fragments of the imide, amide, thioamide, thioimide derivatives. In additional embodiments, the CLM contains a phthalimido group, or an analog or derivative thereof. In the following further embodiments, the CLM contains a phthalimido-glutarimide group, or an analog or derivative thereof. In further embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0019] In some embodiments, the compounds described herein comprise multiple CLMs, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0020] It should be appreciated that the general structures are typical, and the corresponding fragments can be located in space in any desired order or configuration, for example, CLM-L-PTM and PTM-L-CLM, respectively.

[0021] In certain embodiments, the PTM is an AR binding fragment (AVM). In specific embodiments, the AVM is selected from the following structures:

Where:

W ¹ is an aryl, heteroaryl, bicyclic or biheterocyclic compound, each independently substituted with 1 or more of H, halogen, hydroxyl, nitro, CN, C≡CH, C _1-6 alkyl (straight, branched, optionally substituted, e.g., optionally substituted with 1 or more of halogen, C _1-6 alkoxy), C _1-6 alkoxy (straight, branched, optionally substituted, e.g. optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl, or CF ₃ ;

Y ¹ , Y ² are each independently NR ^Y1 , O, S;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond. O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, CS, SO, SO ₂ , heteroaryl or aryl;

Q is a 3-6 membered alicyclic or aromatic ring with 0-4 hetero atoms, optionally substituted with 0-6 R ^Q , each R ^Q is independently H, C _1-6 alkyl (straight, branched, optionally substituted; e.g., optionally substituted with 1 or more of halogen, C _1-6 alkoxy), halogen, C _1-6 alkoxy, or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0- 2 heteroatoms);

R ¹ , R ² , R ^a , R ^b , R ^Y1 , R ^Y2 each independently represents H, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), halogen, C _1-6 alkoxy, cyclic, heterocyclic compound, or R ¹ , R ² together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms);

W ² is a bond, C _1-6 alkyl, C _1-6 heteroalkyl, O, C _1-6 alicyclic, heterocyclic, aryl, heteroaryl, bigeterocyclic, biaryl, or bigeteroaryl, each optionally substituted with 1-10 R ^W2 ;

each R ^W2 is independently H, halogen, C _1-6 alkyl (straight, branched, optionally substituted; e.g., optionally substituted with 1 or more of F), C _1-6 heteroalkyl (straight, branched, optionally substituted), -OR ^W2A , C _3-6 cycloalkyl, C _4-6 cycloheteroalkyl, OC _1-3 alkyl (optionally substituted; e.g. optionally substituted with 1 or more of -F), C _1-6 alicyclic compound (optionally substituted), heterocyclic compound (optionally substituted), aryl (optionally substituted) or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH ₂ , NR ^Y1 R ^Y2 , CN; And

R ^W2A is H, C _1-6 alkyl (straight, branched) or C _1-6 heteroalkyl (straight, branched), each optionally substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or OC _1-3 alkyl.

[0022] In a further aspect, the present disclosure relates to therapeutic compositions containing an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions modulate protein degradation in a patient or subject, eg, an animal such as a human, and may be used to treat or alleviate disease states or conditions that are modulated by protein degradation. In some embodiments, the therapeutic compositions described herein can be used to effect degradation and/or inhibition of proteins of interest to treat or alleviate a disease, such as cancer. According to a further aspect, the present disclosure relates to a method for ubiquitinating/degrading a target protein in a cell. In some embodiments, the method comprises administering a bifunctional compound as described herein, comprising CLM and a PTM, preferably linked via a linker moiety as further described herein, wherein the CLM is attached to the PTM and wherein the CLM recognizes a ubiquitin pathway protein (e.g. , ubiquitin ligase, preferably an E3 ubiquitin ligase such as Cereblon), and RTM recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in close proximity to the ubiquitin ligase, thereby degrading/inhibiting the effects of the target protein and controlling proteins. Protein control provided by the present disclosure refers to the treatment of a disease state, or a condition that is modulated by a target protein, by reducing the content of that protein in the patient's cells.

[0023] In a further aspect, the present disclosure relates to a method for evaluating (ie, determining and/or measuring) CLM binding affinity. In some embodiments, the method comprises providing a test agent or compound of interest, e.g., an agent or compound having an imide moiety, e.g., a phthalimido group, a phthalimido-glutarimide group, a derivatized thalidomide, a derivatized lenalidomide, or a derivatized pomalidomide, and comparing binding affinity and/or Cereblon inhibitory activity of the test agent or compound with an agent or compound with known Cereblon binding and/or inhibitory activity.

[0024] According to a further aspect, the present disclosure relates to methods for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal, such as a human, comprising administering to the subject, in need thereof, a composition comprising an effective amount, e.g., a therapeutically effective amount , a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective in treating or alleviating a disease, disorder, or symptom thereof in a subject.

[0025] According to another aspect, the present disclosure relates to methods for identifying degradation effects of proteins of interest in a biological system using compounds in accordance with the present disclosure.

[0026] The previous general applications are given by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods and processes in accordance with the present disclosure will be clear to a person skilled in the art in light of the present claims, description and examples. For example, various aspects and embodiments of the present invention may be used in numerous combinations, all of which are expressly contemplated by this disclosure. These additional benefits, objectives, and embodiments are expressly included within the scope of this disclosure. Publications and other materials used in this document to highlight the prior art of the invention and, in some cases, to provide additional details regarding the practice, are incorporated by reference.

[0027] Where applicable or not expressly disclaimed, it is contemplated that any of the embodiments described herein may be combined with any one or more embodiments, even if the embodiments are described in various aspects of this disclosure. As such, the previous general applications are given by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods and processes in accordance with the present disclosure will be clear to a person skilled in the art in light of the present claims, description and examples. For example, various aspects and embodiments of the present invention may be used in numerous combinations, all of which are expressly provided for in this disclosure. These additional benefits, objectives, and embodiments are expressly included within the scope of this disclosure. Publications and other materials used in this document to highlight the prior art of the invention and, in some cases, to provide additional details regarding the practice, are incorporated by reference.

Brief description of graphic materials

[0028] The accompanying drawings, which are included in and form part of this specification, illustrate several embodiments of the present disclosure and, together with the present description, serve to explain the principles of the present disclosure. The drawings are for the sole purpose of illustrating an embodiment of the disclosure and should not be construed as limiting the present invention. Additional objects, features and advantages of the present invention will become apparent from the following detailed description given in conjunction with the accompanying drawings showing illustrative embodiments of the present disclosure:

[0029] FIG. 1A and FIG. 1B. An illustration of the general principle of the PROTAC function. Fig. 1A. Exemplary PROTACs contain an androgen receptor-targeting fragment (AVM; dark solid box), an E3 ubiquitin ligase binding fragment, such as a cereblon E3 ubiquitin ligase binding fragment (CLM; light solid triangle), and a linker fragment (L; black line) that attaches or binding AVM to CLM (described herein, L may be absent or represent a bond or fragment of a chemical linker). Fig. 1B illustrates the functional application of the PROTACs described herein. Briefly, CLM recognizes and binds to cereblon E3 ubiquitin ligase, and AVM binds and engages the androgen receptor, and brings it close proximity to cereblon E3 ubiquitin ligase. Typically, E3 ubiquitin ligase forms a complex with an E2 ubiquitin-conjugating protein and either alone or via the E2 protein catalyzes the addition of ubiquitin (dark circles) to a lysine in the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome machinery.

[0030] FIG. 2. Table 2, which includes typical compounds 1-75, as well as a general scheme that can be used to obtain each of the typical compounds. Table 2 also includes DC ₅₀ , D _max. , M/Z+ and 1H NMR data for each of the representative compounds. DC50 categories (µM) (ELISA of AR degradation in LNCaP and/or VCaP cells): A < 1 nM; B: 1-10 nM; C: 10-100 nM; D: > 100 nM. Category D _max. (AR degradation ELISA - maximum inhibition (%) of AR in LNCaP and/or VCaP cells): A >50%; B < 50%.

[0031] FIG. 3. Table 3, which includes exemplary compounds 76-398, as well as a general scheme that can be used to prepare each of the exemplary compounds. Table 3 also includes DC ₅₀ , M/Z+ and 1H NMR data for each of the exemplary compounds. Category DC ₅₀ (μM) (ELISA of AR degradation in LNCaP and/or VCaP cells): A < 1 nM; B: 1-10 nM; C: 10-100 nM; D: > 100 nM.

[0032] FIG. 4. Table 4, which includes typical compounds 399-427, as well as a general scheme that can be used to obtain each of the typical compounds. Table 4 also includes DC ₅₀ , D _max. (%), M/Z+ and 1H NMR data for each representative compound. Category DC ₅₀ (μM) (ELISA of AR degradation in LNCaP and/or VCaP cells): A < 1 nM; B: 1-10 nM; C: 10-100 nM; D: > 100 nM.

[0033] FIG. 5. Table 5 which includes exemplary compounds 428-452. Table 5 also includes DC ₅₀ , D _max. (%), M/Z+ and 1H NMR data for each representative compound. Category DC ₅₀ (μM) (ELISA of AR degradation in LNCaP and/or VCaP cells): A < 1 nM; B: 1-10 nM; C: 10-100 nM; D: > 100 nM.

[0034] FIG. 6. Table 6 which includes a typical 528 connection. Table 6 also includes DC ₅₀ , D _max. , M/Z+ and 1H NMR data for each of the representative compounds. Category DC ₅₀ (μM) (ELISA of AR degradation in LNCaP and/or VCaP cells): A<1 nM; B: 1-10 nM; C: 10-100 nM; D: > 100 nM. Category D _max. (AR degradation ELISA - maximum inhibition (%) of AR in LNCaP and/or VCaP cells): A >50%; B < 50%.

[0035] FIG. 7. Table 7 which includes exemplary compounds 529-625. Table 7 also includes DC ₅₀ , M/Z+ and 1H NMR data for each of the exemplary compounds. Category DC ₅₀ (μM) (ELISA of AR degradation in LNCaP and/or VCaP cells): A < 1 nM; B: 1-10 nM; C: 10-100 nM; D: > 100 nM.

[0036]

Detailed disclosure of the present invention

[0037] The following is a detailed description intended to assist those skilled in the art in carrying out the present invention. Those skilled in the art may make modifications and changes to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings and other references mentioned in this document are expressly incorporated by reference in their entirety.

[0038] The present disclosure relates to the surprising and unexpected discovery that an E3 ubiquitin ligase protein can ubiquitinate a target protein, in particular the androgen receptor, when the E3 ubiquitin ligase protein and the target protein are brought together by a chimeric construct (e.g., PROTAC) as described in herein, in which the fragment that binds the E3 ubiquitin ligase protein is attached, for example, covalently, to the fragment that binds the target androgen receptor protein. Accordingly, the present description relates to compounds, compositions containing them, and related methods of their use for ubiquitination and degradation of a selected target protein, for example, the androgen receptor (see Fig. 1A and Fig. 1B).

[0039] This disclosure relates to certain aspects of US Patent Publication Nos. 2014/0356322 A1, 2015/0291562 A1, and 2016/0214972 A1, all of which are incorporated herein by reference in their entirety for all purposes.

[0040] Unless otherwise noted, all technical and scientific terms used in the present description have the same meaning as generally understood by a person skilled in the art to which this disclosure belongs. The terminology used herein is used to describe specific embodiments only and is not intended to limit the present invention.

[0041] If a range of values is presented, it is understood that each intermediate value up to the tenth unit of the lower limit, unless the context clearly indicates otherwise (for example, as in the case of a group containing the number of carbon atoms, in which case each carbon number is represented, which falls within the limit of the range), between the upper and lower limit of such range, and any other specified or intermediate value in the specified range is covered within the present invention. The upper and lower limits of such smaller ranges that can independently be included in the smaller ranges are also covered within the scope of the present invention, subject to any specifically excluded limit in the claimed range. If the specified range includes one or both of the limits, ranges excluding either or both of such included limits are also included in the present invention.

[0042] The following terms have been used to describe the present disclosure. In cases where the term is not specifically defined in the present description, it is presented in the meaning accepted in the present field by a person skilled in the present field, who uses such a term in the context of its use in describing the present invention.

[0043] As used in the present description and the claims, the singular forms have been used to refer to one or more than one (i.e., at least one) grammatical object of description, unless the context clearly indicates otherwise. By way of example, "element" means one element or more than one element.

[0044] The expression "and/or" used in the present description and in the claims, should be understood as meaning "any or both" elements connected in this way, i.e., elements that are simultaneously present in some cases and separately present in other cases. Many elements listed with "and/or" should be understood in the same way, i.e., "one or more" elements connected in this way. Other elements may optionally be present, with the exception of elements specifically indicated by the "and/or" condition, which are either related or not related to the specifically indicated elements. Thus, as a non-limiting example, a reference to "A and/or B" when used in conjunction with an open wording such as "comprising", in one embodiment, may only refer to A (optionally including elements other than B); according to another embodiment, only to B (optionally including elements other than A); according to another embodiment, to both A and B (optionally including other elements); and so on.

[0045] As used herein and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, if there are individual items in the list, "or" or "and/or" should be interpreted as including, i.e., including at least one, but also including more than one, number or list of items, and optionally additional units not included in the list. Only terms clearly indicated in the opposite sense, such as "only one of" or "exactly one of" or when used in the claims "consisting of", will refer to the inclusion of exactly one element from a number or list of elements. In general, the term "or" when used in the present invention should only be interpreted as meaning exclusive alternatives (i.e., "one or the other, but not both") with preceding exclusivity terms such as "either", "one of" , "only one of" or "exactly one of".

[0046] As used herein, the term "about" and the like, in combination with numerical values or ranges, reflects the fact that there is a certain level of change that is generally recognized and acceptable in the art due to practical and/or theoretical limitations. For example, a slight change is acceptable due to natural changes according to which certain devices operate and/or measurements are made. As described above, the expression "approximately" has generally been used to cover values within the standard deviation or standard error.

[0047] In the claims, as well as in the description above, all transitional phrases such as "comprising", "including", "delivering", "having", "incorporating", "involving", " holding”, “consisting of”, etc. are understood as open-ended phrases, i.e., meaning including without limitation. Only the transition phrases "consisting of" and "consisting primarily of" must be closed or semi-closed transition phrases, respectively, as set out in the US Patent Office's Patent Examining Manual, Section 2111.03.

[0048] As used herein and in the claims, the phrase "at least one" in relation to a list of one or more elements should be understood to mean at least one element selected from any or more of the elements in the list of elements, but optionally including at least one of each individual element specifically listed in the list of elements and not excluding any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically defined in the list of elements to which the phrase "at least one" refers, whether or not related to the elements specifically defined, may optionally be present. Thus, as a non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B" or equivalently "at least one of A and/or B") according to one embodiment may refer to at least one, optionally including more than one A without B (and optionally including elements other than B); according to another embodiment, at least one, optionally including more than one B without A (and optionally including elements other than A); According to yet another embodiment, at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0049] It should also be understood that according to certain methods described in the present invention; which include more than one step or step, the order of the steps or steps of the method is not necessarily the limited order in which the steps or steps of the method are listed, unless the context indicates otherwise.

[0050] The terms “co-administration” and “co-administered” or “combination therapy” can refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and administration at different times (administration of two or more therapeutic agents for a time that is different from the time of administration of the additional therapeutic agent or agents), as well as therapeutic agents are in the patient to some extent, preferably in effective amounts at the same time. In certain preferred aspects, one or more of the compounds described herein are co-administered in combination with at least one additional biologically active agent, in particular including an anticancer agent. According to specific preferred aspects, co-administration of the compounds results in synergistic activity and/or therapy, including anti-cancer activity.

[0051] The term "effective" can mean, but is not limited to, that amount/dose of an active pharmaceutical ingredient that, when used in the context of its intended use, performs or is sufficient to prevent, inhibit the occurrence, ameliorate, slow down, or treat (alleviate a symptom to some degree, preferably all) of the symptoms of a condition, disorder, or disease stage in a subject in need of, or receiving such treatment. The term effectively categorizes all other effective amount or effective concentration terms, such as "effective amount/dose", "pharmaceutically effective amount/dose", or "therapeutically effective amount/dose", which are otherwise described or used herein.

[0052] The effective amount depends on the type and severity of the disease, the composition used, the route of administration, the species of mammal being treated, the physical characteristics of the particular mammal in question, concomitant drug therapy, and other factors that were known to those skilled in the medical arts. The exact amount can be determined by one of skill in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0053] The term "pharmacological composition", "therapeutic composition", "therapeutic composition" or "pharmacologically acceptable composition" can mean, but without limitation, a composition or composition that allows effective distribution of the agent represented by the present disclosure, which is in the form, suitable for administration at the physical location most suitable for their desired activity, eg systemic administration.

[0054] The term "pharmaceutically acceptable" or "pharmacologically acceptable" can mean, but is not limited to, units and compositions that do not produce an adverse, allergic, or other undesirable reaction when administered to an animal or human, if desired.

[0055] The term "pharmaceutically acceptable carrier" or "pharmacologically acceptable carrier" may mean, but is not limited to, any and all solvents, dispersants, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, appropriate for pharmaceutical administration. . Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, standard reference text in the field, which is incorporated into the present invention by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous carriers such as fatty oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where any conventional medium or agent is incompatible with the active compound, its use in compositions is contemplated. Additional active compounds may also be included in the compositions.

и двойная связь, и простая связь представлены или понимаются в пределах контекста показанного соединения и хорошо известных правил для взаимодействий валентностей.[0056] The term "systemic administration" refers to the route of administration, which is, for example, enteral or parenteral, and results in systemic distribution of the agent, which results in systemic absorption or accumulation of drugs in the circulation, followed by distribution throughout the body. Suitable forms depend in part on the application or route of administration, for example, as generally described herein. If the connection is shown

both the double bond and the single bond are presented or understood within the context of the compound shown and the well-known rules for valence interactions.

[0060] Used in the present description, "derivatives" can mean compositions formed from natural compounds or directly by modification, or partial substitution. As used herein, "analogues" may mean compositions having a structure similar to, but not identical to, a natural compound.

[0061] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein by directing the substrate protein to degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, causes the attachment of ubiquitin to lysine in the target protein and subsequently directs specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in combination with E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to target proteins. Typically, a ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; the third joins the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only one ubiquitin is added by a ubiquitin ligase to a substrate molecule. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead, cellular location or function can be altered, for example by binding other proteins that have domains capable of binding ubiquitin. To further complicate matters, E3 can target various lysines in ubiquitin to form chains. The most abundant lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0062] The term "patient" or "subject" is used throughout this specification to describe a cell, tissue, or animal, preferably a mammal, such as a human or a companion animal, that is being treated, including prophylactic treatment, with a composition according to real disclosure. For the treatment of such infections, conditions or disease states that are specific to a particular animal, such as a sick person, the term "sick" refers to that particular animal, including a domestic animal, such as a dog or cat, or a farm animal, such as horse, cow, sheep, etc. In general, in the present disclosure, the term "sick" refers to a sick person, unless otherwise indicated or implied in the context of the use of the term.

[0063] Compounds and compositions

[0064] According to one aspect, the present disclosure relates to compounds useful for regulating the activity of proteins. The composition contains a protein-binding fragment of the ubiquitin pathway (preferably for E3-ubiquitin ligase, alone or in combination with an E2-ubiquitin-conjugating enzyme that is responsible for transferring ubiquitin to target proteins) according to a certain chemical structure, and a protein-targeting fragment that binds or linked together, preferably via a linker, wherein the ubiquitin pathway protein-binding fragment recognizes the ubiquitin pathway protein and the targeting fragment recognizes the target protein (eg, androgen receptor). Such compounds may be referred to herein as PROTAC compounds or simply PROTAC.

[0065] According to one aspect, the present disclosure relates to compounds containing an E3 ubiquitin ligase binding fragment ("ULM"), which is a cereblon E3 ubiquitin ligase binding fragment ("CLM"). In one embodiment, the CLM is coupled to a chemical linker group (L) according to the structure

wherein L is a chemical linker group and CLM is a cereblon E3 ubiquitin ligase binding fragment. The number and/or relative positions of the moieties in the compounds shown herein are by way of example only. The person skilled in the art will understand that the compounds described herein can be synthesized with any desired number and/or relative position of the respective functional fragments.

[0066] The terms "ULM" and "CLM" are used in their broad sense, unless the context indicates otherwise. For example, the term "ULM" includes all ULMs, including those that bind cereblon (i.e. CLM). In addition, the term "CLM" includes all possible cereblon E3 ubiquitin ligase binding fragments.

[0067] According to another embodiment, the present disclosure relates to a compound that contains a plurality of CLMs connected directly or via a chemical linker moiety (L). For example, a connection that has two CLMs can be shown as

[0068] According to some embodiments, if a connection contains multiple CLMs, then the CLMs are identical. In additional embodiments, the compound comprising a plurality of CLMs further comprises at least one PTM attached to the CLM directly or via a chemical linker (L) or both. In some additional embodiments, a compound containing a plurality of CLMs further comprises a plurality of PTMs. In the following additional embodiments, the RTMs are the same or optionally different. In further embodiments, if the PTMs are different, then the respective PTMs may bind to the same protein target or bind specifically to a different protein target.

[0069] In additional embodiments, the present disclosure relates to a compound comprising at least two different CLMs connected directly or via a chemical linker (L), or both. For example, such a connection, having two different CLMs, can be depicted as

[0070] wherein CLM' is a cereblon E3 ubiquitin ligase binding fragment that is structurally different from CLM. In some embodiments, the connection may comprise a plurality of CLMs and/or a plurality of CLM's. In further embodiments, a compound comprising at least two different CLMs, a plurality of CLMs and/or a plurality of CLM's, further comprises at least one PTM connected to the CLM or CLM' either directly or via a chemical linker, or both. According to any of the embodiments described herein, a compound containing at least two different CLMs may further comprise multiple PTMs. In the following additional embodiments, the RTMs are the same or optionally different. In further embodiments, if the PTMs are different, then the respective PTMs may bind to the same protein target, or bind specifically to a different protein target. In the following embodiments, the PTM itself is a ULM or CLM (or ULM' or CLM').

[0071] According to another aspect, the present disclosure relates to bifunctional compounds or PROTAC compounds that contain an E3 ubiquitin ligase binding fragment ("ULM"), which is a Cereblon E3 ubiquitin ligase binding fragment ("CLM"), and a target protein binding fragment ( ie, a protein/polypeptide targeting ligand or "RTM" group) that is an AR binding fragment ("AVM"). According to one embodiment, the structure of a bifunctional compound can be depicted as

[0072] The respective provisions of the AVM and CLM fragments, as well as their number, illustrated herein are presented by way of example only and are not intended to limit the connections in any way. One skilled in the art will appreciate that the bifunctional compounds described herein may be synthesized such that the number and position of the respective functional moieties may vary as desired.

[0073] In some embodiments, compounds having the following general structure ABM-L, wherein ABM is an AR binding moiety as described herein and L is a chemical linker moiety, e.g., a linker as described herein, or optionally connection.

[0074] In some embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of bifunctional compounds can be depicted as

[0075] wherein AVM is an AR binding fragment as described herein, CLM is a Cereblon E3 ligase binding fragment as described herein, and L is a chemical linker moiety, e.g., a linker as described herein, or optional link that connects AVM and CLM.

[0076] In addition, CLM includes all possible cereblon E3 ubiquitin ligase binding fragments. The CLM group and the AVM group may be covalently attached to the linker group via any covalent bond that is appropriate and stable for the linker chemistry.

[0077] In some embodiments, the CLM contains a fragment that is a cereblon E3 ubiquitin ligase (CRBN) ligand. In some embodiments, the CLM contains the chemotype form of the "imide" class of molecules. In some additional embodiments, the CLM contains a phthalimido group, or an analog or derivative thereof. In the following additional embodiments, the CLM contains a phthalimido-glutarimide group, or an analog or derivative thereof. In further embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogues or derivatives thereof.

[0078] It should be appreciated that the general structures are typical, and the corresponding fragments can be located in space in any desired order or configuration, for example, CLM-L-ABM and CLM-L-ABM, respectively. In some additional embodiments, the compounds comprise a plurality of E3 ligase binding moieties and/or a plurality of AVMs.

[0079] In some embodiments, the compounds described herein comprise multiple AVMs (targeting the same or different AR locations), multiple CLMs, one or more ULMs (i.e., fragments that specifically bind to another E3 -ubiquitin ligase, for example, VHL) or a combination thereof. According to any of the aspects of the embodiments described herein, the AVM, CLM, and ULM may be connected directly, or through one or more chemical linkers, or through a combination thereof. In additional embodiments, if a compound has multiple ULMs, then the ULMs may target the same E3 ubiquitin ligase, or each respective ULM may specifically bind to a different E3 ubiquitin ligase. According to the following embodiments, if a connection has multiple AVMs, then the AVMs are the same or optionally different.

[0080] According to some embodiments, if a connection contains multiple CLMs, then the CLMs are identical or optionally different. According to additional embodiments, the compound comprising a plurality of CLMs further comprises at least one AVM connected to the CLM directly or via a chemical linker (L), or both. In some additional embodiments, a compound containing multiple CLMs further comprises multiple AVMs. In the following additional embodiments, the AVMs are the same or optionally different.

[0081] According to some embodiments, the implementation of AVM alone, without the formation of ABM-L-CLM, provides the desired properties of regulation of protein activity.

[0082] According to any of the aspects or embodiments of the compounds described herein, unless otherwise indicated, the compounds are intended to encompass their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs.

[0083] In some embodiments, the compounds described herein comprise multiple PTMs (targeting the same or different protein targets), multiple AVMs, multiple CLMs, one or more ULMs (i.e., fragments that specifically bind with another E3 ubiquitin ligase, such as Cereblon) or a combination thereof. According to any of the aspects of the embodiments described herein, the PTM, AVM, CLM, and ULM may be connected directly, or through one or more chemical linkers, or through a combination thereof. In additional embodiments, if a compound has multiple ULMs, then the ULMs may target the same E3 ubiquitin ligase, or each respective ULM may specifically bind to a different E3 ubiquitin ligase. In further embodiments, if a compound has multiple PTMs, then the PTMs may bind to the same target protein, or each respective PTM may specifically bind to a different target protein.

Exemplary CLMs

[0084] Neoimide compounds

[0085] According to one aspect, the present invention provides compounds useful for binding and/or inhibiting cereblon. In certain embodiments, the compound or CLM is selected from the group consisting of chemical structures:

Where:

W is independently selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl (straight, branched, optionally substituted);

Y is independently selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;

X and Z are each independently O, S, or H ₂ , except that both X and Z cannot be H ₂ ;

G and G' are independently selected from the group consisting of H, alkyl (straight, branched, optionally substituted with R'), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl optionally substituted with R', and benzyl, optionally substituted R';

Q1-Q4 are each independently C optionally substituted with R', N or N-oxide;

A is independently selected from the group consisting of alkyl (straight, branched, optionally substituted), cycloalkyl (optionally substituted), Cl, H, and F;

R contains without limitation -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R''-, - CR'NR'R''-, -aryl, -hetaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O) R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , -CN, - NR'SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN) NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R '', -SF ₅ , -R'NR'R'', (-R'O) _n R'' or -OCF ₃ ;

R' and R'' are each independently a bond, H, alkyl (straight, branched), cycloalkyl, aryl, hetaryl, heterocyclyl, or -C(=O)R, each of which is optionally substituted;

n is an integer from 1 to 10 (eg 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической; и

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; And

R _n contains 1-4 independent functional groups or atoms, and optionally one of which is modified for covalent attachment to AVM, chemical linker group (L), ULM, CLM (CLM'), or combinations thereof.

[0086] Exemplary CLMs

[0087] In any of the compounds described herein, the CLM contains a chemical structure selected from the group:

Where:

W is CH ₂ , CHR, C=O, SO ₂ , NH or N-alkyl (straight, branched, optionally substituted);

X and Z are each independently O, S, or H ₂ , except that both X and Z cannot be H ₂ ;

Y is independently selected from the group CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;

G is H, alkyl (straight, branched), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, heterocyclic, aryl or benzyl, each optionally substituted with R';

Q1-Q4 are each independently C which is optionally substituted with R', N or N-oxide;

A is C ₁ -C ₆ alkyl (straight, branched, optionally substituted), cycloalkyl (optionally substituted), H, Cl or F;

R is -CONR'R'', -OR', -NR'R'', -SR', -SO2R', -SO2NR'R'', -CR'R''-, -CR'NR'R ''-, (-CR'O) _n R'', -aryl, -heteroaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R'' , -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3 , -CN, -NR'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N -CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO2)NR'R'', -SO2NR'COR'', -NO2, - CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', alicyclic, heterocyclic compound, -SF5 or -OCF3;

R' and R'' are each independently a bond, H, N, N-oxide, alkyl (straight, branched), cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R or heterocyclyl, each of which is optional replaced;

n is an integer from 1 to 10;

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической; и

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; And

R _n contains 1-4 independent functional groups or atoms, and optionally one of which is modified for covalent attachment to AVM, chemical linker group (L), ULM, CLM (CLM'), or combinations thereof.

[0088] According to certain embodiments described herein, the CLM or ULM contains a chemical structure selected from the group:

Where:

W is independently selected from the group consisting of CH ₂ , C=O, NH and N-alkyl;

R is H, methyl, or C1-C6 alkyl (straight, branched, optionally substituted);

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической; и

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; And

Rn contains 1-4 independently selected functional groups or atoms, and optionally one of which is modified for covalent attachment to AVM, chemical linker group (L), ULM, CLM (or CLM'), or combinations thereof.

[0089] As used herein, the term "independent" means that a variable that is applied independently changes regardless of application to application.

[0090] The term "alkyl" shall mean within its context a linear, branched or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a C ₁ -C ₁₀ , more preferably a C ₁ -C ₆ alternatively a C ₁ -C ₃ alkyl group , which may be optionally substituted. Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl, among others. In certain embodiments, the alkyl group is terminated with a halo group (At, Br, Cl, F, or I). According to certain preferred embodiments, the compounds of the present disclosure are provided which can be used for covalent bonding with dehalogenase enzymes. These compounds typically contain a side chain (often linked via a polyethylene glycol group) that terminates in an alkyl group containing a halogen substituent (often chlorine or bromine) at its far end, resulting in the compound containing such a moiety being covalently bonded to the protein.

[0091] The term "alkenyl" refers to linear, branched or cyclic C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) hydrocarbon radicals containing at least one C=C bond.

[0092] The term "alkynyl" refers to linear, branched or cyclic C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) hydrocarbon radicals containing at least one C≡C bond.

[0093] The term "alkylene", when used, refers to a -(CH ₂ ) _n - group (n is an integer, typically 0 to 6), which may be optionally substituted. If substituted, the alkylene group is preferably substituted on one or more methylene groups with a C ₁ -C ₆ alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halogen groups, preferably 1 to 3 halogen groups or one or two hydroxyl groups, O-(C ₁ -C ₆ alkyl) groups, or amino acid side chains, as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group) that is further substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, more typically 1 to 4 ethylene glycol units) that is substituted (preferably, but not exclusively at the far end of the polyethylene glycol chain), the alkyl chain is substituted with a simple halogen group, preferably a chlorine group. In other embodiments, the alkylene (often methylene) group may be substituted with an amino acid side group, such as a natural or non-natural amino acid side chain group, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

[0094] The term "unsubstituted" should mean substituted with only hydrogen atoms. The range of carbon atoms that includes C ₀ means that the carbon atom is missing and replaced by H. Thus, the range of carbon atoms that is C ₀ -C ₆ includes carbon atoms 1, 2, 3, 4, 5 and 6 and for C ₀ H stands instead of a carbon atom.

[0095] The term "substituted" or "optionally substituted" shall mean independently (i.e., if more substituents occur, each substituent is independent of the other substituent) one or more substituents (independently up to five substituents, preferably up to three substituents , often 1 or 2 substituents on a moiety in a compound of the present disclosure, and may include substituents that may themselves be further substituted) at the carbon (or nitrogen) position anywhere on the molecule within the context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO ₂ ), halogen (preferably 1, 2 or 3 halogens, in particular on alkyl, especially methyl group such as trifluoromethyl), alkyl group (preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ ), aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), alkoxy (preferably C ₁ -C ₆ alkyl or aryl, including phenyl and substituted phenyl), thioether (C ₁ -C ₆ alkyl or aryl), acyl (preferably C ₁ -C ₆ acyl), ester or thioester (preferably C ₁ -C ₆ alkyl or aryl), including an alkylene ester (so that the attachment is on an alkylene group and not on an ester functional group which is preferably substituted with a C ₁ -C ₆ alkyl or aryl group), preferably C ₁ -C ₆ alkyl or aryl, halogen (preferably F or Cl), amine (including five - or a six-membered cyclic alkyleneamine, additionally including C ₁ -C ₆ alkylamine or C ₁ -C ₆ dialkylamine, while the alkyl groups may be substituted with one or two hydroxyl groups) or optionally substituted -N(C ₀ -C ₆ alkyl) C(O)(O-C ₁ -C ₆ alkyl) group (which may be optionally substituted with a polyethylene glycol chain to which an alkyl group containing one halogen, preferably a chloride substituent is additionally attached), hydrazine, amido, which is preferably substituted with one and or two C ₁ -C ₆ alkyl groups (including carboxamide which is optionally substituted with one or two C ₁ -C ₆ alkyl groups), an alkanol (preferably C ₁ -C ₆ alkyl or aryl), or an alkanoic acid (preferably C ₁ -C ₆ alkyl or aryl). Substituents of the present disclosure may include, for example, -SiR ₁ R ₂ R ₃ groups, where each of R ₁ and R ₂ described in the present invention and R ₃ represents H or C ₁ -C ₆ alkyl group, preferably R ₁ , R ₂ , R ₃ in this context represent a C ₁ -C ₃ alkyl group (including isopropyl or tert-butyl group). Each of the above groups may be connected directly to the substituted moiety or, alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an optionally substituted -(CH ₂ ) _m - or alternatively an optionally substituted -(OCH ₂ ) _m -, -(OCH ₂ CH ₂ ) _m - or -(CH ₂ CH ₂ O) _m - a group which may be substituted by any one or more of the above substituents. Alkylene groups -(CH ₂ ) _m - or -(CH ₂ ) _n - groups or other chains such as ethylene glycol chains as defined above may be substituted anywhere on the chain. Preferred substituents on alkylene groups include halogen or C ₁ -C ₆ (preferably C ₁ -C ₃ ) alkyl groups which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (OC ₁ -C ₆ groups) , up to three halogen groups (preferably F), or amino acid side chains as otherwise described herein, and an optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two C ₀ -C ₆ alkyl substituents, such group(s) may be substituted(s)). In certain embodiments, the alkylene group (often a simple methylene group) is substituted with one or two optionally substituted C ₁ -C ₆ alkyl groups, preferably a C ₁ -C ₄ alkyl group, most commonly methyl or O-methyl groups, or an amino acid side chain, as otherwise as described in the present invention. According to the present disclosure, a moiety in a molecule may optionally be substituted with up to five substituents, preferably up to three substituents. Most often, according to the present invention, the fragments that are substituted are substituted with one or two substituents.

[0096] The term "substituted" (each substituent is independent of any other substituent) should also mean, within the context of application, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto , carboxy, C ₁ -C ₆ ester (hydroxyester or carbonyl ester), C ₁ -C ₆ keto, urethane-OC(O)-NR ₁ R ₂ or -N(R ₁ )-C(O)- OR ₁ , nitro, cyano and amine (especially including C ₁ -C ₆ alkylene-NR ₁ R ₂ , mono- or di-C ₁ -C ₆ alkyl-substituted amines which may be optionally substituted with one or two hydroxyl groups). Each of these groups contains, unless otherwise noted, within the context, from 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, ═O, -(CH ₂ ) _m - (here m and n in the context are 1, 2, 3, 4, 5 or 6), -S-, -S(O)-, SO ₂ - or -NH-C(O) -NH-, -(CH ₂ ) _n OH, -(CH ₂ ) _n SH , -(CH ₂ ) _n COOH, C ₁ -C ₆ alkyl, -(CH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n NHC(O)-R ₁ , -(CH ₂ ) _n C(O)-NR ₁ R ₂ , -(OCH ₂ ) _n OH, -(CH ₂ O) _n COOH, C ₁ -C ₆ alkyl, -( OCH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), -(OCH ₂ ) _n NHC(O)-R ₁ , -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -S(O) ₂ -R _S , -S(O)-R _S ( _RS is C ₁ -C ₆ alkyl or -(CH ₂ ) _m -NR ₁ R ₂ group), NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of the substituent. R ₁ and R ₂ each within the context represents H or C ₁ -C ₆ alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" should also mean, within the chemical context of the particular compound and the substituent used, an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group, as otherwise described herein. Alkylene groups may also be substituted, as otherwise described herein, preferably with optionally substituted C ₁ -C ₆ alkyl groups (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thereby providing a chiral cent), with an amino acid group side chain, as otherwise described in the present invention, an amido group as described above, or a urethane group OC(O)-NR ₁ R ₂ groups, where R ₁ and R ₂ are otherwise described in the present invention, although many other groups can also be used as deputies. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, and preferably 1 or 2 substituents. It is noted that in cases where a compound needs substitution at a particular position of the molecule (mainly due to valency), but no substitution has been noted, then it is implied or understood that such a substituent is H, unless the context of the substitution suggests otherwise. .

[0097] The term “aryl” or “aromatic compound” as used herein refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical containing a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), and it can be linked to the compound of the present disclosure at any available stable position on the ring(s) or as otherwise noted in the chemical structure shown. Other examples of aryl groups in the context may include heterocyclic aromatic ring systems, "heteroaryl" groups containing one or more nitrogen, oxygen or sulfur atoms in the ring (monocyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, and the like, among others, which may be optionally substituted as described above. Among the heteroaryl groups that may be mentioned are nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolysine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazolin, pyrimidine, phenanthroline, obendiazoline, ophthalazine, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, among others, all of which may be optionally substituted.

[0098] The term "substituted aryl" refers to an aromatic carbocyclic group containing at least one aromatic ring or multiple fused rings, at least one of which was aromatic, the ring(s) being substituted(s) with one or more substituents. For example, the aryl group may contain substituent(s) selected from: -(CH ₂ ) _n OH, -(CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n - O-(CH ₂ ) _n -(C ₁ -C ₆ ) alkyl, -(CH ₂ ) _n -C (O) (C ₀ -C ₆ ) alkyl, -(CH ₂ ) _n -C (O) O ( C ₀ -C ₆ ) alkyl, -(CH ₂ ) _n -OC (O) (C ₀ -C ₆ ) alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl) amine, where the alkyl group on the amine optionally substituted with 1 or 2 hydroxyl groups or up to three halogen groups (preferably F, Cl), OH, COOH, C ₁ -C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups ( each of which may be substituted at the ortho, meta and/or para positions of the phenyl ring, preferably the para-), optionally substituted phenyl group (the phenyl group itself is preferably substituted with a linker group attached to an AVM group, including a ULM group), and /or at least one of the F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (in the ortho, meta and/or para positions of the phenyl ring, preferably preferably para-), naphthyl group, which may be an optionally substituted, optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole, an optionally substituted oxazole, including a methyl-substituted oxazole, an optionally substituted thiazole, including a methyl-substituted thiazole, an optionally substituted isothiazole, including a methyl-substituted isothiazole , optionally substituted pyrrole, including methyl-substituted pyrrole, optionally substituted imidazole, including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted diazole group, including methyldiazole group, optionally substituted triazole group, including methyl-substituted triazole group, optionally substituted pyridine groups including halo- (preferably F) or methyl-substituted pyridine group or oxapyridine group (wherein pyridine ova group is connected to the phenyl group using oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

[0099] "Carboxyl" means a -C(O)OR group, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, these basic substituents having meanings that are identical with the definition of the respective groups defined in the present description.

[0100] The term "heteroaryl" or "hetaryl" may mean, but is not limited to, an optionally substituted quinoline (which may be attached to a pharmacophore or substituted at any carbon atom in the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine , optionally substituted azaindolizine (2, 3 or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and/or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with a methyl group, triisopropylsilyl group, optionally substituted with -(CH ₂ ) _m -O-C ₁ -C ₆ alkyl group or optionally substituted -(CH ₂ ) _m -C(O)-O-C ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3 or 4-pyridine) or a chemical structure group:

Where

S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ )) , optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡C-R _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted with O-( C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or halogen groups of up to three);

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or C(O)(C ₁ -C ₆ alkyl), each group optionally substituted with one or two hydroxyl groups or halogen atoms up to three, preferably with fluoro groups, or an optionally substituted heterocycle, e.g. piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and Y ^C is N or CR ^YC , where R is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ )), optional substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl).

[0101] The terms "aralkyl" and "heteroarylalkyl" refer to groups that contain both aryl or, respectively, heteroaryl, as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems according to the above definitions.

[0102] As used herein, the term "arylalkyl" refers to an aryl group, as defined above, attached to an alkyl group as defined above. The arylalkyl group is attached to the parent moiety via an alkyl group, where the alkyl group consists of one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

[0103] The term "heterocycle" refers to a cyclic group that contains at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties fall within the definition of a heterocycle depending on the context in which it is used. Exemplary heteroaryl groups are described above.

[0104] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3- dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2- pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, ocean, tetrahydrothiophenyl, ocean, oxathiolanil, thian, among others.

[0105] Heterocyclic groups may be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, hydroxyaminoacyl, azido , cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic compound, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -aryl, oxo (=O) and -SO ₂ -heteroaryl. Such heterocyclic groups may contain a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolysine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., as well as N-alkoxy nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which any of the heterocyclic rings is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0106] The term "cycloalkyl" can mean, without limitation, monovalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes, as defined herein, for example, saturated monocyclic hydrocarbon groups containing from three to twenty carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "substituted cycloalkyl" may mean, but is not limited to, a monocyclic or polycyclic alkyl group and has been substituted with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, while such typical substituent groups are characterized by meanings that are identical to the definitions of the corresponding groups, as defined in this list.

[0107] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its cyclic structure has been replaced by a heteroatom selected from the group consisting of N, O, S or P and the group has one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, while such an exemplary substituent group has meanings that are identical to the definitions of the corresponding groups as defined in this list.

[0108] The term "hydrocarbyl" should mean a compound that contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.

[0109] According to any of the embodiments described herein, W, X, Y, Z, g, G', R, R', R", Q1-Q4, A and Rn can independently be covalently linked to a linker and/or a linker to which one or more ABM, ULM, CLM or CLM' groups are attached.

[IT] More specifically, non-limiting examples of CLMs include those shown below, as well as those 'hybrid' molecules that result from a combination of 1 or more of the different features shown in the molecules below, where Rn contains 1-4 independently selected functional groups or atom, and optionally one of which is modified for covalent attachment to AVM, chemical linker group (L), ULM, CLM (or CLM'), or combinations thereof.

Example Linkers

[0111] In certain embodiments, the compounds as described herein include one or more AVMs chemically bonded to or connected to one or more ULMs or CLMs via a chemical linker (L). According to certain embodiments, the linker group L is a group containing one or more covalently linked structural units (for example, -A _{1 ...} A _q - or -A _q -), where A ₁ is a group connected to AVM, and A _q is a group connected to the ULM.

[0112] In certain embodiments, the linker group L is selected from A _q -;

A _q is a group that is connected to the ULM or ABM fragment; And

q is an integer greater than or equal to 1,

where A _q is selected from the group consisting of bond, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 =CR ^L2 , C≡С, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(=NCN)NR ^L4 , NR ^L3 C(=NCN), NR ^L3 C(=CNO ₂ )NR ^L4 , C _3-11 cycloalkyl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, C _5-13 spirocycloalkyl optionally substituted with 0-9 R ^L1 and/or R ^L2 groups , C _3-11 heterocyclyl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, C _5-13 spiroheterocycloalkyl optionally substituted with 0-8 R ^L1 and/or R ^L1 groups, aryl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, heteroaryl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, wherein R ^L1 or R ^L2 are each independently optionally connected to other groups to form a cycloalkyl and/or heterocyclyl moiety optionally substituted with 0-4 R ^L5 groups;

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halo, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N(C _{1 -8} alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OC _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N(C _1-8 cycloalkyl) ₂ , N (C _1-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8 alkyl) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH \u003d CH (C _1-8 alkyl), C (C _1-8 alkyl) \u003d CH (C _1-8 alkyl ), C (C _1-8 alkyl) \u003d C (C _1-8 alkyl) ₂ , Si (OH) ₃ , Si (C _1-8 alkyl) ₃ , Si (OH) (C _1-8 alkyl) ₂ , SOS _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N (C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _1-8 alkyl), N (C _1-8 alkyl)CON(C _1-8 alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH (C _1-8 alkyl), N (C _1-8 alkyl) SO ₂ N (C _1-8 alkyl) ₂ , NH SO ₂ NH (C _1-8 alkyl), NH SO ₂ N(C _1-8 alkyl) ₂ , NH SO ₂ NH ₂ .

[0113] 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.

[0114] In certain embodiments, for example, where q is greater than 2, A _q is a group that is connected to the ULM, and A ₁ and A _q are connected via linker units (L).

[0115] In certain embodiments, for example, where q is 2, A _q is a group that is connected to A ₁ and to the ULM.

[0116] According to certain embodiments, for example, where q is 1, the structure of the linker group L is -A ₁ - and A ₁ is a group that is connected to the ULM fragment and the AVM fragment.

[0117] In certain embodiments, the linker (L) contains a group represented by a general structure selected from the group consisting of:

-NR(CH ₂ ) _n -(low alkyl)-, -NR(CH ₂ ) _n -(low alkoxy)-, -NR(CH ₂ ) _n -(low alkoxy)-OCH ₂ -, -NR(CH ₂ ) _n -(low alkoxy)-(lower alkyl)-OCH ₂ -, -NR(CH ₂ ) _n -(cycloalkyl)-(lower alkyl)-OCH ₂ -, -NR(CH ₂ ) _n -(heterocycloalkyl)- , -NR (CH ₂ CH ₂ O) _n - (lower alkyl) -O-CH ₂ -, -N (CH ₂ CH ₂ O) _n - (heterocycloalkyl) -O-CH ₂ -, -NR (CH ₂ CH ₂ O) _n -aryl-O-CH ₂ -, -NR (CH ₂ CH ₂ O) _n - (heteroaryl) -O-CH ₂ -, -NR (CH ₂ CH ₂ O) _n - (cycloalkyl) -O -(heteroaryl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(cycloalkyl)-O-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(lower alkyl )-NH-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(low alkyl)-O-aryl-CH ₂ , -NR(CH ₂ CH ₂ O) _n- cycloalkyl-O- aryl-, -NR(CH ₂ CH ₂ O) _n -cycloalkyl-O-(heteroaryl) 1-, -NR(CH2CH2)n-(cycloalkyl)-O-(heterocycle)-CH ₂ , -NR(CH2CH2)n -(heterocycle)-(heterocycle)-CH ₂ , -N(R1R2)-(heterocycle)-CH2; Where

n can be from 0 to 10;

R may be H, lower alkyl;

R1 and R2 can form a ring with the N compound.

[0118] In certain embodiments, the linker (L) contains a group represented by a general structure selected from the group consisting of:

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-;

Where

m, n, o, p, q and r are each independently 0, 1, 2, 3, 4, 5, 6;

where number is zero, no N-O or O-O bond

R is H, methyl or ethyl; And

X is H or F.

[0119] In certain embodiments, the linker (L) contains a group represented by the general structure:

where m can be 2, 3, 4, 5.

In certain embodiments, the linker (L) contains a group represented by a general structure selected from the group consisting of:

where n and m are each independently 0, 1, 2, 3, 4, 5, 6; and X is H or F.

[0120] In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol having from 1 to about 100 ethylene glycol units, from about 1 to about 50 ethylene glycol units, from 1 to about 25 ethylene glycol units, from about 1 to about 10 ethylene glycol units. units, 1 to about 8 ethylene glycol units and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, or optionally substituted alkyl groups alternating with optionally substituted O, N, S, P, or Si atoms. In some embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In some embodiments, the linker may be asymmetric or symmetrical.

[0121] According to any of the embodiments of the compounds described herein, the linker group may be any suitable moiety described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group that ranges in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, from about 2 to 4 ethylene glycol units.

[0122] According to another embodiment, the present disclosure relates to a compound that contains an AVM moiety as described above that binds to a target protein (e.g., androgen receptor) or polypeptide that is ubiquitinated by ubiquitin ligase and chemically binds directly to the ULM moiety or via a linker moiety L, or alternatively, ABM is a ULM' group, which is also a ubiquitin ligase-binding moiety and may be the same as or different from the ULM group described above, and binds directly to the ULM group either directly or via a linker moiety; a L is a linker moiety as described above, which may or may not be present, and which chemically (covalently) links ULM to AVM, or to a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

[0123] In some embodiments, ULM exhibits activity or binds to E3 ubiquitin ligase with an IC ₅₀ of less than about 200 μM. IC ₅₀ can be determined according to any method known in the art, for example, according to the analysis of polarization fluorescence.

[0124] In some additional embodiments, the bifunctional compounds described herein exhibit activity with an IC ₅₀ of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 µM, or less than about 100, 50, 10, 1, 0.5, 0 .1, 0.05, 0.01, 0.005, 0.001 nM.

[0125] Although the ULM group and the AVM group can be covalently linked to the linker group through any group that is suitable and stable for the chemistry of the linker, according to preferred aspects of the present disclosure, the linker is independently covalently linked to the ULM group and the AVM group, preferably through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, each of which can be inserted anywhere on the ULM group and the AVM group to maximize the binding of the ULM group in the ubiquitin ligase and the AVM group in the target protein to be degraded . In some preferred aspects, the linker may be linked to an optionally substituted alkyl, alkylene, alkene, or alkyne group, aryl group, or heterocyclic group in the ULM and/or AVM groups.

Exemplary Androgen Binding Fragments (AVMs)

[0126] According to another aspect, the present disclosure relates to AR binding fragments (AVMs), which, in some aspects and embodiments, are connected to a linker and/or ULM described herein.

[0127] In any of the compounds described herein, the AVM contains a chemical moiety that binds to the androgen receptor (AR). Various androgen receptor binding compounds have been described in the literature, including various androgen derivatives such as testosterone, dihydrotestosterone and metribolone (also known as methyltrienolone or R1881), as well as non-steroidal compounds such as bicalutamide, enzalutamide. Those skilled in the art will appreciate that these androgen receptor binding compounds are potentially useful as an AVM moiety in a PROTAC compound. Such literature includes, without limitation, G.F. Allan et. al, Nuclear Receptor Signaling, 2003, 1, e009; R.H. Bradbury et. al, Bioorganic & Medicinal Chemistry Letters, 2011 5442-5445; C. Guo et. al, Bioorganic & Medicinal Chemistry Letters, 2012 2572-2578; P.K. Poutiainen et. al, J. Med. Chem. 2012, 55, 6316 - 6327 A. Pepe et. al, J. Med. Chem. 2013, 56, 8280 - 8297; M.E. Jung et al, J. Med. Chem. 2010, 53, 2779-2796, which are incorporated herein by reference.

[0128] According to certain embodiments, the AVM contains a structure selected from, but not limited to, the structures shown below, where the dotted line indicates the point of attachment of the linker fragment or ULM:

Where:

W ¹ is an aryl, heteroaryl, bicyclic or biheterocyclic compound, each independently substituted with 1 or more of H, halogen, hydroxyl, nitro, CN, C=CH, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), C _1-6 alkoxy (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl, or _CF3 ;

Y ¹ , Y ² are each independently NR ^Y1 , O, S;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, C=S, SO, SO ₂ , heteroaryl or aryl;

Q is a 3-6 membered ring with 0-4 heteroatoms, optionally substituted with 0-6 R ^Q , each R ^Q is independently H, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or several of halogen, C _1-6 alkoxy), halogen, C _1-6 alkoxy or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8-membered ring system containing 0-2 heteroatoms;

R ¹ , R ² , R ^a , R ^b , R ^Y1 , R ^Y2 each independently represents H, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), halogen, C _1-6 alkoxy, cyclic, heterocyclic compound, or R ¹ , R ² together with the atom to which they are attached, form a 3-8-membered ring system containing 0-2 heteroatoms;

W ² is a bond, C _1-6 alkyl, C _1-6 heteroalkyl, O, aryl, heteroaryl, alicyclic, heterocyclic, bi-heterocyclic, biaryl or bi-heteroaryl compound, each optionally substituted with 1-10 R ^W2 ;

each R ^W2 is independently H, halogen, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or more F), -OR ^W2A , C _3-6 cycloalkyl, C _4-6 cycloheteroalkyl, C _1-6 alicyclic compound (optionally substituted), heterocyclic compound (optionally substituted), aryl (optionally substituted) or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OC _1-3 alkyl (optionally substituted), OH, NH ₂ , NR ^Y1 R ^Y2 , CN; And

R ^W2A is H, C _1-6 alkyl (straight, branched) or C _1-6 heteroalkyl (straight, branched), each optionally substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halogen, or OC _1-3 alkyl.

[0129] According to any of the embodiments described herein, W ² is covalently attached to one or more ULM or CLM groups or a linker to which one or more ULM or CLM groups are attached, as described in the present invention.

[0130] In certain embodiments, W ¹ is

where each R ₂₂ is independently halogen, H, optionally substituted alkyl, haloalkyl, cyano or nitro; And

each R ₂₃ is independently H, halogen, CF ₃ , optionally substituted alkyl, alkoxy, haloalkyl, cyano, or nitro.

[0131] In certain additional embodiments, W ¹ is selected from the group consisting of:

означает точку присоединения линкера или ULM:[0132] According to specific embodiments, the AVM comprises a structure selected from the following structures shown below, wherein

means the attachment point of the linker or ULM:

Where:

R ^Q2 is H, halogen, CH ₃ or CF ₃ ;

R ^Q3 is H, halogen, hydroxyl, nitro, CN, C=CH, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), C _1-6 alkoxy (straight , branched, optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl, or CF ₃ ;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, heteroaryl or aryl;

R ^Y1 , R ^Y2 each independently represents H or C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _1-6 alkoxy, cyclic or heterocyclic compounds); And

R ^Q is each independently H, C ₁ -C ₆ alkyl (straight, branched, optionally substituted with 1 or more of halo or C _1-6 alkoxy), or two R ^Qs together with the atom to which they are attached form a 3- 8-membered ring system containing 0-2 heteroatoms.

[0133] According to a specific embodiment, each R ^Q is independently H or CH ₃ . According to another embodiment, R ^Q3 is CN.

означает точку присоединения линкера или ULM:[0134] According to specific embodiments, the AVM comprises a structure selected from the following structures shown below, wherein

means the attachment point of the linker or ULM:

Where:

R ^Q2 is H, halogen, CN, CH ₃ or CF ₃ ; And

R ^Q3 is H, halogen, hydroxyl, nitro, CN, C=CH, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), C _1-6 alkoxy (straight , branched, optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl, or CF ₃ ;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, heteroaryl or aryl; And

R ^Y1 , R ^Y2 each independently represents H or C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _1-6 alkoxy, cyclic or heterocyclic compounds); And

X is N or C.

[0135] According to a specific embodiment, R ^Q3 is CN.

[0136] According to certain additional embodiments, the ABM comprises the structure shown below, where the dotted line indicates the point of attachment of the linker fragment or ULM or CLM:

Where:

W ¹ represents

each R ₂₂ is independently H or -CN;

each R ₂₃ is independently H, halogen, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), C ₁ -C ₆ alkoxy or -CF ₃ ;

Y ³ is a bond or O;

Y ⁴ is a bond or NH;

Y ⁵ is a bond, C=O, C ₁ -C ₆ heteroaryl or C ₁ -C ₆ aryl;

R ¹ , R ² each independently represents H or C ₁ -C ₆ alkyl (straight or branched, optionally substituted; for example, optionally substituted with 1 or more of halogen or C _1-6 alkoxy);

W ² is a bond, C _1-6 aryl, C _1-6 heteroaryl, C _1-6 alicyclic or C _1-6 heterocyclic compound, bigeterocyclic compound, biaryl or bigeteroaryl, each optionally substituted with 1-10 R ^W2 ; And

each R ^W2 is independently H or halogen; And

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической.[0137]

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific.

[0138] According to any of the embodiments described herein, W ² is covalently attached to one or more ULM or CLM groups or a linker to which one or more ULM or CLM groups are attached, as described in the present invention.

[0139] In certain additional embodiments, W ¹ is selected from the group consisting of:

[0140] According to any aspect or embodiment described herein, W ² is selected from the group consisting of:

[0141] According to certain embodiments, the AVM contains a structure selected from, but not limited to, the structures shown below, where the dotted line indicates the point of attachment of the linker fragment or ULM:

where W ¹ represents

each R ₂₂ is independently H or -CN;

each R ₂₃ is independently H, halogen or —CF ₃ ;

Y ¹ , Y ² each independently represents O or S;

R ¹ , R ² each independently represents H or a methyl group;

W ² is a bond, C _1-6 aryl or heteroaryl, each optionally substituted with 1, 2 or 3 R ^W2 ; And

each R ^W2 is independently H, halogen, C _1-6 alkyl (optionally substituted with 1 or more F), OC _1-3 alkyl (optionally substituted with 1 or more -F).

[0142] According to any of the embodiments described herein, W ² is covalently attached to one or more ULM or CLM or a linker to which one or more ULM or CLM groups are attached, as described in the present invention.

[0143] In certain additional embodiments, W ¹ is selected from the group consisting of:

и

And

[0144] In certain additional embodiments, W2 is selected from the group consisting of:

[0145] In certain embodiments, the AVM is selected from the group consisting of:

[0146] In certain embodiments, the AVM comprises the structure:

where W ¹ is aryl or heteroaryl, each independently substituted with 1 or more of H, halogen, hydroxyl, nitro, CN, C=CH, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _{1 -6} alkoxy), C _1-6 alkoxy (straight, branched, optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl, or CF ₃ ;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, C=S, SO, SO ₂ , heteroaryl or aryl;

Q is a 4-membered alicyclic ring with 0-2 heteroatoms, optionally substituted with 0-6 R ^Q , each R ^Q is independently H, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _{1 -6} alkoxy) or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8-membered ring system containing 0-2 heteroatoms);

R ^Y1 , R ^Y2 are each independently H, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _1-6 alkoxy);

W ² is a bond, C _1-6 alkyl, C _1-6 heteroalkyl, O, C _1-6 alicyclic compound, heterocyclic compound, aryl, bigeterocyclic compound, biaryl or bigeteroaryl or heteroaryl, each optionally substituted with 1, 2 or 3 R ^W2 ; And

each R ^W2 is independently H, halogen, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more F), C _1-6 heteroalkyl (straight, branched, optionally substituted), -OR ^W2A OC _1-3 alkyl (optionally substituted with 1 or more F), C _3-6 cycloalkyl, C _4-6 cycloheteroalkyl (optionally substituted), C _1-6 alkyl (optionally substituted), C _1-6 alicyclic compound (optionally substituted), heterocyclic compound (optionally substituted), aryl (optionally substituted), heteroaryl (optionally substituted), bicyclic heteroaryl (optionally substituted), aryl, OH, NH ₂ , NR ^Y1 R ^Y2 or CN; And

R ^W2A is H, C _1-6 alkyl (straight, branched) or C _1-6 heteroalkyl (straight, branched), each optionally substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halogen, or OC _1-3 alkyl.

[0147] According to an additional aspect, the present description relates to an androgen receptor binding compound containing the structure:

where W ¹ is an aryl, heteroaryl, bicyclic or biheterocyclic compound, each independently substituted with 1 or more of H, halogen, hydroxyl, nitro, CN, C=CH, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more from halogen, C _1-6 alkoxy), C _1-6 alkoxy (straight, branched, optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl, or CF ₃ ;

Y ¹ , Y ² are each independently NR ^Y1 , O or S;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, C=S, SO, SO ₂ , heteroaryl or aryl;

Q is a 3-6 membered alicyclic or aromatic ring with 0-4 hetero atoms and optionally substituted with 0-6 R ^Q , each R ^Q is independently H, C _1-6 alkyl (straight, branched, optionally substituted with 1 or several of halogen, C _1-6 alkoxy), or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 hetero atoms);

R ¹ , R ² , R ^a , R ^b , R ^Y1 , R ^Y2 are each independently H, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), or R ¹ , R ² together with the atom to which they are attached form a 3-8-membered ring system containing 0-2 heteroatoms);

W ² is a bond, C _1-6 alkyl, C _1-6 heteroalkyl, O, C _1-6 alicyclic compound, heterocyclic compound, aryl, bigeterocyclic compound, biaryl or bigeteroaryl or heteroaryl, each optionally substituted with 1, 2 or 3 R ^W2 ;

each R ^W2 is independently H, halogen, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more F), C _1-6 heteroalkyl (straight, branched, optionally substituted), -OR ^W2A , OC _1-3 alkyl (optionally substituted with 1 or more -F), C _3-6 cycloalkyl, C _4-6 cycloheteroalkyl, C _1-6 alkyl (optionally substituted), C _1-6 alicyclic compound (optionally substituted), heterocyclic compound (optionally substituted) , aryl (optionally substituted) or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH ₂ , NR ^Y1 R ^Y2 , CN; And

R ^W2A is H, C _1-6 alkyl (straight, branched) or C _1-6 heteroalkyl (straight, branched), each optionally substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or OC _1-3 alkyl.

[0148] In certain embodiments, the androgen receptor binding fragment is characterized by the structure:

where W ¹ represents

each R ₂₂ is independently H or -CN;

each R ₂₃ is independently H, halogen or —CF ₃ ;

Y ³ is a bond or O;

Q is a 4-membered ring optionally substituted with 0-4 R ^Q , each R ^Q is independently H or methyl;

Y4 is a bond or NH;

Y5 is a bond, C=O or C=S;

each W ² is independently a bond, C _1-6 aryl or heteroaryl, each is optionally substituted with 1, 2 or 3 R ^W2 , each R ^{W 2} is independently H, halogen, a 6-membered alicyclic ring with 1 or 2 heteroatoms or 5- membered aromatic ring with 1 or 2 or 3 heteroatoms.

[0149] In certain additional embodiments, W ² is selected from the group consisting of:

[0150] According to any of the embodiments described herein, W ² is covalently attached to one or more ULM or CLM or a linker to which one or more ULM or CLM groups are attached, as described in the present invention.

[0151] In certain additional embodiments, W ¹ is selected from the group consisting of:

[0152] In certain embodiments, the androgen-binding fragment is characterized by the structure:

where W ¹ is aryl, independently substituted with 1 or more of halogen, CN;

Y ³ each independently represents a bond, NR ^Y2 , CR ^Y1 R ^Y2 , C=O;

Q is a 5-membered aromatic ring with 1 or 2 heteroatoms;

R ^Y1 , R ^Y2 are each independently H, C _1-6 alkyl (straight, branched);

W ² is a bond, aryl or heteroaryl, each optionally substituted with 1, 2 or 3R ^W2 ; And

each R ^W2 is independently H, halogen, C _1-6 alkyl (optionally substituted with 1 or more F), OC _1-3 alkyl (optionally substituted with 1 or more -F).

[0153] According to any of the embodiments described herein, W ² is covalently attached to one or more ULM or CLM or a linker to which one or more ULM or CLM groups are attached, as described in the present invention.

[0154] In certain embodiments, W ¹ is

where each R ₂₂ is independently halogen or CN; And

each R ₂₃ is independently H or halogen.

[0155] In certain additional embodiments, W ¹ is selected from the group consisting of:

[0156] According to certain additional embodiments, Q is

[0157] According to certain additional embodiments, W ² is

[0158] According to certain additional embodiments, (Y ³ ) _0-5 is

[0159] According to certain embodiments, the AVM contains a structure selected from, but not limited to, the structures shown below, where the dotted line indicates the point of attachment of the linker fragment or ULM:

Where:

W ¹ represents

each R ₂₂ is independently H or -CN;

each R ₂₃ is independently H, halogen or —CF ₃ ;

Y ¹ , Y ² each independently represents O or S;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, C=S, SO or SO ₂ ;

R ¹ , R ² each independently represents H or a methyl group;

W ² is a bond, C _1-6 aryl or heteroaryl, each optionally substituted with 1, 2 or 3 R ^W2 ; And

each R ^W2 is independently H, halogen, C _1-6 alkyl (optionally substituted with 1 or more F), C _3-6 cycloalkyl, C _4-6 cycloheteroalkyl, OC _1-3 alkyl (optionally substituted with 1 or more -F) .

[0160] According to any of the embodiments described herein, W ² is covalently attached to one or more ULM or CLM or a linker to which one or more ULM or CLM groups are attached, as described in the present invention.

[0161] In certain additional embodiments, W ¹ is selected from the group consisting of:

[0162] In certain additional embodiments, W2 is selected from the group consisting of:

[0163] According to certain embodiments, the ABM comprises the structure shown below, where the dotted line indicates the point of attachment of the linker fragment or ULM or CLM:

Where:

W ¹ represents

each R ₂₂ is independently H or -CN;

each R ₂₃ is independently H, halogen or —CF ₃ ;

Y ³ is a bond or O;

Y ⁴ is a bond or NH;

Y ⁵ is a bond, C=O, C ₁ -C ₆ heteroaryl or C ₁ -C ₆ aryl;

R ¹ , R ² each independently represents H or C ₁ -C ₆ alkyl (straight or branched, optionally substituted with 1 or more of halogen or C _1-6 alkoxy);

W ² is a bond, C _1-6 aryl, C _1-6 heteroaryl, C _1-6 alicyclic, or C _1-6 heterocyclic, each optionally substituted with 1-10 R ^W2 ; And

each R ^W2 is independently H or halogen; And

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической.[0164]

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific.

[0165] According to any of the embodiments described herein, W ² is covalently attached to one or more ULM or CLM or a linker to which one or more ULM or CLM groups are attached, as described in the present invention.

[0166] In certain additional embodiments, W ¹ is selected from the group consisting of:

[0167] In certain additional embodiments, W ² is selected from the group consisting of:

[0168] In certain embodiments, the AVM androgen receptor binding compound is selected from the group consisting of:

trans-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile;

cis-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile;

trans-6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridazine-3-carboxamide;

trans-tert-Butyl-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate;

trans-4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide;

trans-5-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrazine-2-carboxamide;

trans-2-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide;

4-Methoxy-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide;

trans-1-(2-Hydroxyethyl)-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-1H-pyrazole-4-carboxamide;

trans-6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide;

trans-4-[(5-Hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide and

trans-tert-Butyl 2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)aminopentyl}oxy)acetate; And

N-((1r,3r)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-methylbenzamide.

[0169] The term "hydrocarbyl" should mean a compound that contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.

[0170] The term "unsubstituted" should mean substituted with only hydrogen atoms. The range of carbon atoms that includes C ₀ means that the carbon atom is missing and replaced by H. Thus, the range of carbon atoms that is C ₀ -C ₆ includes carbon atoms 1, 2, 3, 4, 5 and 6 and for C ₀ H is instead of a carbon atom. The term "substituted" or "optionally substituted" shall mean independently (i.e., if more substituents occur, each substituent is independent of another substituent) one or more substituents (independently up to five substituents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound of the present disclosure, and may include substituents that may themselves be further substituted) at the carbon (or nitrogen) position anywhere on the molecule within the context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO ₂ ), halogen (preferably 1, 2 or 3 halogens, in particular on alkyl, especially a methyl group such as trifluoromethyl), alkyl group (preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ ), aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), alkoxy (preferably C ₁ -C ₆ alkyl or aryl, including phenyl and substituted phenyl), thioether (C ₁ -C ₆ alkyl or aryl), acyl (preferably C ₁ -C ₆ acyl), ester or thioester (preferably C ₁ -C ₆ alkyl or aryl), including an alkylene ester (so that the attachment is on an alkylene group and not on an ester functional group which is preferably substituted with a C ₁ -C ₆ alkyl or aryl group), preferably C ₁ -C ₆ alkyl or aryl, halogen (preferably F or Cl), amine (including five - or a six-membered cyclic alkyleneamine, additionally including C ₁ -C ₆ alkylamine or C ₁ -C ₆ dialkylamine, while the alkyl groups may be substituted with one or two hydroxyl groups) or optionally substituted -N(C ₀ -C ₆ alkyl) C(O)(O-C ₁ -C ₆ alkyl) group (which may be optionally substituted with a polyethylene glycol chain to which an alkyl group is additionally attached containing one halogen, preferably a chloride substituent), hydrazine, amido, which is preferably substituted with one or two i C ₁ -C ₆ alkyl groups (including carboxamide which is optionally substituted with one or two C ₁ -C ₆ alkyl groups), alkanol (preferably C ₁ -C ₆ alkyl or aryl) or alkanoic acid (preferably C ₁ -C ₆ alkyl or aryl). Substituents of the present disclosure may include, for example, SiR ₁ R ₂ R ₃ groups, where each of R ₁ and R ₂ described in the present invention and R ₃ represents H or C ₁ -C ₆ alkyl group, preferably R ₁ , R ₂ , R ₃ in this context are C ₁ -C ₃ alkyl group (including isopropyl or tert-butyl group). Each of the above groups may be connected directly to the substituted moiety or, alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an optionally substituted -(CH ₂ ) _m- or alternatively an optionally substituted -(OCH ₂ ) _m- , -(OCH ₂ CH ₂ ) _m- or -(CH ₂ CH ₂ O) _m- group which may be substituted by any one or more of the above substituents. Alkylene groups -(CH ₂ ) _m- or -(CH ₂ ) _n- groups or other chains such as ethylene glycol chains as defined above may be substituted anywhere on the chain. Preferred substituents on alkylene groups include halogen or C ₁ -C ₆ (preferably C ₁ -C ₃ ) alkyl groups, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (OC ₁ -C ₆ groups) , up to three halogen groups (preferably F), or amino acid side chains as otherwise described herein, and an optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two C ₀ -With ₆ alkyl substituents, such group(s) may be substituted(s)). In certain embodiments, the alkylene group (often a simple methylene group) is substituted with one or two optionally substituted C ₁ -C ₆ alkyl groups, preferably a C ₁ -C ₄ alkyl group, most commonly methyl or O-methyl groups, or an amino acid side chain, as otherwise as described in the present invention. According to the present disclosure, a moiety in a molecule may optionally be substituted with up to five substituents, preferably up to three substituents. Most often, according to the present invention, the fragments that are substituted are substituted with one or two substituents.

[0171] The term "substituted" (each substituent was independent of any other substituent) should also mean, within its context of use, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamido, keto, carboxy, C ₁ -C ₆ ester (hydroxyester or carbonyl ester), C ₁ -C ₆ keto, urethane-OC(O)-NR ₁ R ₂ or -N(R ₁ )-C(O) -OR ₁ , nitro, cyano and amine (especially including C ₁ -C ₆ alkylene-NR ₁ R ₂ , mono- or di-C ₁ -C ₆ alkyl-substituted amines, which may be optionally substituted with one or two hydroxyl groups). Each of these groups contains, unless otherwise indicated, within the context of 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-,=O, -(CH ₂ ) _m- (where m and n are in the context of 1, 2, 3 , 4, 5 or 6), -S-, -S(O)-, SO ₂ - or -NH-C(O) -NH-, -(CH ₂ ) _n OH, -(CH ₂ ) _n SH, -(CH ₂ ) _n COOH, C ₁ -C ₆ alkyl, -(CH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl ), -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n NHC (O)-R ₁ , -(CH ₂ ) _n C(O)-NR ₁ R ₂ , -(OCH ₂ ) _n OH, -(CH ₂ O) _n COOH, C ₁ -C ₆ alkyl, -(OCH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), -(OCH ₂ ) _n NHC(O)-R ₁ , - (CH ₂ O) _n C(O)-NR ₁ R ₂ , -S(O) ₂ -R _S , -S(O)-R _S ( _RS is C ₁ -C ₆ alkyl or -(CH ₂ ) _m -NR ₁ R ₂ group), NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of the substituent. R ₁ and R ₂ each within the context represents H or C ₁ -C ₆ alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" should also mean, within the chemical context of the particular compound and the substituent used, an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group, as otherwise described herein. Alkylene groups may also be substituted, as otherwise disclosed herein, preferably with optionally substituted C ₁ -C ₆ alkyl groups (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thereby providing a chiral center), an amino acid group side chain, as otherwise as described in the present invention, an amido group as described above in the present invention, or a urethane group O-C(O)-NR ₁ R ₂ where R ₁ and R ₂ as otherwise described in the present invention, although many other groups can also be used as substitutes. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, and preferably 1 or 2 substituents. It is noted that in cases in which a compound at a particular position is necessarily substituted (mainly due to valency) but no substitution is noted, then such a substituent is construed or understood to be H, unless the context of the substitution suggests otherwise.

[0172] Exemplary AR-PROTAC Compounds

[0173] As described above, in some aspects, the present description relates to bifunctional PROTAC compounds containing at least one AVM group, a linker, and at least one ULM (or CLM) group, as described in the present invention.

[0174] In certain embodiments, the compound is selected from the group consisting of compounds 1-625 (i.e., the chemical structures described in Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7 of Figures 2, 3 , 4, 5, 6 and 7, respectively) and their salts and polymorphs.

[0175] In additional embodiments, the compound is selected from the group consisting of: 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2 ,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidine-1 -yl}-2-(trifluoromethyl)benzonitrile (1); 4-(3-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] amino}ethoxy)-ethoxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (2); 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4, 7,10,13,16-pentaoxa-1-azaoctadecan-18-yl}oxy)-phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)-benzonitrile (3); 4-[3-(4-{2-[2-(2-{[2-(2,6-dioxo-piperidin-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 (4); 4-[3-(4-{3-[2-(2-{[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4 -yl]amino}-ethoxy)ethoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (5); 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4, 7,10-trioxa-1-azatetradexan-14-yl}oxy)-phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)-benzonitrile (6); 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4, 7,10-trioxa-1-azatridecan-13-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (7); 4-(3-{4-[(1-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl }-4,7,10-trioxa-1-azadecan-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (8 ); 4-(3-{4-[(1-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl }-4,7,10-trioxa-1-azadecan-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-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4 -yl]amino}-ethoxy)propoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (10); 4-{4,4-dimethyl-3-[4-({1-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1Н -isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl}oxy)phenyl]-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (11 ); 4-[3-(4-{4-[(5-{[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl ]amino}pentyl)oxy]phenyl}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (12); 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl ]oxy}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (13); 4-{3-[4-({1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-1,4, 7,10-tetraoxatridecan-13-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (14); 6-[4-(2-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl)piperazin-1- yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (15); 6-{4-[2-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy )ethyl]-piperazin-1-yl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-pyridine-3-carboxamide (16 ); 4-(3-{4-[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy} ethyl)-1H-1,3-benzodiazol-5-yl]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (17); 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-propoxy) pentyl]amino}-3-fluoro-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (18); 6-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}ethyl)piperazin-1- yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (19); 6-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl)piperazine -1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-pyridine-3-carboxamide (20); 6-(4-{3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl] propyl} piperazin-1-yl)- N-[(1R,3R-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (21); {[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}ethoxy)ethyl]-piperazin-1-yl}-N- [(1R,3R-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (22);4-{4-[4-(2-{ [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}ethyl)piperazin-1-yl]butyl}-N-[( 1R,3R)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (23); (2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino}propoxy)-ethyl]piperazin-1-yl}-N-[( 1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (24); -(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-propoxy)ethyl]piperazin-1-yl} -N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]pyridine-3-carboxamide (25); 4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl )-N-[(1R,3R)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (26); 4-{3-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}- propyl)piperazin-1-yl]propyl}-N-[(1R,3R)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (27); 4-[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl] -N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (28); 6-{4-[2-(3-{[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl ]amino}-propoxy)ethyl]piperazin-1-yl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3- carboxamide (29); 4-(4-{4-[2-({2-[(3S)-2,6-dioxo-piperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}oxy )ethyl]piperazin-1-yl}butyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-benzamide (30); 4-(4-{4-[2-({2-[(3S)-2,6-dioxo-piperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy )ethyl]piperazin-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-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl ]amino}ethyl)piperazin-1-yl]butyl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (32); 6-{4-[5-({2-[(3S)-2,6-dioxo-piperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)-pentyl ]piperazin-1-yl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (33); 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl }oxy)ethyl]piperazin-1-yl}butyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-benzamide (34) ; 6-{4-[5-({2-[(3S)-2,6-dioxo-piperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}oxy)pentyl] piperazin-1-yl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (35); 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1 -yl}butyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-benzamide (36); 4-{4-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl ]amino}ethyl)piperazin-1-yl]butyl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (37); 6-(4-{6-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]hexyl}piperazin-1-yl)- N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (38); 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1 -yl}butyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (39); 4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl )-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (40); 6-{4-[5-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}oxy) pentyl]-piperazin-1-yl}-N-[(1R,3R)-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-pyridine-3-carboxamide (41); 6-[4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}pentyl)piperazin-1- yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]pyridine-3-carboxamide (42); 4-[4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}pentyl)piperazin-1- yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (43); 4-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}pentyl )-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (44); 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}- butyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (45); 4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1 -yl}hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (46); 4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}butyl)-N-[(1R, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (47); 4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}pentyl)-N-[(1R, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (48); 4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}ethoxy)propyl]-N -[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (49); 4-[4-(2-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}ethoxy)butyl]-N -[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (50); 4-[5-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}ethoxy)-pentyl]- N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (51); 4-[6-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}-ethoxy)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-pyrazol-1-yl]propan-2-yl]-5-{[4-(4-{[2- (2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-butyl)piperazin-1-yl]methyl}-1H-pyrazol- 3-carboxamide (53); 4-(4-{6-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]hexyl}-piperazin-1- yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (54); 4-(3-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}propyl)-N-[(1R, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (55); N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl]-5-[(3-{4-[2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propoxy)methyl]-1H-pyrazole-3-carboxamide ( 56); 4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}propyl)-1H-1 ,2,3-triazol-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (57); 6-[4-(6-{[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino} hexyl)-piperazin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-pyridine-3-carboxamide (58) ; N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl]-5-({3-[4-(2-{ [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl)piperazin-1-yl]propoxy}methyl)- 1H-pyrazole-3-carboxamide (59); (60); 4-[4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-oxy}pentyl)-1H- 1,2,3-triazol-1-yl]-N-[(1R,3R))-3-(3-chloro-4-cyanophenoxy)cyclobutyl]-benzamide (61); 6-{4-[2-(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl} butoxy)ethyl]piperazin-1-yl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (62) ; 6-{4-[2-(4-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl} butoxy)ethyl]-piperazin-1-yl}-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-pyridine-3-carboxamide ( 63); 6-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl }pentyl)oxy]ethyl}piperazin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (64); 6-(4-{2-[(5-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl }pentyl)-oxy]ethyl}piperazin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3- carboxamide (65); 4-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl }pentyl)oxy]ethyl}-piperazin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-benzamide (66 ); 4-(4-{2-[(5-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl }pentyl)oxy]ethyl}piperazin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (67); 4-(4-{6-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]hexyl}piperazin-1-yl)- N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (68); 4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-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-dioxo-piperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperazin-1-yl )hexyl]-N-[(1R,3R)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (70); 4-[6-(4-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperazin-1-yl )hexyl]-N-[(1R,3R)-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (71); 6-[4-(6-{[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}hexyl) -piperazin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-pyridine-3-carboxamide (72); 6-[4-(6-{[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy} hexyl)piperazin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (73); 4-[6-(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}piperazin-1-yl )-hexyl]-N-[(1R,3R)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]-benzamide (74); and 4-[6-(4-{2-[(3R)-2,6-dioxo-piperidin-3-yl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}piperazin-1- yl)hexyl]-N-[(1R,3R)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (75); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(6-((2-(2,6-dioxopiperidin -3-yl)-6-fluoro-1-oxoisoindolin-5-yl)amino)hexyl)piperazin-1-yl)nicotinamide (76); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)nicotinamide (77); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(1-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinamide (78); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((5-(2-((S )-2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)oxy)ethyl)piperazin-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-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)oxy)ethyl)piperazin-1-yl)benzamide (80); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)-hexyl)benzamide (81); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)hexyl)benzamide (82); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((1R,4R)-5-(5-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-2,5-diazabicyclo[2. 2. 1]heptan-2-yl)-nicotinamide (83); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1-oxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)benzamide (84); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(1-(5-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (85); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(4-(2-((R)-2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentyl)benzamide (86); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(4-(2-((R)-2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentyl)benzamide (87); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidin- 3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)benzamide (88); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidin- 3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)-benzamide (89); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(6-((2-(2,6-dioxopiperidin -3-yl)-6-fluoro-1-oxoisoindolin-5-yl)oxy)hexyl)-piperazin-1-yl)nicotinamide (90); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-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-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)benzamide (92); N-((1R,3R-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidin-3 -yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)hexyl)benzamide (93);N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)hexyl)nicotinamide (94) ; N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(4-(2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)pentyl)benzamide (95); N-((1R,3R)-3-(3 -chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxo-piperidin-3-yl)-3-oxoisoindolin-5-yl )oxy)pentyl)piperazin-1-yl)-nicotinamide (96); -(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)butyl)benzamide ( 97); -dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 3,6-dihydropyridin-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-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-benzamide (99); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1-oxoisoindolin-5-yl)oxy)pentyl)-1H-1,2,3-triazol-1-yl)benzamide (100); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-((1S,4S)-5-(2-( (R)-2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-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-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1-oxoisoindolin-5-yl)oxy)pentyl)-1H-1,2,3-triazol-1-yl)-nicotinamide (102); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1-yl)hexyl)nicotinamide (103); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridin-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-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)benzamide (105); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-(3-((2-(2, 6-dioxo-piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)azetidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)benzamide (106); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(1-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1H-1,2,3-triazol-4-yl)ethyl)piperazin-1-yl)nicotinamide (107); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(3-(1-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1H-1,2,3-triazol-4-yl)propyl)piperazin-1-yl)-nicotinamide (108); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (109); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidin- 3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (110); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(3-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)nicotinamide (111); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-nicotinamide (112); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(3-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-piperidin-4-yl)nicotinamide (113); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)-nicotinamide (114); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)nicotinamide (115); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-4-(5-((2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-3-(hydroxymethyl)-piperazin-1-yl)-benzamide (116); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(3-(3-((2-(2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)azetidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)nicotinamide (117); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (118); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(4-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)nicotinamide (119); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)-nicotinamide (120); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)butyl)nicotinamide (121); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)nicotinamide (122); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1-yl)butyl)nicotinamide (123); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butyl)nicotinamide (124); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butyl)nicotinamide (125); N-((1R,3R)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (126); N-((1R,3R)-3-(3,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3 -yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)-nicotinamide (127); N-((1R,3R)-3-(3-chloro-4cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(5-(3-((2-(2,6-dioxo-piperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)pentyl)nicotinamide (128); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide (129); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidin-1-yl)butyl)nicotinamide (130); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)nicotinamide (131); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)-pyrimidine-5-carboxamide (132); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(3-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)ethyl)-3,5-difluorobenzamide (133); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R)-4-(5-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-3,5-dimethylpiperazin-1-yl)benzamide (134); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(2-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)nicotinamide (135); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-nicotinamide (136); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(5-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)nicotinamide (137); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(5-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)-nicotinamide (138); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-((S)-2, 6-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (139); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-((S)-2, 6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (140); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(9-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5. 5]undecan-4-yl)ethyl)-benzamide (141); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)pyrimidine-5-carboxamide (142); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carboxamide (143); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carboxamide (144); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (145); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)nicotinamide (146); N-((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((4-(4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)methyl)-1H-pyrazole-3-carboxamide (147); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(9-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5. 5]undecan-4-yl)propyl)benzamide (148); N-((1R,3R)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide (149); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-5-carboxamide (150); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-((S)-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (151); N-((1R,3R)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)nicotinamide (152); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)-piperidin-1-yl)nicotinamide (153); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-3-oxopiperazin-1-yl)nicotinamide (154); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(4-(3-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)butyl)piperazin-1-yl)pyrimidine-5-carboxamide (155); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3-(3-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)propyl)piperazin-1-yl)pyrimidine-5-carboxamide (156); 2-chloro-4-(3-(4-(5-(4-(2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl )-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-benzonitrile (157); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (158); 2-chloro-4-(5-(4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl )-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3. 4]octan-7-yl)benzonitrile (159); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-nicotinamide (160); N-((1R,3R)-3-(3,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-5-carboxamide (161); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(2-(2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3. 5]nonan-7-yl)nicotinamide (162); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(7-(2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3. 5]nonan-2-yl)nicotinamide (163); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(2-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)nicotinamide (164); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(3-(2-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)azetidin-1-yl)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-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)-2,6-difluorobenzamide (166); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((1-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-1,4-diazepan-1-yl)pyrimidine-5-carboxamide (167); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)-1-oxa-4,9-diazaspiro[5. 5]undecan-9-yl)benzamide (168); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-1-oxa-4,9-diazaspiro[5. 5]undecan-9-yl)benzamide (169); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(4-(2-(2,6-dioxopiperidin- 3-yl)-6-fluoro-1,3-dioxoisoindolin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,5-diazabicyclo[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-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)piperidin-1-yl)benzamide (172); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3,5-difluorobenzamide (173); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide (174); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((1R,4R)-5-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,5-diazabicyclo[2. 2. 1]heptan-2-yl)methyl)piperidin-1-yl)benzamide (175); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((1S,4S)-5-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,5-diazabicyclo[2. 2. 1]heptan-2-yl)methyl)piperidin-1-yl)-benzamide (176); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)-3-fluorobenzamide (177); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((1R,3R)-3-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)benzamide (178); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)-5-fluoronicotinamide (179); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-4-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (180); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-4,6-difluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)benzamide (181); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-((4-(2-(2 ,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)benzamide (182); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl)-benzamide (183); N-((1R,3R)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-methyl)cyclohexyl)benzamide (184); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (185); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)benzamide (186); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide (187); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide (188); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)azetidin-1-yl)benzamide (189); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(3-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)ethyl)piperidin-1-yl)benzamide (190); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azepan-1-yl)pyrimidine-5-carboxamide (191); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)cyclohexyl)benzamide (192); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((3S,5R)-4-(3-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)nicotinamide (193); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R-4-(3-((2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)benzamide (194); N-((1R,3R)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((3S,5R)-4-(3-((2-(2,6-dioxo-piperidine-3- yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide (195);N-((1R,3R)-3-(3 -chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1S,3S)-3-(((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)oxy)methyl)cyclobutyl)piperazin-1-yl)benzamide (196);N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-Tetramethylcyclobutyl)-4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl) -2-fluorobenzamide (197); -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)benzamide (198);N -((1R,3R)-3-(3-chloro-4-cyanoph enoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)piperidin-4-yl)methyl)(methyl)-amino)pyrrolidin-1-yl)benzamide (199); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-(((1-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)(methyl)amino)pyrrolidin-1-yl)-benzamide (200); H-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(((1-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)(methyl)amino)methyl)pyrrolidin-1-yl)benzamide (201); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((2S,6R)-4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-dimethylpiperazin-1-yl)ethyl)benzamide (202); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-[1,3'-biazetidine]-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)ethyl)piperazin-1-yl)benzamide (204); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(1-(2-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)azetidin-3-yl)piperazin-1-yl)benzamide (205); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(4-(1-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)ethyl)-benzamide (206); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((2R,6R)-4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-dimethylpiperazin-1-yl)ethyl)benzamide (207); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-((4-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)benzamide (208); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((28.68)-4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-dimethylpiperazin-1-yl)ethyl)-benzamide (209); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-((4-(2-(2,6-dioxpiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-azetidin-1-yl)benzamide (210); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)benzamide (211); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(6-(2,6 -dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-2-yl)piperazin-1-yl)ethyl)piperidin-1-yl) benzamide (212); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (213); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)octahydroisoquinodin-2(1H)-yl)nicotinamide (215); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(2-(((1R,3R)-3- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-cyclobutyl)(methyl)amino)ethyl)azetidin-1-yl)benzamide (216); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin -3-yl)-4-fluoro-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)benzamide (217); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((1R,3R)-3-((4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-cyclobutyl)benzamide (218); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((1S,3S)-3-((4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclobutyl)benzamide (219); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((4aR,6S,8aR)-6-(4-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-octahydroisoquinolin-2(1H)-yl)nicotinamide (220); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((4aR,6R,8aR)-6-(4-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-octahydroisoquinolin-2(1H)-yl)nicotinamide (221); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyridazin-3-carboxamide (222); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(4-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyrrolidin-1-yl)benzamide (223); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(1-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)benzamide (224); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(4-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)benzamide (225); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(4-(2-(2, 6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-carbonyl)-pyrrolidin-1-yl)benzamide (226); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-((4-(2-(2,6-dioxopiperidin -3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)benzamide (227); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3R)-1-(2-(2 ,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-piperazin-1-yl)benzamide (228); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)-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)carbamoyl)phenyl)piperidine-4- yl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-N-methylpyrrolidin-3-carboxamide (230); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2,6-dimethylpiperidin-1-yl)pyrimidine-5-carboxamide (232 ); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((2S,4S,6R)-4-((4-( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2,6-dimethylpiperidin-1-yl)pyrimidine-5-carboxamide (233 ); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((2S,6S)-4-((4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2,6-dimethylpiperidin-1-yl)-pyrimidin-5-carboxamide (234) ; N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(3-(3-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)propyl)azetidin-1-yl)benzamide (235); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(7-((3-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1-yl)methyl)octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)nicotinamide (236); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((1R,3R)-3-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)methyl)(methyl)amino)piperidin-1-yl)benzamide (237); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((1'-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)amino)-benzamide (238); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)benzamide (239); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((1R,3R)-3-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)-benzamide (240); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((1S,4S,5R)-5-((4-( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[2. 2. 1]heptan-2-yl)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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[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-dioxopiperidin -3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (243); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-((2-((2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)(methyl)amino)pyrrolidin-1-yl)benzamide (244); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(3-((2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)pyrrolidin-1-yl)benzamide (245); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzamide (246); N-((1R,3R)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (247); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-((S)-2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-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-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butyl)benzamide (249); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-((S)-2, 6-dioxo-piperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-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-dioxo-piperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)benzamide (251); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(5-((2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)benzamide (252); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-((2S,6R)-4-( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-dimethylpiperazin-1-yl)hexyl)-benzamide (253); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3-(2-(4-(2-(2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl)oxetan-3-yl)methyl)benzamide (254); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)benzamide (255); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-((1S,4S)-5-(2-( (S)-2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5-diazabicyclo[2. 2. 1]heptan-2-yl)hexyl)benzamide (256); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-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-dioxo-piperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5-diazabicyclo[2. 2. 1]heptan-2-yl)-hexyl)benzamide (258); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-((1R,4R)-5-(2-( (R)-2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5-diazabicyclo[2. 2. 1]heptan-2-yl)hexyl)benzamide (259); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3-(2-(4-(2-(2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)oxetan-3-yl)methyl)benzamide (260); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperidin-4-yl)nicotinamide (261); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperidin-4-yl)nicotinamide (262); N-((1R,3R)-3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)-nicotinamide (263); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)pyrazin-2-carboxamide (264); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)pyridazin-3-carboxamide (265); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-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-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-1H-pyrazole-4-carboxamide (267); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-1H-pyrazole-3-carboxamide (268); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(4-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (269); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-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-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (271); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-((R-2,6 -dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )piperazin-1-yl)propyl)benzamide (273);N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4 -(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)butyl)nicotinamide (274); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(5-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (275); N -((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(5-(5-((2-(2,6-dioxopiperidin- N-(( S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyraz ol-1-yl)propan-2-yl)-5-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1 -yl)propoxy)methyl)-1H-pyrazole-3-carboxamide (277); N-((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((4-(4-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide (278); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((2R)-4-(5-((2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-2-(hydroxymethyl)piperazin-1-yl)nicotinamide (279); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(5-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (280); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-2-oxopiperazin-1-yl)nicotinamide (281); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(1-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperidin-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-dioxoisoindolin-5-yl)oxy)propyl)piperidin-4-yl)benzamide (283); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-3-oxopropyl)-benzamide (284); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-((R)-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (285); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)azetidin-1-yl)nicotinamide (286); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)azetidin-1-yl)nicotinamide (287); 4-(3-(4-(5-(4-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)-3- fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)-benzonitrile (288); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridazin-3-carboxamide (289); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrazin-2-carboxamide (290); N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-(3-(4-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-piperazin-1-yl)propoxy)ethyl)-1H-pyrazole-3-carboxamide (291); H-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-((3S)-4-(5-((2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-3-(hydroxymethyl)piperazin-1-yl)-picolinamide (292); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide (293); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(9-(2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5. 5]undecan-3-yl)nicotinamide (294); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(9-(2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5. 5]undecan-3-yl)-pyrimidine-5-carboxamide (295); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((1R,4R)-5-(2-( 2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,5-diazabicyclo[2. 2. 1]heptan-2-yl)ethyl)benzamide (296); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)-2,6-difluorobenzamide (297); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)-2,6-difluorobenzamide (298); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)-2-fluorobenzamide (299); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (300); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3'-((4-(2-(2,6-dioxpiperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-carboxamide (301); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-(trifluoromethyl)benzamide (302); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3'-(2-(4-(2-(2,6-dioxopiperidin) -3-yl)-1,3-dioxoisoindolin-5-yl)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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-3,5-dimethylpiperazin-1-yl)benzamide (304); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(2-(2,6-dioxpiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-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 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-2-carboxamide (306); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidin -3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide (307); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl)-benzamide (308); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(3-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)ethyl)piperazin-1-yl)benzamide (309); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methylpyrimidin-5-carboxamide (310); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (311); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(4-(2-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)ethyl)benzamide (312); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3'-(2-(4-(2-(2,6-dioxopiperidin) -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)-3,5-dimethylpiperazin-1-yl)benzamide (314); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzamide (315); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide (316); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((3S)-4-(5-((2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-3-(hydroxymethyl)-piperazin-1-yl)nicotinamide (317); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)-4-fluoronicotinamide (318); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)-2,6-difluorobenzamide (319); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(3-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)azetidin-1-yl)-benzamide (320); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-((1-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)pyrrolidin-1-yl)benzamide (321); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3S)-1-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzamide (322); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3R)-1-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzamide (323); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butyl)benzamide (324); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-((1-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)pyrrolidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide (326); N-((1R ,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-((4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)benzamide (327); N-((1R,3S)-3-(3-chloro- 4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1, 3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-pyrrolidin-1-yl)benzamide (328); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-Tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperazin-1-yl)benzamide (329); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(1-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)propyl)benzamide (330); N-((1R,3R)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butyl)piperazin-1-yl)benzamide (331); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((4-(2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)cyclobutan-1-carboxamide (332); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(2-(2,6-dioxpiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazin-2-carboxamide (333); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-((((1R,3R)- 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidin-1-yl)-benzamide (334) ; N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3R)-1-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methoxy)piperidin-1-yl)benzamide (335); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3S)-1-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methoxy)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)-methyl)azetidin-1-yl)benzamide (337); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-((((1R,3S)- 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidin-1-yl)-benzamide (338) ; N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)-4-fluoronicotinamide (339); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((3S)-1-(2-( 2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)(methyl)amino)piperidin-1-yl)-benzamide (340); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((3R)-1-(2-( 2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-pyrrolidin-3-yl)methyl)(methyl)amino)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-octahydroisoquinolin-2(1H)-yl)nicotinamide (342); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide (343); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)benzamide (344); N-((1R,3S)-3-(3-chloro-4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- 4-yl)butyl)piperazin-1-yl)benzamide (331);N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3 -(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)cyclobutan-1 -carboxamide (332);N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(2 (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazin-2-carboxamide (333); N-((1R ,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-((((1R,3R)-3-((2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidin-1-yl)-benzamide (334); N-(( 1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3R)-1-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methoxy)piperidin-1-yl)benzamide (335); N-((1R,3S)-3-(3-chloro -4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-4-(4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)-methyl)azetidin-1-yl)benzamide (337); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-((((1R,3S)- 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidin-1-yl)-benzamide (338) ; N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)-4-fluoronicotinamide (339); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((3S)-1-(2-( 2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)(methyl)amino)piperidin-1-yl)-benzamide (340); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((3R)-1-(2-( 2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-pyrrolidin-3-yl)methyl)(methyl)amino)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-octahydroisoquinolin-2(1H)-yl)nicotinamide (342); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide (343); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)benzamide (344); N-((1R,3S)-3-(3-chloro-4-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)-pyrazin-2- carboxamide (359); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(3-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyridazin-3-carboxamide (360); 2-chloro-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (361); 2-chloro-Н-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2 ,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)benzamide (362); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)pyrimidine-2-carboxamide (363); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)-picolinamide (364); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((3S,5S)-4-(3-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide (365); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(2-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)propyl)benzamide (366); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-cyclobutyl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)butyl)-1H-1,2,3-triazol-1-yl)benzamide (367); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((5-(2-((R )-2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)oxy)ethyl)piperazin-1-yl)nicotinamide (368); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-((5-(2-((8 )-2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)oxy)ethyl)piperazin-1-yl)benzamide (369); (2S)-1-(4-(((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylciutobutyl)carbamoyl)phenyl)-N-(4-( 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butyl)-N-methylpyrrolidin-2-carboxamide (370); (2R)-1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)benzyl)-N-(2-( 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)-N-methylpyrrolidin-2-carboxamide (371); (2S)-1-(4-(((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)-benzyl)-N-(2- (4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)-ethyl)-N-methylpyrrolidin-2-carboxamide (372); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(2-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-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-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (374); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-(3-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)ethyl)-1H-pyrazole-4-carboxamide (375); 4-(3-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl) phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (376); 2-chloro-4-(3-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin- 1-yl)-phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (377); 4-(5-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl) phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3. 4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (378); N-((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)methyl)-1H-pyrazole-3-carboxamide (379); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)picolinamide (380); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-(4-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)picolinamide (381); 4-(3-(6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl) -pyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)-benzonitrile (382); 4-(3-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazine-1-carbonyl) -3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (383); N-((1R,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((18.48)-5-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-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)-carbamoyl)pyridin-2-yl)-1-(5- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-1-methylpiperazin-1-ium (385); 4-(3-(2-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)oxy) phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (386); 4-(3-(2-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)hexyl)oxy) phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (387); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-fluorobenzamide (388); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propyl)piperazin-1-yl)benzamide (389); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(1-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethyl)benzamide (390); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,6-difluorobenzamide (391); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin -3-yl)-1-oxoisoindolin-4-yl)oxy)propyl)piperazin-1-yl)-benzamide (392); 4-(3-(2-(2-(4-((1-(2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl )piperazin-1-yl)ethyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (393); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(1-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)propyl)benzamide (394); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)piperidin-1-yl)benzamide (395); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-((1-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1N-pyrazol-3-carboxamide (396); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-4-yl)-1N-pyrazole-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-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide (398); N-((1S,4S)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-5-yl)-piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide (399); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide (400); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (401); N-((1S,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (402); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (403); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxo-piperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazin-2-carboxamide (404); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)pyridazin-3-carboxamide (405); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide (406); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro -1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (407); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro -1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)pyrazin-2-carboxamide (408); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)-piperazin-1-yl)piperidin-1-yl)benzamide (409); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)-piperidin-4-yl)piperazin-1-yl)benzamide (410); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)-piperidin-4-yl)piperazin-1-yl)pyridazin-3-carboxamide (411); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxamide (412); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)-pyridazin-3-carboxamide (413); N-((1R,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-methyl)pyrrolidin-1-yl)pyrimidine-5-carboxamide (414); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)pyridazin-3-carboxamide (415); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)benzamide (416); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(2-((2-(2,6-dioxo-piperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carboxamide (417); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(3-((2-(2,6-dioxo-piperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carboxamide (418); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-4-methylcyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (419); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(2-((2-(2,6-dioxo-piperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)pyrazin-2-carboxamide (420); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxo-piperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)picolinamide (421); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro -1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)-5-fluoronicotinamide (422); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(3-((2-(2,6-diox-piperidin-3-yl)-6-fluoro -1,3-dioxoisoindolin-5-yl)oxy)propyl)-piperazin-1-yl)pyrazin-2-carboxamide (423); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)-piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-5-carboxamide (424); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxo-piperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide (425); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyrazin-2-carboxamide (426); N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxo-piperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridazin-3-carboxamide (427); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (428); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-1H-pyrazole-4-carboxamide (429); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-1H-pyrazole-3-carboxamide (430); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(4-((2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (431); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (432); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-(3-(4-(2-(1-methyl -2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-propoxy)ethyl)-1H-pyrazole-4-carboxamide (433); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)picolinamide (434); N-((1R,3R)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(1- methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)picolinamide (435); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-(4-(2-(1-methyl-2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)picolinamide (436); 6-(4-(4-((2-(1-butyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)-N ,N-dimethylpyridazine-3-carboxamide (437); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(4-((2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)pyrimidine-5-carboxamide (438); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)benzamide (439); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (440); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methylmethyl carbonate (441); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)-phenyl )piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-piperidin-1-yl)methylethyl carbonate (442); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl) piperidin-4-yl)methyl)-piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl-isopropyl carbonate (443); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl(tetrahydro-2H-pyran-4-yl)-carbonate (444); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-piperidin-1-yl)methyl(2-acetamidoethyl)carbamate (445); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-carbamoyl)phenyl) )piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl-(2-(2-aminoacetamido)ethyl)carbamate (446); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl) -piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl(2-((S)-2-aminopropanamido) ethyl) carbamate (447); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)-phenyl )piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-piperidin-1-yl)methyl(2-((S)-2-amino- 3-methylbutanamido)ethyl)carbamate (448); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-carbamoyl)phenyl) )piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl(2-((S)-2-(( S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamate (449); (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl) piperidin-4-yl)methyl)-piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl(2,5,8,11-tetraoxatridecan-13 -yl) carbonate (450); 2-chloro-4-(3-(3-fluoro-4-(5-(4-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )piperazin-1-yl)pentyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (451); 2-chloro-4-(5-(3-fluoro-4-(5-(4-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )piperazin-1-yl)pentyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3. 4]octan-7-yl)benzonitrile (452); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)piperazin-1-yl)methyl)-piperidin-1- yl) benzamide (528); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-4-methylene-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (529); rac-N-(1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)azetidin-3-yl )-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-N-methylpiperidine-4-carboxamide (530); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(3-((2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyridazin-3-carboxamide (531); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(3-((2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyrazin-2-carboxamide (532); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)- 6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carboxamide (533); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl) -6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-5-carboxamide (534); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-methyl)piperidin-1-yl)-4-(2-(2-methoxyethoxy)ethoxy) nicotinamide (535); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(2-((2R,6R)-4-(2-(2,6-dioxo-piperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)-2,6-dimethylpiperazin-1-yl)ethyl)-benzamide (536); rac-N-((1R,3R)-3-(3,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-methyl)piperidin-1-yl)benzamide (537); rac-N-((1R,3R)-3-(4-cyano-2-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (538); rac-N-((1R,3R)-3-(2,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (539); N-((1R,3R)-3-(4-cyano-2,6-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (540); rac-N-((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (541); N-((1R,4R)-4-(4-cyano-3-methylphenoxy)cyclohexyl)-5-(4-((((1R,3R)-3-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-1-yl)pyrazine-2-carboxamide (542); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)thio)ethyl)piperazin-1-yl)benzamide (543); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3-((2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (544); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-6,7-difluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (545 ); rac-2-chloro-4-(((1R,4R)-4-(5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)piperazin-1-yl)methyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)cyclohexyl)oxy)benzonitrile (546); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)nicotinamide (547); rac-N-((1R,4R)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3- yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)pyridazin-3-carboxamide (548); rac-N-((1R,4R)-4-(4-cyano-3-methylphenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6 -fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide (549); rac-N-((1R,3R)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (550); rac-N-((1R,3R)-3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (551); rac-N-((1R,3R)-3-((5-cyanopyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (552); rac-N-((1R,3R)-3-(3,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (553); rac-N-((1R,3R)-3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (554); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((1R,4R,5S)-5-((4 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[2. 2. 1]heptan-2-yl)pyrimidine-5-carboxamide (555); rac-N-((1R,3R)-3-((5-cyano-3-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (556); rac-N-((1R,3R)-3-((5-cyanopyrimidin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (557); rac-N-((1R,3R)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (558); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyrazin-2-carboxamide (559); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyrimidine-5-carboxamide (560); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((1R,4R,5R)-5-((4 -(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)(methyl)amino)pyrrolidin-1-yl)benzamide (562); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1R,3S)-3-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclopentyl)piperazin-1-yl)benzamide (563); rac-N-((1R,3R)-3-((6-cyano-5-methylpyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (564); rac-N-((1R,3R)-3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-( (4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (565); rac-N-((1,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-((4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyrazine-2-carboxamide (566); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyrazin-2-carboxamide (567); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (568); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-6 -fluoro-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)-4-fluoronicotinamide (569); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-7 -fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide (570); rac-N-((1R,3R)-3-(3-xnop-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (571); rac-N-((1R,3R)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (572); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-((4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyridazin-3-carboxamide (573); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyrimidine-5-carboxamide (574); rac-N-((1R,4R)-4-(4-cyano-3-methylphenoxy)cyclohexyl)-2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyrimidine-5-carboxamide (575); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-((4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyridazin-3-carboxamide (576); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide (577); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (578); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((((1R,3R)-3-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-1-yl)pyrazine-2-carboxamide (579); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-((((1R,3R)-3-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (580); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (581 ); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2 ,6-dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridazin-3-carboxamide (582); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-methyl)piperidin-1-yl)-4-(2-morpholinoethoxy)nicotinamide (583); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(3-((((1,3R)-3-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)azetidin-1-yl)pyrimidine-5-carboxamide (584) ; rac-N-((1R,3R)-3-((5-cyano-6-ethylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (585); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-((((1R,3R)-3-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)-(isopropyl)amino)methyl)azetidin-1-yl)pyridazin-3-carboxamide (586) ; rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-((4-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-azetidin-1-yl)benzamide (587); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(1-((1-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)benzamide (588); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(((1-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)methyl)pyrrolidin-1-yl)benzamide (589); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl)-piperazin-1-yl)benzamide (590); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6 -dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide (591); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)pyridazin-3-carboxamide (592); rac-2-chloro-4-(((1R,4R)-4-(5-(4'-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)-1-methyl-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1-methyl-1H-imidazol-2-yl)cyclohexyl)oxy)benzonitrile (593 ); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4 ,6-difluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)pyridazin-3-carboxamide (594); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-pyrimidin-5-carboxamide (595); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl)-4-(3-((4-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)-piperazin-1-yl)methyl)azetidin-1-yl)benzamide (596); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((((1R,3R)-3- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-1-yl)pyrazine-2-carboxamide ( 597); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(1-((1-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)pyrimidine-5-carboxamide (598); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6- dioxopiperidin-3-yl)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyridazin-3-carboxamide (599); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((((1R,3R)-3- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyridazine-3-carboxamide ( 600); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((((1R,3R)-3-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-1-yl)picolinamide (601); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (602); rac-2-chloro-4-(((1R,4R)-4-(2-(4-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)phenyl)-1H-imidazol-5-yl)cyclohexyl)oxy)benzonitrile (603); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazole-3-carboxamide (604); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(3-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-1H-pyrazole-3-carboxamide (605); rac-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazole-3-carboxamide (606); 3-chloro-5-(5-(4-(1-((1-(2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl)piperidin-4-yl)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3. 4]octan-7-yl)picolinonitrile (607); 3-chloro-5-(5-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) methyl)piperidin-1-yl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3. 4]octan-7-yl)picolinonitrile (608); rac-N-((1,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)benzamide (609); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-1-methyl-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (610); rac-N-((1,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-4-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)pyridazin-3-carboxamide (611); 3-chloro-5-(5-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) methyl)piperidin-1-yl)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3. 4]octan-7-yl)picolinonitrile (612); 3-chloro-5-(5-(4-(1-((1-(2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-piperidin-4-yl )methyl)piperidin-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]imidazol-3-yl)phenoxy)ethyl)piperidin-4-yl)methyl) piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (614); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((((1R,3R)-3- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyrimidin-5-carboxamide (615 ); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzamide (616); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((1R,4R)-4-((1-( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)(methyl)-amino)cyclohexyl)-1H-pyrazole-3-carboxamide (617); 5-(4-((1-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl )-2-(2,6-diox-piperidin-3-yl)isoindoline-1,3-dione (618); rac-N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-((((1R,3R)-3- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)azetidin-1-yl)pyrazine-2-carboxamide ( 619); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((1R,4R)-4-((((1R,3R )-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)cyclohexyl)-1H-pyrazol-3 -carboxamide (620); N-((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((((1R,3R)-3-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-1-yl)pyrimidine-5-carboxamide ( 623); N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin -3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (624); and N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-((((1R,3R)-3-((2-(2,6-dioxopiperidine -3-yl)-1-oxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)-methyl)piperidin-1-yl)pyrimidine-5-carboxamide (625).

[0176] According to another embodiment, the present disclosure relates to a library of compounds. The library contains more than one compound, with each compound having the formula ABM-L-ULM, wherein ULM is a ubiquitin pathway protein-binding moiety (preferably an E3 ubiquitin ligase-binding moiety as further described herein), e.g., CLM, and AVM is an AR binding protein fragment, wherein the AVM connects (preferably via a linker fragment) to the ULM, and the ubiquitin pathway protein binding fragment recognizes a ubiquitin pathway protein, in particular E3 ubiquitin ligase.

[0177] The present disclosure includes, respectively, compositions containing pharmaceutically acceptable salts, in particular acid addition or base addition salts of compounds in accordance with the present disclosure.

[0178] The term "pharmaceutically acceptable salt" is used throughout this specification to describe, where applicable, the salt form of one or more of the compounds described herein, which are provided to enhance the solubility of the compound in the gastric juice of a patient's gastrointestinal tract to promote dissolution and bioavailability of compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, among many other acids and bases known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as phosphate neutralizing salts in accordance with the present disclosure.

[0179] The acids that are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds useful in the present disclosure are acids that form non-toxic acid addition salts, i. salts containing pharmacologically acceptable anions, such as hydrochloric, hydrobromic, hydroiodic, nitrate, sulfate, bisulfate, phosphate, hydrophosphate, acetate, lactate, citrate, hydrocitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate , ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts, among many others.

[0180] Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of the compounds or derivatives of the present disclosure. The chemical bases that can be used as reagents to prepare the pharmaceutically acceptable base salts of the compounds of the present invention, which are acidic in nature, are bases which form non-toxic base salts with these compounds. Such non-toxic base salts include, but are not limited to, salts derived from pharmacologically acceptable cations such as alkali metal (e.g., potassium and sodium) and alkaline earth metal (e.g., calcium, zinc, and magnesium) cations, ammonium, or water-soluble addition salts. amine such as N-methylglucamine (meglumine), and lower alkanolammonium, as well as other basic salts of pharmaceutically acceptable organic amines, among others.

[0181] Compositions

[0182] According to another aspect, the present disclosure relates to compositions containing the compounds described herein, including their salts, and a pharmaceutically acceptable carrier. In some embodiments, the compositions are therapeutic or pharmaceutical compositions containing an effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0183] The amount of a compound in a pharmaceutical composition according to the present disclosure that can be combined with carrier materials to form a single dosage form will vary depending on the recipient and the disease being treated, the specific route of administration. Typically, an amount of 0.1 mg/kg to 1000 mg/kg body weight/day of the active ingredients is administered, depending on the efficacy of the agent. The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine LD ₅₀ (dose lethal to 50% of the population) and ED ₅₀ (dose therapeutically effective to 50% of the population). The ratio of doses of toxic and therapeutic effects is a therapeutic index and can be expressed as the ratio LD ₅₀ /ED ₅₀ . Compounds that exhibit large therapeutic indices are preferred. Since compounds that exhibit toxic side effects can be used, care should be taken to develop a delivery system that targets such compounds to the affected tissue site to minimize potential damage to non-infected cells and thereby reduce side effects. Data obtained from cell culture assays and animal studies can be used in formulating a dosage range for human use. The dosage of such compounds preferably lies in the range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration used. For any compound used in the method of the present disclosure, the therapeutically effective dose can first be assessed in cell culture assays. The dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC ₅₀ (ie, the concentration of test compound that achieves half-maximal symptom inhibition) as determined in cell culture. Such information can be used to more accurately determine doses applicable to humans. Plasma levels can be measured, for example, using high performance liquid chromatography.

[0184] The compositions of the present disclosure may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, and may also be administered in controlled release formulations. Pharmaceutically acceptable carriers that may be used in such pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, partially glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose agents, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates , waxes, block polymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin.

[0185] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired administration without causing serious toxic effects to the patient being treated. The preferred dose of active compound for all conditions mentioned herein is in the range of from about 10 ng/kg to 300 mg/kg, preferably from 0.1 to 100 mg/kg per day, more often from 0.5 to about 25 mg per kilogram. body weight of the recipient/patient per day. A typical dosage for topical administration will range from 0.01-5% w/w in a suitable vehicle.

[0186] The compound is conveniently administered in any suitable unit dosage form, including but not limited to less than 1 mg, from 1 mg to 3000 mg, preferably from 5 to 500 mg of the active ingredient per unit dosage form. An oral dosage of about 25-250 mg is often convenient.

[0187] The active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or aqueous media, or by bolus administration of the active ingredient. Oral administration is also suitable for generating effective plasma concentrations of the active agent.

[0188] The concentration of active compound in the drug composition will depend on the absorption, distribution, inactivation, and release rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values will also vary with the severity of the condition to be alleviated. In addition, it should be noted that for any given subject, specific dosage regimens will need to be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are provided by way of example only. and are not intended to limit the scope or implementation of the claimed composition. The active ingredient may be administered all at once or may be divided into several smaller doses for administration at varying time intervals.

[0189] When administered intravenously, the preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0190] In one embodiment, active compounds are provided with carriers that will protect the compound from rapid elimination from the body, such as in controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0191] Liposomal suspensions can also serve as pharmaceutically acceptable carriers. They can be obtained according to methods known to experts in this field, for example, described in US patent No. 4522811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving the appropriate lipid(s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachodoylphosphatidylcholine, and cholesterol) in an inorganic solvent, which is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. The aqueous solution of the active compound is then introduced into the container. The container is then manually rotated to release the lipid material from the walls of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0192] routes of administration

[0193] According to any of the aspects or embodiments described herein, therapeutic compositions containing the compounds described herein may be in any suitable dosage form configured to be delivered by any suitable route. For example, the compounds may be administered by any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, rectally, nasally, buccally, vaginally, or via implanted reservoir or aerosol form.

[0194] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and itracranial injection or infusion techniques. Preferably the compositions are administered orally, intraperitoneally or intravenously.

[0195] The compounds described herein can be administered in single or divided doses by the oral, parenteral, or topical routes. Administration of the active compound may vary from continuous (intravenous drip) to multiple oral administrations per day (e.g., Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancing agent), buccal , sublingual and suppository administration, among other routes of administration. Enteric-coated oral tablets can also be used to enhance the bioavailability of compounds by the oral route. The most effective dosage form will depend on the pharmacokinetics of the particular agent chosen, as well as the severity of the disease in the patient.

[0196] Administration of the compounds as sprays, sprays, or aerosols for intranasal, intratracheal, or pulmonary administration can also be used. The compounds described herein may be administered in immediate release, intermediate release, or delayed or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository form and transdermal or other topical forms. Intramuscular injections in liposomal form can also be used to control or delay the release of the compound at the injection site.

[0197] Sterile injectable forms of the compositions described herein may be an aqueous or oily suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents, as well as suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or vehicle, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are traditionally used as a solvent or suspension medium. Any fine fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain an alcoholic diluent or long chain dispersant such as Ph alcohol. Helv or similar alcohol.

[0198] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including, without limitation, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and cornstarch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Oral compositions typically include an inert diluent or food carrier. They may be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound or its prodrug derivative can be administered with adjuvants and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and/or adjuvants are included as part of the composition.

[0199] Tablets, pills, capsules, lozenges, and the like. may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an adjuvant such as starch or lactose, a dispersing agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterote; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavor such as mint, methyl salicylate, or orange flavor. If the unit dosage form is a capsule, it may contain, in addition to the material of the above type, a liquid carrier such as a fixed oil. In addition, unit dosage forms may contain various other materials that modify the physical form of the dosage unit, such as sugar coatings, shellac, or enteric agents.

[0200] The active compound, or a pharmaceutically acceptable salt thereof, may be administered as a component of an elixir, suspension, syrup, cachet, chewing gum, or the like. The syrup may contain, in addition to active compounds, sugar as a sweetener, and some preservatives, dyes and coloring agents, as well as flavorings.

[0201] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. They can be prepared by mixing the agent with a suitable non-irritating adjuvant which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0202] Pharmaceutical compositions in accordance with the present disclosure can also be administered topically. Suitable local formulations are easily obtained for each of these sites or organs. Topical application for the lower intestinal tract can be in the form of a rectal suppository (see above) or in a suitable enema formulation. Acceptable for topical administration, transdermal patches can also be used. For topical application, pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. In certain preferred aspects of the present disclosure, the compounds may be applied to a stent to be surgically implanted in a patient to inhibit or reduce the likelihood of occlusion in the patient's stent.

[0203] Alternatively, the pharmaceutical compositions may be formulated into a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, without limitation, mineral oil, sorbitan monostearate, polysorbate 60, wax cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0204] For ophthalmic use, pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. preservative. Alternatively, for ophthalmic applications, the pharmaceutical compositions may be formulated as an ointment such as petrolatum.

[0205] Pharmaceutical compositions in accordance with the present disclosure can also be administered using a nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art relating to pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons, and/or other conventional solubilizing or dispersing agents. funds.

[0206] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical administration may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and tonicity correctors such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0207] It should also be appreciated that the specific dosage and treatment regimen for any particular patient will depend on a number of factors, including the potency of the particular compound used, age, body weight, general health, sex, nutrition, time of administration, rate of release , combinations of drugs and the opinion of the attending physician, as well as the severity of the specific disease or condition being treated.

[0208] A patient or subject in need of therapy using the compounds described herein can be treated by administering to the patient (subject) an effective amount of the compound, including pharmaceutically acceptable salts, solvates or polymorphs thereof, optionally in a pharmaceutically acceptable carrier or diluent , either alone or in combination with other known agents.

[0209] Co-administration

[0210] Disease conditions or conditions that can be treated using compounds or compositions in accordance with the present disclosure include, without limitation, for example, cancer (eg, prostate cancer) and Kennedy's disease. In some embodiments, the therapeutic or pharmaceutical compositions comprise an effective amount of an additional biological or bioactive agent, such as an agent effective in the treatment of cancer, which is co-administered.

[0211] The term "co-administration" or "combination therapy" means that at least two compounds or two compositions are administered to a patient at the same time, such that effective amounts or concentrations of each of the two or more compounds can be in the patient at this point in time. Although the compounds of the present disclosure may be co-administered to a patient at the same time, the term encompasses both the administration of two or more agents at the same time or at different points in time, provided that effective concentrations of all co-administered compounds or compositions are present in the subject. at this time. In certain preferred aspects of the present disclosure, one or more of the compounds of the present invention described above are co-administered in combination with at least one additional bioactive agent, especially an anticancer agent. According to particularly preferred aspects of the present disclosure, the co-administration of the compounds provides a synergistic therapy, including anti-cancer therapy.

[0212] According to another aspect, the present disclosure relates to a composition containing an effective amount of two or more of the PROTAC compounds described herein, and a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an effective or synergistic amount of another bioactive agent other than a PROTAC compound.

[0213] Pharmaceutical compositions comprising combinations of an effective amount of at least one difunctional compound according to the present disclosure and one or more compounds described hereinafter, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive, or adjuvant , represent a further aspect of the present disclosure.

[0214] The term "bioactive agent" is used to describe an agent, other than the PROTAC compounds described herein, that is used in combination with compounds of the present invention as an agent with biological activity to provide the intended therapy, inhibition and/or prevention/prophylaxis for which the compounds of the present invention are used. Preferred bioactive agents for use herein include those having pharmacological activity similar to that for which the compounds of the present invention are used or administered, and include, for example, anti-cancer agents.

[0215] The term "additional anticancer agent" is used to describe an anticancer agent that can be combined with the PROTAC compounds of the present disclosure for the treatment of cancer. Such agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI -258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 Inhibitor, Androgen Receptor Inhibitor, VEGFR Inhibitor, EGFR TK Inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, EGFR TK inhibitor, IGFR-TK inhibitor, anti-HGF antibody, PI3 kinase inhibitors, AKT inhibitor, JAK inhibitor /STAT, checkpoint inhibitor 1 or 2, focal adhesion kinase inhibitor, MAP kinase (mek) inhibitor, VEGF decoy antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrin, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR ₁ KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib ; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5- yl)ethyl]-benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylethylbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)-6-Azgly-10] acetate salt (pyro-Glu-His-Trp-Ser- Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH ₂ acetate [C ₅₉ H ₈₄ N ₁₈ O ₁₄ -(C ₂ H ₄ O ₂ ) _x , where x = 1-2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib- EGF, Erbitux, EKB-569, PKI-166, GW-572016, Lonafarnib, BMS-214662, Tipifarnib, Amifostine, NVP-LAQ824, Suberoylanalide Hydroxamic Acid, Valproic Acid, Trichostatin A, FK-228, SU11248, Zorafenib, KRN951, Aminoglumide , amzacrine, anagrelide, L-asparaginase, Bacille Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubi cine, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, glivec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitoxantrone, metomycin, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine , altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitin ib, bortezimibe, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxy tamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339 ZK186619 Topotecan LY294002, LY292223, LY292696, LY293684, LY293646, вортманнин, ZM336372, L-779,450, PEG-филграстим, дарбепоэтин, эритропоэтин, гранулоцитарный колониестимулирующий фактор, золендронат, преднизон, цетуксимаб, гранулоцитарно-моноцитарный колониестимулирующий фактор, гистрелин, пегилированный интерферон альфа-2а, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nit rogen mustard, methylprednisolone, ibrithumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosrorin, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, paltora NK-1 antagonist , aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

[0216] Methods of treatment

[0217] In another aspect, the present disclosure relates to methods for modulating ubiquitination and protein degradation in a subject, e.g., in a cell, tissue, mammal, or human patient, the method comprising administering an effective amount of a PROTAC compound described herein, or a composition, containing an effective amount of it, to the subject, while the compound or composition containing it is effective for modulating ubiquitination and degradation of the protein in the subject. In some embodiments, the protein is an androgen receptor (AR).

[0218] In some embodiments, the present disclosure relates to a method for regulating androgen receptor protein activity in a patient as needed, comprising administering to said patient an amount of a compound described herein.

[0219] According to the following additional embodiments, the present disclosure relates to a method of treating a disease state or condition in a patient in which a deregulated protein activity is responsible for said disease state or condition, wherein said method comprises administering to said patient an effective amount of a compound described herein to regulate said protein activity in said patient. In some embodiments, the protein is AR.

[0220] As used herein, the terms "treat", "treatment process", "treatment", etc. refers to any act of providing benefit to the patient to whom the compounds of the present invention may be administered, including the treatment of any disease state or condition that is modulated by the protein to which the compounds of the present invention bind. Disease conditions or conditions, including cancer, that can be treated using the compounds of the present disclosure are set forth above.

[0221] According to another aspect, the present disclosure relates to methods for modulating ubiquitination and degradation of an AR protein in a subject, for example, in a cell, tissue, mammal, or human patient, the method comprising administering an effective amount of a compound described herein, or a composition, containing an effective amount of a compound described herein to a subject, wherein the compound or composition containing it is effective to modulate ubiquitination and degradation of the AR protein in the subject.

[0222] In another aspect, the present disclosure relates to methods for treating or alleviating a symptom of a disease associated with AR activity in a subject, e.g., in a cell, tissue, mammal, or human patient, the method comprising administering an effective amount of a compound described herein , or a composition containing an effective amount thereof, to a subject in need thereof, wherein the compound or composition containing the same is effective in treating or alleviating a symptom of a disease associated with AR activity in the subject.

[0223] In some embodiments, the disease or disorder is asthma, multiple sclerosis, cancer, prostate cancer, Kennedy's disease, ciliopathy, cleft palate, diabetes mellitus, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity , refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, Prader-Willi syndrome (PKD1) or 4 (PKD2), sickle cell disease, Tay-Sachs disease, Turner syndrome. The method according to claim 48, wherein said cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatic cell carcinomas and renal cell carcinomas, cancer of the bladder, intestines, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, in particular Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, sarcomenycomeal cell tumors, neurofibromas and schwannomas; colon cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms tumor or teratocarcinoma. In some embodiments, the disease being treated is cancer, such as prostate cancer, or Kennedy's disease. In a preferred embodiment, the subject is a human.

[0224] In another aspect, the present disclosure relates to methods for treating or alleviating a symptom of a disease associated with AR activity in a subject, e.g., in a cell, tissue, mammal, or human patient, the method comprising administering an effective amount of a compound described herein , or a composition containing an effective amount thereof, and an effective or synergistic amount of another bioactive agent to the subject in need of it, while the composition containing them is effective in treating or alleviating a symptom of a disease associated with AR activity in the subject. In some embodiments, the disease being treated is cancer, such as prostate cancer, or Kennedy's disease. In a preferred embodiment, the subject is a human. In some additional embodiments, the additional bioactive agent is an anticancer agent.

[0225] According to alternative aspects, the present disclosure relates to a method of treating a disease state by degradation of a protein or polypeptide, by which the disease state or condition is modulated, comprising administering to said patient or subject an effective amount of at least one compound described herein above, optionally in combinations with an additional bioactive agent. The method of the present disclosure may be used to treat a wide variety of disease states or conditions, including cancer, by administering effective amounts of at least one compound described herein.

[0226] According to another aspect, the present disclosure relates to methods for identifying degradation effects of proteins of interest in a biological system using compounds in accordance with the present disclosure.

[0227] Sets

[0228] According to another aspect, the present disclosure relates to kits containing the compounds or compositions described herein. The kit may be provided, distributed, or sold as a unit to carry out the methods of the present disclosure. In addition, kits in accordance with the present disclosure may preferably contain instructions that describe the proper use. Such kits can be conveniently used, for example, in a clinical setting, to treat patients who exhibit symptoms of, for example, cancer, prostate cancer, or Kennedy's disease.

[0229] EXAMPLES

[0230] General chemistry - analysis and synthesis

[0231] Unless otherwise noted, all materials/reagents were obtained from commercial sources and used without further purification. Reactions were monitored by LC-MS and/or thin layer chromatography (TLC) on silica gel 60 F ₂₅₄ (0.2 mm) pre-coated with aluminum foil or with glass support and displayed using UV light. Flash chromatography (alternatively referred to as "ISCO chromatography") was performed using ISCO CombiFiash RF 75 PSI or equivalent with RediSep normal phase silica gel cartridges. Preparative TLC was performed on Whatman LK6F Silica Gel 60A with 20×20 cm, 1000 µm thick plates or equivalent.

[0232] ¹ HNMR (300 or 400 MHz) and ¹³ NMR (100.6 MHz) spectra were recorded on Bruker spectrometers at room temperature with TMS or residual solvent peak as internal standard. The positions of a line or multiple lines are presented in (δ) and the coupling constants (J) are presented in absolute terms in hertz (Hz). Multiplicities in ¹ NMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or wide (broadened).

[0233] Preparative HPLC purifications were performed on a ^Waters® UV-Directed Purification System equipped with a 2545 Binary Gradient Module, 2767 Sample Manager and a 2489 UV/VIS detector, controlled by MassLynx V4.1 software. All purifications were completed using the following columns: Atlantis Prep T3 OBD column, SunFire Prep C18 OBD column, and XBridge Prep Phenyl OBD column. The mobile phases were water (with 0.1% TFA or 0.01% NH ₄ HCO ₃ ) and acetonitrile; all reagents used were HPLC grade. The flow rate was 30 ml/min. After the 1:1000 LC packings columns, a flow splitter allowed a small amount of eluent to be transferred to the UV detector. The electrospray source was set to 3.0 kV capillary voltage, cone voltage 30 V, source temperature 110° C., desolvation temperature 350° C., desolvation gas flow 600 l/h, and cone gas flow 60 l/h. For the analyzer, the multiplier was set to 550 for the preparative tuning method.

[0234] Analytical LC-MS data was obtained on a Shimadzu LCMS-2020 with a mobile phase of 0.05% TFA in acetonitrile (A) and 0.05% TFA in water with HPLC grade (B); 0.1% FA in acetonitrile (A) and 0.1% FA in water, HPLC grade (B); acetonitrile (A) and 5 mM ammonium bicarbonate in HPLC grade water (B).

[0235] Shimadzu LCMS-2020 equipped with LC-20AD or 30AD pumps, SPD-M20A PDA and Alltech 3300 ELSD. The system used the following conditions for 2.0 min, 2.6 min, 3 min, 3.6 min, 5 min, or 5.6 min.

[0236] Duration 2.0 minutes: Kinetex XB-C 18 100A column, 2.6 µm, 3.0 x 50 mm. The flow rate is 1.5 ml/min, the duration is 2.0 min and the gradient profiles are 0.01 min 10% A, 1.10 min 100% A, 1.60 min 100% A, 1.70 min 10% A, 2.00 min 10% A.

[0237] Duration 2.6 minutes: Shim-pack VP-ODS column, 2.2 µm, 3.0 x 50 mm. The flow rate is 1.5 ml/min, the duration is 2.6 min and the gradient profiles are 0.01 min 5% A, 1.20 min 100% A, 2.20 min 100% A, 2.30 min 5% A, 2.60 min 5% A.

[0238] Duration 3.0 minutes: ACE UltraCore Super C18 column, 2.5 µm, 3.0 x 50 mm. The flow rate is 1.5 ml/min, the duration is 3.0 min and the gradient profiles are 0.01 min 10% A, 2.00 min 95% A, 2.60 min 95% A, 2.70 min 10% A, 3.00 min 10% A

[0239] Duration 3.6 minutes: Shim-pack VP-ODS column, 2.2 µm, 3.0 x 50 mm. The flow rate is 1.5 ml/min, the duration is 3.6 min and the gradient profiles are 0.01 min 5% A, 2.20 min 100% A, 3.20 min 100% A, 3.30 min 5% A, 3.60 min 5% A.

[0240] Duration 5.0 minutes: ACE UltraCore Super C18 column, 2.5 µm, 3.0 x 50 mm. The flow rate is 1.5 ml/min, the duration is 5.0 min and the gradient profiles are 0.01 min 10% A, 4.00 min 60% A, 4.70 min 60% A, 4.80 min 10% A, 5.00 min 10% A.

[0241] Duration 5.6 minutes: Shim-pack VP-ODS column, 2.2 µm, 3.0 x 50 mm. The flow rate is 1.5 ml/min, the duration is 5.6 min and the gradient profiles are 0.01 min 5% A, 3.00 min 50% A, 5.00 min 50% A, 5.20 min 5% A, 5.60 min 5% A.

[0242] Alternatively, analytical LC-MS data was obtained on an Agilent infinity 1260 LC, Agilent 6230 TOF mass spectrometer. The analysis was carried out on a Poroshell 120 EC C18 column (inner diameter 50 mm × 3.0 mm, packing diameter 2.7 μm) at 45°C.

Solvents used:

A = 0.1% v/v solution of formic acid in water.

B = 0.1% v/v solution of formic acid in acetonitrile.

The gradient used is:

[0243] UV detection is an average signal from a wavelength of 210 nm to 350 nm and mass spectra were recorded on a mass spectrometer using positive electrospray ionization.

[0244] Unless otherwise noted, all compounds were obtained with LC-MS purity >95%.

[0245] Chemical synthesis

[0246] PROTAC ABM-L-ULM or their pharmaceutically acceptable salts, polymorphs, prodrugs, solvate forms and isotope-containing derivatives thereof can be prepared by the general approaches described below (Schemes 1 and 2, and General Schemes 1-122, 1A- 22A and 1B-25B), along with synthetic methods known in the art of organic chemistry, or modifications and derivatizations known to those skilled in the art.

[0247] Scheme 1:

[0248] Scheme 2:

[0249] General scheme 1:

[0250] General scheme 2:

[0251] General scheme 3:

[0252] General scheme 4:

[0253] General scheme 5:

[0254] General scheme 6:

[0255] General scheme 7:

[0256] General scheme 8:

[0257] General scheme 9:

[0258] General scheme 10:

[0259] General scheme 11:

[0260] General scheme 12:

[0261] General scheme 13:

[0262] General scheme 14:

[0263] General scheme 15:

[0264] General scheme 16:

[0265] General scheme 17:

[0266] General scheme 18:

[0267] General scheme 19:

[0268] General scheme 20:

[0269] General scheme 21:

[0270] General scheme 22:

[0271] General scheme 23:

[0272] General scheme 24:

[0273] General scheme 25:

[0274] General scheme 26:

[0275] General scheme 27:

[0276] General scheme 28:

[0277] General scheme 29:

[0278] General scheme 30:

[0279] General scheme 31:

[0280] General scheme 32:

[0281] General scheme 33:

[0282] General scheme 34:

[0283] General scheme 35:

[0284] General scheme 36:

[0285] General scheme 37:

[0286] General scheme 38:

[0287] General scheme 39:

[0288] General scheme 40:

[0289] General scheme 41:

[0290] General scheme 42:

[0291] General scheme 43:

[0292] General scheme 44:

[0293] General scheme 45:

[0294] General scheme 46:

[0295] General scheme 47:

[0296] General scheme 48:

[0297] General scheme 49:

[0298] To a solution of tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate 3 (15 g, 51.4 mmol) in DCM (100 ml) was added Dess-Martin periodinan (26.1 g , 61.6 mmol) in an ice water bath and the clear solution was stirred at room temperature for 2 hours. The solvent was evaporated and EtOAc was added. The mixture was passed through a plug of silica gel, washed with EtOAc and the solvent was evaporated to give the crude material. (This was combined with another batch of crude material that started with 10 g of purification starting material.) The crude material was dry loaded into ISCO (0-10% MeOH/DCM) for separation. A light yellow solid 16.11 g 4 (yield 65%) was obtained as a product.

[0299] To a mixture of tert-butyl 4-(4-formylpiperidin-1-yl)benzoate 4 (15.79 g, 54.2 mmol) and 2-(2,6-diox-piperidin-3-yl)-5- (piperazin-1-yl)isoindoline-1,3-dione dihydrochloride 5 (22.5 g, 54.2 mmol) in DCM (500 ml) was added sodium acetate (4.44 g, 54.2 mmol). The reaction mixture was allowed to stir for 3 minutes and immersed in an ice water bath. NaBH(OAc) ₃ (20.0 g, 94.8 mmol) was added over 10 minutes and the bath was removed after an additional 10 minutes. After 21 hours, water (500 ml) and DCM (150 ml) were added, the organic layer was removed and the aqueous layer was extracted with DCM (150 ml), the combined organics were dried with Na ₂ SO ₄ and evaporated to give crude product 6 which was loaded dry with silica gel in ISCO (0-10% MeOH/DCM, 750 g column) for separation. The fractions were collected and dried, exchanged with DCM twice and dried under high vacuum for 26 hours to give 18.15 g of compound 6 (60% yield) as a yellow solid.

[0300] 4N HCl in dioxane (40 mL, 29.3 mmol) was added to tert-butyl-4-(4-((4-(2-(2,6-diox-piperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate 6 (18.15 g, 29.3 mmol) and the reaction mixture was heated to 50°C for 7 hours. The solvent was evaporated and the DCM was exchanged twice, dried under high vacuum overnight. This was again exchanged with DCM twice, dried under high vacuum for 8 hours to give 18.77 g (101% yield) of compound 7 as a light brown solid.

[0301] To a solution of 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride 8 (8.9 g, 28.2 mmol) and 4-(4 -((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid dihydrochloride 7 (18 .7 g, 29.6 mmol) in DCM (300 mL) was added Hunig's base (24.2 mL, 140 mmol) and HATU (11.0 g, 29.0 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for 17 hours, during which time it was washed twice with us. NaHCO ₃ (250 ml), dried over Na ₂ SO ₄ and evaporated to dryness. The crude material was loaded dry with silica gel into an ISCO column (0% 3CV, 0-10% MeOH/DCM 30 CV, 750 g column) to separate the mixture. The product was dried in a heated vacuum oven at 40° C. for 16 hours to give compound 9 19.6 g (85% yield, 99.55% pure in 18 min by analytical method) as a yellow solid.

[0302] General scheme 50:

[0303] General scheme 52:

[0304] General scheme 53:

[0305] General scheme 54:

[0306] General scheme 55:

[0307] General scheme 56:

[0308] General scheme 57:

[0309] General scheme 58:

[0310] General scheme 59:

[0311] General scheme 60:

[0312] General scheme 61:

[0313] General scheme 62:

[0314] General scheme 63:

[0315] General scheme 64:

[0316] General scheme 65:

[0317] General scheme 66:

[0318] General scheme 67:

[0319] General scheme 68:

[0320] General scheme 69:

[0321] General scheme 70:

[0322] General scheme 71:

[0323] General scheme 72:

[0324] General scheme 73:

[0325] General scheme 74:

[0326] General scheme 75:

[0327] General scheme 76:

[0328] General scheme 77:

[0329] General scheme 78:

[0330] General scheme 79:

[0331] General scheme 80:

[0332] General scheme 81:

[0333] General scheme 82:

[0334] General scheme 83:

[0335] General scheme 84:

[0336] General scheme 85:

[0337] General scheme 86:

[0338] General scheme 87:

[0339] General scheme 88:

[0340] General scheme 89:

[0341] General scheme 90:

[0342] General scheme 91:

[0343] General scheme 92:

[0344] General scheme 93:

[0345] General scheme 94:

[0346] General scheme 95:

[0347] General scheme 96:

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[0349] General scheme 98:

[0350] General scheme 99:

[0351] General scheme 100:

[0352] General scheme 101:

[0353] General scheme 102:

[0354] General scheme 103:

[0355] General scheme 104:

[0356] General scheme 105:

[0357] General scheme 106:

[0358] General scheme 107:

[0359] General scheme 108:

[0360] General scheme 109:

[0361] General scheme 110:

[0362] General scheme 111:

[0363] General scheme 112:

[0364] General scheme 113:

[0365] General scheme 114:

[0366] General scheme 115:

[0367] General scheme 116:

[0368] General scheme 117:

[0369] General scheme 118:

[0370] General scheme 119:

[0371] General scheme 120:

[0372] General scheme 121:

[0373] General scheme 122:

[0374] General scheme 1A:

[0375] General scheme 2A:

[0376] General scheme 3A:

[0377] General scheme 4A:

[0378] General scheme 5A:

[0379] General scheme 6A:

[0380] General scheme 7A:

[0381] General scheme 8A:

[0382] General scheme 9A:

[0383] General scheme 10A:

[0384] General scheme 11A:

[0385] General scheme 12A:

[0386] General scheme 13A:

[0387] General scheme 14A:

[0388] General scheme 15A:

[0389] General scheme 16A:

[0390] General scheme 17A:

[0391] General scheme 18A:

[0392] General scheme 19A:

[0393] General scheme 20A:

[0394] General scheme 21A:

[0395] General scheme 22A:

[0396] General scheme 1B

[0397] General scheme 2B

[0398] 3B General Circuit

[0399] General circuit 4B

[0400] General circuit 5V

[0401] General circuit 6B

[0402] General circuit 7B

[0403] General circuit 8V

[0404] General circuit 9B

[0405] General circuit 10V

[0406] General circuit 11B

[0407] General circuit 12V

[0408] General circuit 13V

[0409] General circuit 14V

[0410] General circuit 15V

[0411] General circuit 16V

[0412] General circuit 17V

[0413] General circuit 18V

[0414] General circuit 19B

[0415] General circuit 20V

[0416] General circuit 21 V

[0417] General circuit 22 V

[0418] General circuit 23 V

[0419] General circuit 24 V

[0420] General circuit 25 V

[0421] Method for the synthesis of compound 406:

[0422] Synthesis of tert-butyl-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-carbamate

[0423] In a 50 ml round bottom flask was placed tert-butyl-N-[(1R,4R)-4-hydroxycyclohexyl]carbamate (500.0 mg, 2.32 mmol, 1.00 equiv.), N,N- dimethylformamide (10.0 mL), sodium hydride (82.8 mg, 3.45 mmol, 1.50 equiv.), 2-chloro-4-fluorobenzonitrile (432.6 mg, 2.78 mmol, 1.20 equiv. .). The resulting solution was stirred for 2 hours at 0° C. in an ice-water bath. Then, the reaction mixture was quenched by adding 20.0 ml of water. The resulting solution was extracted with ethyl acetate (40.0 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (40.0 ml). The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/2). The collected fractions were pooled and concentrated in vacuo. This gave 470.0 mg (58%) of tert-butyl N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate as a yellow oil.

[0424] LC-MS (ES ⁺ ): m/z 295.0 [MH ⁺ ], t _R = 1.199 min (run 1.90 minutes).

[0425] Chemical formula: C ₁₈ H ₂₃ ClN ₂ O ₃ [350,14].

[0426] Synthesis of 4-(((1R,4R)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile

[0427] In a 50 ml round bottom flask was placed tert-butyl-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate (470.0 mg, 1.34 mmol, 1, 00 equiv.), methanol (5.0 ml), hydrogen chloride. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This gave 340.0 mg (88%) of 2-chloro-4-[[(1R,4R)-4-aminocyclohexyl]oxy]benzonitrile hydrochloride as a yellow solid.

[0428] LC-MS (ES ⁺ ): m/z 250.90 [MH ⁺ ], t _R = 0.537 min (run 1.90 minutes).

[0429] Chemical formula: C ₁₃ H ₁₅ ClN ₂ O [250.09].

[0430] Synthesis of 6-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide: To a round bottom flask 6-[4-(hydroxymethyl)piperidin-1-yl]pyridazine-3-carboxylic acid (1.0 g, 4.21 mmol, 1.00 equiv.), 2-chloro-4-[ (1R,4R)-4-aminocyclohexyl]oxybenzonitrile (1.2 g, 4.18 mmol, 1.00 equiv.), N,N-dimethylformamide (30 mL), N,N,N',N'-tetramethyl -O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.4 g, 6.31 mmol, 1.50 equiv.), N,N-diisopropylethylamine (1.6 g, 12.38 mmol, 3, 00 equiv.). The resulting solution was stirred for 1 hour at room temperature. Then, the reaction mixture was quenched by adding water (50 ml) and was extracted with ethyl acetate (50 ml × 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (v/v=12:1). This gave 1.1 g (56%) of 6-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-pyridazine -3-carboxamide as a yellow oil.

[0431] LC-MS (ES ⁺ ): m/z 470.0 [MH ⁺ ], t _R =0.90 min (run 1.8 minutes).

[0432] Synthesis of 6-(4-formylpiperidin-1-yl)-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl]pyridazine-3-carboxamide: To a 100 round bottom flask ml was placed 6-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl]pyridazine-3-carboxamide (700.0 mg , 1.49 mmol, 1.00 equiv.), dichloromethane (20 mL), (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzyodoxol-3(1H)-one (947, 2 mg, 2.23 mmol, 1.50 equiv.). The resulting solution was stirred for 3 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (v/v=1:3). This gave 390.0 mg (56%) of 6-(4-formylpiperidin-1-yl)-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide as a yellow solid.

[0433] LC-MS (ES ⁺ ): m/z 468.2 [MH ⁺ ], t _R =1.06 min (run 2.0 minutes).

[0434] Synthesis of 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5- yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazin-3-carboxamide: To a 100 round bottom flask ml was placed 6-(4-formylpiperidin-1-yl)-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (180.0 mg, 0.38 mmol, 1.00 equiv.), dichloromethane (10 mL), 2-(2,6-diox-piperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)-2,3-dihydro-1H -isoindole-1,3-dione hydrochloride (152.7 mg, 0.38 mmol, 1.00 equiv.), sodium triacetoxyborohydride (244.6 mg, 3.00 equiv.). The resulting solution was stirred for 3 hours at room temperature. Then, the reaction mixture was quenched by adding water (30 ml), extracted with ethyl acetate (30 ml×3), washed with brine (30 ml) and concentrated under reduced pressure. The solid was filtered off. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD 19×150 mm 5 µm column; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile (48.0% to 73.0% in 8 min); detector: UV 254 nm. This gave 146.1 mg (47%) of 6-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro -1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl]pyridazin-3 -carboxamide as a yellow solid.

[0435] ¹ H-NMR (400 MHz, DMSO): δ 11.11 (s, 1H), 8.58 (d, J=8.2 Hz, 1H), 7.86 (d, J=8, 8 Hz, 1H), 7.81 (d, J=9.5 Hz, 1H), 7.73 (d, J=11.4 Hz, 1H), 7.46 (d, J=7.4 Hz , 1H, 7.39 (d, J=2.4 Hz, 1H, 7.34 (d, J=9.7 Hz, 1H, 7.15-7.12 (m, 1H, 5.13-5 .08 (m, 1H, 4.59-4.45 (m, 3H), 3.90-3.83 (m, 1H, 3.27 (s, 4H), 3.03 (m, 2H), 2.97-2.82(m, 1H), 2.64-2.53(m, 5H), 2.46(m, 1H), 2.23(m, 2H), 2.14-2, 09 (m, 2H), 2.07-2.02 (m, 1H, 1.96-1.79 (m, 5H), 1.65 (m, 2H), 1.52 (m, 2H), 1.19-10.09 (m, 2H) LC-MS (ES ⁺ ): m/z 812.25 [MH ⁺ ], t _R = 1.57 min (3.0 minute run).

[0436] Chemical formula: C ₄₁ H ₄₃ ClFN ₉ O ₆ [811,30].

[0437] Total H from H-NMR data: 43.

[0438] Method for the synthesis of compound 109:

[0439] 1. Synthesis of benzyl 6-(6-hydroxyhex-1-yn-1-yl)pyridine-3-carboxylate

[0440] A solution of benzyl 6-chloropyridine-3-carboxylate (2.8 g, 11.31 mmol, 1.00 equiv.) in triethylamine (50 ml), copper(1) iodide ( 1.2 g, 6.30 mmol, 1.50 equiv.), tetrakis(triphenylphosphine)palladium (2.5 g, 0.50 equiv.), hex-5-yn-1-ol (1.3 g, 13.25 mmol, 1.00 equiv.). The resulting solution was stirred for 3 hours at 90° C. in an oil bath. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). The collected fractions were pooled and concentrated in vacuo. This gave 1.1 g (31%) of benzyl 6-(6-hydroxyhex-1-yn-1-yl)pyridine-3-carboxylate as a yellow oil. LC-MS (ES ⁺ ): m/z 309.95 [MH ⁺ ], t _R =0.873 min (run 1.90 minutes).

[0441] 2. Synthesis of 6-(6-hydroxyhexyl)pyridine-3-carboxylic acid

[0442] A solution of benzyl 6-(6-hydroxyhex-1-yn-1-yl)pyridine-3-carboxylate (1.1 g, 3.56 mmol, 1.00 equiv.) was placed in a 250 ml round bottom flask. in methanol (40 ml), palladium charcoal (2 g, 10.00 equiv.), hydrogen (gas). The resulting solution was stirred for 48 hours at room temperature. The resulting solution was diluted with 200 ml of methanol. The resulting mixture was concentrated under vacuum. This gave 700 mg (88%) of 6-(6-hydroxyhexyl)pyridine-3-carboxylic acid as a yellow oil.

[0443] LC-MS (ES ⁺ ): m/z 223.95 [MH ⁺ ], t _R = 0.377 min (run 1.90 minutes).

[0444] 3. Synthesis of 6-(6-hydroxyhexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide

[0445] A solution of 6-(6-hydroxyhexyl)-pyridine-3-carboxylic acid (430 mg, 1.93 mmol, 1.00 equiv.) in N,N-dimethylformamide (20 ml) was placed in a 100 ml round bottom flask. , N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.5 g, 3.94 mmol, 2.00 equiv), N,N-diisopropylethylamine ( 1 ml, 0.30 equiv.), 2-chloro-4-[(1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile (690 mg, 2.48 mmol, 1.30 equiv.). The resulting solution was stirred for 2 hours at room temperature. Then, the reaction mixture was quenched by adding 50 ml of water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/hexane (1/3). The collected fractions were pooled and concentrated in vacuo. The result was 580 mg (62%) 6-(6-hydroxyhexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-pyridine -3-carboxamide as a yellow solid.

[0446] LC-MS (ES ⁺ ): m/z 484.10/486.10 [MH ⁺ ], t _R = 0.927 min (run 1.90 minutes).

[0447] 4. Synthesis of 6-(5-[[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]pyridin-2-yl )hexyl-4-methylbenzene-1-sulfonate

[0448] A solution of 6-(6-hydroxyhexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl] was placed in a 100 ml round bottom flask pyridine-3-carboxamide (580 mg, 1.20 mmol, 1.00 equiv.) in dichloromethane (20 mL), 4-toluenesulfonyl chloride (750 mg, 3.93 mmol, 1.50 equiv.), triethylamine (690 mg , 6.82 mmol, 3.00 equiv.), 4-dimethylaminopyridine (35 mg, 0.29 mmol, 0.10 equiv.). The resulting solution was stirred for 20 hours at room temperature. Then, the reaction mixture was quenched by adding water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine. The solid was dried in an oven under reduced pressure. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 430 mg (56%) of 6-(5-[[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]pyridine-2- yl)hexyl-4-methylbenzene-1-sulfonate as a yellow solid.

[0449] LC-MS (ES ⁺ ): m/z 638.40/640.40 [MH ⁺ ], t _R = 1.336 min (2.00 minute run).

[0450] 5. Synthesis of 6-(6-[4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine -1-yl]hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide

[0451] A solution of 6-(5-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoylpyridin-2-yl )hexyl-4-methylbenzene-1-sulfonate (220 mg, 0.34 mmol, 1.00 equiv.) in acetonitrile (5 ml), 2-(2,6-dioxopiperidin-3-yl)-5-(piperazine -1-yl)-2,3-dihydro-1H-isoindol-1,3-dione; trifluoroacetic acid (162 mg, 0.35 mmol, 1.50 equiv.), potassium carbonate (25 mg, 0.18 mmol, 3.00 equiv.), sodium iodide (25 mg, 0.50 equiv.). The resulting solution was stirred for 12 hours at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (3 ml) was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile (56.0% to 65.0% over 8 min); detector: UV 254 nm. Received 41.3 mg of the product. This gave 41.3 mg (15%) of 6-(6-[4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol- 5-yl]piperazin-1-yl]hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide in form of a yellow solid.

[0452] ¹ H-NMR (300 MHz, CD ₃ OD): δ 8.86 (s, 1H, 8.16-8.09 (m, 1H, 7.72-7.64 (m, 2H), 7.47-7.33(m, 2H), 7.24-7.17(m, 1H), 7.12(s, 1H), 6.98-6.89(m, 1H, 5.09 -5.02(m, 1H, 4.26(s, 1H, 4.15(s, 1H), 3.48-3.42(m, 4H), 2.92-2.49(m, 9H ), 2.46-2.35 (m, 2H), 2.16-2.01 (m, 1H, 1.81-1.71 (m, 2H), 1.59-1.47 (m, 2H), 1.42-1.36 (m, 4H), 1.27-1.18 (m, 12H), LC-MS (ES ⁺ ): m/z 808.85/810.85 [MH ⁺ ], t _R =4.79 min (run 8.0 minutes).

[0453] Chemical formula: C ₄₄ H ₅₀ ClN ₇ O ₆ [807.35/809.35].

[0454] Total H from H-NMR data: 48.

[0455] Method for the synthesis of compound 158:

[0456] 1. Synthesis of benzyl 4-fluorobenzoate: Into a 500 ml round bottom flask were placed 4-fluorobenzoic acid (14 g, 99.9 mmol, 1.0 equiv.), N,N-dimethylformamide (150.0 ml) , (bromomethyl)benzene (18.7 g, 109.3 mmol, 1.1 equiv.), cesium carbonate (27.6 g, 84.7 mmol, 2.0 equiv.). The resulting solution was stirred for 4 hours at room temperature. Then, the reaction mixture was quenched by adding 150 ml of water. The resulting solution was extracted with ethyl acetate (100 ml x 3), the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/6). This gave 18.0 g (78%) of benzyl 4-fluorobenzoate as a solid.

[0457] 2. Synthesis of benzyl 4-[4-(hydroxymethyl)piperidin-1-yl]benzoate: Into a 100 mL round bottom flask was placed benzyl 4-fluorobenzoate (5.0 g, 21.7 mmol, 1.1 equiv.), N,N-dimethylformamide (30.0 ml), piperidin-4-ylmethanol (2.3 g, 19.9 mmol, 1.0 equiv.), N,N-diisopropylethylamine (7.6 g, 59.1 mmol, 3.0 equiv.). The resulting solution was stirred for 2 hours at 100°C. Then, the reaction mixture was quenched by adding 60.0 ml of water. The resulting solution was extracted with ethyl acetate (60 ml x 3), the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/1). This gave 3.6 g (55%) of benzyl 4-[4-(hydroxymethyl)piperidin-1-yl]benzoate as a white oil.

[0458] LC-MS (ES ⁺ ): 326.30 m/z [MH ⁺ ], t _R = 1.18 min (run 1.90 minutes).

[0459] 3. Synthesis of benzyl 4-(4-formylpiperidin-1-yl)benzoate: Benzyl 4-[4-(hydroxymethyl)piperidin-1-yl]benzoate (500 mg, 1 .54 mmol, 1.00 equiv.), dichloromethane (15.0 ml), (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzyodoxol-3(1H)-one (978 mg , 2.31 mmol, 1.5 equiv.). The resulting solution was stirred for 4 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:4). This gave 420.0 mg (85%) of benzyl 4-(4-formylpiperidin-1-yl)benzoate as a yellow solid.

[0460] LC-MS (ES ⁺ ): 323.95 m/z [MH ⁺ ], t _R =1.04 min (run 1.80 minutes).

[0461] 4. Synthesis of benzyl-4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5- yl]piperazin-1-yl]methyl)piperidin-1-yl]benzoate: To a 150 ml round bottom flask was placed benzyl 4-(4-formylpiperidin-1-yl)benzoate (500.0 mg, 1.5 mmol, 1.0 equiv.), dichloromethane (20.0 mL), 2-(2,6-diox-piperidin-3-yl)-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-1 ,3-dione-trifluoroacetyl (747 mg, 1.7 mmol, 1.1 equiv.), sodium triacetoxyborohydride (1.39 g, 6.5 mmol, 4.0 equiv.). The resulting solution was stirred for 4 hours at room temperature. Then, the reaction mixture was quenched by adding water (100.0 ml). The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 500.0 mg (50%) benzyl-4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]benzoate as a yellow solid.

[0462] LC-MS (ES ⁺ ): 650.45 m/z [MH ⁺ ], t _R = 1.37 min (run 1.90 minutes).

[0463] 5. Synthesis of 4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] piperazin-1-yl]methyl)piperidin-1-yl]benzoic acid: To a solution of benzyl-4-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]benzoate (500.0 mg, 0.8 mmol, 1.0 equiv) in 20, 0 ml of methanol (30.0 ml) in a 100 ml round bottom flask under nitrogen atmosphere was added Pd/C (10%, 300 mg). The flask was then evacuated and purged with hydrogen. The reaction mixture was hydrogenated at room temperature for 12 hours under a hydrogen balloon, and then filtered through a pad of Celite and concentrated under reduced pressure. This gave 300.0 mg (69.0%) of 4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]benzoic acid as a yellow solid.

[0464] LC-MS (ES ⁺ ): 560.35 m/z [MH ⁺ ], t _R =0.74 min (run 1.90 minutes).

[0465] 6. Synthesis of 4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide: 4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine was placed in a 100 ml flask -1-yl]methyl)piperidin-1-yl]benzoic acid (300.0 mg, 0.5 mmol, 1.0 equiv.), N,N-dimethylformamide (15.0 mL), N,N,N ',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (307.0 mg, 0.8 mmol, 1.5 equiv), 2-chloro-4-[(1R,3R) -3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrochloride (170.0 mg, 0.5 mmol, 1.0 equiv.), N,N-diisopropylethylamine (207.0 mg, 1.6 mmol , 3.0 equiv.). The resulting solution was stirred for 1 hour at room temperature. Then, the reaction mixture was quenched by adding water (80 ml). The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined and concentrated in vacuo. The crude product (5 ml) was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mmol/l ammonium bicarbonate) and acetonitrile (59.0% to 80.0% over 8 min); detector: UV 220 nm. Received 4 ml of the product. This gave 114 g (25921%) of 4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5 -yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide as a yellow solid.

[0466] ¹ H-NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H, 7.86 (d, J=8.7 Hz, 1H, 7.67 (dd, J=17.8 , 8.4 Hz, 3H), 7.44 (d, 3=9.2 Hz, 1H, 7.34-7.13 (m, 3H), 7.02-6.87 (m, 3H), 5.04 (dd, J=12.6, 5.3 Hz, 1H), 4.28 (s, 1H), 4.02 (d, J=9.0 Hz, 1H), 3.82 (d , J=12.5 Hz, 2H), 3.58-3.30 (m, 5H), 2.90-2.66 (m, 3H), 2.6-2.47 (m, 3H), 2.50-2.42 (m, 4H), 2.17 (d, J=6.5 Hz, 2H), 1.98 (dt, J=10.0, 4.5 Hz, 1H, 1, 77 (d, J=11.9 Hz, 3H), 1.18 (s, 6H), 1.09 (s, 6H).

[0467] LC-MS (ES ⁺ ): 820.60 m/z [MH ⁺ ], t _R = 2.99 min (run 4.8 minutes).

[0468] Method for the synthesis of compound 357:

[0469] 1. Synthesis of tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate

-фосфанил)ацетата (15,2 г, 35,41 ммоль, 2,493 эквив.) в THF (90 мл) в круглодонной колбе емкостью 250 мл перемешивали в течение 1 часа при комнатной температуре. Затем, добавляли трет-бутил-6-оксо-2-азаспиро[3.3]гептан-2-карбоксилат (3 г, 14,20 ммоль, 1 эквив.), и перемешивали реакционную смесь дополнительно в течение 6 часов при 35°С. Затем, фильтровали через Celite, и промывали осадок на фильтре THF. Неочищенное вещество подвергали очистке на колонке с силикагелем, элюируя этилацетатом/петролейным эфиром (1:5). В результате получали 3,3 г (82,60%) трет-бутил-6-(2-этокси-2-оксоэтилиден)-2-азаспиро[3.3]гептан-2-карбоксилата в виде бесцветного масла.[0470] A mixture of t-BuOK (3.98 g, 35.47 mmol, 2.498 equiv.) and ethyl-2-(bromotriphenyl-

-phosphanyl)acetate (15.2 g, 35.41 mmol, 2.493 equiv.) in THF (90 ml) in a 250 ml round bottom flask was stirred for 1 hour at room temperature. Then, tert-butyl-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 14.20 mmol, 1 equiv.) was added and the reaction mixture was stirred for an additional 6 hours at 35°C. Then, filtered through Celite and washed the filter cake with THF. The crude material was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This gave 3.3 g (82.60%) of tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate as a colorless oil.

[0471] LC-MS (ES ⁺ ): m/z 226.1 [M-(t-Bu)+H ⁺ ], t _R =1.267 min (2.0 min run).

[0472] 2. Synthesis of tert-butyl 6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0473] To a solution of tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (3.296 g, 11.72 mmol, 1 equiv.) in ethanol (330 ml ) Pd/C (661.8 mg) was added in a 500 ml three-necked round bottom flask under a stream of N ₂ . The reaction flask was evacuated/purged with H ₂ three times. The resulting mixture was stirred for 3 hours at room temperature under H ₂ atmosphere. Then, the mixture was filtered through a pad of Celite. The collected filtrate was concentrated under reduced pressure and dried under vacuum. This gave 3.12 g (93.99%) of tert-butyl 6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate as a colorless oil.

[0474] LC-MS (ES ⁺ ): m/z 228.1 [M-(t-Bu)+H ⁺ ], t _R =1.254 min (2.0 min run).

[0475] 3. Synthesis of tert-butyl 6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0476] In a 250 ml round bottom flask was placed tert-butyl 6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (3.08 g, 10.87 mmol, 1 equiv. .), THF (120 ml), DIBAL-H in THF (1 M) (32.6 ml, 229.28 mmol, 3 equiv.). The resulting solution was stirred for 3 hours at room temperature. Then, the reaction mixture was quenched by adding water (60 ml x 1). The resulting solution was extracted with ethyl acetate (120 ml x 2). The resulting mixture was washed with saline (100 ml × 1). The organic layer was dried over anhydrous sodium sulfate, concentrated and dried under vacuum. This gave 2.53 g (96.45%) of tert-butyl 6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate as a white solid.

[0477] LC-MS (ES ⁺ ): m/z 186.1 [M-(t-Bu)+H ⁺ ], t _R =1.061 min (2.0 min run).

[0478] 4. Synthesis of 2-[2-azaspiro[3.3]heptan-6-yl]ethan-1-ol trifluoroacetate

[0479] A solution of t-butyl 6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (2.52 g, 10.44 mmol, 1 equiv.) in DCM (120 ml), trifluoroacetic acid (7.7 ml). The resulting solution was stirred for 4 hours at room temperature. The resulting mixture was evaporated to dryness and dried under vacuum. This gave 2.66 g (99.80%) of 2-[2-azaspiro[3.3]heptan-6-yl]ethan-1-ol trifluoroacetate as a light yellow oil.

[0480] 5. Synthesis of tert-butyl 4-[6-(2-hydroxyethyl)-2-azaspiro[3.3]heptan-2-yl]benzoate

[0481] To a solution of tert-butyl-4-fluorobenzoate (10.25 g, 52.24 mmol, 5.012 equiv.) in DMSO (50 mL) in a 250 mL round bottom flask was added DIEA (14 mL, 84.71 mmol, 8.128 equiv.). The mixture was stirred for 5 minutes and then 2-[2-azaspiro[3.3]heptan-6-yl]ethan-1-ol trifluoroacetate (2.66 g, 10.42 mmol, 1 equiv.) was added. The resulting solution was stirred for 16 hours at 130°C. After cooling to room temperature, the reaction mixture was quenched by adding water (100 ml×1). The resulting solution was extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with water (50 ml x 2) and brine (50 ml x 1). The organic layer was dried over anhydrous sodium sulfate. The crude material was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:2). This gave 311.5 mg (9.42%) of tert-butyl 4-[6-(2-hydroxyethyl)-2-azaspiro[3.3]heptan-2-yl]benzoate as a light yellow solid.

[0482] LC-MS (ES ⁺ ): m/z 318.2 [MH ⁺ ], t _R =1.314 min (run 2.0 minutes).

[0483] 6. Synthesis of tert-butyl-4-[6-(2-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol- 5-yl]oxy]ethyl)-2-azaspiro[3.3]heptan-2-yl]benzoate

[0484] To a solution of PPh ₃ (361.7 mg, 1.38 mmol, 1.506 equiv.) in THF (15 ml) was added dropwise with stirring DIAD (280.2 mg, 1.39 mmol, 1.513 equiv.) at room temperature in an atmosphere of N ₂ . To the mixture was added tert-butyl 4-[6-(2-hydroxyethyl)-2-azaspiro[3.3]heptan-2-yl]benzoate (290.7 mg, 0.92 mmol, 1 equiv), 2-( 2,6-diox-piperidin-3-yl)-5-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione (377.4 mg, 1.38 mmol, 1.503 equiv.). The resulting solution was stirred for 4 hours at room temperature. Then, the reaction mixture was quenched by adding water (20 ml). The resulting solution was extracted with ethyl acetate (30 ml x 3), and the combined organic layers were washed with brine (20 ml x 1). The organic layer was dried over anhydrous sodium sulfate. The crude material was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:1). The result was 90.8 mg (17.28%) tert-butyl-4-[6-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3 -dihydro-1H-isoindol-5-yl]oxy]ethyl)-2-azaspiro[3.3]heptan-2-yl]benzoate as a light brown solid.

[0485] LC-MS (ES ⁺ ): m/z 574.05 [MH ⁺ ], t _R = 1.443 min (2.0 minute run).

[0486] 7. Synthesis of 4-[6-(2-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] hydroxy]ethyl)-2-azaspiro[3.3]heptan-2-yl]benzoic acid

[0487] To a solution of tert-butyl-4-[6-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5 -yl]oxy]ethyl)-2-azaspiro[3.3]heptan-2-yl]benzoate (70.2 mg, 0.12 mmol, 1 equiv.) in DCM (2.0 mL) was added TFA (0.6 ml, 8.08 mmol, 66.008 equiv.). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was evaporated to dryness and dried under vacuum. This gave 63.3 mg (99.95%) of 4-[6-(2-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -isoindol-5-yl]oxy]ethyl)-2-azaspiro[3.3]heptan-2-yl]benzoic acid as a light brown solid.

[0488] LC-MS (ES ⁺ ): m/z 518.2 [MH ⁺ ], t _R =1.166 min (run 2.0 minutes).

[0489] 8. Synthesis of 4-[6-(2-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] hydroxy]ethyl)-2-azaspiro[3.3]heptan-2-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0490] To a solution of 4-[6-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy ]ethyl)-2-azaspiro[3.3]heptan-2-yl]benzoic acid (63.3 mg, 0.12 mmol, 1 equiv.) in DMF (3.4 ml) was added DIEA (0.32 ml, 1 .94 mmol, 15.830 equiv.), then HATU (51.5 mg, 0.14 mmol, 1.107 equiv.), and finally 2-chloro-4-[(1R,3R)-3-amino-2,2 ,4,4-tetramethylcyclobutoxy]benzonitrile hydrochloride (43.4 mg, 0.14 mmol, 1.126 equiv.). The resulting solution was stirred for 3 hours at room temperature. Then, the reaction mixture was quenched by adding water (10 ml). The resulting solution was extracted with dichloromethane (20 ml x 3); the combined organic layers were washed with water (10 ml x 2) and brine (10 ml x 1). The organic layer was dried over anhydrous sodium sulfate. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep OBD C18 column, 19×250 mm, 5 µm; mobile phase: water (10 mmol/l NH ₄ HCO ₃ ) and acetonitrile (phase B 20% to 60% over 8 min); detector: UV 254/220 nm. The result was 57.4 mg (60.30%) 4-[6-(2-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -isoindol-5-yl]oxy]ethyl)-2-azaspiro[3.3]heptan-2-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-tetramethylcyclobutyl]benzamide as a white solid.

[0491] ¹ H-NMR (300 MHz, d6-DMSO) δ 1.13 (s, 6H), 1.22 (s, 6H), 1.88-2.01 (m, 5H), 2.29 (d, J=5.7 Hz, 3H), 2.44-2.56 (m, 2H), 2.79-2.84 (m, 1H, 3.73 (s, 2H), 3.84 (s, 2H), 3.98 (d, J=9.0 Hz, 1H), 4.07 (t, H=6.2 Hz, 2H), 4.25 (s, 1H, 5.02- 5.08 (m, 1H), 6.34 (d, J=8.4 Hz, 2H), 6.93 (dd, J1=2.1 Hz, J2=8.7 Hz, 1H, 7.13 (d, J=2.4 Hz, 1H, 7.26-7.29(m, 1H, 7.35-7.39(m, 2H), 7.63-7.66(m, 2H), 7.75-7.85 (m, 2H), 11.05 (s, 1H; LC-MS (ES ⁺ ): m/z 778.30 [MH ⁺ ], t _R = 3.222 min (run 4.60 minutes); LC-MS (ES ⁺ ): m/z 778.30/780.30 [MH ⁺ ], t _R =3.222 min (run 4.60 minutes).

[0492] Chemical formula: C ₄₃ H ₄₄ ClN ₅ O ₇ [777.29/779.29].

[0493] Total H from H-NMR data: 44.

[0494] Method for the synthesis of compound 579:

[0495] Synthesis of tert-butyl-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-carbamate

[0496] In a 50 ml round bottom flask was placed tert-butyl-N-[(1R,4R)-4-hydroxycyclohexyl]carbamate (500.0 mg, 2.32 mmol, 1.00 equiv.), N,N- dimethylformamide (10.0 mL), sodium hydride (82.8 mg, 3.45 mmol, 1.50 equiv.), 2-chloro-4-fluorobenzonitrile (432.6 mg, 2.78 mmol, 1.20 equiv. .). The resulting solution was stirred for 2 hours at 0° C. in an ice-water bath. Then, the reaction mixture was quenched by adding 20.0 ml of water. The resulting solution was extracted with ethyl acetate (40.0 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (40.0 ml). The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/2). The collected fractions were pooled and concentrated in vacuo. This gave 470.0 mg (58%) of tert-butyl N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate as a yellow oil.

[0497] LC-MS (ES ⁺ ): m/z 295.0 [MH ⁺ ], t _R = 1.199 min (run 1.90 minutes).

[0498] Chemical formula: C ₁₈ H ₂₃ ClN ₂ O ₃ [350.14]

[0499] 2. Synthesis of 4-(((1R,4R)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride:

[0500] In a 50 ml round bottom flask was placed tert-butyl-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate (470.0 mg, 1.34 mmol, 1, 00 equiv.), methanol (5.0 ml), hydrogen chloride. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This gave 340.0 mg (88%) of 4-(((1R,4R)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride as a yellow solid.

[0501] LC-MS (ES ⁺ ): m/z 250.90 [MH ⁺ ], t _R = 0.537 min (run 1.90 minutes).

[0502] Chemical formula: C ₁₃ H ₁₅ ClN ₂ O [250.09].

[0503] 3. Synthesis of methyl 5-(4-(hydroxymetal)piperidin-1-yl)pyrazine-2-carboxylate

[0504] To a 50 mL round bottom flask were placed methyl 5-chloropyrazine-2-carboxylate (2 g, 11.59 mmol, 1 equiv.), DMSO (15 mL, 0.19 mmol, 0.017 equiv.), DIEA ( 0.2 ml, 0.000 equiv.), piperidin-4-ylmethanol (1.3 mg, 0.01 mmol, 1 equiv.). The resulting solution was stirred for 16 hours at 120° C. in an oil bath. The resulting solution was extracted with ethyl acetate (30 ml x 3), and the organic layers were combined. The resulting mixture was washed with brine (10 ml x 1). The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column eluting with dichloromethane/methanol (1:1). This gave 2.21 g (65%) of methyl 5-[4-(hydroxymethyl)piperidin-1-yl]pyrazine-2-carboxylate as a white solid.

[0505] LC-MS (ES+): m/z 251.13 [MH+], t _R =0.6l min (1.9 minute run).

[0506] 4. Synthesis of 5-[4-(hydroxymethyl)piperidin-1-yl]pyrazine-2-carboxylic acid

[0507] Methyl 5-[4-(hydroxymethyl)-piperidin-1-yl]pyrazin-2-carboxylate (2.21 g, 8.79 mmol, 1 equiv.), methanol ( 40 ml), lithium hydroxide (0.633 mg, 0.03 mmol, 0.003 equiv.), water (10 ml). The resulting solution was stirred for 16 hours at room temperature. The resulting mixture was concentrated. The pH value was adjusted to 4 by adding 1M HCl. The resulting solution was extracted with dichloromethane (30 ml×3) and the organic layers combined. The resulting mixture was washed with saline (10 ml × 1). The resulting mixture was concentrated under vacuum. This gave 1.7042 g (81.67%) of 5-[4-(hydroxymethyl)piperidin-1-yl]pyrazine-2-carboxylic acid as a white solid.

[0508] LC-MS (ES+): m/z 237.11 [MH+], t _R = 0.75 min (2.0 minute run).

[0509] 5. Synthesis of 5-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1S,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyrazine-2-carboxamide

[0510] In a 100 ml round bottom flask were placed 5-[4-(hydroxymethyl)-piperidin-1-yl]pyrazine-2-carboxylic acid (310 mg), DMF (15 ml), DIEA (563.69 mg), 2-chloro-4-[[(1S,4S)-4-aminocyclohexyl]oxy]benzonitrile (250 mg), BOP (386.28 mg). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was extracted with ethyl acetate (50 ml x 3), and the organic layer was washed with brine (30 ml x 1). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10:1). The collected fractions were pooled and concentrated in vacuo. The result was 243.5 mg of 5-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1S,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-pyrazine-2-carboxamide as a white solid.

[0511] LC-MS (ES+): m/z 469.19 [MH+], t _R = 0.99 min (1.9 minute run).

[0512] 6. Synthesis of 5-(4-formylpiperidin-1-yl)-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl]pyrazine-2-carboxamide

[0513] 5-[4-(hydroxymethyl)-piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyrazine- 2-carboxamide (150.1 mg, 0.32 mmol, 1 equiv.), dichloromethane (15 ml, 0.18 mmol, 0.553 equiv.), Dess-Martin reagent (271.37 mg). The resulting mixture was extracted with dichloromethane (50 ml x 3), and the organic layer was washed with brine (30 ml x 1). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 200 mg of 5-(4-formylpiperidin-1-yl)-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyrazine-2-carboxamide (crude) as white solid.

[0514] LC-MS (ES+): m/z 467.17 [MH+], t _R = 1.03 min (1.9 min run).

[0515] 7. Synthesis of 5-(4-[[(propan-2-yl)[(1R,3R)-3-[[2-(2,6-diox-piperidin-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindol-5-yl]oxy]cyclobutyl]amino]methyl]piperidin-1-yl)-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy) cyclohexyl]pyrazine

[0516] 5-(4-Formylpiperidin-1-yl)-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyrazine-2-carboxamide ( 220 mg, 0.47 mmol, 1 equiv), dichloromethane (20 ml, 0.24 mmol, 0.501 equiv), titanium(IV) isopropoxide (2 ml, 0.01 mmol, 0.015 equiv), 2-( 2,6-dioxopiperidin-3-yl)-5-[(1R,3R)-3-[(propan-2-yl)amino]cyclobutoxy]-2,3-dihydro-1H-isoindole-1,3-dione (420 mg, 1.09 mmol, 2.318 equiv.), NaH(OAc) ₃ (340 mg). The resulting solution was stirred for 16 hours at 60° C. in an oil bath. The resulting mixture was extracted with dichloromethane (50 ml x 3) and the organic layer was washed with brine (30 ml x 1). The crude product was purified by preparative HPLC under the following conditions: XSelect CSH Prep C18 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mmol/l NH ₄ HCO ₃ ) and acetonitrile (phase B from 30% to 55% over 8.5 min); detector: UV 254/220 nm. This gave 26 mg (6.60%) of 5-(4-[[(propan-2-yl)[(1R,3R)-3-[[2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]cyclobutyl]amino]methyl]piperidin-1-yl)-N-[(1R,4R)-4-(3-chloro -4-cyanophenoxy)cyclohexyl]pyrazine as a light yellow solid.

[0517] ¹ H-NMR (300 MHz, DMSO-d6) 11.09 (s, 1H), 8.56 (s, 1H, 8.23 (s, 1H, 8.12-8.05 (m, 1H, 7.92-7.82(m, 2H), 7.40-7.36(s, 1H, 7.26-7.20(m, 2H), 7.12-7.09(m, 1H, 5.12-5.10(m, 1H, 4.90-4.81(s, 1H, 4.51-4.48(m, 3H), 3.91-3.80(s, 1H , 3.72-3.62(m, 1H, 3.00-2.81(m, 4H), 2.79-2.68(m, 1H, 2.50-2.42(m, 3H) , 2.30-2.00(m, 7H), 1.99-1.81(m, 4H), 1.80-1.36(m, 5H), 1.21-1.01(m, 2H), 0.91-0.71 (m, 6H), LC-MS (ES ⁺ ): m/z 837.30/839.30 [MH ⁺ ], t _R = 2.934 min (run 4.80 minutes ).

[0518] Chemical formula: C ₄₄ H ₄₉ ClN ₆ O ₇ [836.34/838.34].

[0519] Total H from H-NMR data: 49.

[0520] Method for the synthesis of compound 278:

[0521] Step 1: [(R)-tert-butyl-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate].

[0522]

[0523] Mixture of (R)-2-((tert-butoxycarbonyl)amino)propyl-4-methylbenzenesulfonate (12.6 g, crude), 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile ( 7.1 g, 34.9 mmol) and cesium carbonate (5.8 g, 48.8 mmol) in acetonitrile (100 ml) were stirred at 70° C. for 2 hours. Completion of the reaction was detected by TLC. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (50 ml x 2).

The combined organic layers were washed with brine (100 ml), dried over magnesium sulfate and evaporated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 50%-100% ethyl acetate in hexane) to give t- butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate (7.0 g, 58% yield) as a white solid.

[0524] ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.16 (d, J=6.8 Hz, 3H), 1.42 (s, 9H), 4.02-4.11 (m , 1H), 4.16-4.30 (m, 2H), 6.61 (d, J=2.4 Hz, 1H, 7.46 (d, J=2.4 Hz, 1H), 7, 67(d, J=8.0Hz, 1H, 7.74-7.80(m, 1H, 7.96(s, 1H.

[0525] Chemical formula: C ₁₈ H ₂₁ ClN ₄ O ₂ ; Molecular weight: 360.84.

[0526] Total H from H-NMR data: 20.

[0527] Step 2: [(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile hydrochloride]

[0528]

[0529] (R)-tert-Butyl-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate solution (7.0 g, 19 .4 mmol) in a solution of hydrogen chloride in dioxane (4M, 15 ml) was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure to give a crude residue which was triturated with dichloromethane (25 ml). The resulting solid was collected by filtration and dried under vacuum to give (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile hydrochloride (4.3 g, 85% yield ) as a white solid, which was used in the next step without further purification.

[0530] Step 3: [tert-butyl-4-(prop-2-yn-1-yl)piperazine-1-carboxylate].

[0531]

[0532] A mixture of tert-butyl-piperazine-1-carboxylate (10 g, 53.7 mmol), N-ethyl-N-isopropylpropan-2-amine (12.6 g, 97.6 mmol) and 3-bromoprop- 1-yne (5.8 g, 48.8 mmol) in acetonitrile (50 ml) was stirred for 2 hours. Completion of the reaction was detected by TLC. The reaction mixture was partitioned between ethyl acetate (80 ml) and water (80 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (45 ml x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 50% ethyl acetate in hexane) to give t-butyl- 4-(prop-2-yn-1-yl)piperazine-1-carboxylate (10.5 g, 96% yield) as a pale yellow oil.

[0533] ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (s, 9H), 2.26 (t, J=2.4 Hz, 1H), 2.51 (t, J=4 .8 Hz, 4H), 3.32 (d, J=2.4 Hz, 2H), 3.47 (t, J=4.8 Hz, 4H).

[0534] Chemical formula: C ₁₂ H ₂₀ N ₂ O ₂ ; Molecular weight: 224.30.

[0535] Total H from H-NMR data: 20.

[0536] Step 2: [tert-butyl-4-((3-(ethoxycarbonyl)-1H-pyrazol-5-yl)methyl)piperazine-1-carboxylate].

[0537]

[0538] Mixture of tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate (3.0 g, 13.4 mmol), ethyl diazoacetate (2.3 g, 20.1 mmol) and zinc trifluoromethanesulfonate (974 mg, 2.68 mmol) in triethylamine (9.3 ml, 67 mmol) was stirred at 100° C. overnight. Completion of the reaction was detected by TLC. The reaction mixture was left to cool to room temperature and partitioned between ethyl acetate (50 ml) and water (20 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 100%-200% ethyl acetate in hexane) to give t- butyl 4-((3-(ethoxycarbonyl)-1H-pyrazol-5-yl)methyl)piperazine-1-carboxylate (2.1 g, 47% yield) as a yellow oil.

[0539] LC-MS: (ES ⁺ ): m/z 339.5 [M+H] ⁺ . t _R \u003d 1.772 min.

[0540] Step 3: [5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxylic acid].

[0541]

[0542] A mixture of tert-butyl 4-((3-(ethoxycarbonyl)-1H-pyrazol-5-yl)methyl)piperazin-1-carboxylate (500 mg, 1.48 mmol) and lithium hydroxide monohydrate (250 mg, 5.91 mmol) in a mixture of tetrahydrofuran (10 ml)-water (2.5 ml)-methanol (2.5 ml) was stirred at 45°C overnight. Completion of the reaction was detected by TLC. The reaction mixture was acidified by adding dilute hydrochloric acid (1 N) to pH 6-7, and the resulting mixture was concentrated under reduced pressure to give 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-1H-pyrazole -3-carboxylic acid (1.1 g, crude) as a yellow solid.

[0543] LC-MS: (ES ⁺ ): m/z 311.3 [M+H] ⁺ . t _R =1.378 min.

[0544] Step 4: [(R)-tert-butyl-4-((3-((1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2- yl)carbamoyl)-1H-pyrazol-5-yl)methyl)piperazin-1-carboxylate].

[0545]

[0546] 5-((4-(tert-Butoxycarbonyl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxylic acid mixture (1.1 g, crude), (R)-4-(1 -(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile hydrochloride (336 mg, 1.29 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (371 mg, 1.94 mmol), 1-hydroxybenzotriazole (262 mg, 1.94 mmol) and N-ethyl-N-isopropylpropan-2-amine (835 mg, 6.5 mmol) in anhydrous N,N-dimethylformamide (8 ml) were stirred at room temperature for 2 hours and then 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (980 mg, 2.58 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Completion of the reaction was detected by TLC. The mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 100%-200% ethyl acetate in hexane) to give ( R)-tert-butyl-4-((3-((1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamoyl)-1H-pyrazole -5-yl)methyl)piperazin-1-carboxylate (300 mg, 37% yield in 2 divided doses) as a white solid.

[0547] ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.21 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 2.42 (t, J=4 .8 Hz, 4H), 3.44 (t, J=4.8 Hz, 4H), 3.62 (s, 2H), 4.24-4.29 (m, 1H), 4.40-4 .46 (m, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.68 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7 .68 (d, J=8.0 Hz, 1H), 7.74-7.78 (m, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.27 (d, .7=1.2 Hz, 1H).

[0548] Chemical formula: C ₂₇ H ₃₃ ClN ₈ O ₃ ; Molecular weight: 553.06.

[0549] Total H from H-NMR data: 31.

[0550] LC-MS: (ES ⁺ ): m/z 553.3 [M+H] ⁺ . t _R =2.181 min.

[0551] Step 5: [(R)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(piperazin-1 -ylmethyl)-1H-pyrazole-3-carboxamide dihydrochloride].

[0552]

[0553] A solution of tert-butyl-4-(2-(2-(4-(5-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethyl)piperazin-1-carboxylate (160 mg, 0.29 mmol) in a solution of hydrogen chloride in dioxane (4M, 5 ml) was stirred at room temperature in within 2 hours. The volatiles were removed under reduced pressure to give a crude residue which was triturated with dichloromethane (25 ml). The resulting solid was collected by filtration and dried under vacuum to give (R)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)- 5-(piperazin-1-ylmethyl)-1H-pyrazol-3-carboxamide dihydrochloride (130 mg, 86% yield) as a white solid.

[0554] ¹ H-NMR (400 MHz, CD ₃ OD): δ 1.31 (d, J=6.8 Hz, 3H), 3.50-3.62 (m, 8H), 4.30- 4.48 (m, 4H), 4.58-4.64 (m, 1H), 6.78 (d, J=2.0 Hz, 1H), 7.00-7.03 (m, 1H) , 7.73 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 8 .03 (s, 1H).

[0555] Chemical formula: C ₂₂ H ₂₇ Cl ₃ N ₈ O; Molecular weight: 525.86.

[0556] Total H from H-NMR data: 23.

[0557] LC-MS: (ES ⁺ ): m/z 453.3 [M+H] ⁺ . t _R \u003d 1.916 min.

[0558] Stage 6: [4-chlorobutyl-4-methylbenzenesulfonate]

[0559]

[0560] A mixture of 4-chlorobutan-1-ol (5 g, 46.05 mmol), triethylamine (9.3 g, 92.1 mmol), N,N-dimethylpyridin-4-amine (562 mg, 4.61 mmol) and 4-methylbenzene-1-sulfonyl chloride (9.63 g, 50.66 mmol) in dichloromethane (40 ml) was stirred at room temperature for 1.5 hours. Completion of the reaction was detected by TLC. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 20% ethyl acetate in hexane) to give 4-chlorobutyl-4 -methylbenzenesulfonate (12.0 g, 99% yield) as a colorless oil.

[0561] ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.80-1.84 (m, 4H), 2.46 (s, 3H), 3.49-3.53 (m, 2H) , 4.04-4.08 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H).

[0562] Chemical formula: C ₁₁ H ₁₅ ClO ₃ S; Molecular weight: 262.75.

[0563] Total H from H-NMR data: 15.

[0564] LC-MS: (ES ⁺ ): m/z 263.1 [M+H] ⁺ . t _R =2.888 min.

[0565] Step 7: [5-(4-chlorobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione]

[0566]

[0567] A mixture of 4-chlorobutyl-4-methylbenzenesulfonate (0.96 g, 3.65 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1 g, 3.65 mmol) and potassium carbonate (0.76 g, 5.47 mmol) in N,N-dimethylformamide (10 ml) was stirred at 70° C. overnight. Completion of the reaction was detected by TLC. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 33%-50% ethyl acetate in hexanes) to give 5- (4-chlorobutoxy)-2-(2,6-diox-piperidin-3-yl)isoindoline-1,3-dione (220 mg, 18% yield) as a white solid.

[0568] LC-MS: (ES ⁺ ): m/z 365.1 [M+H] ⁺ . t _R \u003d 2.547 min.

[0569] Step 8: [N-((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((4- (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide]

[0570]

A mixture of (R)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(piperazin-1-ylmethyl)-1H- pyrazole-3-carboxamide dihydrochloride (130 mg, 0.25 mmol), 5-(4-chlorobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (90 mg, 0. 25 mmol), N-ethyl-M-isopropylpropan-2-amine (162 mg, 1.25 mmol) and potassium iodide (124 mg, 0.75 mmol) in acetonitrile (3 ml) were stirred at 100°C in a sealed tube during the night. Completion of the reaction was detected by TLC. The mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 8% methanol in dichloromethane) to give N-((R)- 1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((4-(4-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide (45 mg, 24% yield) as a white solid.

[0571] ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.11 (d, J=5.6 Hz, 3H), 1.23 (s, 1H), 1.57 (s, 1H ), 1.70-1.80 (m, 2H), 1.98-2.08 (m, 2H), 2.22-2.40 (m, 8H), 2.52-2.68 (m , 2H), 2.84-2.94 (m, 1H), 3.30 (s, 1H), 3.51 (s, 2H), 4.18 (t, J=6.4 Hz, 2H) , 4.42-4.48 (m, 3H), 5.08-5.15 (m, 1H), 6.43 (s, 1H), 6.94 (d, J=2.4 Hz, 1H ), 7.32-7.6 (m, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.80-7.85 (m, 2H), 7.99 (s, 2H), 8.08 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 11.1 (s, 1H), 13.1 (s, 1H).

[0572] Chemical formula: C ₃₉ H ₄₁ ClN ₁₀ O ₆ ; Molecular weight: 781.26.

[0573] Total H from H-NMR data: 41.

[0574] LC-MS: (ES ⁺ ): m/z 781.4 [M+H] ⁺ . t _R =2.113 min.

[0575] Method for the synthesis of compound 612:

[0576] Synthesis of tert-butyl 4-[[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl]-piperazin-1-carboxylate: A solution of 1, 2-difluoro-4-nitrobenzene (977.5 mg, 6.1 mmol, 1.0 equiv) in dimethyl sulfoxide (10 mL), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate ( 1.5 g, 5.1 mmol, 0.8 equiv.), N,N-diisopropylethylamine (2.0 g, 15.3 mmol, 2.5 equiv.). The resulting solution was stirred overnight at 100° C. in an oil bath. Then, the reaction mixture was quenched by adding 10 ml of ice water. The resulting solution was extracted with ethyl acetate (20 ml×2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:0). This gave 1.5 g (58%) of tert-butyl 4-[[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate as a yellow solid.

[0577] LC-MS (ES ⁺ ): m/z 423.30 [MH ⁺ ], t _R =1.58 min (run 1.9 minutes).

[0578] Synthesis of tert-butyl 4-[[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl]-piperazin-1-carboxylate: To a solution of tert-butyl-4-[[1- (2-fluoro-4-nitrophenyl)-piperidin-4-yl]methyl]piperazin-1-carboxylate (1.5 g, 3.6 mmol, 1.0 equiv) in 15 ml i-PrOH in a round bottom flask Pd/C (10%, 40.0 mg) was added to 100 ml under nitrogen atmosphere. The flask was then evacuated and purged with hydrogen. The reaction mixture was hydrogenated at room temperature for 4 hours under a hydrogen balloon, and then filtered through a pad of Celite and concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This gave 1.2 g (86%) of tert-butyl 4-[[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl]piperazine-1-carboxylate as a pink solid.

[0579] LC-MS (ES ⁺ ): m/z 393.10 [MH ⁺ ], t _R =0.74 min (run 1.9 minutes).

[0580] 3. Synthesis of tert-butyl 4-[(1-[4-[(1-cyanocyclobutyl)amino]-2-fluorophenyl]piperidin-4-yl)methyl]piperazin-1-carboxylate: A solution of tert-butyl 4-[[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate (1.2 g, 3.1 mmol, 1.0 equiv.) in tetrahydrofuran (10 ml), cyclobutanone (428.6 mg, 6.1 mmol, 2.0 equiv.), ZnCl ₂ (2.1 g, 15.4 mmol, 5.0 equiv.), TMSCN (606.1 mg). The resulting solution was stirred overnight at room temperature. Then, the reaction mixture was quenched by adding 10 ml of 1 mm FeSO ₄ . The resulting solution was extracted with ethyl acetate (20 ml×2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column eluting with dichloromethane/methanol (5:1). This gave 990.0 mg (69%) of tert-butyl 4-[(1-[4-[(1-cyanocyclobutyl)amino]-2-fluorophenyl]piperidin-4-yl)methyl]piperazin-1-carboxylate as a black solid.

[0581] LC-MS (ES ⁺ ): m/z 472.35 [MH ⁺ ], t _R =1.50 min (run 1.9 minutes).

[0582] 4. Synthesis of tert-butyl-4-[(1-[4-[7-(5-chloro-6-cyanopyridin-3-yl)-8-imino-6-sutfanylidene-5,7-diazaspiro[ 3.4]octan-5-yl]-2-fluorophenyl]piperidin-4-yl)methyl]-piperazin-1-carboxylate: A solution of tert-butyl-4-[(1-[4-[ (1-cyanocyclobutyl)amino]-2-fluorophenyl]piperidin-4-yl)methyl]-piperazin-1-carboxylate (402.6 mg, 1.3 mmol, 1.0 equiv.) in toluene (10 ml), 3-chloro-5-isothiocyanatopyridine-2-carbonitrile (200.0 mg, 1.5 mmol, 1.2 equiv.), 4-dimethylamino-pyridine (156.4 mg, 1.9 mmol, 1.5 equiv. ). The resulting solution was stirred overnight at 100° C. in an oil bath. Then, the reaction mixture was quenched by adding 5 ml of ice water. The resulting solution was extracted with ethyl acetate (20 ml×2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:0). The result was 230.0 mg (30.4%) tert-butyl-4-[(1-[4-[7-(5-chloro-6-cyanopyridin-3-yl)-8-imino-6-sulfanylidene -5,7-diazaspiro[3.4]octan-5-yl]-2-fluorophenyl]piperidin-4-yl)methyl]-piperazin-1-carboxylate as a yellow solid.

[0583] LC-MS (ES ⁺ ): m/z 667.30 [MH ⁺ ], t _R =1.52 min (run 1.9 minutes).

[0584] 5. Synthesis of 3-chloro-5-(5-[3-fluoro-4-[4-(piperazin-1-ylmethyl)piperidin-1-yl]-phenyl]-8-oxo-6-sulfanylidene- 5,7-diazaspiro[3.4]octan-7-yl)pyridine-2-carbonitrile hydrochloride: A solution of tert-butyl-4-[(1-[4-[7-(5-chloro- 6-cyanopyridin-3-yl)-8-imino-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluorophenyl]piperidin-4-yl)methyl]piperazin-1-carboxylate ( 230.0 mg, 0.3 mmol, 1.0 equiv.) in methanol (10 ml), hydrogen chloride (8 ml). The resulting solution was stirred for 2 hours at 80° C. in an oil bath. Then, the reaction mixture was quenched by adding 5 ml of ice water. The resulting solution was extracted with ethyl acetate (20 ml×2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 200.1 mg (96%) of 3-chloro-5-(5-[3-fluoro-4-[4-(piperazin-1-ylmethyl)-piperidin-1-yl]phenyl]-8-oxo -6-sulfanylidene-5,7-diazaspiro[3.4]octan-7-yl)pyridine-2-carbonitrile hydrochloride as a yellow solid.

[0585] LC-MS (ES ⁺ ): m/z568.25 [MH ⁺ ], t _R =1.26 min (run 1.9 minutes).

[0586] 6. Synthesis of 3-chloro-5-(5-[4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3- dihydro o-1 H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-3-fluorophenyl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octane- 7-yl)pyridine-2-carbonitrile: A solution of 3-chloro-5-(5-[3-fluoro-4-[4-(piperazin-1-ylmethyl)piperidin-1- yl]phenyl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-7-yl)pyridine-2-carbonitrile hydrochloride (100.0 mg, 0.2 mmol, 1.0 equiv.) in dimethyl sulfoxide (10 ml), 2-(2,6-diox-piperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (40.6 mg, 0.2 mmol , 0.9 equiv.), N,N-diisopropylethylamine (56.9 mg, 0.44 mmol, 2.66 equiv.). The resulting solution was stirred for 2 hours at 130° C. in an oil bath. Then, the reaction mixture was quenched by adding 5 ml of ice water. The resulting solution was extracted with ethyl acetate (20 ml×2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: mobile phase A: water (10 mmol/l ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 20 ml/min; gradient: 56% B to 76% B over 8 min; 254 nm; t _R . 7.6 min; received 5 ml of product. This gave 72.7 mg (60%) of 3-chloro-5-(5-[4-[4-([4-[2-(2,6-diox-piperidin-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-3-fluorophenyl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4 ]octan-7-yl)pyridine-2-carbonitrile as a yellow solid.

[0587] ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.54 (d, J= 1.9 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.37 (s, 1H), 7.33-7.13 (m, 4H), 5.09 ( dd, J=12.6, 5.4 Hz, 1H), 3.50-3.45 (m, 6H), 2.90-2.81 (m, 4H), 2.71-2.2, 60 (m, 3H), 2.61-2.45 (m, 5H), 2.38-2.36 (m, 1H), 2.30-2.28 (m, 2H), 2.05- 1.99 (m, 2H), 1.89-1.80 (m, 2H), 1.76-1.72 (m, 1H), 1.61-1.55 (m, 1H), 1. 39-1.22 (m, 2H); LC-MS (ES ⁺ ): m/z 824.35 [MH ⁺ ], t _R =1.27 min (run 2.9 minutes).

[0588] Chemical formula: C ₄₁ H ₃₉ ClFN ₉ O ₅ S [823,25].

[0589] Total H from H-NMR data: 39.

[0590] Method for the synthesis of compound 603:

[0591] 1. Synthesis of 4-fluoro-N-hydroxybenzene-1-carboximidamide: Into a 250 mL round bottom flask were placed 4-fluorobenzonitrile (5.00 g, 41.28 mmol, 1 equiv), hydroxylamine hydrochloride (14.0 g, 201.47 mmol, 4.880 equiv.), ethanol (150 ml) and N-ethyl-N-isopropylpropan-2-amine (27.0 g, 208.90 mmol, 5.060 equiv.). The resulting mixture was stirred for 4 hours at 85° C. in an oil bath. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column eluting with methanol/ethyl acetate (1:10). This gave 5.70 g (89.57%) of 4-fluoro-N-hydroxybenzene-1-carboximidamide as a white solid.

[0592] LC-MS (ES ⁺ ): m/z 155.30 [MN] ⁺ , t _R =0.60 min (2.00 minute run).

[0593] 2. Synthesis of 3-(4-fluorophenyl)-5-methyl-1,2,4-oxadiazole: 4-fluoro-N-hydroxybenzene-1-carboximidamide (5.70 g, 36.98 mmol, 1.0 equiv), acetyl acetate (54.1 g, 529.93 mmol, 14.3 equiv) and acetic acid (5 ml). The resulting solution was stirred for 16 hours at 120° C. in an oil bath. Then, the reaction mixture was quenched by adding 150 ml of water. The pH value of the solution was adjusted to 7 by adding NaHCO ₃ . The resulting solution was extracted with ethyl acetate (30 ml×2) and the organic layers combined. The resulting mixture was washed with brine (30 ml×2). The mixture was dried over anhydrous sodium sulfate and the solid was filtered off. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 6.10 g (92.59%) of 3-(4-fluorophenyl)-5-methyl-1,2,4-oxadiazole as a white solid.

[0594] LC-MS (ES ⁺ ): m/z 178.95 [MN] ⁺ , t _R =1.18 min (run 2.00 minutes).

[0595] 3. Synthesis of tert-butyl-4-([1-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]azetidin-3-yl]methyl)piperazin-1- carboxylate: To a 30 ml sealed tube was placed 3-(4-fluorophenyl)-5-methyl-1,2,4-oxadiazole (523.0 mg, 2.94 mmol, 1.5 equiv), tert-butyl- 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate (500.0 mg, 1.96 mmol, 1 equiv.), dimethyl sulfoxide (15 ml, 211.18 mmol, 107.852 equiv.) and Cs ₂ CO ₃ ( 1.91 g, 5.86 mmol, 3.0 equiv.). The resulting suspension was stirred for 20 hours at 150° C. in an oil bath. Then, the reaction mixture was quenched by adding 150 ml of water. The resulting solution was extracted with ethyl acetate (30 ml×2) and the organic layers combined. The resulting mixture was washed with brine (30 ml×2). The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 380.0 mg (46.93%) tert-butyl-4-([1-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]azetidin-3-yl ]methyl)piperazine-1-carboxylate as a light yellow solid.

[0596] LC-MS (ES ⁺ ): m/z 414.40 [MN] ⁺ , t _R =0.90 min (2.00 minute run).

[0597] 4. Synthesis of tert-butyl 4-[[1-(4-carbamimidoylphenyl)azetidin-3-yl]methyl]-piperazin-1-carboxylate: In a nitrogen-purged 100 ml round-bottom flask, while maintaining an inert atmosphere of nitrogen, the tert-Butyl 4-([1-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]azetidin-3-yl]methyl)piperazine-1-carboxylate (380.0 mg , 0.92 mmol, 1 equiv.), methanol (50 ml), AcOH (2 ml, 34.90 mmol, 37.981 equiv.) and 10% Pd/C (300 mg). The flask was quickly evacuated/refilled with hydrogen three times and finally connected to an H ₂ balloon (10 L). The resulting suspension was stirred for 16 hours at room temperature. The solids were filtered off and additionally washed successively with 200 ml of methanol and 200 ml of acetonitrile. The combined filtrate was concentrated under reduced pressure. This gave 100.0 mg (29.14%) of tert-butyl 4-[[1-(4-carbamimidoylphenyl)azetidin-3-yl]methyl]piperazine-1-carboxylate as a white solid.

[0598] LC-MS (ES ⁺ ): m/z 374.05 [MN] ⁺ , t _R =0.75 min (2.00 minute run).

[0599] 5. Synthesis of 2-chloro-4-[[(1R,4R)-4-(2-bromoacetyl)cyclohexyl]oxy]benzonitrile: In a nitrogen-purged 100 ml three-necked round bottom flask, while maintaining an inert atmosphere of nitrogen, was placed (1R ,4R)-4-(3-Chloro-4-cyanophenoxy)cyclohexane-1-carboxylic acid (400.0 mg, 1.43 mmol, 1.0 equiv.), dichloromethane (30 mL), oxalyl chloride (220.0 mg, 1.73 mmol, 1.2 equiv.) and a drop of N,N-dimethylacetamide (30.0 mg, 0.41 mmol, 0.29 equiv.). The resulting solution was stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (20 ml). (Trimethylsilyl)diazomethane (2.2 mL, 4.4 mmol, 3.0 equiv., 2M in hexane) was added to the solution. The resulting solution was stirred for 2 hours at room temperature and then cooled in an ice-water bath. A solution of HBr in AcOH (40%) (1.05 g, 5.17 mmol, 3.613 equiv.) was added to the cooled mixture, and then the cooling bath was removed. The resulting solution was allowed to react with stirring for an additional 2 hours at room temperature. Then, the reaction mixture was quenched by adding 100 ml of water. The resulting solution was extracted with ethyl acetate (30 ml×2) and the organic layers combined. The resulting mixture was washed with brine (30 ml×2). The mixture was dried over anhydrous sodium sulfate and the solid was filtered off. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This gave 380 mg (74.51%) of 2-chloro-4-[[(1R,4R)-4-(2-bromoacetyl)cyclohexyl]oxy]benzonitrile as a white solid.

[0600] LC-MS (ES ⁺ ): m/z 355.85 [MN] ⁺ , t _R = 1.05 min (1.90 minute run).

[0601] 6. Synthesis of tert-butyl-4-[[1-(4-[5-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl]-1H-imidazole-2- yl]phenyl)azetidin-3-yl]methyl]piperazin-1-carboxylate: Into a 50 ml three neck round bottom flask was placed tert-butyl 4-[[1-(4-carbamimidoylphenyl)azetidin-3-yl]methyl]piperazine -1-carboxylate (100.0 mg, 0.27 mmol, 1.0 equiv.), tetrahydrofuran (15 ml) and NaHCO ₃ solution (113.0 mg, 1.35 mmol, 5.0 equiv.) in water (3 ml). After stirring the mixture at room temperature for 5 minutes, a solution of 2-chloro-4-[[(1R,4R)-4-(2-bromoacetyl)cyclohexyl]oxy]benzonitrile (96.0 mg, 0.27 mmol, 1 equiv.) in THF (5 ml). The resulting solution was stirred for 24 hours at 50° C. in an oil bath. Then, the reaction mixture was quenched by adding 150 ml of water. The resulting solution was extracted with ethyl acetate (30 ml×2) and the organic layers combined. The resulting mixture was washed with brine (50 ml×2). The mixture was dried over anhydrous sodium sulfate and the solid was filtered off. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column eluting with methanol/ethyl acetate (1:10). This gave 50.0 mg (29.43%) tert-butyl-4-[[1-(4-[5-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]- 1H-imidazol-2-yl]phenyl)-azetidin-3-yl]methyl]piperazine-1-carboxylate as an off-white solid.

[0602] LC-MS (ES ⁺ ): m/z 631.15 [MN] ⁺ , t _R =0.94 min (run 2.00 minutes).

[0603] 7. Synthesis of 4-[[1-(4-[5-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-1H-imidazol-2-yl]phenyl)azetidine -3-yl]methyl]piperazin-1-ium trifluoroacetate: In a 100 ml round bottom flask was placed tert-butyl-4-[[1-(4-[5-[(1R,4R)-4-(3-chloro -4-cyanophenoxy)cyclohexyl]-1H-imidazol-2-yl]phenyl)azetidin-3-yl]methyl]-piperazin-1-carboxylate (50.0 mg, 0.08 mmol, 1 equiv.), dichloromethane ( 20 ml, 314.60 mmol, 3971.566 equiv) and 2,2,2-trifluoroacetaldehyde (5 ml). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This gave 50.0 mg (97.84%) of 4-[[1-(4-[5-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-1H-imidazole- 2-yl]phenyl)azetidin-3-yl]methyl]piperazin-1-ium trifluoroacetate as an off-white solid.

[0604] 8. Synthesis of 2-chloro-4-[[(1R,4R)-4-(2-[4-[3-([4-[2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)azetidin-1-yl]phenyl]-1H-imidazol-5-yl)cyclohexyl]oxy]benzonitrile : 4-[[1-(4-[5-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-1H-imidazol-2-yl]phenyl )azetidin-3-yl]methyl]piperazin-1-ium trifluoroacetate (50.0 mg, 0.08 mmol, 1 equiv.), 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2 ,3-dihydro-1H-isoindole-1,3-dione (54.0 mg, 0.20 mmol, 2.522 equiv.), dimethyl sulfoxide (4 ml, 56.31 mmol, 726.583 equiv.) and N-ethyl-N -isopropylpropan-2-amine (2 ml, 12.10 mmol, 156.134 equiv.). The resulting solution was stirred for 3 hours at 130° C. in an oil bath. Then, the reaction mixture was quenched by adding 150 ml of water. The resulting solution was extracted with ethyl acetate (30 ml×2) and the organic layers combined. The resulting mixture was washed with brine (50 ml×2). The mixture was dried over anhydrous sodium sulfate and the solid was filtered off. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column eluting with methanol/ethyl acetate (1:10). The crude product was further purified by preparative HPLC (column: XBridge Prep C18 OBD, 5 μm, 19×150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml /min, gradient: 45% B to 63% B over 8 min, 254 nm, t _R : 7.8 min). This gave 31.5 mg (51.62%) of 2-chloro-4-[[(1R,4R)-4-(2-[4-[3-([4-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)azetidin-1-yl]-phenyl]-1H-imidazol-5 -yl)cyclohexyl]oxy]benzonitrile as a yellow solid.

[0605] ¹ H-NMR (300 MHz, Me ₂ SO-d ₆ ): δ 11.08 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.71-7 .67 (m, 3H), 7.39-7.25 (m, 3H), 7.13 (dd, J=8.8, 2.3 Hz, 1H), 6.74 (s, 1H), 6.45 (d, J=8.4 Hz, 2H), 5.07 (dd, J=12.7, 5.5 Hz, 1H), 4.60 (broad s, 1H), 3.98 (t, J=7.6 Hz, 2H), 3.54-3.30 (m, 7H), 3.29-3.120 (m, 5H), 3.11-2.79 (m, 3H), 2.67-2.55 (m, 3H), 2.18-2.01 (m, 5H), 1.75-1.35 (m, 4H); LC-MS (BS ⁺ ): m/z 787.50 [MH ⁺ ], HPLC: t _R =5.13 min (10.00 minute run).

[0606] Chemical formula: C ₄₃ H ₄₃ ClN ₈ O ₅ [787.31].

[0607] Total H from H-NMR data: 43.

[060S] Method for the synthesis of compound 609:

[0609] 1. Synthesis of tert-butyl-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate

[0610]

[0611] A solution of tert-butyl N-[(1R,3R)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl]carbamate (600, 0 mg, 2.47 mmol, 1.00 equiv.) in N,N-dimethylformamide (10.0 mL). Then, at 0° C., sodium hydride (198.0 mg, 8.25 mmol, 2.00 equiv.) was added in portions. After 30 minutes, 2-chloro-4-fluorobenzonitrile (459.0 mg, 2.95 mmol, 1.20 equiv.) was added to the mixture. The resulting solution was stirred for 1 hour at 70°C. The reaction mixture was cooled to room temperature in a water bath. Then, the reaction mixture was quenched by adding water (20 ml). The resulting solution was extracted with ethyl acetate (20 ml×3) and the organic layers combined. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/5). The result was 100.0 mg (11%); tert-Butyl N-[(1R,3R)-3-(3-chlorocyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate as a colorless oil.

[0612] LC-MS (ES ⁺ ): m/z 279.10 [MH-100] ⁺ , t _R =1.20 min (run 2.5 minutes).

[0613] 2. Synthesis of 2-chloro-4-[(1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutoxy]-benzonitrile

[0614]

[0615] In a nitrogen-purged 100 ml round flask, while maintaining an inert atmosphere of nitrogen, was placed tert-butyl-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl]carbamate (500.0 mg, 1.32 mmol, 1.00 equiv.), hydrogen chloride in dioxane (3 mL, 4M), 1,4-dioxane (3 mL). The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. This gave 447.0 mg (87%) of 2-chloro-4-[(1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile as a white solid.

[0616] 3. Synthesis of tert-butyl-4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1 -carboxylate

[0617] A solution of 2-(2,6-diox-piperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (5 g, 18.10 mmol, 1.00 equiv) in methyl sulfoxide (30 ml), methyl sulfoxide (30 ml), N,N-diisopropylethylamine (12.5 ml, 2.00 equiv), tert-butylpiperazine-1-carboxylate (3.75 g, 20.13 mmol, 1.10 equiv.). The resulting solution was stirred for 16 hours at 110° C. in an oil bath. Then, the reaction mixture was quenched by adding water (100 ml). The resulting solution was extracted with ethyl acetate (100 ml×3) and the organic layers combined. The resulting mixture was washed with brine (200 ml). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 6.5 g (81%) tert-butyl-4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5- yl]piperazine-1-carboxylate as a yellow solid.

[0618] LC-MS (ES ⁺ ): m/z 443.00 [MH ⁺ ], t _R = 1.156 min (run 2.0 minutes).

[0619] 4. Synthesis of tert-butyl-4-[2-(2,6-diox-piperidin-3-yl)-3-hydroxy-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-5 -yl]piperazine-1-carboxylate

[0620] Into a nitrogen-purged 50 ml sealed tube, while maintaining an inert atmosphere of nitrogen, was placed tert-butyl-4-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3- dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (2 g, 4.52 mmol, 1.00 equiv.), tetrahydrofuran (30 mL). Then, under stirring at -75°C for 20 minutes was added dropwise methylmagnesium bromide (6 ml). The resulting solution was stirred for 4 hours at 60°C. Then, the reaction mixture was quenched by adding water (50 ml). The resulting solution was extracted with ethyl acetate (30 ml×3) and the organic layers combined. The resulting mixture was washed with saturated aqueous sodium chloride solution (50 ml). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:0). The result was 1.5 g (72%) tert-butyl-4-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-3-methyl-1-oxo-2,3-dihydro- 1H-isoindol-5-yl]piperazine-1-carboxylate as a crude yellow oil.

[0621] 5. Synthesis of 3-[3-methyl-1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidin-2,6-dione

[0622] Into a 100 ml round bottom flask was placed tert-butyl-4-[2-(2,6-diox-piperidin-3-yl)-3-hydroxy-3-methyl-1-oxo-2,3-dihydro-1H -isoindol-5-yl]piperazine-1-carboxylate (1.5 g, 3.27 mmol, 1.00 equiv.), dichloromethane (20 ml), triethylsilane (15 ml). Then, boron trifluoroether (15 ml) was added dropwise with stirring. The resulting solution was stirred for 16 hours at 25°C. The resulting solution was diluted with water (35 ml). The resulting solution was extracted with ethyl acetate (15 ml×3), the aqueous layers were combined and concentrated in vacuo. This gave 1.12 g (100%) of 3-[3-methyl-1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidin-2, 6-dione as crude yellow oil.

[0623] LC-MS (ES ⁺ ): m/z 343.00 [MH ⁺ ], t _R = 0.658 min (2.0 minute run).

[0624] 6. Synthesis of tert-butyl-4-[2-(2,6-diox-piperidin-3-yl)-3-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine -1-carboxylate

[0625] 3-[3-Methyl-1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidin-2,6 was placed in a 100 ml round bottom flask -dione (1.12 g, 3.27 mmol, 1.00 equiv.), dichloromethane (50 ml), (Boc) ₂ O (1.5 g, 6.87 mmol, 2.10 equiv.). Then, triethylamine (4 ml) was added dropwise with stirring. The resulting solution was stirred for 16 hours at 25°C. The resulting solution was diluted with water (50 ml). The resulting solution was extracted with dichloromethane (20 ml×3) and the organic layers combined. The resulting mixture was washed with saturated aqueous sodium chloride solution (15 ml×2). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (8:2). The crude product was purified by preparative HPLC under the following conditions: XBridge Prep CI8 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mmol/l NH ₄ HCO ₃ ) and ACN (ACN from 32.0% to 41.0% in 9 min); detector: UV 254 nm. This gave 435 mg (30%) tert-butyl-4-[2-(2,6-diox-piperidin-3-yl)-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-5- yl]piperazine-1-carboxylate as a yellow oil.

[0626] LCMS42-PH-ARV-LS-046-E-20-3(60861-135Q)1T.

[0627] LC-MS (ES ⁺ ): m/z 443.40 [MH ⁺ ], t _R = 2.034 min (run 4.6 minutes).

[0628] 7. Synthesis of 3-[3-methyl-1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidin-2,6-dione trifluoroacetate

[0629] tert-Butyl-4-[2-(2,6-diox-piperidin-3-yl)-3-methyl-1-oxo-2,3-dihydro-1H-isoindol-5 -yl]piperazine-1-carboxylate (435 mg, 0.98 mmol, 1.00 equiv.), dichloromethane (30 ml), trifluoroacetic acid (1 ml). The resulting solution was stirred for 3 hours at 25°C. The resulting mixture was concentrated under vacuum. This gave 500 mg (1.11%) of 3-[3-methyl-1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidin-2, 6-dione trifluoroacetate as a crude yellow oil.

[0630] 8. Synthesis of 4-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl]benzamide

[0631] In a 25 ml round bottom flask was placed 4-[4-(hydroxymethyl)piperidin-1-yl]benzoic acid (250 mg, 1.06 mmol, 1.00 equiv.), N,N-dimethylformamide (6 ml ), HATU (485 mg, 1.28 mmol, 1.20 equiv.). Then, N,N-diisopropylethylamine (550 mg, 4.26 mmol, 4.01 equiv.) was added over 5 minutes. 2-Chloro-4-[(1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrochloride (335 mg, 1.06 mmol, 1.00 equiv.) was added to the mixture. The resulting solution was stirred for 2 hours at 25°C. The resulting solution was diluted with water (25 ml). The resulting solution was extracted with ethyl acetate (15 ml×3) and the organic layers combined. The resulting mixture was washed with saturated aqueous sodium chloride solution (20 ml). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10:1). The result was 514 mg (98%) 4-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl]benzamide as an off-white solid.

[0632] LC-MS (ES ⁺ ): m/z 496.05 [MH ⁺ ], t _R = 1.133 min (run 2.0 minutes).

[0633] 9. Synthesis of 4-(4-formylpiperidin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0634] 4-[4-(hydroxymethyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-tetramethylcyclobutyl]benzamide (600 mg, 1.21 mmol, 1.00 equiv.), dichloromethane (20 mL). Then, at 0° C., the Dess-Martin reagent (1.02 g) was added in portions. The resulting solution was stirred for 2 hours at 25°C. Then, the reaction mixture was quenched by adding saturated sodium bicarbonate solution (50 ml) and sodium thiosulfate solution (50 ml). The resulting solution was extracted with dichloromethane (30 ml×3) and the organic layers combined. The resulting mixture was washed with saturated aqueous sodium chloride solution (50 ml). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 450 mg (75%) of 4-(4-formylpiperidin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl]benzamide as an off-white solid.

[0635] LC-MS (ES ⁺ ): m/z 494.10 [MH ⁺ ], t _R = 1.074 min (run 1.9 minutes).

[0636] 10. Synthesis of 4-[4-([4-[2-(2,6-dioxogohsheridin-3-yl)-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-5- yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0637] 4-(4-Formylpiperidin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl]benzamide (130 mg, 0.26 mmol, 1.00 equiv.), 3-[3-methyl-1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindole -2-yl]piperidin-2,6-dione trifluoroacetate (110 mg, 0.24 mmol, 0.92 equiv.), dichloromethane (20 mL). Then, while stirring for 16 hours, DIEA (0.3 ml) was added dropwise. Sodium triacetoxyborohydride (550 mg) was added portionwise to the mixture. The resulting solution was stirred for 16 hours at 25°C. Then, the reaction mixture was quenched by adding water (20 ml). The resulting solution was extracted with dichloromethane (15 ml×3) and the organic layers combined. The resulting mixture was washed with saturated aqueous sodium chloride solution (20 ml). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mmol/l NH ₄ HCO ₃ ) and ACN (ACN 53.0% to 72.0% over 8 min); detector: UV 254 nm. This gave 53.4 mg (25%) of 4-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-3-methyl-1-oxo-2,3-dihydro-1H -isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl]benzamide as a white solid.

[0638] ¹ H-NMR-PH-ARV-LS-046-E-0: (300 MHz, DMSO, ppm) δ 10.90-10.88 (broad, 1H), 7.92- 7.89 (d, J=9 Hz, 1H), 7.75-7.72 (d, J=9 Hz, 2H), 7.51-7.44 (m, 2H), 7.21 (br ., 1H), 7.10-6.94 (m, 5H), 4.65-4.64 (m, 1H), 4.54-4.52 (m, 1H), 4.32 (s, 1H), 4.06-4.03 (d, J=9 Hz, 1H), 3.88-3.84 (m, 2H), 3.31-3.28 (m, 4H), 2.83 -2.75(m, 3H), 2.63-2.58(m, 6H), 2.22-2.20(m, 2H), 1.96-1.94(m, 1H), 1 .83-1.79 (m, 3H), 1.43-1.38 (m, 3H), 1.21 (s, 6H), 1.18-1.17 (m, 2H), 1.12 (s, 6H); LC-MS (ES ⁺ ): m/z 820.30/822.30 [MH ⁺ ], t _R =2.042 min (3.0 min run).

[0639] Chemical formula: C ₄₆ H ₅₄ ClN ₇ O ₅ [819.39/821.39].

[0640] Total H from H-NMR data: 54.

[0641] Method for the synthesis of compound 88:

[0642] Synthesis of 4-(6-[4-[2-(2,6-diox-piperidin-3-yl)-6-fluoro-3-hydroxy-1-oxo-2,3-dihydro-1H-isoindole-5 -yl]piperazin-1-yl]hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide: To a 100 round bottom flask ml was placed a solution of 4-(6-[4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] piperazin-1-yl]hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (330 mg, 0.40 mmol, 1.00 equiv.) in acetic acid (20 ml), Zn (100 mg, 3.00 equiv.). The resulting solution was stirred for 30 minutes at room temperature. The resulting solution was diluted with 100 ml of methyl alcohol. The resulting mixture was concentrated under vacuum. As a result, 320 mg (97%) of 4-(6-[4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-hydroxy-1-oxo-2,3-dihydro- 1H-isoindol-5-yl]piperazin-1-yl]hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide in white oil, m/z 827.40 [MH ⁺ ], t _R =0.799 min (1.90 minute run).

[0643] 2. Synthesis of 4-(6-[4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl ]piperazin-1-yl]hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylalbutyl]benzamide

[0644] A solution of 4-(6-[4-[2-(2,6-diox-piperidin-3-yl)-6-fluoro-3-hydroxy-1-oxo-2,3- dihydro-1H-isoindol-5-yl]-piperazin-1-yl]hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl ]benzamide (320 g, 386.76 mmol, 1.00 equiv.) in trifluoroacetic acid (10 ml), triethylsilane (3 ml, 0.30 equiv.). The resulting solution was stirred for 30 minutes at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified under the following conditions: XBridge Prep OBD C18 column 19×250 mm, 5 µm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 55% B to 75% B over 8 min; 220 nm; t _R : 6.05 min. This gave 49.2 mg of 4-(6-[4-[2-(2,6-diox-piperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-5- yl]piperazin-1-yl]-hexyl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide as a white solid. [(1R,3R)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide as a white solid.

[0645] ¹ H-NMR (300 MHz, CD ₃ OD): δ 7.81-7.69 (m, 3H), 7.53-7.46 (m, 1H), 7.35-7.27 (m, 3H), 7.15 (s, 1H), 6.97-6.94 (m, 1H), 5.17-5.04 (m, 1H), 4.52-4.39 (m , 2H), 4.27 (s, 1H), 4.16 (s, 1H), 3.84-3.55 (m, 4H), 3.36 (s, 2H), 3.27-3, 11 (m, 4H), 3.01-2.61 (m, 4H), 2.22-2.07 (m, 1H), 1.87-1.63 (m, 4H), 1.52- 1.38 (m, 4H), 1.33-1.16 (m.12), m/z 811.45 [MH ⁺ ], t _R = 2.415 min (run 3.20 min).

[0646] Chemical formula: C ₄₅ H ₅₂ ClFN ₆ O ₅ [810,37].

[0647] Total H from H-NMR data: 52.

[0649] 1. Synthesis of 5-bromo-3-fluorobenzene-1,2-dicarboxylic acid

[0650] To a 100 ml round bottom flask was placed 4-bromo-2-fluoro-6-methylbenzoic acid (2.5 g, 10.73 mmol, 1.00 equiv.), sodium hydroxide (1.72 g, 43. 00 mmol, 4.00 equiv.), water (20 ml), KMnO ₄ (3.41 g, 2.00 equiv.). The resulting solution was stirred for 16 hours at 100° C. in an oil bath. Solids were filtered off. The pH value of the solution was adjusted to 3 by adding hydrogen chloride (2 mol/l). The resulting solution was extracted with dichloromethane (10 ml×1) and the organic layers combined. The resulting solution was extracted with ethyl acetate/methanol = 10:3 (10 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 518 mg (18%) of 5-bromo-3-fluorobenzene-1,2-dicarboxylic acid as a white solid and 1.365 g as a white solid.

[0651] LC-MS (ES ⁺ ): m/z 264.75 [MH ⁺ ], t _R =0.675 min (run 2.0 minutes).

[0652] 2. Synthesis of 1,2-dimethyl-5-bromo-3-fluorobenzene-1,2-dicarboxylate

[0653] In a 100 ml round bottom flask were placed 5-bromo-3-fluorobenzene-1,2-dicarboxylic acid (1.4 g, 5.32 mmol, 1.00 equiv.), methanol (40 ml), sulfuric acid (2 ml). The resulting solution was stirred for 16 hours at 70°C. Then, the reaction mixture was quenched by adding water (10 ml). The pH value of the solution was adjusted to 7 by adding sodium carbonate. The resulting solution was extracted with ethyl acetate (20 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/hexane (1:10). This gave 1.15 g (74%) of 1,2-dimethyl-5-bromo-3-fluorobenzene-1,2-dicarboxylate as a colorless oil.

[0654] LC-MS (ES ⁺ ): m/z 292.80 [MH ⁺ ], t _R = 0.939 min (2.0 minute run).

[0655] 3. Synthesis of 1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-fluorobenzene-1,2-dicarboxylate

[0656] Into a 50 mL round bottom flask was placed 1,2-dimethyl-5-bromo-3-fluorobenzene-1,2-dicarboxylate (500 mg, 1.72 mmol, 1.00 equiv), t-butyl piperazine -1-carboxylate (481 mg, 2.58 mmol, 1.50 equiv), Rouphos Pd (66 mg, 0.09 mmol, 0.05 equiv), Cs ₂ CO ₃ (1.66 g, 5, 09 mmol, 3.00 equiv.), toluene (20 ml). The resulting solution was stirred for 12 hours at 100° C. in an oil bath. The resulting solution was diluted with water (40 ml). The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 600 mg (88%) of 1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-fluorobenzene-1,2-dicarboxylate as a solid.

[0657] LC-MS (ES ⁺ ): m/z 397.25 [MH ⁺ ], t _R = 1.238 min (2.0 minute run).

[0658] 4. Synthesis of 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-fluorobenzene-1,2-dicarboxylic acid

[0659] 1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-fluorobenzene-1,2-dicarboxylate (800 mg, 2 .02 mmol, 1.00 equiv), methanol/water/THF (16 mL), sodium hydroxide (242.4 mg, 6.06 mmol, 3.00 equiv). The resulting solution was stirred for 16 hours at 25°C. The resulting solution was diluted with 16 ml of water (30 ml). The pH value of the solution was adjusted to 8 by adding hydrogen chloride (2 mol/l). Citric acid monohydrate was used to adjust to pH 3. The resulting solution was extracted with ethyl acetate/methanol=10:1 (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 740 mg (100%) of 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-fluorobenzene-1,2-dicarboxylic acid as a yellow solid.

[0660] LC-MS (ES ⁺ ): m/z 369.00 [MN ⁺ ], t _R =0.804 min (run 2.0 minutes).

[0661] 5. Synthesis of tert-butyl-4-[2-(2,6-diox-piperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl ]piperazine-1-carboxylate

[0662] 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-fluorobenzene-1,2-dicarboxylic acid (560 mg, 1.52 mmol, 1 .00 equiv.) in acetonitrile (25 mL), CDI (986.6 mg, 6.08 mmol, 4.00 equiv.), DIEA (785.6 mg, 6.08 mmol, 4.00 equiv.), 3-aminopiperidine-2,6-dione (375.5 mg, 2.93 mmol, 1.50 equiv.). The resulting solution was stirred for 5 hours at 70° C. in an oil bath. The resulting solution was diluted with water (40 ml). The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/hexane (1:1). The result was 700 mg (100%) tert-butyl-4-[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol- 5-yl]piperazin-1-carboxylate as a yellow solid.

[0663] LC-MS (ES ⁺ ): m/z 483.05 [MNa ⁺ ], t _R = 0.884 min (2.0 minute run).

[0664] 6. Synthesis of 2,2,2-trifluoroacetaldehyde-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-6-(piperazin-1-yl)-2,3-dihydro-1H- isoindole-1,3-dione

[0665] tert-Butyl-4-[2-(2,6-diox-piperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole was placed in a 100 ml round bottom flask -5-yl]piperazin-1-carboxylate (710 mg, 1.54 mmol, 1.00 equiv.), dichloromethane (10 ml), trifluoroacetic acid (3 ml). The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was concentrated under vacuum. The crude product was purified by recrystallization from ethanol. This gave 320 mg (45%) of 2,2,2-trifluoroacetaldehyde-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-6-(piperazin-1-yl)-2,3-dihydro -1H-isoindole-1,3-dione as a yellow solid.

[0666] LC-MS (ES ⁺ ): m/z 361.2 [MH ⁺ ], t _R =0.210 min (run 2.0 minutes).

[0667] 7. Synthesis of 2-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol- 5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl] pyrimidine-5-carboxamide

[0668] 2-(4-Formylpiperidin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl]pyrimidine-5-carboxamide (110 mg, 0.22 mmol, 1.00 equiv.), 2,2,2-trifluoroacetaldehyde-2-(2,6-dioxopiperidin-3-yl)-4-fluoro- 6-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (104 mg, 0.23 mmol, 1.30 equiv.), dichloromethane (10 mL), acetyl ethaneperoxoate sodioboranyl acetate (70.67 mg, 0.33 mmol, 1.50 equiv.). The resulting solution was stirred for 15 minutes at 25°C. The resulting solution was left under stirring for the reaction to proceed for an additional 1 hour at 25°C. The resulting solution was left under stirring for the reaction to proceed for an additional 2 hours at 25°C. The resulting solution was diluted with dichloromethane (30 ml). The resulting mixture was washed with water (30 ml×1). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/ethyl acetate (3:1). The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mmol/l NH ₄ HCO ₃ ) and acetonitrile (acetonitrile from 32.0% to 75.0% over 8 min); detector: UV 254/220 nm. This gave 145 mg (78%) of 2-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H -isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl]pyrimidine-5-carboxamide as a yellow solid.

[0669] ¹ H-NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.75 (s, 2H), 7.90 (d, J=8.7 Hz, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.07-6.99 (m, 2H), 5.10 (m, 1H) , 4.74 (d, J=13.2 Hz, 2H), 4.29 (s, 1H), 4.04 (d, J=9.0 Hz, 1H), 3.50 (s, 4H) , 3.00-2.95 (m, 3H), 2.53-2.50 (m, 5H), 2.21-2.19 (m, 2H), 2.08-1.81 (m, 5H), 1.21-1.04 (m, 14H); LC-MS (ES ⁺ ): m/z 840.30/842.30 [MH ⁺ ], t _R =3.099 min (5.0 min run).

[0670] Chemical formula: C ₄₃ H ₄₇ ClFN ₉ O ₆ [839.33/841.33].

[0671] Total H from H-NMR data: 47.

[0672] Method for the synthesis of compound 358:

[0673] 1. Synthesis of ethyl 4,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0674] A solution of ethyl 3-oxobutanoate (10 g, 76.84 mmol, 1.00 equiv.) in ethanol (200 ml), urea (6.9 g, 114.89 mmol, 1.50 equiv.), acetaldehyde (5 g, 113.50 mmol, 1.50 equiv.), hydrogen chloride (2 ml, 0.30 equiv.). The resulting solution was stirred for 5 hours at 85° C. in an oil bath. The resulting mixture was concentrated under vacuum. This gave 12 g (79%) of ethyl 4,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate as a white solid, m/z: 199.13 [MH ⁺ ], t _R =0.865 min (run 2.00 minutes).

[0675] 2. Synthesis of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate

[0676] Nitric acid (20 ml, 5.00 equiv.) was placed in a 100 ml round bottom flask for 5 minutes. Ethyl 4,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2 g, 10.09 mmol, 1.00 equiv.) was then added dropwise with stirring. The resulting solution was stirred for 3 hours at 0° C. in an ice-water bath. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column eluting with dichloromethane/methanol (1:7). The collected fractions were pooled and concentrated in vacuo. This gave 1.1 g (56%) of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate as a yellow oil. m/z: 197.14 [MH ⁺ ], t _R =0.477 min (1.80 minute run).

[0677] 3. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate

[0678] A solution of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate (300 mg, 1.53 mmol, 1.00 equiv.) in phosphoroyl trichloride ( 10 ml), N,N-diethylaniline (0.1 ml, 0.10 equiv.). The resulting solution was stirred for 3 hours at 105° C. in an oil bath. Then, the reaction mixture was quenched by adding water. The resulting solution was extracted with ethyl acetate, the organic layers were combined and concentrated in vacuo. This gave 100 mg (30%) of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate as a yellow solid. m/z: 214.85 [MH ⁺ ], t _R =0.842 min (1.90 minute run).

[0679] 4. Synthesis of ethyl 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-4,6-dimethylpyrimidine-5-carboxylate

[0680] A solution of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate (100 mg, 0.47 mmol, 1.00 equiv.) in tetrahydrofuran (20 ml), triethylamine ( 0.3 ml, 0.30 equiv.), tert-butyl piperazine-1-carboxylate (104 mg, 0.56 mmol, 1.20 equiv.). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:4). The collected fractions were pooled and concentrated in vacuo. This gave 180 mg (94%) of ethyl 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-4,6-dimethylpyrimidine-5-carboxylate as a yellow solid. m/z: 365.13 [MN ⁺ ], t _R =1.418 min (2.00 minute run).

[0681] 5. Synthesis of 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-4,6-dimethylpyrimidine-5-carboxylic acid

[0682] A solution of ethyl 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-4,6-dimethylpyrimidine-5-carboxylate (170 mg, 0.47 mmol , 1.00 equiv.) in methanol/water (50/10 ml), sodium hydroxide (93 mg, 2.33 mmol, 5.00 equiv.). The resulting solution was stirred for 12 hours at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 by adding hydrogen chloride (1 mol/l). The resulting solution was extracted with ethyl acetate and the organic layers combined. The residue was applied to a silica gel column eluting with dichloromethane/methanol (4:1). The collected fractions were pooled and concentrated in vacuo. This gave 150 mg (89%) of 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-4,6-dimethylpyrimidine-5-carboxylic acid as a white solid, m/z 337, 24 [MH ⁺ ], t _R =1.106 min (2.00 minute run).

[0683] 6. Synthesis of tert-butyl-4-(4,6-dimethyl-5-[[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl ]carbamoyl]pyrimidin-2-yl)piperazine-1-carboxylate

[0684] A solution of 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-4,6-dimethylpyrimidine-5-carboxylic acid (130 mg, 0.39 mmol, 1.00 equiv.) in N,N-dimethylformamide (30 ml), N,N,N',N'-tetramctyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (220 mg, 1.50 equiv. .), N,N-diisopropylethylamine (0.3 ml, 0.30 equiv.), 2-chloro-4-[(1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrochloride (129 mg, 0.41 mmol, 1.20 equiv.). The resulting solution was stirred for 30 minutes at room temperature. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate (100%). The collected fractions were pooled and concentrated in vacuo. This gave 150 mg (63%) tert-butyl-4-(4,6-dimethyl-5-[[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4, 4-tetramethylcyclobutyl]-carbamoyl]pyrimidin-2-yl)piperazine-1-carboxylate as a yellow solid. m/z 597.13 [MN ⁺ ], t _R =1.428 min (2.00 minute run).

[0685] 7. Synthesis of 4,6-dimethyl-2-(piperazin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4 hydrochloride, 4-tetramethylcyclobutyl]pyrimidine-5-carboxamide

[0686] In a 100 ml round bottom flask was placed tert-butyl-4-(4,6-dimethyl-5-[[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-Tetramethylcyclobutyl]carbamoyl]-pyrimidin-2-yl)piperazine-1-carboxylate (140 mg, 0.23 mmol, 1.00 equiv.), dioxane/HCl (20 ml, 3.00 equiv.). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This gave 160 mg (122%) of 4,6-dimethyl-2-(piperazin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide hydrochloride as a yellow solid, m/z: 497.22 [MH ⁺ ], t _R = 1.046 min (2.00 minute run).

[0687] 8. Synthesis of 2-[4-(3-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl] hydroxy]propyl)piperazin-1-yl]-4,6-dimethyl-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine- 5-carboxamide

[0688] A solution of 4,6-dimethyl-2-(piperazin-1-yl)-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-tetramethylcyclobutyl]-pyrimidine-5-carboxamide hydrochloride (140 mg, 0.26 mmol, 1.00 equiv.) in acetonitrile (10 mL), potassium carbonate (181 mg, 1.31 mmol, 5, 00 equiv.), sodium iodide (51 mg, 1.50 equiv.), 5-(3-bromopropoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindol- 1,3-dione (125 mg, 0.32 mmol, 1.20 equiv). The resulting solution was stirred for 12 hours at 70° C. in an oil bath. The resulting solution was diluted with 20 ml of acetonitrile. The resulting mixture was concentrated under vacuum. The crude product (50 ml) was purified by preparative HPLC under the following conditions: mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 ml/min; gradient: 30% B to 48% B over 8 min; 254 nm; t _R . 7.83 min. This gave 51 mg (28%) of 2-[4-(3-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5 -yl]oxy]propyl)piperazin-1-yl]-4,6-dimethyl-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl ]pyrimidine-5-carboxamide as an off-white solid.

[0689] ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.60 (d, J=8, 6 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.22 (dd, J=8.3, 2.3 Hz, 1H), 6.99 (d, J= 2.4 Hz, 1H), 6.83 (dd, J=8.8, 2.4 Hz, 1H), 5.96 (d, J=8.6 Hz, 1H), 4.99 (dd, J=11.9, 5.5 Hz, 1H), 4.24 (dt, J=11.9, 7.0 Hz, 7H), 4.08 (s, 1H), 3.09 (s, 9H ), 2.98-2.77 (m, 5H), 2.40(s, 2H), 2.21-2.14 (m, 1H), 1.27 (d, J=3.9 Hz, 12H); LC-MS (ES ⁺ ): m/z: 811.32 [MH ⁺ ], t _R = 6.278 min (run 10.00 minutes).

[0690] Chemical formula: C ₄₂ H ₄₇ ClN ₈ O ₇ [810,33].

[0691] Total H from H-NMR data: 46.

[0692] Method for the synthesis of compound 584:

[0693] 1. Synthesis of 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid

[0694] In a 100 ml round bottom flask were placed 4-bromo-2-methoxy-6-methylbenzonitrile (800 mg, 3.54 mmol, 1.00 equiv.), water (10 ml), sodium hydroxide (708 mg, 17 .70 mmol, 5.00 equiv.), KMnO ₄ (1.12 g, 7.09 mmol, 2.00 equiv.). The resulting solution was stirred for 16 hours at 100° C. in an oil bath. Solids were filtered off. The pH value of the solution was adjusted to 3 by adding hydrogen chloride (2 mol/l). The resulting solution was extracted with dichloromethane (15 ml×3) and the aqueous layers were combined. The resulting solution was extracted with ethyl acetate/methanol=10:1 (15 ml×3), the organic layers were combined, dried in an oven under reduced pressure and concentrated under vacuum. This gave 330 mg (34%) of 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid as a white solid.

[0695] 2. Synthesis of 1,2-dimethyl-5-bromo-3-methoxybenzene-1,2-dicarboxylate

[0696] In a 100 ml round bottom flask were placed 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid (330 mg, 1.20 mmol, 1.00 equiv.), methanol (20 ml), sulfuric acid (5 ml). The resulting solution was stirred for 16 hours at 70° C. in an oil bath. The resulting solution was diluted with water (40 ml). The pH value of the solution was adjusted to 8 by adding sodium carbonate. The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:10). This gave 340 mg (93%) of 1,2-dimethyl-5-bromo-3-methoxybenzene-1,2-dicarboxylate as a white solid.

[0697] LC-MS (ES+): m/z 302.85 [MH+], t _R = 0.906 min (2.0 min run).

[0698] 3. Synthesis of 1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate

[0699] Into a 100 ml round bottom flask was placed 1,2-dimethyl-5-bromo-3-methoxybenzene-1,2-dicarboxylate (300 mg, 0.99 mmol, 1.00 equiv), t-butyl piperazine -1-carboxylate (277 mg, 1.49 mmol, 1.50 equiv.), RouphosPd (39 mg, 0.05 mmol, 0.05 equiv.), Cs ₂ CO ₃ (978 mg, 3.00 mmol, 3.00 equiv.), toluene (15 ml). The resulting solution was stirred for 12 hours at 100° C. in an oil bath. The resulting solution was diluted with water (30 ml). The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/ethyl acetate (10:1). This gave 340 mg (84%) of 1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate as a light yellow oil. .

[0700] LC-MS (ES+): m/z 409.05 [MH+], t _R = 0.963 min (2.0 minute run).

[0701] 4. Synthesis of 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylic acid

[0702] 1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate (340 mg, 0 .83 mmol, 1.00 equiv.), methanol/H ₂ O/THF (8 ml), sodium hydroxide (100 mg, 2.50 mmol, 3.00 equiv.). The resulting solution was stirred for 12 hours at 25°C. The resulting solution was diluted with water (30 ml). The pH value of the solution was adjusted to 8 by adding hydrogen chloride (2 mol/l). Used citric acid monohydrate to adjust to pH 3. The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 300 mg (95%) of 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylic acid as a colorless oil.

[0703] LC-MS (ES+): m/z 306.95 [MH+], t _R = 0.853 min (2.0 minute run).

[0704] 5. Synthesis of tert-butyl-4-[2-(2,6-diox-piperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl ]piperazine-1-carboxylate

[0705] In a 100 ml round bottom flask was placed tert-butyl 4-(7-methoxy-1,3-dioxo-1,3-dihydro-2-benzofuran-5-yl)piperazine-1-carboxylate (260 mg, 0.72 mmol, 1.00 equiv.), 3-aminopiperidine-2,6-dione hydrochloride (153.6 mg, 0.93 mmol, 1.30 equiv.), pyridine (10 mL). The resulting solution was stirred for 4 hours at 120° C. in an oil bath. The resulting solution was diluted with water (30 ml). The resulting solution was extracted with ethyl acetate (30 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (100:1). The result was 280 mg (83%) tert-butyl-4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol- 5-yl]piperazin-1-carboxylate as a yellow solid.

[0706] LC-MS (ES+): m/z 417.05 [MH+], t _R = 0.852 min (2.0 minute run).

[0707] 6. Synthesis of 2-(2,6-diox-piperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-dione

[0708] tert-Butyl-4-[2-(2,6-diox-piperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole was placed in a 50 ml round bottom flask -5-yl]piperazin-1-carboxylate (270 mg, 0.57 mmol, 1 equiv), dichloromethane (6 ml, 0.07 mmol, 0.124 equiv), TFA (2 ml, 0.02 mmol, 0.031 equiv.). The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was concentrated to give 2-(2,6-diox-piperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-dione as a brown oil.

[0709] LC-MS (ES+): m/z 373.05 [MH+], t _R = 0.155 min (2.0 minute run).

[0710] 7. Synthesis of 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol- 5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazin-3-carboxamide

[0711] 2,2,2-trifluoroacetaldehyde-2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)-2,3- dihydro-1H-isoindole-1,3-dione (130 mg, 0.28 mmol, 1.078 equiv.), dichloromethane (10 ml, 0.12 mmol), 6-(4-formylpiperidin-1-yl)-N- [(1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (120 mg, 0.26 mmol, 1 equiv), NaBH(OAc) ₃ (163.4 mg, 0.77 mmol, 3.006 equiv.). The resulting solution was stirred for 2 hours at 25°C. The resulting solution was diluted with dichloromethane (30 ml). The resulting mixture was washed with H ₂ O (30 ml×3). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column eluting with dichloromethane/ethyl acetate (3:1). The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mM NH ₄ HCO ₃ ) and acetonitrile (43% to 65% phase B over 8 min); detector: UV. This yielded 70 mg (33.11%) of 6-[4-([4-[2-(2,6-dioxo-piperidin-3-yl)-7-methoxy-1,3-Dioxo-2,3-dihydro -1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1R,4R)-4-(3-chloro-4-cyanophenoxy)-cyclohexyl]pyridazin-3 -carboxamide as a yellow solid.

[0712] ¹ H-NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.57 (d, J=8.4 Hz, 1H), 7.87-7.79 (m , 2H), 7.39-7.32 (m, 2H), 7.15-7.12 (m, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 5, 04-4.98 (m, 1H), 4.50-4.47 (m, 3H), 4.93-3.85 (m, 4H), 3.35-3.33 (m, 5H), 3.07-2.81 (m, 3H), 2.51 (s, 3H), 2.27-22.1 (m, 2H), 2.09-2.01 (m, 2H), 2. 00-1.49(m, 11H), 1.23-1.11(m, 3H); LC-MS (ES+): m/z 824.25/826.25 [MH+], t _R =182 min (3.0 min run).

[0713] Chemical formula: C ₄₂ H ₄₆ ClN ₉ O ₇ [823.32/825.32].

[0714] Total H from H-NMR data: 46.

[0715] Method for the synthesis of compound 618:

[0716] 1. Synthesis of N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrole-5-amine

[0717] In a 250 ml round bottom flask were placed 5-methoxy-3,4-dihydro-2H-pyrrole (4.4 g, 1 equiv.), MeOH (50 ml), 2,2-dimethoxyethane-1-amine ( 4.6 g). The resulting solution was stirred for 12 hours at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. This gave 5.7 g of N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrole-5-amine as a brown oil.

[0718] LC-MS (ES ⁺ ): m/z 173.00 [MH ⁺ ], t _R =0.17 min (run 1.9 minutes).

[0719] 2. Synthesis of 5H,6H,7H-pyrrolo[1,2-a]imidazole

[0720] N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrole-5-amine (5.72 g, 33.21 mmol, 1 equiv.), formic acid (100 ml). The resulting solution was stirred for 16 hours at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. This gave 3.1 g (86.31%) of 5H,6H,7H-pyrrolo[1,2-a]imidazole as a brown solid.

[0721] LC-MS (ES ⁺ ): m/z 108.95 [MH ⁺ ], t _R =0.15 min (run 1.9 minutes).

[0722] 3. Synthesis of [5H,6H,7H-pyrrolo[1,2-a]imidazol-3-yl]boronic acid

[0723] 5H,6H,7H-pyrrolo[1,2-a]imidazole (1.0 g, 9.25 mmol, 1 equiv.) was placed in a nitrogen-purged 100 ml round-bottom flask while maintaining an inert nitrogen atmosphere. Then, THF (20 ml, 246.86 mmol, 26.696 equiv.) was added. The resulting solution was cooled to -78°C. n-BuLi (10 mL, 106.16 mmol, 11.480 equiv) was added to the mixture. The resulting solution was stirred for 10 minutes at -78°C. B(Oi-Pr) ₃ (5.0 g, 26.59 mmol, 2.875 equiv.) was added to the mixture. The resulting solution was stirred for 6 hours at room temperature. The pH value was adjusted to 2 by adding 2M HCl. The resulting mixture was concentrated under vacuum. This gave 2.1 g of [5H,6H,7H-pyrrolo[1,2-a]imidazol-3-yl]boronic acid (crude) as a brown solid.

[0724] LC-MS (ES ⁺ ): m/z 512.4 [MH ⁺ ], t _R =1.27 min (run 1.9 minutes).

[0725] 4. Synthesis of tert-butyl 4-[[1-(4-nitrophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate

[0726] A solution of 1-fluoro-4-nitrobenzene (3 g, 21.26 mmol, 1.00 equiv.) in DMSO (80 ml) was placed in a 250 ml round bottom flask. Then, DIEA (2.7 g, 20.89 mmol, 1.00 equiv.) was added in several portions over 2 minutes. tert-Butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (6 g, 21.17 mmol, 1.00 equiv.) was added to the mixture. The resulting solution was stirred for 6 hours at 100° C. in an oil bath. Then, the reaction mixture was quenched by adding water (100 ml). The resulting solution was extracted with ethyl acetate (100 ml×2) and the organic layers combined. The resulting mixture was washed with brine (30 ml×2). The resulting solution was concentrated under vacuum. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 8.0 g (93%) of tert-butyl 4-[[1-(4-nitrophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate as a light yellow solid.

[0727] LC-MS (ES ⁺ ): m/z 405.10 [MH ⁺ ], t _R =0.65 min (run 1.9 minutes).

[0728] 5. Synthesis of tert-butyl 4-[[1-(4-aminophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate

[0729] A solution of tert-butyl 4-[[1-(4-nitrophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate (4.8 g, 11, 87 mmol, 1.00 equiv.) in methanol (60 ml). Then, Pd/C (0.96 g, 0.20 equiv.) was added. The flask was then evacuated and purged with hydrogen. The reaction mixture was hydrogenated at room temperature for 3 hours under a hydrogen balloon, and then filtered through a pad of Celite and concentrated under reduced pressure. This gave 2.7 g (61%) of tert-butyl 4-[[1-(4-aminophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate as a light yellow solid.

[0730] LC-MS (ES ⁺ ): m/z 375.10 [MH ⁺ ], t _R =0.73 min (2.0 minute run).

[0731] 6. Synthesis of tert-butyl 4-[[1-(4-bromophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate

[0732] In a nitrogen-purged 250 ml round-bottom flask, while maintaining an inert atmosphere of nitrogen, was placed tert-butyl-4-[[1-(4-aminophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate (2.0 g ), acetonitrile (100 mg). Then, tert-butyl nitrite (770 mg) was added. The mixture was stirred for 30 minutes. Copper bromide (1.4 g) was added to the mixture. The resulting solution was stirred for 3 hours at 0° C. in an ice-water bath. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (0:100-1:2). This gave 320 mg of tert-butyl 4-[[1-(4-bromophenyl)piperidin-4-yl]methyl]piperazin-1-carboxylate as a white solid.

[0733] LC-MS (ES ⁺ ): m/z 438.15 [MH ⁺ ], t _R =0.69 min (run 1.9 minutes).

[0734] 7. Synthesis of tert-butyl 4-([1-[4-(1,2-dimethyl-1H-imidazol-5-yl)phenyl]-piperidin-4-yl]methyl)piperazin-1-carboxylate

[0735] In a nitrogen-purged 25 ml sealed tube, while maintaining an inert atmosphere of nitrogen, was placed tert-butyl-4-[[1-(4-bromophenyl)-piperidin-4-yl]methyl]piperazine-1-carboxylate (230 mg) , [5H,6H,7H-pyrrolo[1,2-a]imidazol-3-yl]boronic acid (1.0 g), dioxane / H ₂ O (8 ml / 2 ml), Na ₂ CO ₃ (170 mg), Pd(dppf)Cl ₂ (50 mg). The resulting solution was stirred for 3 hours at 90° C. in an oil bath. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10:1). This gave 150 mg of tert-butyl 4-([1-[4-(1,2-dimethyl-1H-imidazol-5-yl)phenyl]piperidin-4-yl]methyl)piperazin-1-carboxylate as brown oil.

[0736] LC-MS (ES ⁺ ): m/z 466.30 [MH ⁺ ], t _R =0.61 min (run 1.9 minutes).

[0737] 8. Synthesis of 1-[[1-(4-[5H,6H,7H-pyrrolo[1,2-a]imidazol-3-yl]phenyl)piperidin-4-yl]methyl]piperazine

[0738] In a 100 ml round bottom flask was placed tert-butyl-4-[[1-(4-[5H,6H,7H-pyrrolo[1,2-a]imidazol-3-yl]phenyl)piperidin-4- yl]methyl]piperazine-1-carboxylate (100 mg, 0.21 mmol, 1 equiv.), trifluoroacetyl (4 ml), dichloromethane (20 ml). The resulting solution was stirred for 4 hours at room temperature. The resulting mixture was concentrated under reduced pressure. This gave 80 mg (90.91%) of 1-[[1-(4-[5H,6H,7H-pyrrolo[1,2-a]imidazol-3-yl]phenyl)-piperidin-4-yl] methyl]piperazine as a brown oil.

[0739] LC-MS (ES ⁺ ): m/z 366.00 [MH ⁺ ], t _R =0.63 min (run 2.0 minutes).

[0740] 9. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-[[1-(4-[5H,6H,7H-pyrrolo[1,2-a]imidazole-3 -yl]phenyl)piperidin-4-yl]methyl]piperazin-1-yl)-2,3-dihydro-1H-isoindol-1,3-dione

[0741] 1-[[1-(4-[5H,6H,7H-pyrrolo[1,2-a]imidazol-3-yl]phenyl)piperidine -4-yl]methyl]piperazine (100 mg, 0.27 mmol, 1 equiv.), DMSO (5 ml), DIEA (1.5 mg), 2-(2,6-diox-piperidin-3-yl)- 5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (80 mg, 0.29 mmol, 1.059 equiv.). The resulting solution was stirred for 3 hours at 130° C. in an oil bath. The resulting solution was extracted with ethyl acetate (30 ml×3). The resulting mixture was washed with brine (30 ml×1). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column, 5 μm, 19×150 mm; mobile phase: water (10 mmol/l NH ₄ HCO ₃ ) and acetonitrile (38% to 55% phase B over 8 min); detector: UV. This gave 30.6 mg (17.99%) of 2-(2,6-diox-piperidin-3-yl)-5-(4-[[1-(4-[5H,6H,7H-pyrrolo[1, 2-a]imidazol-3-yl]phenyl)piperidin-4-yl]methyl]piperazin-1-yl)-2,3-dihydro-1H-isoindol-1,3-dione as a yellow solid.

[0742] ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.37-7.25 ( m, 4H), 7.04-6.89 (m, 3H), 5.06 (dd, J=12.7, 5.4 Hz, 1H), 4.09 (t, J=7.0 Hz , 2H), 3.70 (d, J=12.2 Hz, 2H), 3.43-3.41 (m, 5H), 2.90-2.49 (m, 12H), 2.20- 2.10 (m, 2H), 2.00-1.90 (m, 1H), 1.80-1.73 (m, 3H), 1.21-1.17 (m, 2H); LC-MS (ES ⁺ ): m/z 622.35 [M+H ⁺ ], t _R =0.68 min (run 2.90 minutes).

[0743] Chemical formula: C ₃₅ H ₃₉ N ₇ O ₄ [621,31].

[0744] Total H from H-NMR data: 39.

[0745] Method for the synthesis of compound 77:

[0746] Step 1: [6-(4-(t-butoxycarbonyl)piperazin-1-yl)nicotinic acid].

[0747]

[0748] Mixture of tert-butyl 4-(5-((benzyloxy)carbonyl)pyridin-2-yl)piperazine-1-carboxylate (2.0 g, 5.03 mmol) and palladium charcoal (10%, 200 mg ) in ethanol (20 ml) was stirred at 30° C. overnight under a hydrogen atmosphere (balloon). Completion of the reaction was detected by TLC. The palladium charcoal was removed by filtration and washed with ethanol (20 ml×2). The combined filtrates were concentrated under reduced pressure to give 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (1.6g, crude) as a colorless oil which was used in the next step without purification.

[0749] Step 2: [tert-butyl-4-(5-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridine- 2-yl)piperazine-1-carboxylate].

[0750]

[0751] To a stirred solution of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (300mg, 0.97mmol), 4-((1R,3R)-3-amino-2,2 ,4,4-tetramethyl-cyclobutoxy)-2-chlorobenzonitrile hydrochloride (306 mg, 0.97 mmol) and N-ethyl-N-isopropylpropan-2-amine (309 mg, 2.4 mmol) in anhydrous N,N- dimethylformamide (8 ml) was added HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (684 mg, 1.8 mmol) at 0°C, obtained the mixture was allowed to warm to room temperature and stirred for 20 minutes. Completion of the reaction was detected by TLC. The mixture was partitioned between ethyl acetate (50 ml) and water (80 ml). The organic layer was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 10% methanol in dichloromethane) to give t-butyl -4-(5-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazin-1-carboxylate ( 400 mg, 72% yield as a white solid.

[0752] Step 3: [N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide]

[0753]

[0754] Tert-butyl-4-(5-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridin-2-yl mixture )piperazine-1-carboxylate (80 mg, 0.14 mmol) in a solution of hydrogen chloride in dioxane (4M, 2 ml) was stirred at room temperature for 2 hours. Completion of the reaction was detected by TLC. The volatiles were evaporated under reduced pressure. The residue was taken up in dichloromethane (20 mL) and washed with aqueous sodium bicarbonate (1N, 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 10% methanol in dichloromethane) to give [N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (32 mg, yield 50%) as a white solid.

[0755] LC-MS: (ES ⁺ ): m/z 468.6 [M+H] ⁺ . t _R =2.285 min.

[0756] ¹ H-NMR (400 MHz, CD ₃ OD): δ 1.07-1.38 (m, 12H), 3.12-3.40 (m, 4H), 3.51-3.86 (m, 1H), 3.94 (br, 3H), 4.17-4.30 (m, 2H), 6.99-7.15 (m, 2H), 7.74 (s, 1H) , 8.05(s, 1H), 8.48-8.68(m, 2H).

[0757] Chemical formula: C ₂₅ H ₃₀ ClN ₅ O ₂ ; Molecular weight: 467.99.

[0758] Total H from H-NMR data: 28.

[0759] Step 4: [2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperazin-1-yl)isoindoline-1,3-dione]

[0760]

[0761] A mixture of 2-(piperazin-1-yl)ethanol (235.6 mg, 1.8 mmol), 2-(2,6-diox-piperidin-3-yl)-5-fluoroisoindolin-1,3-dione ( 500 mg, 1.8 mmol) and N-ethyl-N-isopropylpropan-2-amine (468 mg, 3.6 mmol) in 1-methylpyrrolidin-2-one (5 ml) was stirred at 90°C for 12 hours . Completion of the reaction was detected by TLC. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (50 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2-3% methanol in dichloromethane) to give 2- (2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperazin-1-yl)isoindoline-1,3-dione (370 mg, 62%) as a yellow oil.

[0762] Step 2: [2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl-4-methylbenzenesulfonate]

[0763]

[0764] To a solution of 2-(2,6-diox-piperidin-3-yl)-5-(4-(2-hydroxyethyl)piperazin-1-yl)isoindoline-1,3-dione (370 mg, 0.96 mmol ), N,N-dimethylpyridine-4-amine (12 mg, 0.1 mmol) and triethylamine (291 mg, 2.87 mmol) in dichloromethane (10 ml) at 0°C was added 4-toluenesulfonyl chloride (201 mg, 1 .05 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Completion of the reaction was detected by TLC. The reaction mixture was diluted with dichloromethane (10 ml), washed with water (10 ml×2), then brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(4-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl-4-methylbenzenesulfonate (200 mg, 38%) as a yellow solid, which was used in the next step without additional cleaning.

[0765] LC-MS: (ES ⁺ ): m/z 541.20 [M+H] ⁺ . t _R =1.965 min.

[0766] Step 3: [N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)nicotinamide]

[0767]

[0768] A mixture of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl-4-methylbenzenesulfonate (139 mg, 0 .25 mmol), N-ethyl-N-isopropylpropan-2-amine (55.3 mg, 0.43 mmol) and N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (100 mg, 0.21 mmol) in anhydrous N,N-dimethylformamide (2 ml) was stirred at 50° C. for 16 hours. Completion of the reaction was detected by TLC. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 10% methanol in dichloromethane) to give N-((1R,3R )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)-piperazin-1-yl)nicotinamide (40 mg, 18%) as a yellow solid.

[0769] ¹ H-NMR (400 MHz, δ6-DMSO): δ 1.12 (s, 6H), 1.22 (s, 6H), 1.99-2.05 (m, 1H), 2, 54-2.73 (m, 12H), 2.84-2.92 (m, 1H), 3.41-3.70 (m, 10H), 4.06 (d, J=9.2 Hz, 1H), 4.30 (s, 1H), 5.05-5.10 (m, 1H), 6.89 (d, J=9.2 Hz, 1H), 6.99-7.02 (m , 1H), 7.21 (d, J=2.4 Hz, 1H), 7.25-7.30 (m, 1H), 7.37 (broad, 1H), 7.63 (d, J =9.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.96-7.99 (m , 1H), 8.63 (d, J=2.0 Hz, 1H), 11.08 (s, 1H).

[0770] Chemical formula: C ₄₄ H ₅₀ ClN ₉ O ₆ ; Molecular weight: 836.38.

[0771] Total H from H-NMR data: 50.

[0772] LC-MS: (ES ⁺ ): m/z 836.40 [M+H] ⁺ . t _R =2.408 min.

[0773] Method for the synthesis of compound 383:

[0774] Synthesis of tert-butyl 4-[(4-bromo-2-fluorophenyl)carbonyl]piperazine-1-carboxylate

[0775] In a 100 ml round bottom flask were placed 4-bromo-2-fluorobenzoic acid (5.0 g, 22.83 mmol, 1.00 equiv.), N,N-dimethylformamide (20.0 ml), HATU ( 10.5 g, 27.61 mmol, 1.20 equiv), DIEA (11.9 g, 92.08 mmol, 4.00 equiv), tert-butyl piperazine-1-carboxylate (4.3 g , 23.09 mmol, 1.00 equiv.). The resulting solution was stirred overnight at room temperature. Then, the reaction mixture was quenched by adding 20.0 ml of water. The resulting solution was extracted with ethyl acetate (40.0 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (40.0 ml). The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/4). The collected fractions were pooled and concentrated in vacuo. This gave 8.82 g (100%) of tert-butyl 4-[(4-bromo-2-fluorophenyl)carbonyl]piperazine-1-carboxylate as a yellow solid.

[0776] 2. Synthesis of 2-[[4-([4-[(tert-butoxy)carbonyl]piperazin-1-yl]carbonyl)-3-fluorophenyl]amino]-2-methylpropanoic acid

[0777] In a 100 ml round bottom flask was placed tert-butyl-4-[(4-bromo-2-fluorophenyl)carbonyl]piperazine-1-carboxylate (4.0 g, 10.33 mmol, 1.00 equiv.) , N,N-dimethylformamide (10.0 ml), potassium carbonate (3.58 g, 25.90 mmol, 2.50 equiv.), CuI (393.8 mg, 2.07 mmol, 0.20 equiv. ), 2-acetylcyclohexan-1-one (261.0 mg, 1.86 mmol, 0.20 equiv.), 2-amino-2-methylpropanoic acid (1.6 g, 15.52 mmol, 1.50 equiv. .). The resulting solution was stirred overnight at 105.0° C. in an oil bath. Then, the reaction mixture was quenched by adding 20.0 ml of water. The resulting solution was extracted with ethyl acetate (40.0 ml) and the organic layers combined. The pH value of the solution was adjusted to 8 by adding hydrogen chloride (1.0 mol/l). The resulting solution was extracted with ethyl acetate (40.0 ml), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 3.9 g (92%) of 2-[[4-([4-[(tert-butoxy)carbonyl]piperazin-1-yl]carbonyl)-3-fluorophenyl]amino]-2-methylpropanoic acid in form of a yellow solid.

[0778] LC-MS (ES ⁺ ): m/z 410.2 [MH ⁺ ], t _R =1.049 min (run 2.0 minutes).

[0779] Chemical formula: C ₂₀ H ₂₈ FN ₃ O ₅ [409,20].

[0780] 3. Synthesis of tert-butyl 4-([2-fluoro-4-[(1-methoxy-2-methyl-1-oxopropan-2-yl)amino]phenyl]carbonyl)piperazine-1-carboxylate

[0781] 2-[[4-([4-[(tert-Butoxy)-carbonyl]piperazin-1-yl]carbonyl)-3-fluorophenyl]amino]-2-methylpropanoic acid ( 2.7 g, 6.59 mmol, 1.00 equiv), N,N-dimethylformamide (20.0 ml), potassium carbonate (2.7 g, 19.54 mmol, 3.00 equiv), CH ₃ I (2.8 g, 19.73 mmol, 3.00 equiv.). The resulting solution was stirred overnight at room temperature. Then, the reaction mixture was quenched by adding 20.0 ml of water. The resulting solution was extracted with ethyl acetate (40.0 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (40.0 ml). The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/1). The collected fractions were pooled and concentrated in vacuo. This gave 2.2 g (79%) tert-butyl-4-([2-fluoro-4-[(1-methoxy-2-methyl-1-oxopropan-2-yl)amino]phenyl]carbonyl) piperazine-1-carboxylate as a yellow solid.

[0782] LC-MS (ES ⁺ ): m/z 424.05 [MH ⁺ ], t _R = 0.920 min (run 1.90 minutes).

[0783] Chemical formula: C ₂₁ H ₃₀ FN ₃ O ₅ [423,22].

[0784] 4. Synthesis of tert-butyl-4-[(4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl] -2-fluorophenyl)carbonyl]piperazine-1-carboxylate

[0785] In a 100 ml round bottom flask was placed tert-butyl-4-([2-fluoro-4-[(1-methoxy-2-methyl-1-oxopropan-2-yl)amino]phenyl]carbonyl)piperazine- 1-carboxylate (500.0 mg, 1.18 mmol, 1.00 equiv), N,N-dimethylformamide (5.0 mL), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (404.3 mg, 1 .77 mmol, 1.50 equiv.), t-BuOK (198.24 mg, 1.77 mmol, 1.50 equiv.). The resulting solution was stirred overnight at 100.0° C. in an oil bath. Then, the reaction mixture was quenched by adding 20.0 ml of water. The resulting solution was extracted with ethyl acetate (40.0 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (40.0 ml). The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/1). The collected fractions were pooled and concentrated in vacuo. The result was 500.0 mg (68%) tert-butyl-4-[(4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene -imidazolidin-1-yl]-2-fluorophenyl)carbonyl]piperazine-1-carboxylate as a yellow solid.

[0786] 5. Synthesis of 4-(3-[3-fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)- 2-(trifluoromethyl)benzonitrile hydrochloride

[0787] In a 50 ml round bottom flask was placed tert-butyl-4-[(4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidine- 1-yl]-2-fluorophenyl)carbonyl]piperazine-1-carboxylate (120.0 mg, 0.19 mmol, 1.00 equiv.), methanol (3.0 ml), hydrogen chloride (0 mg). The resulting solution was stirred for 2 hours at room temperature. The crude product (ml) was purified by preparative HPLC under the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): XBridge Prep C18 OBD column, 5 µm, 19×150 mm; mobile phase: water (0.1% FA) and acetonitrile (25.0% to 62.0% acetonitrile over 8 min); This gave 89.9 mg (83%) of 4-(3-[3-fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidine- 1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride as a yellow solid.

[0788] ¹ H-NMR (300 MHz, CD ₃ OD) δ 8.17-8.15 (d, J=5.4 Hz, 2H), 8.01-7.98 (d, J=8, 4 Hz, 1H), 7.64-7.58 (m, 1H), 7.41-7.37 (m, 2H), 5.49 (s, 1H), 3.83 (s, 2H), 3.46 (s, 2H), 3.01-2.92 (d, J=28.5 Hz, 4H), 1.60 (s, 6H), 1.38 (s, 1H).

[0789] LC-MS (ES ⁺ ): m/z 520.05 [MH ⁺ ], t _R = 1.315 min (3.0 minute run).

[0790] Chemical formula: C ₂₄ H ₂₁ F ₄ N ₅ O ₂ S [519,14].

[0791] Total H from H-NMR data: 22.

[0792] 6. Synthesis of 4-[3-(4-[[4-(4-[[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -isoindol-5-yl]oxy]butyl)piperazin-1-yl]carbonyl]-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

[0793] 4-(3-[3-Fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidine-1 -yl)-2-(trifluoromethyl)benzonitrile hydrochloride (150.0 mg, 0.27 mmol, 1.00 equiv.), CH ₃ CN (5.0 ml), potassium carbonate (149.1 mg, 1.08 mmol, 4.00 equiv.), NaI (40.5 mg, 1.00 equiv.), 5-(4-bromobutoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro -1H-isoindole-1,3-dione (220.0 mg, 0.54 mmol, 2.00 equiv.). The resulting solution was stirred overnight at 70.0° C. in an oil bath. The crude product (ml) was purified by preparative HPLC under the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): XBridge Prep C18 OBD column, 5 µm, 19×150 mm; mobile phase: water (0.1% FA) and acetonitrile (25.0% to 62.0% over 8 min); detector: UV 254 nm. Received ml of product. This gave 27.2 mg (12%) of 4-[3-(4-[[4-(4-[[2-(2,6-diox-piperidin-3-yl)-1,3-dioxo-2, 3-dihydro-1H-isoindol-5-yl]oxy]butyl)piperazin-1-nl]carbonyl]-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2 -(trifluoromethyl)benzonitrile as a white solid.

[0794] ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.04-7.95 (m, 3H), 7.84-7.77 (m, 2H), 7.60-7.55 (m , 1H), 7.34-7.33 (d, J=1.8 Hz, 1H), 7.21-7.09 (m, 3H), 4.98-4.93 (m, 1H), 4.14-4.10(m, 2H), 3.91(s, 2H), 3.49(s, 2H), 2.94-2.72(m, 3H), 2.67-2, 56 (m, 5H), 2.25-2.13 (m, 2H), 1.92-1.88 (m, 2H), 1.76 (s, 2H), 1.68 (s, 6H) .

[0795] LC-MS (ES ⁺ ): m/z 848.20 [MH ⁺ ], t _R = 3.304 min (5.0 minute run).

[0796] Chemical formula: C ₄₁ H ₃₇ F ₄ N ₇ O ₇ S [847,24].

[0797] Total H from H-NMR data: 37.

[0798] Scheme for the synthesis of compound 450:

[0799] Experimental:

[0800] Stage 1: [chloromethyl-2,5,8,11-tetraoxatridecan-13-ylcarbonate]

[0801] A mixture of 2,5,8,11-tetraoxatride ecan-13-ol (4 .16 g, 20 mmol) and triethylamine (2 g, 20 mmol) in dichloromethane (5 ml). The resulting reaction mixture was stirred at 0° C. for 0.5 hour. Completion of the reaction was detected by TLC. The reaction mixture was partitioned between tert-butyl methyl ether (100 ml) and water (60 ml). The organic layer was collected, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 30% ethyl acetate in hexane) to give chloromethyl-2, 5,8,11-tetraoxatrndecan-13-yl carbonate (2.2 g, 35.2% yield) as a colorless oil.

[0802] ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.38 (s, 3H), 3.54-3.56 (m, 2H), 3.64-3.66 (m, 10H) , 3.74-3.76 (m, 2H), 4.36-4.38 (m, 2H), 5.74 (s, 2H).

[0803] Chemical formula: C ₁₁ H ₂₁ ClO ₇ ; Molecular weight: 300.73;

[0804] Total H from H-NMR data: 21.

[0805] Step 2: [(3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl-2,5,8 ,11-Tetraoxatridecan-13-ylcarbonate]

[0806] A mixture of N-((1R,3R-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-piperidin-1-yl)benzamide (320 mg, 0.39 mmol), cesium carbonate (190 mg , 0.58 mmol) and chloromethyl-2,5,8,11-tetraoxatridecan-13-yl carbonate (140 mg, 0.47 mmol) in N,N-dimethylformamide (6 ml) were stirred at room temperature for 2 hours. Completion of the reaction was detected by TLC The mixture was partitioned between ethyl acetate (50 ml) and water (40 ml) The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which purified by silica gel flash chromatography (eluting with 2.5% methanol in dichloromethane) to give (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro- 4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxpiperi din-1-yl)methyl-2,5,8,11-tetraoxatridecan-13-yl carbonate (160 mg, 38% yield) as a yellow solid.

[0807] LC-MS: (ES ⁺ ): m/z 1084.7 [M+H] ⁺ , t _R =2.550 min.

[0808] ¹ H-NMR (400 MHz, DMSO-d6): δ 1.13 (s, 6H), 1.18-1.27 (m, 2H), 1.22 (s, 6H), 1, 77-1.83 (m, 3H), 2.04-2.12 (m, 1H), 2.21-2.22 (m, 2H), 2.31-2.45 (m, 1H), 2.58-2.67 (m, 3H), 2.73-2.85 (m, 3H), 3.01-3.12 (m, 1H), 3.23 (s, 3H), 3. 31-3.33 (m, 2H), 3.40-3.52 (m, 15H), 3.59-3.62 (m, 2H), 3.86 (d, J=12.4 Hz, 2H), 4.05 (d, J=9.2 Hz, 1H), 4.19-4.21 (m, 2H), 4.32 (s, 1H), 5.25-5.29 (m , 1H), 5.67-5.69 (m, 2H), 6.96 (d, J=8.8 Hz, 2H), 7.00 (dd, J=2.4, 8.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.50 (d, J=9.2 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.92 (d, J= 8.8 Hz, 1H).

[0809] Chemical formula: C ₅₆ H ₇₀ ClN ₇ O ₁₃ ; Molecular weight: 1084.65;

[0810] Total H from H-NMR data: 70.

[0811] Scheme for the synthesis of compound 448:

[0812] Experimental:

[0813] Stage 1: [benzyl-(2-aminoethyl)carbamate]

[0814] To a stirred solution of ethane-1,2-diamine (10 g, 166 mmol) in anhydrous dichloromethane (50 ml) at 0° C. was added dropwise benzyl chloroformate (2.83 g, 16.6 mmol) over 30 min. in dichloromethane (10 ml). The reaction mixture was stirred at 0°C for 3 hours. Completion of the reaction was detected by TLC. The solution was acidified by adding dilute hydrochloric acid (1N) to pH 4-5 and extracted with ethyl acetate (100 ml). The aqueous layer was collected, basified to pH 9-10 with saturated sodium hydroxide solution and extracted with ethyl acetate (50 ml x 2). The combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give benzyl-(2-aminoethyl)carbamate (1.31 g, 40% yield) as a colorless oil which was used in the next step without further purification.

[0815] LC-MS: (ES ⁺ ): m/z 195.2 [M+H] ⁺ , t _R = 1.198 min.

[0816] ¹ H-NMR (400 MHz, CDCl ₃ ): 2.787 (t, J=6.0 Hz, 2H), 3.14-3.28 (m, 2H), 5.07 (s, 2H) , 7.27-7.35 (m, 5H).

[0817] Chemical formula: C ₁₀ H ₁₄ N ₂ O ₂ ; Molecular weight: 194.23;

[0818] Total H from H-NMR data: 11.

[0819] Stage 2:

[0820] To a stirred solution of benzyl-(2-aminoethyl)carbamate (400 mg, 2.06 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (447 mg, 2.06 mmol) and N-ethyl-N-isopropylpropan-2-amine (797 mg, 6.18 mmol) in anhydrous N,N-dimethylformamide (4 ml) was added HATU (2-(7-aza-1H-benzotriazole -1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (1.56 g, 4.12 mmol) and stirred for 20 minutes. Completion of the reaction was detected by TLC. The mixture was partitioned between ethyl acetate (40 ml) and water (20 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 5% methanol in dichloromethane) to give compound 448-2 (670 mg, 83% yield) as a white solid.

[0821] ¹ H-NMR (400 MHz, CDCl ₃ ): 0.88 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 1.43 (s, 9H), 2.07-2.15 (m, 1H), 3.33-3.38 (m, 4H), 3.85 (t, J=1.2 Hz, 3H), 5, 08 (s, 2H), 7.30-7.35 (m, 5H).

[0822] Chemical formula: C ₂₀ H ₃₁ N ₃ O ₅ ; Molecular weight: 393.48;

[0823] Total H from H-NMR data: 28.

[0824] Stage 3: [(S)-tert-butyl-(1-((2-aminoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate]

[0825] Palladium charcoal (10%, 200 mg) was added to a stirred solution of compound 448-2 (670 mg, 1.70 mmol) in methanol (20 ml). The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature overnight. Completion of the reaction was detected by TLC. The palladium charcoal was removed by filtration and washed with methanol (5 ml x 2). The combined filtrates were concentrated under reduced pressure to give (S)-tert-butyl-(1-((2-aminoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (470 mg, crude) in as a colorless oil, which was used in the next step without purification.

[0826] ¹ H-NMR (400 MHz, CDCl ₃ ): 0.92 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 2.08-2.20 (m, 1H), 2.84 (t, J=5.6 Hz, 2H), 3.27-3.38 (m, 2H), 3, 85-3.89 (m, 1H).

[0827] Chemical formula: C ₁₂ H ₂₅ N ₃ O ₃ ; Molecular weight: 259.35;

[0828] Total H from H-NMR data: 21.

[0829] Step 4: (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl-(2-((S )-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)ethyl)carbamate

[0830] To a stirred solution of N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (300 mg, 0.36 mmol) and cesium carbonate ( 179 mg, 0.55 mmol) in dichloromethane (8 ml) and acetonitrile (1 ml) under nitrogen was added chloromethyl-(4-nitrophenyl)carbonate (102 mg, 0.44 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. Completion of the reaction was detected by TLC. (S)-tert-Butyl-(1-((2-aminoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (93mg, 0.36mmol) was added to the reaction mixture and stirring was continued the resulting mixture in a nitrogen atmosphere for 2 hours. Completion of the reaction was detected by TLC. The mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2.5% methanol in dichloromethane) to give the desired product (240 mg, 59% yield) as a yellow solid.

[0831] LC-MS: (ES ⁺ ): m/z 1135.7 [M+H] ⁺ , t _R = 2.578 min.

[0832] Step 5: [(3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl-(2-(( S)-2-amino-3-methylbutanamido)ethyl)carbamate]

[0833] Solution (3-(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl-(2-((S)- 2-((tert-butoxycarbonyl)amino)-3-methyl butanamido)ethyl)carbamate (230 mg, 0.20 mmol) in dichloromethane (6 ml) in 4M hydrogen chloride in dioxane (2 ml) was stirred at room temperature for 2 hours. Completion of the reaction was detected by TLC. The solution was basified to pH 9-10 with saturated sodium bicarbonate solution and extracted with dichloromethane (15 ml x 2). The organic layers were combined, washed with brine (30 ml), dried over sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 2.5% methanol in dichloromethane) to give (3 -(5-(4-((1-(4-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidine- 4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl-(2-((S)-2-amino-3- methylbutanamido)ethyl)carbamate (140 mg, 67% yield) as a yellow solid.

[0834] LC-MS: (ES ⁺ ): m/z 1035.6 [M+H] ⁺ , t _R = 2.215 min.

[0835] ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 0.76 (d, J=6.8 Hz, 3H), 0.84 (d, 7=6.8 Hz, 3H), 1.12 (s, 6H), 1.18 (s, 2H), 1.22 (s, 6H), 1.80-1.87 (m, 4H), 2.07-2.09 (m, 2H), 2.21 (d, J=6.0 Hz, 2H), 2.50 (s, 4H), 2.58-2.62 (m, 2H), 2.76-2.85 (m , 3H), 2.90 (d, J=5.2 Hz, 1H), 3.00-3.06 (m, 3H), 3.11 (t, J=6.0 Hz, 2H), 3 .45 (s, 4H), 3.86 (d, J=12.0 Hz, 2H), 4.05 (d, J=9.2 Hz, 1H), 4.32 (s, 1H), 5 .20-5.24 (m, 1H), 5.55-5.61 (m, 2H), 6.95 (d, J=9.2 Hz, 2H), 6.99-7.02 (m , 1H), 7.20 (d, J=2.4 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.32-7.35 (m, 2H), 7 .48 (d, J=9.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.8 Hz, 2H).

[0836] Chemical formula: C ₅₄ H ₆₇ ClN ₁₀ O ₉ ; Molecular weight: 1035.62;

[0837] Total H from H-NMR data: 67.

[0838] Synthesis of AVM Fragments

[0839] AVM-1: 2-chloro-4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile

[0840] Step 1: Synthesis of 2-chloro-4-isothiocyanatobenzonitrile (B).

[0841] To a stirred solution of 4-amino-2-chlorobenzonitrile (A, 1 g, 6.55 mmol) in dichloromethane (9 ml) was added sodium bicarbonate (2.21 g, 26.31 mmol) and water (9 ml) . The resulting mixture was cooled to 0°C, and thiophosgene (817 mg, 7.11 mmol) was added dropwise thereto over 30 minutes at 0°C. The resulting mixture was then warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (200 ml), washed with brine (50 ml×2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:30)) to give the desired product (yield: 71%) ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.69 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.28 (m, 1H);

[0842] Step 2: Synthesis of 2-chloro-4-[3-(4-hydroxyphenyl)-5-imino-4,4-dimethyl-2-sulfanylideneimidazolidin-1-yl]benzonitrile (D).

[0843] To a stirred solution of 2-chloro-4-isothiocyanatobenzonitrile (B, 399 mg, 2.05 mmol) in toluene (5 mL) was added 2-[(4-hydroxyphenyl)amino]-2-methylpropanenitrile (C, 300 mg , 1.70 mmol) and 4-dimethylaminopyridine (312 mg, 2.55 mmol). The resulting solution was then heated in an oil bath to 100° C. and stirred at the same temperature for 16 hours. Formation of the target product was detected by LC-MS. The reaction mixture was concentrated in vacuo to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:1)) to give the desired product (yield: 48%) as brown solid. LC-MS (ES ⁺ ): m/z 370.95 [MH ⁺ ], t _R =0.74 min (2.0 minute run);

[0844] Step 3: Synthesis of 2-chloro-4-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]benzonitrile (AVM-1).

[0845] To a stirred solution of 2-chloro-4-[3-(4-hydroxyphenyl)-5-imino-4,4-dimethyl-2-sulfanylidenimidazolidin-1-yl]benzonitrile (D, 300 mg, 0.81 mmol ) in methanol (6 ml) was added aqueous hydrogen chloride (2N, 3.0 ml). The resulting solution was then heated in an oil bath to 100°C and stirred at the same temperature for 2 hours. The reaction mixture was diluted with water (30 ml), extracted with ethyl acetate (60 ml × 3), washed with water (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (yield: 93%) as a yellow solid, which was used in the next step without any further purification. LC-MS (ES ⁺ ): m/z 372.00 [MH ⁺ ], t _R =0.97 min (run 2.0 minutes).

[0846] Unless otherwise noted, subsequent intermediates and their analogs (e.g., but not limited to analogs with substituents such as halogens) were synthesized according to procedures similar to those described above for the synthesis of AVM-1 using the appropriate starting materials and reagents.

[0847] AVM-2: 2-fluoro-4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile:

[0848] AVM-3: 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile:

[0849] AVM-4: 5-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile:

мм

mm

[0850] AVM-5: 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-methoxybenzonitrile:

[0851] AVM-6: 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-methylbenzonitrile:

[0852] AVM-7: 3-chloro-5-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile:

[0853] AVM-8: 4-(1-(4-hydroxyphenyl)-4-oxo-2-thioxo-8-oxa-1,3-diazaspiro[4.5]decan-3-yl)-2-(trifluoromethyl) benzonitrile:

[0854] ABM-9: 4-(1-(4-hydroxyphenyl)-8-methyl-4-oxo-2-thioxo-1,3,8-triazaspiro[4.5]decan-3-yl)-2-( trifluoromethyl)benzonitrile:

[0855] AVM-10: 4-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile

[0856] AVM-11: 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile:

[0857] AVM-12: 4-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)butanoic acid :

[0858] AVM-13: 2-chloro-4-(3-(4'-hydroxybiphenyl-4-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile:

[0859] AVM-14: 4-(3-(4'-Hydroxybiphenyl-4-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile:

[0860] AVM-15: 5-(3-(4'-hydroxybiphenyl-4-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)pico linonitrile:

[0861] AVM-16: 4-(3-(3-fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile:

[0862]

[0863] AVM-17: 1-(4-hydroxyphenyl)-5,5-dimethyl-3-(4-nitro-3-(trifluoromethyl)phenyl)-2-thioxoimidazolidin-4-one:

[0864]

[0865] AVM-18: 4-(3-(3,5-difluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile:

[0866]

[0867] AVM-19: 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile:

[0868]

[0869] AVM-20: 4-(3-(6-hydroxypyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile:

[0870]

[0871] AVM-21: 2-chloro-4-(3-(3-fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile:

[0872]

[0873] AVM-22: 4-(3-(3-fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-methoxybenzonitrile:

[0874]

[0875] AVM-23: 5-(3-(3-fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile:

[0876]

[0877] AVM-24: 5-(3-(2-fluoro-4'-hydroxybiphenyl-4-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl )picolinonitrile:

[0878]

[0879] AVM-25: 4-(4,4-dimethyl-5-oxo-3-(4-(piperidin-4-yl)phenyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile :

[0880]

[0881] AVM-26: trans-2-chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]-benzonitrile.

[0882]

[0883] AVM-27: cis-2-chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile

[0884]

[0885] AVM-28: trans-6-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridazine-3-carboxamide

[0886]

[0887] AVM-29: trans-tert-butyl-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate.

[0888]

[0889] AVM-30: trans-4-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0890]

[0891] Step 1: Synthesis of tert-butyl-(4-((trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)carbamate

[0892] To a suspension of 4-((tert-butoxycarbonyl)amino)benzoic acid (1.50 g, 6.34 mmol) in methylene chloride (40 ml) was added N,N-diisopropylethylamine (3.30 ml, 19.0 mmol ) followed by 4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride (2.0 g, 6.34 mmol). The mixture was stirred for several minutes and then HATU (2.41 g, 6.34 mmol) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. The mixture was diluted with methylene chloride (40 ml), washed with 1N aqueous HCl (2×), saturated aqueous sodium bicarbonate (2×), brine, and dried over anhydrous Na ₂ SO ₄ . The crude product was used in the next step;

[0893] Step 2: Synthesis of trans-4-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0894] To a premixed solution of tert-butyl-(4-((trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)carbamate (2.00 g , 4.01 mmol) in MeOH (2 ml) was added 4M HCl in dioxane (1.38 ml, 40.0 mmol) and left to stir at room temperature for 1 hour to complete the reaction. The reaction mixture was concentrated in vacuo to a solid which was dissolved in 5% MeOH in DCM. The organic layer was washed with sodium bicarbonate (2x), filtered through a Biotage Universal Phase Separator and then concentrated in vacuo to a solid. The crude product was recrystallized from EtOH/heptanes to give the title product as a white solid, 1.2 g, 75% yield. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ 7.72 (d, J=8.80 Hz, 1H), 7.61 (d, J=8.61 Hz, 2H), 7.13 ( d, J=2.35 Hz, 1H), 6.98 (dd, J=2.45, 8.71 Hz, 1H), 6.69 (d, J=8.61 Hz, 2H), 4, 28 (s, 1H), 4.12 (s, 1H), 1.27 (s, 6H), 1.22 (s, 6H). LC-MS (ES+): m/z 398.16/400.15 [MH ⁺ ].

[0895] Unless otherwise noted, subsequent intermediates and their analogs (for example, but not limited to analogs with substituents such as halogens) were synthesized according to procedures similar to those described above for the synthesis of AVM-30 using the appropriate starting materials and reagents.

[0896] AVM-31: trans-5-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrazine-2-carboxamide

[0897]

[0898] AVM-32: trans-2-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide

[0899]

[0900] AVM-33: 4-methoxy-N-[(1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0901]

[0902] AVM-34: trans-1-(2-hydroxyethyl)-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-1H-pyrazole-4-carboxamide

[0903]

[0904] AVM-35: trans-6-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide

[0905]

[0906] AVM-36: trans-4-[(5-hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0907]

[0908] AVM-37: trans-tert-butyl-2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl )aminopentyl}oxy)acetate

[0909]

[0910] ABM-38: N-((1R,3R)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-methylbenzamide

[0911] AVM-39: N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-methylpyridazine-3-carboxamide

[0912] AVM-40: N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-methylpyridazine-3-carboxamide

[0913] CLM Fragment Synthesis

[0914] Some non-limiting examples of methods for producing CLM fragments described herein are summarized and presented below.

where R contains 1-4 independently selected functional groups or atoms, one of which is optionally modified for covalent attachment to the AVM, chemical linker group (L), ULM, CLM (or CLM'), or combinations thereof.

[0915] As shown in Sample Reaction 1, dimethyl phthalate derivatives can be condensed with glutamine (racemate or enantiomer) or glutamine analogs, followed by reaction with agents such as carbonyldiimidazole to form 2-(2,6-dioxpiperidine-3-) derivatives. yl)-2,3-dihydro-1H-isoindole-1,3-dione.

[0916] Alternatively, as shown in Type Reaction 2, the phthalimide intermediate resulting from the condensation described above can be separately prepared and/or isolated, followed by reaction with dehydrating agents such as trifluoroacetamide, POCl ₃ or acetic anhydride, with the formation of target derivatives of 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione. A phthalimide intermediate of the same type may also react with Lawesson's reagent prior to the dehydration step to give thio analogs such as those shown in Sample Reactions 8 and 9.

[0917] C protected examples of 2-(2,6-diox-piperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives such as the N ¹ -BOC examples shown in the exemplary example 3 can be deprotected by using, in this case, reagents such as TFA or silica to give the desired derivatives 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole- 1,3-diones.

[0918] Phthalic anhydrides, such as those shown in Example 4, can be ring-opened by reaction with amines such as 3-aminopiperidine-2,6-dione to form carboxylate intermediates, which upon treatment with carbonyldiimidazole and benzotriazole can form target derivatives of 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione. Alternatively, the two components can be combined in the presence of acetic acid to give the desired product as shown in Sample Reaction 13.

[0919] In a similar reaction, anhydride derivatives similar to those shown in Sample Reaction 5 can react with amines (ammonia, in the example shown) and then with carbonyldiimidazole to form the desired derivatives of 2-(2,6-dioxpiperidine- 3-yl)-2,3-dihydro-1H-isoindole-1,3-dione.

[0920] When phthaloyl chloride is available, direct condensation with glutamine (racemate or enantiomer) or glutamine analogs is possible, followed by interaction with agents such as carbonyldiimidazole to form 2-(2,6-dioxopiperidin-3-yl)-2 derivatives ,3-dihydro-1H-isoindole-1,3-dione as shown in Sample Reaction 6.

[0921] o-Bromobenzamides can be reacted with a source of CO, such as the acid chloride provided in typical reaction 7, in the presence of a palladium catalyst and an associated phosphine ligand to give the desired 2-(2,6-diox-piperidin-3-yl) derivatives -2,3-dihydro-1H-isoindole-1,3-dione. Alternatively, CO gas itself can be used in combination with rhodium(II) catalysts and copper carbonate to give the desired products.

[0922] Derivatives of 2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2,3-dihydro-1H-isoindole-1,3-dione and 5-(1,3 -dioxo-2,3-dihydro-1H-isoindol-2-yl)-1,3-diazinan-2,4,6-trione can be prepared by methods similar to some of the methods described above for derivatives of 2-(2, 6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindol-1,3-dione. In typical reactions 20 and 21, phthalic anhydride can react with derivatives of 5-amino-1,2,3,4-tetrahydropyrimidine-2,4-dione or 5-amino-1,3-diazinan-2,4,6 -trione, respectively, in the presence of acetic acid with the formation of target products.

[0923] Alternatively, 5-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1,3-diazinan-2,4,6-trione derivatives can be prepared by reactions of 5-amino-1,3-diazinan-2,4,6-trione derivatives with phthalic acid mono-tert-butyl esters in the presence of Hunig's base, carbodiimide, and benzotriazole as shown in Sample Reaction 12. Similar conditions can be used for the preparation of 2-(2,6-diox-piperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives from phthalic acid mono-tert-butyl esters as shown in Sample Reaction 14.

[0924] Compounds such as 3-(2,6-diox-piperidin-3-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione can be prepared from anthranilic acid derivatives by reacting 3-aminopiperidine -2,6-diones with carbodiimide as shown in Sample Reaction 16. The benzamide intermediate can be isolated (or prepared separately) and reacted with carbodiimide to give 3-(2,6-dioxopiperidin-3-yl) derivatives -1,2,3,4-tetrahydroquinazoline-2,4-dione as shown in Type Reaction 15.

[0925] Analogs of 3-(2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-1,3-benzoxazin-2,4-dione can be prepared by activating salicylic acids with chloroformates followed by condensation with 3 -aminopiperidine-2,6-diones as shown in Type Reaction 17.

[0926] The 3,3-dichloro-2,1λ ⁶ -benzoxathiol-1,1-diones shown in Sample Reaction 18 can be prepared by reacting 2-sulfobenzoic acids with POCl ₃ and PCl ₅ . These compounds can react with amino derivatives to obtain, for example, the desired derivatives of 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1λ ⁶ ,2-benzothiazole-1,1,3-trione.

[0927] As shown in Sample Reaction 19, saccharin anions can be alkylated with electrophiles such as 3-bromo-3-methylpiperidin-2-one to give the desired 2-(3-methyl-2-oxo-piperidin-3-yl )-2,3-dihydro-1λ ⁶ ,2-benzothiazole-1,1,3-trione.

[0928] Analogues of 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1λ ⁶ ,2-benzothiazole-1,1,3-trione can also be prepared by reacting methyl-2-[ (2,6-dioxopiperidin-3-yl)sulfamoyl]benzoate with strong bases such as sodium hydride (see Type Reaction 20).

[0929] By deprotonating 2-methyl-2,3-dihydro-1H-inden-1,3-dione derivatives with sodium ethoxide, followed by reaction with electrophiles such as 3-bromopiperidine-2,6-dione, 3-( 2-methyl-1,3-dioxo-1H-inden-2-yl)piperidin-2,6-dione as shown in Sample Reaction 21.

[0930] Preparation of N ¹ -substituted compounds such as 2-[1-(benzyloxy)-2,6-dioxopiperidin-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione (typical reaction 22) can be achieved by reacting 2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)glutaric acid with N-benzylhydroxylamine and trifluoroacetic anhydride.

[0931] In turn, molecules such as 2-[1-(benzyloxy)-2,6-dioxopiperidin-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione (typical reaction 23 ) can undergo benzyl removal under hydrogenation reaction conditions to give N ¹ -hydroxy analogs such as 2-(1-hydroxy-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindol-1, 3-dione.

[0932] In type reaction 24, methyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (or analogs) reacts with 3-aminopiperidin-2-one to give 2-(2 -oxopiperidin-3-yl)-2,3-dihydro-1H-isoindol-1,3-diones.

[0933] The same amine can also be reacted with phthalic anhydride derivatives in the presence of a Lewis acid such as zinc bromide and trimethylsilyl ether to give the same type of product as shown in Sample Reaction 25. The intermediates of this reaction, when isolated or obtained otherwise (type reaction 26) can be subjected to complete cyclization through the use of a dehydrating agent.

[0934] Isomeric derivatives such as 2-(6-oxo-piperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, shown in Sample Reaction 27, can be obtained from the reaction of phthalic acid and 5-aminopiperidin-2-one.

[0935] Preparation of N ¹ -substituted compounds such as 2-(1-benzyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,4-dione (type reactions 28 and 29) can be achieved in many ways. For example, anhydride (2-(2,6-dioxooxan-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione) can be condensed with 3-aminopiperidin-2,6-dione in the presence of DMAP and carbonyldiimidazole (type reaction 28), or derivatives of 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione can be alkylated with electrophiles such as benzyl bromide in the presence of base as shown in the standard reaction 29.

[0936] In some cases, protecting group and/or functional group interconversion (FGI) strategies may be required to facilitate the preparation of target substances. Such chemical processes are well known to the organic chemist and many of them can be found in the literature such as "Greene's Protective Groups in Organic Synthesis" by Peter G.M. Wuts and Theodora W. Greene (Wiley), and Organic Synthesis: The Disconnection Approach by Stuart Warren and Paul Wyatt (Wiley).

[0937] Synthesis of linker L

[0938] L-1: 2-(3-(5-(tosyloxy)pentyloxy)propoxy)acetic acid

[0939]

[0940] Step 1: Synthesis of ({[5-(prop-2-en-1-yloxy)pentyl]oxy}methyl)benzene

[0941] Sodium hydride was added in portions to a stirred solution of 5-(benzyloxy)pentan-1-ol (W, 4.0 g, 20.59 mmol) in N,N-dimethylformamide (50 ml) at 0° C. under nitrogen. (1.24 g, 51.67 mmol). The resulting mixture was then stirred at room temperature for 1 hour. To this mixture was added 3-bromoprop-1-ene (3.71 g, 30.67 mmol) and the reaction mixture was stirred overnight at 60° C. in an oil bath. The formation of the target product was detected by LC-MS. The reaction mixture was cooled to 0°C, and then extinguished by adding water (100 ml), the resulting mixture was extracted with ethyl acetate (200 ml×2). The organic layers were combined, washed with saturated aqueous sodium chloride (60 ml), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:40)) to give 4.57 g X. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7, 36 (s, 4H), 7.32 (m, 1H), 5.98 (m, 1H), 5.33 (m, 1H), 5.21 (m, 1H), 4.53 (s, 2H ), 3.99 (m, 2H), 3.53 (m, 4H), 1.72 (m, 4H), 1.52 (m, 2H). LC-MS (ES ⁺ ): m/z 235.00 [MH ⁺ ], t _R =1.18 min (run 2.0 minutes).

[0942] Step 2: Synthesis of 3-{[5-(benzyloxy)pentyl]oxy}propan-1-ol (Y)

[0943] A solution of ({[5-(prop-2-en-1-yloxy )pentyl]-oxy}methyl)benzene (X, 3.0 g, 12.80 mmol) in anhydrous tetrahydrofuran (20 mL). The resulting solution was stirred overnight at room temperature. The formation of the target product was detected by LC-MS. Methanol (15 ml, with 30% sodium hydroxide and 30% H ₂ O ₂ ) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 2 hours. Then, this mixture was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride (100 ml), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:1)) to give 1.96 g of Y as a light yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.34 (m, 5H), 4.49 (s, 2H), 3.75 (m, 2H), 3.59 (m, 2H), 3 .49 (m, 4H), 2.65 (br s, 1H), 1.84 (m, 2H), 1.68 (m, 4H), 1.50 (m, 2H). LC-MS (ES ⁺ ): m/z 253.17 [MH ⁺ ], t _R =1.44 min (run 2.6 minutes).

[0944] Step 3: Synthesis of tert-butyl 2-(3-{[5-(benzyloxy)pentyl]oxy}propoxy)acetate (Z)

[0945] A solution of NaOH in water (37 %, 30 ml) followed by tert-butyl-2-bromoacetate (11.39 g, 58.39 mmol) and TBACl (4.17 g). The resulting mixture was stirred at room temperature overnight. The formation of the target product was detected by LC-MS. The reaction mixture was then extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride (60 ml), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2) to give 3.2 g of Z as a yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.34 (s, 4H), 7.29 (m, 1H), 4.50 (s, 4H), 4.3 (m, 2H), 3.51 (m, 4H), 3.42 ( m, 2H), 1.98 (m, 2H), 1.67 (m, 4H), 1.48 (s, 9H), 1.46 (m, 2H) LC-MS (ES ⁺ ): m /z 367.25 [MN ⁺ ], t _R =l.28 min (run 2.0 minutes).

[0946] Step 4: Synthesis of tert-butyl 2-[3-[(5-hydroxypentyl)oxy]propoxy]acetate (AA)

[0947] To a stirred solution of tert-butyl 2-(3-{[5-(benzyloxy)pentyl]oxy}-propoxy)acetate (Z, 3.2 g, 8.73 mmol) in methanol (30 mL) in AcOH (1.5 ml), palladium charcoal (1.5 g) were added under nitrogen atmosphere. Hydrogen was introduced into the reaction mixture from a balloon, and the reaction mixture was stirred at room temperature for 3 hours. The solid was removed by filtration, the solution was concentrated in vacuo to give 2.3 g of AA as a light yellow oil, which was used in the next step without any further purification. LC-MS (ES ⁺ ): m/z 277.10 [MN ⁺ ], t _R =0.S6 min (2.0 minute run).

[0948] Step 5: Synthesis of tert-butyl 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetate (AB)

[0949] To a stirred solution of tert-butyl 2-[3-[(5-hydroxypentyl)oxy]propoxy]-acetate (AA, 2.3 g, 8.32 mmol) in dichloromethane (30 ml) at room temperature was added 4-methylbenzene-1-sulfonyl chloride (3.17 g, 16.63 mmol), triethylamine (2.52 g, 24.90 mmol) and 4-dimethylaminopyridine (203 mg, 1.66 mmol). The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2)) to give 2.6 g of AB as a yellow oil . ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.77 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 4.51 (s , 2H), 4.31 (m, 2H), 4.13 (m, 2H), 3.52 (m, 4H), 2.05 (s, 3H), 1.97 (m, 2H), 1 .69 (m, 4H), 1.48 (s, 9H), 1.46 (m, 2H). LC-MS (ES ⁺ ): m/z 431.20 [MH ⁺ ], t _R =1.21 min (2.0 minute run).

[0950] Step 1: Synthesis of 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetic acid (L-1)

[0951] To a stirred solution of tert-butyl 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]-pentyl}oxy)propoxy]acetate (AB, 1.3 g, 3.02 mmol) in dichloromethane (10 ml) trifluoroacetic acid (10 ml) was added at room temperature. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated in vacuo to give 1.5 g of L-1 (crude) which was used in the next step without any further purification. LC-MS (ES ⁺ ): m/z 375.34 [MH ⁺ ], (t _R =1.39 min (run 2.6 minutes).

[0952]

[0953] The following linkers (L) were prepared in a manner similar to that described for the preparation of L-1.

[0954]

[0955] L-2: 2-(3-(3,3-dimethyl-5-(tosyloxy)pentyloxy)propoxy)acetic acid

[0956]

[0957]

[0958] L-3: 2-(3-(3-hydroxy-5-(tosyloxy)pentyloxy)propoxy)acetic acid

[0959]

[0960]

[0961] L-4: 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetic acid

[0962]

[0963] To a stirred solution of ethyl 2-[2-(2-{2-[(4-methylbenzenesulfonyl)oxy]-ethoxy}ethoxy)ethoxy]acetate (AS, 2 g, 5.12 mmol, 1.00 eq. .) in methanol (20 ml) was added a solution of NaOH (500 mg, 12.50 mmol) in water (4 ml) and the resulting mixture was stirred at room temperature for 2 hours. Then, aqueous hydrogen chloride (1M) was added to the reaction mixture to adjust to pH~5. The precipitated solids were collected by filtration to obtain L-4 (yield: 98%). Mass spectrometry (ES+): m/z 363, [MH ⁺ ].

[0964]

[0965] The following linkers (L) were prepared in a manner similar to that described for the preparation of L-4. [0966]

[0967] L-5: 2-(2-((2R,3R)-3-(2-(tosyloxy)ethoxy)butan-2-yloxy)ethoxy)acetic acid

[0968]

[0969]

[0970] L-6: 2-(2-((2S,3S)-3-(2-(tosyloxy)ethoxy)butan-2-yloxy)ethoxy)acetic acid

[0971]

[0972]

[0973] L-7: 2-(4-(4-(tosyloxy)butoxy)butoxy)acetic acid

[0974]

[0975] Step 1: Synthesis of 4-{4-[(4-methylbenzenesulfonyl)oxy]6utoxy}butan-1-ol (AE)

[0976] Ag ₂ O (4.25 g, 18.49 mmol) was added to a stirred solution of 4-(4-hydroxybutoxy)butan-1-ol (AD, 2 g, 12.33 mmol) in dichloromethane (20 ml) , KI (409 mg, 2.46 mmol) and TsCl (2.345 g, 12.30 mmol). The resulting mixture was stirred at room temperature for 12 hours. The formed inorganic salt was removed by filtration, and the organic solution was concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (o6./o6.=1:1)) to give AE (yield: 28%) as a colorless oil.

[0977] Step 2: Synthesis of ethyl 2-(4-{4-([(4-methylbenzenesulfonyl)oxy]butoxy}butoxy)-acetate (AF)

[0978] BF ₃ ⋅ Et ₂ O (49.4 mg, 0.35 mmol) followed by ethyl 2-diaz o acetate (794 mg, 6.96 mmol) at 0°C. The resulting mixture was stirred overnight at room temperature. Then, the reaction mixture was quenched by adding water (2.0 ml). The resulting mixture was extracted with dichloromethane (50 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:4)) to give AF (yield: 93%) as a light yellow oil. Mass Spectrometry (ES ⁺ ): m/z 403.10 [MH ⁺ ].

[0979] Step 3 Synthesis of 2-(4-{4-[(4-methylbenzenesulfonyl)oxy]butoxy}butoxy)-acetic acid (L-7)

[0980] To a stirred solution of ethyl 2-(4-{4-[(4-methylbenzenesulfonyl)oxy]butoxy}-butoxy)acetate a (AF, 1.3 g, 3.23 mmol) in methanol (25 mL) a solution of NaOH (388 mg, 9.70 mmol) in water (6 ml) was added at room temperature. The resulting solution was stirred at room temperature for 4 hours. Most of the organic solvent was removed under reduced pressure, and aqueous hydrogen chloride (1.0 M) was added to the resulting mixture to adjust to pH~5. Then, the solution was extracted with ethyl acetate (250 ml×3), the organic layers were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 1-7 (yield: 93%) as a light yellow oil. Mass spectrometry (ES ⁺ ): m/z 375.05 [MH ⁺ ].

[0981]

[0982] L-8: tert-Butyl-2-(3-(4-(tosyloxy)butoxy)propoxy)acetate

[0983]

[0984] Step 1. Synthesis of 3-[4-(benzyloxy)butoxy]propan-1-ol (AN)

[0985] Sodium hydride (840 mg, 35.00 mmol), the resulting mixture was stirred at room temperature for 30 minutes. Then, 4-(benzyloxy)butyl-4-methylbenzene-1-sulfonate (AG, 6.68 g, 19.97 mmol) was added to the mixture, and the reaction mixture was stirred overnight at 50°C. The formation of the desired product was detected by TLC, at which point the reaction mixture was allowed to cool to room temperature. Water (10 ml) was slowly added to quench the reaction mixture; then, the resulting mixture was extracted with ethyl acetate (80 ml×2). The organic layers were combined, washed with saturated aqueous sodium chloride (20 ml), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v ./v = 1:2)) to give AN (yield: 67%) as a light yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.38-7.29 (m, 5H), 4.52 (m, 2H), 3.80 (m, 2H), 3.61 (m, 2H ), 3.49-3.46 (m, 4H), 2.04 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H); Mass spectrometry (ES ⁺ ): m/z 239.05 [MH ⁺ ].

[0986] Step 2. Synthesis of tert-butyl 2-[3-[4-(benzyloxy)butoxy]propoxy]acetate (AI).

[0987] tert-Butyl-2-bromoacetate (7 .76 g, 39.78 mmol), TBAC (2.78 g, 10.00 mmol) followed by aqueous sodium hydroxide (37%, 15 ml). The resulting mixture was stirred overnight at room temperature. The reaction mixture was then extracted with dichloromethane (100 ml×3), the organic layers were combined, washed with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:5)) to give AI (57% yield) as a yellow oil. Mass Spectrometry (ES ⁺ ): m/z 353.10 [MH ⁺ ].

[0988] Step 3. Synthesis of tert-butyl 2-[3-(4-hydroxybutoxy)propoxy]acetate (AJ)

[0989] To a stirred mixture of tert-butyl 2-[3-[4-(benzyloxy)butoxy]propoxy]acetate (AI, 1 g, 2.84 mmol), palladium charcoal (10%, 200 mg) in methanol ( 20 ml) acetic acid (0.05 ml) was added under a nitrogen atmosphere. Then, hydrogen was introduced into the reaction mixture from a balloon, and then the reaction mixture was stirred overnight at room temperature. Insoluble solids were removed by filtration, and the dissolved phase was concentrated under reduced pressure to obtain the desired product (yield: 94%) as a yellow oil. Mass Spectrometry (ES ⁺ ): m/z 263.05 [MH ⁺ ].

[0990] Step 4. Synthesis of tert-butyl 2-(3-{4-[(4-methylbenzenesulfonyl)oxy]butoxy}-propoxy)acetate (L-8)

[0991] To a stirred solution of tert-butyl 2-[3-(4-hydroxybutoxy)propoxy]acetate (AJ, 700 mg, 2.67 mmol) in dichloromethane (10 mL) was added 4-methylbenzene-1-sulfonyl chloride ( 558.4 mg, 2.93 mmol), TEA (539.5 mg, 5.33 mmol) and 4-dimethylamino pyridine (32.6 mg, 0.27 mmol). The resulting mixture was stirred overnight at room temperature. Most of the solvent was removed under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2)) to give the title product (yield: 52 %) as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.79 (d, 7=8.4 Hz, 2H), 7.35 (d, 7=8.0 Hz, 2H), 4.05 (m, 2H), 3.95 (s, 2H), 3.59 (m, 2H), 3.48 (m, 2H), 3.38 (m, 2H), 2.46 (s, 3H), 1, 82 (m, 2H), 1.70 (m, 2H), 1.57 (m, 2H), 1.50 (s, 9H); Mass spectrometry (ES ⁺ ): m/z 417.05 [MH ⁺ ].

[0992]

[0993] L-9: tert-Butyl-2-(4-(3-(tosyloxy)propoxy)butoxy)acetate

[0994]

[0995] L-9 was obtained in a manner similar to that used to obtain L-8, except that AK was used instead of AG. Mass Spectrometry (ES ⁺ ): m/z 439.15 [MNa ⁺ ].

[0996]

[0997] L-10: tert-Butyl-2-(6-(tosyloxy)hexa-2,4-diynyloxy)acetate

[0998]

[0999] Step 1: Synthesis of tert-butyl-2-[(6-hydroxyhexa-2,4-diin-1-yl)oxy]acetate (AR)

[1000] Sodium hydride (32 mg , 1.33 mmol). The resulting mixture was then warmed to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C, and then tert-butyl-2-bromoacetate (176 mg, 0.90 mmol) was added and the resulting mixture was stirred at 0°C for 2 hours. Formation of the desired product was detected by LC-MS. Then, the reaction mixture was quenched at 0°C by the addition of water (10 ml, added slowly) and was extracted with ethyl acetate (20×2 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2)) with obtaining AP (yield: 49%) as a yellow oil.

[1001] Step 2: Synthesis of tert-butyl 2-({6-[(4-methylbenzenesulfonyl)oxy]hexa-2,4-diin-1-yl}oxy)acetate (L-10)

[1002] To a stirred solution of tert-butyl 2-[(6-hydroxyhexa-2,4-diin-1-yl)oxy]acetate (AP, 50 mg, 0.22 mmol) in ether (2 ml) at 0 °C was added 4-toluenesulfonyl chloride (51 mg, 0.27 mmol) followed by several portions of potassium hydroxide (125 mg, 2.23 mmol) at 0°C. The resulting mixture was stirred at 0°C for 4 hours. The formation of the target product was detected by LC-MS. Water (10 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2)) with obtaining L-10 (yield: 71%) as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.83 (d, J=6.0 Hz, 2H), 7.39 (d, J=6.0 Hz, 2H), 4.79 (s , 2H), 4.37 (s, 2H), 4.05 (s, 2H), 2.48 (s, 3H), 1.51 (s, 9H); LC-MS (ES ⁺ ): m/z 401.05 [MNa ⁺ ], t _R =1.71 min (run 2.6 minutes).

[1003]

[1004] The following linkers (L) were prepared in a manner similar to that described for the preparation of L-10.

[1005]

[1006] L-11: tert-butyl 3-(6-(tosyloxy)hexa-2,4-diynyloxy)propanoate

[1007]

[1008]

[1009] L-12: tert-Butyl 4-(6-(tosyloxy)hexa-2,4-diynyloxy)butanoate

[1010]

[1011]

[1012] L-13: ethyl 2-(2-(2-aminoethoxy)ethoxy)acetate hydrochloride

[1013]

[1014] Step 1: Synthesis of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]car6amate (AR)

[1015] Aqueous sodium bicarbonate solution (20% ( wt./mass), 40 ml) and (Boc) ₂ O (11.4 g, 52.23 mmol, added in several portions). The resulting mixture was then slowly warmed to room temperature and stirred at room temperature for 5 hours. Most of the solvent was removed under reduced pressure, the resulting residue was diluted with water (300 ml) and was extracted with ethyl acetate (100 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (20 ml×2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain AR (yield: 98%) as a colorless oil.

[1016] Step 2: Synthesis of ethyl 2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]-acetate (AS)

[1017] 1-diazo- 3-methoxypropan-2-one (3.34 g, 29.27 mmol) and BF ₃ -Et ₂ O (0.2 ml). The resulting solution was stirred at room temperature for 2 hours. Water (20 ml) was added to the reaction mixture, the aqueous layer was separated, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue. The residue was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2)) to give AS (yield: 18%) as a yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.254.22 (q, J=7.2 Hz, 2H), 4.14 (s, 2H), 3.74 (broad, 2H), 3, 72 (broad, 1H), 3.67-3.32 (m, 4H), 1.414 (s, 9H), 1.31 (t, J=7.2 Hz, 3H).

[1018] Step 3: Synthesis of ethyl 2-[2-(2-aminoethoxy)ethoxy]acetate hydrochloride (L-13)

[1019] To a stirred solution of etcl-2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)-ethoxy]acetate (AS, 500 mg, 1.72 mmol) in 1,4-dioxane (10 ml) at room temperature for 2 hours by bubbling introduced hydrogen chloride (gas.). Then, the solvent was removed under vacuum to obtain L-13 (yield: 99%). LC-MS (ES ⁺ ): m/z 192.00 [MH ⁺ ], t _R =0.41 min (run 2.0 minutes).

[1020] L-14: ethyl 2-(5-aminopentyloxy)acetate

[1021]

[1022] Stage 1: Synthesis of tert-butyl-5-hydroxypentylcarbamate (AU)

[1023] To a stirred solution of 5-aminopentan-1-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 ml) at 0°C was added di-tert-butyl dicarbonate (6.56 g, 30. 06 mmol). The resulting mixture was then stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2)) to give AU (yield: 98%) as a colorless oils. LC-MS (ES ⁺ ): m/z 204.00 [MH ⁺ ], t _R =1.29 min (run 2.6 minutes).

[1024] Step 2: Synthesis of ethyl 2-[(5-{[(tert-butoxy)carbonyl]amino}pentyl)oxy]acetate (AV)

[1025] To a stirred solution of tert-butyl-N-(5-hydroxypentyl)carbamate (AU, 1.5 g, 7.38 mmol) in dichloromethane (10 ml) at 0°C was added BF ₃ ⋅Et ₂ O (0 .1 ml). Then, a solution of ethyl 2-diazoacetate (850 mg, 7.45 mmol) in dichloromethane (2 ml) was added to this mixture at 0°C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (30 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v = 1:7)) with obtaining AV (yield: 15%) as a colorless oil. LC-MS (ES ⁺ ): m/z 290.05 [MH ⁺ ], t _R =1.55 min (run 2.6 minutes).

[1026] Step 3: Synthesis of ethyl 2-(5-aminopentyloxy)acetate (L-14)

[1027] To a stirred solution of ethyl 2-[(5-{[(tert-butoxy)carbonyl]amino}-pentyl)oxy]acetate (AV, 400 mg, 1.38 mmol) in dichloromethane (5 ml) at room temperature, trifluoroacetic acid (5 ml) was added. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum to give L-14 (yield: 84%) as a yellow oil. LC-MS (ES ⁺ ): m/z 190.00 [MH ⁺ ], t _R =1.01 min (run 2.6 minutes).

[1028]

[1029] L-15: methyl 2-(2-(2-(methylamino)ethoxy)ethoxy)acetate

[1030]

[1031] Step 1: Synthesis of 2-[2-(benzylamino)ethoxy]ethane-1-ol (AQ)

[1032] Sodium triacetoxyborohydride (15, 8 g, 74.5 mmol). The resulting solution was then stirred at room temperature for 4 hours. Water (50 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 ml×2). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography on silica gel (eluent: dichloromethane/methanol (v/v=3:1) to give AC (yield: 85%) as white solid LC-MS (ES ⁺ ): m/z 195.95 [MH ⁺ ], t _R =0.22 min (run 2.0 minutes).

[1033] Step 2: Synthesis of 2-{2-[benzyl(methyl)amino]ethoxy}ethan-1-ol (AY)

[1034] Formaldehyde (38% in water) (4.9 ml) and sodium triacetoxyborohydride (17.0 g). The resulting solution was stirred at room temperature for 2 hours. Saturated aq. sodium bicarbonate (100 ml) and then most of the organic solvent was removed under reduced pressure. The resulting mixture was extracted with ethyl acetate (200 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate, then concentrated under reduced pressure and then under high vacuum to give AY (yield: 33%) as a yellow oil. LC-MS (ES ⁺ ): m/z 210.00 [MH ⁺ ], t _R =0.43 min (run 2.0 minutes).

[1035] Step 3: Synthesis of methyl 2-(2-{2-[benzyl(methyl)amino]ethoxy}ethoxy)acetate (AZ)

[1036] To a stirred solution of 2-{2-[benzyl(methyl)amino]ethoxy}ethan-1-ol (AY, 2 g) in dichloromethane (20 ml) was added a solution of sodium hydroxide (37%) in water (20 ml ) followed by t-6util-2-bromoacetate (7.76 g) and TBAC (2.78 g) at room temperature. The resulting mixture was stirred at room temperature for 15 hours. The aqueous layer was separated, and aq. hydrogen chloride (4N) to adjust to pH~3, after which it was concentrated under reduced pressure to obtain a crude residue. Then, methanol (20 ml) was added to this residue, and insoluble salts were filtered off, the solution was concentrated under vacuum to obtain 2-(2-[2-[benzyl(methyl)amino]ethoxy]ethoxy)acetic acid (yield: 78% o) in the form of a yellow oil. To a stirred solution of the above 2-(2-{2-[6enzyl(methyl)amino]ethoxy}ethoxy)acetic acid (2 g, 7.48 mmol, 1.00 equiv) in methanol (50 ml) at room temperature sulfuric acid (2 ml) was added slowly. The resulting solution was stirred at 70°C in an oil bath for 3 hours. Most of the solvent was removed under reduced pressure to give a residue which was diluted with H ₂ O (30 ml). Then, sodium carbonate was added to the mixture to adjust to pH~8. The mixture was then extracted with ethyl acetate (50 ml×2), the organic layers were combined, dried over anhydrous sodium sulfate, then concentrated under reduced pressure and then under high vacuum to give AZ (yield: 29%) as a yellow oil. LC-MS (ES ⁺ ): m/z 281.95 [MH ⁺ ], t _R =0.30 min (2.0 minute run).

[1037] Step 4: Synthesis of methyl 2-{2-[2-(methylamino)ethoxy]ethoxy}acetate (L-15)

[1038] To a stirred mixture of methyl 2-(2-{2-[benzyl(methyl)amino]ethoxy}ethoxy)acetate (AZ, 600 mg, 2.13 mmol) and palladium charcoal (300 mg) in methanol (30 ml) in a nitrogen atmosphere, hydrogen was added from a balloon. The resulting mixture was stirred at room temperature for 15 hours. The solid was removed by filtration and the solution was concentrated in vacuo to give L-15 (400 mg) as a yellow oil which was used in the next step without any further purification. LC-MS (ES ⁺ ): m/z 191.95 [MH ⁺ ], t _R =0.31 min (2.0 minute run).

[1039] L-16: ethyl 2-(5-(methylamino)pentyloxy)acetate

[1040]

[1041] Step 1: Synthesis of ethyl 2-[(5-{[(tert-butoxy)carbonyl](methyl)amino}pentyl)oxy]acetate (BB)

[1042] To a stirred solution of ethyl 2-[(5-{[(tert-butoxy)carbonyl]amino}pentyl)oxy]acetate (BA, 1.1 g, 3.8 mmol) in N,N-dimethylformamide (10 ml) CH ₃ I (0.71 ml, 11.4 mmol) was added at 0°C followed by sodium hydride (304 mg, 7.60 mmol, 60% in mineral oil) in several portions at 0°C. The resulting mixture was stirred at room temperature for 16 hours. Water (1.0 ml) was added and the resulting mixture was extracted with ethyl acetate (50 ml×2). The organic layers were combined, washed with saturated aqueous sodium chloride (100 ml), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether (vol. ./vol.=1:10)) to obtain BB (yield: 21%) as a yellow oil. LC-MS (ES ⁺ ): m/z 326.20 [MNa ⁺ ], t _R =1.55 min (run 2.6 minutes).

[1043] Step 2: Synthesis of ethyl 2-{[5-(methylamino)pentyl]oxy}acetate (L-16)

[1044] To a stirred solution of ethyl 2-[(5-{[(tert-butoxy)carbonyl](methyl)amino}-pentyl)oxy]acetate (BB, 240 mg, 0.79 mmol) in dichloromethane (5 ml ) was added trifluoroacetic acid (0.5 ml). The resulting solution was stirred at room temperature for 16 hours. The solvents were removed under reduced pressure and then under high vacuum to give L-16 (yield: 99%) as a yellow oil. LC-MS (ES ⁺ ): m/z 204.20 [MH ⁺ ], t _R =0.56 min (2.0 minute run).

[1045] L-17: 2-(3-(2-(tosyloxy)ethoxy)proxy)acetic acid

[1046]

[1047] Step 1: Synthesis of t-butyl 2-{3-[2-(benzyloxy)ethoxy]propoxy}acetate (BD)

[104S] To a stirred solution of 3-[2-(benzyloxy)ethoxy]propan-1-ol (BC, 1.3 g, 8.56 mmol) and tert-butyl-2-bromoacetate (6.6 g, 33, 84 mmol, 4.00 equiv.) in dichloromethane (40 mL) was added TBAC (2.4 g) and aq. sodium hydroxide solution (37%, 40 ml). The resulting mixture was stirred at room temperature overnight. The formation of the target product was detected by LC-MS. The reaction mixture was then extracted with ethyl acetate (150×3 ml), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether (vol. /vol.=1:2)) to obtain BD (yield: 90%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.35-7.27 (m, 5H), 4.57 (s, 2H), 3.94 (s, 2H), 3.63-3, 57 (m, 8H), 1.96-1.87 (m, 2H), 1.47 (s, 9H); LC-MS (ES ⁺ ): m/z 347.10 [MNa ⁺ ], t _R =1.72 min (run 2.6 minutes).

[1049] Step 2: Synthesis of tert-butyl 2-[3-(2-hydroxyethoxy)propoxy]acetate (BE)

[1050] To a stirred mixture of tert-butyl 2-{3-[2-(benzyloxy)ethoxy]propoxy}acetate (BD, 2.5 g, 7.71 mmol) and palladium charcoal (2.0 g) in methanol (20 ml) in a nitrogen atmosphere, hydrogen was supplied from a balloon. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. Reaction completion was detected by LC-MS. The solids were removed by filtration, and the solution was concentrated under vacuum to give BE (yield: 99%) as a colorless oil. LC-MS (ES ⁺ ): m/z 257.10 [MNa ⁺ ], t _R =1.21 min (run 2.6 minutes).

[1051] Step 3: Synthesis of tert-butyl 2-(3-{2-[(4-methylbenzenesulfonyl)oxy]ethoxy}-propoxy)acetate (BF)

[1052] To a stirred solution of tert-butyl 2-[3-(2-hydroxyethoxy)propoxy]acetate (BE, 1.8 g, 7.68 mmol) in dichloromethane (50 mL) was added 4-toluenesulfonyl chloride (2.2 g, 11.54 mmol), triethylamine (2.33 g, 23.03 mmol) and 4-dimethylaminopyridine (95 mg, 0.78 mmol). The resulting mixture was stirred overnight at room temperature. The formation of the target product was detected by LC-MS. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether (v/v=1:2)) to give BF (yield: 80%) as yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.80 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.15 (t , J=3.6 Hz, 2H), 3.93 (s, 2H), 3.61 (t, J=3.6 Hz, 2H), 3.55-3.49 (m, 4H), 2 .45 (s, 3H), 1.85-1.78 (m, 2H), 1.48 (s, 9H); LC-MS (ES ⁺ ): m/z 411.00 [MNa ⁺ ], t _R =1.12 min (2.0 minute run).

[1053] Step 4: Synthesis of 2-(3-{2-[(4-methylbenzenesulfonyl)oxy]ethoxy}propoxy)acetic acid (L-17)

[1054] To a stirred solution of tert-butyl 2-(3-{2-[(4-methylbenzenesulfonyl)oxy]-ethoxy}propoxy)acetate (BF, 400 mg, 1.03 mmol) in dichloromethane (3 mL) at room temperature was added trifluoroacetic acid (1 ml). The resulting solution was stirred at room temperature for 1 hour. Reaction completion was detected by LC-MS. The reaction mixture was concentrated under reduced pressure to give L-17 (350 mg) as a yellow oil which was used in the next step without further purification. LC-MS (ES ⁺ ): m/z 332.90 [MH ⁺ ], t _R =0.81 min (run 2.0 minutes).

[1055] Unless otherwise noted, subsequent intermediates and their analogs (for example, but not limited to analogs with substituents such as halogens) were synthesized according to procedures similar to those described above for the synthesis of L-17 using the appropriate starting materials and reagents.

[1056] L-18: 2-(2-hydroxyethoxy)ethyl-4-methylbenzenesulfonate

[1057]

[1058] L-19: ethyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate

[1059]

[1060] L-20: ethyl 3-(2-(2-(tosyloxy)ethoxy)ethoxy)propanoate

[1061]

[1062] L-21: ethyl 5-(tosyloxy)pentanoate

[1063]

[1064] L-22: ethyl 3-(2-(tosyloxy)ethoxy)propanoate

[1065]

[1066] L-23: ethyl 2-(5-(tosyloxy)pentyloxy)acetate

[1067]

[1068] L-24: ethyl 3-(5-(tosyloxy)pentyloxy)propanoate

[1069]

[1070] L-25: 5-hydroxypentyl 4-methylbenzenesulfonate

[1071]

[1072] L-26: ethyl 2-(5-(tosyloxy)pentyloxy)acetate

[1073]

[1074] L-27: ethyl 2-(3-(tosyloxy)propoxy)acetate

[296]

[1076] L-28: ethyl 2-(2-(tosyloxy)ethoxy)acetate

[1077]

[1078] L-29: ethyl 2-(4-(2-(tosyloxy)ethoxy)butoxy)acetate

[1079]

[1080] L-30: 2-(2-(2-hydroxyethoxy)ethoxy)ethyl-4-methylbenzenesulfonate

[1081]

[1082] L-31: 2-((2R,3R)-3-(2-hydroxyethoxy)butan-2-yloxy)ethyl-4-methylbenzenesulfonate

[1083]

[1084] L-32: 1-methyl-4-((1-methylpiperidin-4-yl)methyl)piperazine

[1085]

[1086] When referring to specific exemplary compounds provided herein, the description uses the terms "Example No.". For example, Compound 1 (Table 2 in FIG. 2) is also referred to as Example 1. Categories DC ₅₀ (μM) (AR degradation ELISA in LNCaP and/or VCaP cells) from Table 2-7 are as follows: A < 1 nM; B: 1-10 nM; C: 10-100 nM; D: > 100 nM. Category D _max. (AR degradation ELISA - maximum inhibition (%) of AR in LNCaP and/or VCaP cells): A >50%; B < 50%.

[1087] Androgen receptor ELISA assay. Compounds were evaluated in this assay in LNCaP and/or VCaP cells using similar protocols. Protocols used with VCaP cells are described below. The androgen receptor ELISA was performed using a PathScan AR Sandwich ELISA (Cell Signaling, Cat # 12850) according to the following assay steps.

[1088] VCaP cells were plated at 40,000 cells/well in a volume of 100 μl/well in VCaP assay medium [RPMI without phenol red (Gibco, catalog # 11835-030); 5% charcoal-purified (dextran-treated) FBS (Omega Scientific, cat. no. FB-04); 1% penstrep (Life Technologies, Gibco cat#: 10378-016)] in Corning 3904 plates. Cells were grown for a minimum of 3 days.

log дозах (10 мкл PROTAC + 20 мкл DMSO) из ряда Н в ряд В, оставляли ряд А для DMSO; (iv) всего 7 доз (конечная концентрация в этом 1000х планшете будет составлять 3 мМ, 1 мМ, 333 мкМ, 111 мкМ и т.д.). (2) (i) Готовили 10х стоковый планшет в среде; (ii) переносили 2,5 мкл 1000х стокового раствора в новый 10х стоковый планшет (использовали 12-канальную пипетку, начинали с А (контроль DMSO) через Н. При добавлении 247,5 мкл среды в этот планшет он будет служить 10х стоковым планшетом; (iii) готовили среду + 1 нМ R1881 для получения 10х стокового планшета; (iv) добавляли 247,5 мкл среды с 1 нМ R1881 в каждую лунку 10х стокового планшета, перемешивали.[1089] Cells were first treated with a dose of compounds diluted in 0.01% DMSO, a polypropylene plate was used, avoiding the use of end columns, according to the following protocol: (1) (i) prepare a 1000x stock plate in DMSO; (ii) 20 mM stock solution was diluted 1/6.7 with DMSO (5 µl + 28.3 µl DMSO) = 3 mM in the H series; (iii) performed serial dilutions in

log doses (10 µl PROTAC + 20 µl DMSO) from row H to row B, leaving row A for DMSO; (iv) 7 doses total (final concentration in this 1000x plate would be 3mM, 1mM, 333µM, 111µM, etc.). (2) (i) Prepared 10x stock plate in medium; (ii) transfer 2.5 µl of 1000x stock solution to a new 10x stock plate (use a 12-channel pipette, start with A (DMSO control) through H. Adding 247.5 µl of medium to this plate will serve as a 10x stock plate; (iii) prepare medium + 1 nM R1881 to obtain a 10x stock plate (iv) add 247.5 µl of medium with 1 nM R1881 to each well of a 10x stock plate, mix.

Then 22 μl of 10x stock solution was added to the cells and incubated for 5 hours. 1x Cell Signaling Cell Lysis Buffer (Catalog # 9803; comes with kit) was prepared for 50 µl/well. Kept on ice. The medium was aspirated and 100 μl of 1x cell lysis buffer/well was added. Cells were placed in a mixer located in a cold room for 10 minutes and mixed at speed 7. The lysate mixture was mixed and 20 μl was transferred to 100 μl of ELISA plate diluent (0.15 μg/ml - 0.075 μg/ml). The mixture of lysate and diluent was kept at 4°C overnight in a mixer located in a cold room at speed 5 (gentle rotation).

[1090] A mixture of lysate and diluent was mixed for 30 minutes at 37°C. The anti-mouse AR antibody, anti-mouse antibody, TMB and STOP solution were brought to room temperature. 1x ELISA buffer included in the kit was prepared and loaded into the reservoir. The main program was run on a plate washing machine. The medium from the plates was discarded, the ELISA plate was vigorously tapped on a paper towel and washed with 4 x 200 µl ELISA wash buffer using a plate washer for the first three washes and an 8-way aspirator for the fourth wash to aspirate the solution more thoroughly.

[1091] Added 100 μl/well Ab to detect mouse AR; covered and shaken at 37°C for 1 hour; medium was discarded from plates, plates tapped on paper towel, washed with 4 x 200 μl of ELISA wash buffer using a plate washer for the first three washes and an 8-way aspirator for the fourth wash; 100 μl/well of HRP-conjugated anti-mouse Ab (included in the kit) was added; covered and shaken at 37°C for 30 minutes; ensured bringing the TMB reagent to room temperature; medium from the plates was discarded, plates tapped on paper towel, washed with 4×200 μl of ELISA wash buffer with a plate washer for the first three washes and an eight-way aspirator for the fourth washes; tapping tablets on paper towels; 100 μl TMB was added and shaken for 2 minutes while observing the color. 100 μl STOP solution was added when a light blue color appeared. The plates were shaken and read at 450 nM.

[1092] The progression of prostate cancer in patients treated with antiandrogen therapy typically involves one of several mechanisms of increased androgen receptor (AR) signaling, including increased intratumoral androgen synthesis, increased AR expression, and AR mutations. PROTAC (PROteolysis TArgeting Chimera), which uses bifunctional molecules that simultaneously bind a chosen target and an E3 ligase, cause ubiquitination via induced proximity and degradation of the target pathological protein. Unlike traditional targeted inhibition, which is a competitive process, degradation is a progressive process. As such, it is less sensitive to endogenous ligand increase, target expression, or target mutations. Thus, this technology seems to be ideal for examining the mechanisms of AR resistance in prostate cancer patients.

[1093] Data was analyzed and plotted using GraphPad Prism software. The compounds described in this application were analyzed, and the effectiveness of c-myc suppression is shown in table 2-7.

[1094] Apoptosis in VCaP cells. VCaP cells can be cultured in charcoal-purified medium containing 0.1 nM R1881 for 48 hours. The extent of apoptosis can then be determined using the CaspaseGlo assay (Promega).

[1095] Antiproliferation in LNCaP F876L. LNCaP cells transduced with the AR construct were cultured in charcoal-purified serum-containing medium. The indicated doses of enzalutamide or typical compounds can be added within 7 days. The CellTiterGlo reagent (Promega) can be used to assess proliferation.

[1096] PSA suppression in LNCaP F876L. LNCaP F876L cells transduced with the AR construct were cultured in charcoal-purified serum-containing medium supplemented with 0.1 nM R1881 for 7 days. Secreted PSA in the medium was detected using a PSA ELISA (Sigma).

[1097] Involution of the prostate in a mouse model of C57 B6. Male C57BL/6 mice aged 12 weeks were treated with AR PROTAC and its inactive epimeric counterpart, which is unable to bind to cereblon E3 ligase. Compounds were administered for 10 days, after which the prostate glands were isolated and weighed.

[1098] Inhibition of tumor growth in a VCaP xenograft model

[1099] YcaR xenograft and drug treatment. Three million VCaP cells in 75% MatriGel/25% RPMI suspension were implanted subcutaneously in CB17 SCID mice. When tumors reached 200–300 mm3, mice were surgically castrated, which led to temporary tumor stasis. The mice were allowed to recover for at least one week. Mice were then dosed with enzalutamide (PO, QD, 30 mg/kg bw) or AR PROTAC (IP, QD, at 30, 10, and 3 mg/kg bw) as indicated by oral gavage. Sixteen hours after the last dose, mice were sacrificed and the tumors were excised.

[1100] Tissue lysis buffer. Final concentrations: 25 mM HEPES (pH 7.4), 50 mM NaCl, 1% NP-40, 0.1% SDS, protease inhibitor tablets/without EDTA mini (A32955) 1/10 ml (for DNA problem, tablets were used protease inhibitor with EDTA); if phosphoproteins were observed at the endpoint, a phosphatase inhibitor was added. One μl per mg of tissue was used. Protease inhibitor mini cocktail was added to lysis buffer prior to homogenization.

[1101] Tissue lysis. A five mm stainless steel bead for a 2 ml tube or a 2.5 mm bead for a 1.5 ml tube was added to a frozen tumor piece on dry ice. The granule and tumor were transferred to wet ice. 1 μl of tissue lysis buffer per mg of tissue was added to the mixture of tumor and granules. Grinding with tissue granules was carried out for 4 minutes, at 25 Hz, 4°C. The granules were removed with a magnet. The lysates were spinned for 15 minutes at 14,000×g, 4°C. The entire volume of lysate was transferred to a block plate. Tumor lysate was normalized, typically ~50 µg/µl.

[1102] Western blotting. 10 μg/lane for LnCAP lysates and 5 μg/lane for VCaP lysates were used. The samples were processed at 150 V for 85 minutes. Transferred to a nitrocellulose membrane. The nitrocellulose membrane was blocked for 1 hour at room temperature with 3% BSA. Primary antibody: anti-AR Cell Signaling No. 5153 1/2000 o.n., mitoC abeam No. ab92824 1:1000, ERG Abeam No. ab92513 1:1000. Secondary antibody: Cell Signaling No. 7074/7076 1/20000 for 1 hour (HRP-conjugated anti-mouse/rabbit). Detected using Femto (THERMO FISHER) or Clarity (BIO-RAD).

[1103] Xenograft data is shown in Table 8 below.

[1104] AR degradation by PROTAC is E3 ligase dependent. AR PROTAC was added to LNCaP cells at the indicated concentrations for 24 hours in the presence or absence of 10 μM Cereblon E3 ligand ligand. (A) The activity of AR PROTAC against AR degradation was examined to determine if reduced degradation was observed as a result of the competition of the cereblon E3 ligase ligand with AR PROTAC for the binding of cereblon E3 ligase. (B) LNCaP cells were treated with AR PROTAC and its inactive epimeric counterpart, which is unable to bind to cereblon E3 ligase.

[1105] Oral PROTAC prodrug pharmacokinetics and subcutaneous PROTAC pharmacokinetics

[1106] Exemplary procedure for determining pharmacokinetic parameters

[1107] Male CD-I mice (6-8 weeks old, weighing 20-30 g, 3 per study) with free access to food and water were administered the test article at a dose of 10 mg/kg by oral gavage or subcutaneous injection into the composition indicated in tables 20 and 21, at a dose of 10 ml/kg.

[1108] Approximately 0.04 ml blood samples were taken from the dorsal metatarsal vein serially at time points of 0.25, 0.5, 1, 2, 4, 8 and 24 hours; heparin was used as an anticoagulant. Samples were centrifuged at 4000 g for 5 minutes at 4°C, then stored at -75°C until analysis.

[1109] Plasma samples were analyzed by LC/MS/MS to determine the amount of unchanged, input test product and/or derivatives, as appropriate. WinNonlin (Phoenix™) was used for pharmacokinetic calculations and simulations to generate parameters such as Cmax _. and AUC.

[1110] Specific embodiments

[1111] In certain embodiments, provided herein is a compound having a structure selected from the group consisting of Examples 1-452 and 528-625 (see Tables 2-7), a salt, a polymorph, and a prodrug thereof. In certain additional embodiments, provided herein is a composition comprising at least one of the compounds of Examples 1-452 or 528-625, including a salt, a polymorph, and a prodrug thereof. In still further embodiments, provided herein is a therapeutic composition comprising at least one of the compounds of Examples 1-452 or 528-625, including a salt, polymorph, and prodrug thereof, and a pharmaceutically acceptable carrier.

[1112] In an aspect of the present disclosure, a compound is provided having the structure:

ABM-L-CLM,

where AVM is an androgen receptor (AR) binding fragment, L is a chemical linker fragment, CLM is a cereblon E3-ubiquitin ligase binding fragment, where AVM contains a structure selected from the group consisting of:

Where:

W ¹ is an aryl, heteroaryl, bicyclic or biheterocyclic compound, each independently substituted with 1 or more of H, halogen, hydroxyl, nitro, CN, C≡CH, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), C _1-6 alkoxy (straight, branched, optionally substituted, e.g. optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl or CF ₃ ;

Y ¹ , Y ² each independently represents NR ^Y1 , O, S, SO ₂ , heteroaryl or aryl;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, C=O, C=S, SO, SO ₂ , heteroaryl or aryl;

Q is a 3-6 membered ring with 0-4 heteroatoms, optionally substituted with 0-6 R ^Q , each R ^Q is independently H, alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), halogen, C _1-6 alkoxy or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

R ¹ , R ² , R ^a , R ^b , R ^Y1 , R ^Y2 each independently represents H, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen, C _1-6 alkoxy), halogen, C _1-6 alkoxy, cyclic, heterocyclic compound or R ¹ , R ² together with the atom to which they are attached, form a 3-8-membered ring system containing 0-2 heteroatoms);

W ² is a bond, C _1-6 alkyl, C _1-6 heteroalkyl, O, aryl, heteroaryl, alicyclic, heterocyclic, bi-heterocyclic, biaryl or bi-heteroaryl compound, each optionally substituted with 1-10 R ^W2 ;

each R ^W2 is independently H, halogen, C _1-6 alkyl (straight or branched, optionally substituted; for example, optionally substituted with 1 or more of F), -OR ^W2A , C _3-6 cycloalkyl, C _4-6 cycloheteroalkyl, C _1-6 alicyclic compound (optionally substituted), heterocyclic compound (optionally substituted), aryl (optionally substituted) or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OC _1-3 alkyl (optionally substituted; for example, optionally substituted with 1 or more from -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN; And

R ^W2A is H, C _1-6 alkyl (straight, branched) or C _1-6 heteroalkyl (straight, branched), each optionally substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halogen, or OC _1-3 alkyl.

[1113] According to any aspect or embodiment described herein, W ¹ is selected from the group consisting of:

[1114] According to any aspect or embodiment described herein, W ² is selected from the group consisting of:

[1115] According to any aspect or embodiment described herein, the CLM contains a chemical group derived from an imide, thioimide, amide, or thioamide that binds to cereblox E3 ubiquitous ligase.

[1116] In any aspect or embodiment described herein, the chemical group is a phthalimido group, or an analog or derivative thereof.

[1117] In any aspect or embodiment described herein, CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

[1118] According to any aspect or embodiment of the present invention, a CLM has a chemical structure represented by:

Where

W is selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

each X is independently selected from the group consisting of O, S and H ₂ ;

Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z is selected from the group consisting of O, S and H ₂ ;

G and G' are each independently selected from the group consisting of H, alkyl (straight, branched, optionally substituted), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl optionally substituted with R', and benzyl, optionally substituted R';

Q ₁ , Q ₂ , Q ₃ and Q ₄ are carbon C optionally substituted with a group independently selected from R', N or N-oxide;

A is selected from the group consisting of H, alkyl, cycloalkyl, Cl and F;

R is selected from the group consisting of -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R'' -, -CR'NR'R''-, -aryl, -hetaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P (O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , - CN, -NR'SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N -CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', - NO ₂ , -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R ')R'', -SF ₅ , -R'NR'R'', (-R'O) _n R'' or/and -OCF ₃ ;

R' and R'' are each independently selected from the group consisting of a bond, H, alkyl (straight, branched), cycloalkyl, aryl, hetaryl, heterocyclyl, or -C(=O)R, each of which is optionally substituted;

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической; и

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; And

R _n is a functional group or an atom,

where n is an integer from 1 to 10 (for example, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and

where n is 1, R _n is modified to covalently attach to a linker group (L), and

if n is 2, 3 or 4 then one R _n is modified to covalently attach to the linker group (L) and any other R _n is optionally modified to covalently attach to an AVM, CLM, second CLM with the same chemical structure as CLM, CLM', second linker, or any of several or combinations thereof.

[1119] According to any aspect or embodiment described herein, a CLM or ULM has a chemical structure represented by:

Where:

W is independently selected from the group CH2, C=O, NH and N-alkyl;

R is independently selected from H, methyl, alkyl;

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической; и

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; And

Rn contains 1A independently selected functional groups or atoms, and optionally one of which is modified to covalently attach to an AVM, chemical linker group (L), ULM, CLM (or CLM'), or combinations thereof.

[1120] Another aspect of the present disclosure relates to a bifunctional compound containing the chemical structure: ABM-L-CLM, where AVM is an androgen receptor (AR) binding moiety, L is absent (bond) or is a chemical linker, and CLM is cereblon E3 -ubiquitin ligase fragment, which is a chemical group derived from imide, thioimide, amide or thioamide, where AVM contains a structure selected from the group consisting of:

Where:

W ¹ is an aryl, heteroaryl, bicyclic or biheterocyclic compound, each independently substituted with 1 or more of H, halogen, hydroxyl, nitro, CN, C≡CH, C _1-6 alkyl (straight, branched, optionally substituted, e.g., optionally substituted with 1 or more of halogen, C _1-6 alkoxy), C _1-6 alkoxy (straight, branched, optionally substituted; for example, optionally substituted with 1 or more of halogen), C _2-6 alkenyl, C _2-6 alkynyl, or _CF3 ;

Y ¹ , Y ² are each independently NR ^Y1 , O, S;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=O, C=S, SO, SO ₂ , heteroaryl or aryl;

Q is a 3-6 membered ring with 0-4 heteroatoms, optionally substituted with 0-6 R ^Q , each R ^Q is independently H, C _1-6 alkyl (straight, branched, optionally substituted; for example, optionally substituted with 1 or several of halogen, C _1-6 alkoxy), halogen, C _1-6 alkoxy, or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

R ¹ , R ² , R ^a , R ^b , R ^Y1 , R ^Y2 are each independently H, C _1-6 alkyl (straight, branched, optionally substituted; e.g., optionally substituted with 1 or more halo C _1-6 alkoxy ), halogen, C _1-6 alkoxy, cyclic compound, heterocyclic compound or R ¹ , R ² together with the atom to which they are attached, form a 3-8-membered ring system containing 0-2 heteroatoms);

W ² is a bond, C _1-6 alkyl, C _1-6 heteroalkyl, O, aryl, heteroaryl, alicyclic, heterocyclic, bi-heterocyclic, biaryl or bi-heteroaryl compound, each optionally substituted with 1-10 R ^W2 ;

each R ^W2 is independently H, halo, C _1-6 alkyl (straight or branched, optionally substituted; for example, optionally substituted with 1 or more of F), -OR ^W2A , C _3-6 cycloalkyl, C _4-6 cycloheteroalkyl, C _1-6 alkyl (optionally substituted), C _1-6 alicyclic compound (optionally substituted), heterocyclic compound (optionally substituted), aryl (optionally substituted) or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OC _1-3 alkyl ( optionally substituted, eg optionally substituted with 1 or more of -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN; And

RW2A is H, C1-6 alkyl (straight, branched) or C1-6 heteroalkyl (straight, branched), each optionally substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or OC1-3 alkyl.

[1121] According to any aspect or embodiment described herein, W ¹ is selected from the group consisting of:

[1122] According to any aspect or embodiment described herein, W ² is selected from the group consisting of:

[1123] In any aspect or embodiment described herein, the CLM contains a chemical group derived from an imide, thioimide, amide, or thioamide that binds a cereblon E3 ubiquitin ligase.

[1124] In any aspect or embodiment described herein, the chemical group is a phthalimido group or an analog or derivative thereof.

[1125] In any aspect or embodiment described herein, CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

[1126] According to any aspect or embodiment of the present invention, CLM has a chemical structure represented by:

Where

W is selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

each X is independently selected from the group consisting of O, S and H ₂ ;

Y is selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z is selected from the group consisting of O, S and H ₂ ;

G and G' are independently selected from the group consisting of H, alkyl (straight or branched optionally substituted; e.g. optionally substituted with R'), OH, R'OCOOR, R'OCONRR'', CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';

Q ₁ Q ₂ , Q ₃ and Q ₄ are independently carbon C optionally substituted with a group independently selected from R', N or N-oxide;

A is independently selected from the group H, alkyp, cycloapkyl, Cl and F;

R contains -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R''-CR'R''-,-CR'NR'R''-,(-CR'O) _n R'', -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R'' -F(O)R 'R'', -OP(O)(OR')R'', -OF(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , -CN, -NR 'SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR 'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , - CO ₂ R', -C(C=N-OR')R''-CR'=CR'R'',-CCR',-S(C=O)(C=N-R')R'' , SF ₃ or -OCF ₃ ;

R' and R'' are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, hetaryl, heterocyclyl, -C(=O)R, each of which is optionally substituted;

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической; и

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; And

R _n contains a functional group or atom,

where n is an integer from 1 to 10 (for example, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and where

where n is 1, R _n is modified to covalently attach to a linker group (L), and

if n is 2, 3 or 4 then one R _n is modified to covalently attach to the linker group (L) and any other R _n is optionally modified to covalently attach to ABM, CLM, a second CLM with the same chemical structure as CLM, CLM', second linker, or any of several or combinations thereof.

[1127] According to any aspect or embodiment of the present invention, a CLM or ULM has a chemical structure represented by:

Where:

W is independently selected from the group CH ₂ , C=O, NH and N-alkyl;

R is independently selected from H, methyl, alkyl;

представляет собой связь, которая может быть стереоспецифической ((R) или (S)) или не стереоспецифической, и

is a bond that may be stereospecific ((R) or (S)) or non-stereospecific, and

Rn contains 1A independently selected functional groups or atoms, and optionally one of which is modified for covalent attachment to AVM, chemical linker group (L), ULM, CLM (or CLM'), or combinations thereof.

[1128] According to any aspect or embodiment described in the present invention, the linker group L is a group that contains a chemical structural unit represented by the formula:

_-Aq- ,

where A _q is a group connected to at least one of CLM, AVM or both; And

q is an integer greater than or equal to 1,

where Aq is selected from the group consisting of bond, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 =CR ^L2 , C≡C, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(=NCN)NR ^L4 , NR ^L3 C(=NCN), NR ^L3 C(=CNO ₂ )NR ^L4 , C3-11 cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C5-13 spirocycloalkyl optionally substituted with 0-9 R ^L1 and/or R ^L1 groups, C3-11 heterocyclyl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, C5-13 spiroheterocycloalkyl optionally substituted with 0-8 R ^L1 and/or R ^L2 groups, aryl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, heteroaryl, optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, wherein R ^L1 or R ^L2 are each independently optionally connected to other groups to form a cycloalkyl and/or heterocyclyl moiety optionally substituted with 0-4 R ^L5 groups;

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halo, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N(C _{1 -8} alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OC _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N(C _1-8 cycloalkyl) ₂ , N (C _1-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8 alkyl) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH \u003d CH (C _1-8 alkyl), C (C _1-8 alkyl) \u003d CH (C _1-8 alkyl ), C (C _1-8 alkyl) \u003d C (C _1-8 alkyl) ₂ , Si (OH) ₃ , Si (C _1-8 alkyl) ₃ , Si (OH) (C _1-8 alkyl) ₂ , SOS _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N (C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _1-8 alkyl), N (C _1-8 alkyl)CON(C _1-8 alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH (C _1-8 alkyl), N (C _1-8 alkyl) SO ₂ N (C _1-8 alkyl) ₂ , NH SO ₂ NH (C _1-8 alkyl), NH SO ₂ NH (C _1-8 alkyl) ₂ , NH SO ₂ NH ₂ .

[1129] According to any aspect or embodiment described herein, the linker (L) contains a group represented by a general structure selected from the group consisting of:

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2)pO(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)oO(CH2) _p -O(CH2) _q -O(CH2) _r -0-;

-(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-;

где m, n, о, р, q и r каждый независимо представляет собой 0, 1, 2, 3, 4, 5, 6, при условии, что если число равно нулю, отсутствует N-O или О-О связь, R выбран из группы Н, метила или этила и X выбран из группы Н или F.

where m, n, o, p, q and r are each independently 0, 1, 2, 3, 4, 5, 6, provided that if the number is zero, there is no NO or O-O bond, R is selected from group H, methyl or ethyl; and X is selected from group H or F.

[1130] According to any aspect or embodiment described herein, the linker (L) contains a group represented by the general structure:

where m can be 2, 3, 4, 5.

[1131] According to any aspect or embodiment described herein, the linker (L) contains a group represented by a general structure selected from the group consisting of:

where n and m are each independently 0, 1, 2, 3, 4, 5, 6 and X is H or F.

[1132] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[1133] According to any aspect or embodiment described herein, L is a polyethylene group, optionally substituted with aryl or phenyl, containing from 1 to 10 ethylene glycol units.

[1134] In any aspect or embodiment described herein, the compound comprises a plurality of LCMs, a plurality of AVMs, a plurality of linkers, or any combination thereof.

[1135] In any aspect or embodiment described herein, a compound is a member selected from the group consisting of Examples 1-452 and 528-625 (e.g., compounds of Tables 2-7), a salt, a polymorph, an isotopic derivative thereof and a prodrug.

[1136] According to any aspect or embodiment described herein, the compound is selected from Tables 2-7 (ie, exemplified compounds 1-452 and 528-625).

[1137] According to any aspect or embodiment described herein, the AVM is selected from the group consisting of:

Where:

R ^Q2 is H, halogen, CH ₃ or CF ₃ ;

RQ3 is H, halogen, hydroxyl, nitro, CN, C≡CH, C1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C1-6 alkoxy), C1-6 alkoxy (straight, branched, optional substituted with 1 or more of halo), C2-6 alkenyl, C2-6 alkynyl, or CF3;

Y ³ , Y ⁴ , Y ⁵ each independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 , C=0, heteroaryl or aryl;

R ^Y1 , R ^Y2 each independently represents H or C _1-6 alkyl (straight, branched, optionally substituted with 1 or more of halogen, C _1-6 alkoxy, cyclic or heterocyclic compounds);

R ^Q is each independently H, C ₁ -C ₆ alkyl (straight, branched, optionally substituted with 1 or more of halo or C _1-6 alkoxy), or two R ^Qs together with the atom to which they are attached form a 3- 8-membered ring system containing 0-2 heteroatoms; And

X is N or C.

[1138] According to any aspect or embodiment described herein, each R ^Q is independently H or CH ₃ .

[1139] According to any aspect or embodiment described herein, R ^Q3 is CN;

[1140] According to any aspect or embodiment described herein, the AVM is selected from the group consisting of:

[1141] An additional aspect of the present disclosure relates to a composition containing an effective amount of a compound or difunctional compound according to any one of paragraphs. 1-25 and a pharmaceutically acceptable carrier.

[1142] According to any aspect or embodiment described herein, the composition further comprises at least one additional biologically active agent.

[1143] According to any aspect or embodiment described herein, the biologically active agent is an anticancer agent.

[1144] An additional aspect of the present disclosure relates to a therapeutic composition containing an effective amount of at least two different compounds, as described in any of paragraphs. 1-25.

[1145] Another aspect of the present disclosure relates to a method of treating a disease or disorder in a subject, the method comprising the steps of administering a composition containing a pharmaceutically acceptable carrier and an effective amount of a compound or difunctional compound as described in any of paragraphs. 1-25, to a subject in need thereof, wherein the compound is effective in treating or improving at least one symptom of the disease or disorder.

[1146] According to any aspect or embodiment described herein, the disease or disorder is cancer or Kennedy's disease, or both.

[1147] According to any aspect or embodiment described herein, the cancer is prostate cancer.

[1148] According to any aspect or embodiment described herein, the composition further comprises an effective amount of at least one additional anticancer agent.

[1149] The contents of all references, patents, pending patent applications, and published patents cited in this application are hereby expressly incorporated by reference. Except for the examples, or if otherwise expressly indicated, all numerical values in the present description, indicating the amount of substances, etc. should be understood as modified by the word "approximately". It should be understood that the upper and lower amounts, range limits, and ratios set forth herein may be independently combined. Likewise, ranges and amounts for each element of the disclosure may be used in conjunction with ranges or amounts for any of the other elements.

[1150] Those skilled in the art will determine, or be able to ascertain, the use of no more than routine experimentation, many equivalents to specific embodiments, and the methods described herein. It is envisaged that such equivalents are covered by the scope of the following claims.

[1151] It should be understood that the detailed examples and embodiments described herein are by way of example only in illustrative forms and are not intended to limit the disclosure in any way. Various modifications or changes in light of this will be suggested to those skilled in the art and are included within the spirit and scope of this application and are construed within the scope of the appended claims. For example, the relative amounts of the ingredients may be varied to optimize the desired effects, additional ingredients may be added and/or similar ingredients may be substituted by one or more of the ingredients described. Additional advantageous features and functionalities associated with the systems, methods and processes of the present disclosure will be apparent from the appended claims. Moreover, those skilled in the art will determine, or be able to ascertain, the use of no more than routine experimentation, many equivalents to specific embodiments, and the methods described herein. It is envisaged that such equivalents are covered by the scope of the following claims.

Claims (78)

1. A compound characterized by the structure: ABM-L-CLM, or a pharmaceutically acceptable salt thereof, wherein: (a) L is a chemical linker fragment containing a chemical structural unit represented by the formula:

where (AL) _q is a group connected to CLM and AVM; q is an integer from 1 to 8; each A ^L is selected from CR ^L1 R ^L2 , O, NR ^L3 , C _3-11 cycloalkyl, azetidinyl, piperazinyl, piperidinyl; And R ^L1 , R ^L2 and R ^L3 are each independently H, C _1-6 alkyl; (b) CLM is a cereblon E3 ubiquitin ligase binding fragment represented by the chemical structure:

where W is selected from CH ₂ and C=O; each X is O; Z is O; G is H; each of Q ₁ , Q ₂ , Q ₃ and Q ₄ is C; A is H; n is an integer from 1 to 3; each R is independently -OR', -NR'R'', -SR', piperazinyl, piperidinyl, -F, -Br, -I, -CF ₃ , -CN, -NO ₂ , -CO ₂ R', - or -OCF ₃ where one R is modified to covalently attach to the RTM via a chemical linker moiety (L); R' and R'' are independently selected from bond, H, alkyl; And

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; And (c) The AVM contains a structure selected from the group consisting of:

Where: W ¹ is phenyl independently substituted with 1-3 of: H; halogen; CN; straight or branched C _1-6 alkyl optionally substituted with 1-3 substituents selected from halogen and C _1-6 alkoxy; each of Y ³ , Y ⁴ , Y ⁵ independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 or C=O; Q is a 5- or 6-membered alicyclic or aromatic ring with 0-2 heteroatoms, optionally substituted with 1 R ^Q , each R ^Q is independently: straight or branched C _1-6 alkyl; R ^Y1 and R ^Y2 are H; W ² is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl or pyrazolyl, each optionally substituted with 1 R ^W2 ; each R ^W2 is a halogen; And

denotes the point of attachment of the AVM to the chemical linker moiety (L). 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where W ¹ is selected from:

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W ² is pyridazinyl. 4. The connection according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein CLM is characterized by the chemical structure represented by:

Where: W is C=O; A is H; And

is a bond, which may be stereospecific ((R) or (S)) or non-stereospecific. 5. Connection according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, where AVM is represented by the chemical structure:

6. The connection according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof, wherein the chemical linker moiety (L) contains a group represented by:

Where: each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, or 4. 7. Connection according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof, wherein the chemical linker moiety (L) is selected from:

8. Connection according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof, wherein the chemical linker moiety (L) is a polyethylene group containing 1 or 2 ethylene glycol units. 9. The compound according to claim 1, where the compound is:

or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, where the compound is:

or a pharmaceutically acceptable salt thereof. 11. The connection according to any one of paragraphs. 1-8 or a pharmaceutically acceptable salt thereof, wherein AVM is:

Where: R ^Q2 is H, halogen, CH ₃ or CF ₃ ; And R ^Q3 is H, halogen, CN, straight or branched C _1-3 alkyl, or CF ₃ ; each of Y ³ , Y ⁴ , Y ⁵ independently represents a bond, O, NR ^Y2 , CR ^Y1 R ^Y2 or C=O; R ^Y1 and R ^Y2 are H; And X is N or C. 12. Connection according to any one of paragraphs. 1-8 or a pharmaceutically acceptable salt thereof, wherein AVM is:

13. Pharmaceutical composition for the treatment of prostate cancer, containing an effective amount of the compound according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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