Compounds and their uses in the treatment of cancer - Patents.com

Abstract

The compound of formula (I) or a pharma- ceutically acceptable salt thereof is a PROTAC compound useful in the treatment of prostate cancer. [Formula 1] TIFF2025502985000704.tif20160

Description

[Technical Field]

[0001] This disclosure relates to certain proteolysis-directed chimeric molecule (PROTAC) compounds and, at a minimum, their ability to degrade the androgen receptor (AR) and, therefore, their use for treating androgen receptor-dependent diseases or disorders in mammals. Degradation of the androgen receptor may, for example, provide an anti-tumor effect, and thus, this disclosure relates, in part, to the use of such compounds and pharmaceutical compositions containing them for the treatment of cancer. It also relates to intermediate compounds that may be useful in the preparation of such PROTACs. [Background technology]

[0002] Traditional small molecule drugs bind reversibly (or sometimes irreversibly) to target proteins as a means of modulating a given biological activity. In contrast, PROTACs bind to their target proteins, but in doing so, cause their degradation. After achieving this effect, a PROTAC can, in theory, repeat the process with another target protein. Thus, unlike "traditional small molecule" inhibitors, PROTAC-driven degradation mechanisms could theoretically operate sub-stoichiometrically—meaning that even more modest exposures of PROTAC compounds could achieve desired levels of efficacy in vivo. In practice, this can be attributed to the degradation potency (DC) of a PROTAC. 50 and D max ) may mean that a compound may have an improved effect than that reflected by its binding affinity alone.

[0003] At a simplistic level, PROTAC molecules are often described as having three parts: (1) a part that can bind to a target protein to be degraded, (2) a second part that can bind to an E3 ubiquitin ligase, and finally a linker that connects (1) and (2) together.

[0004] During use, a PROTAC simultaneously binds to both a target protein and an E3 ubiquitin ligase, forming a ternary complex. The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex, ubiquitinating the target protein. This has the effect of tagging the target protein for degradation by the cellular proteasome machinery. The PROTAC then dissociates from the target protein and can catalytically initiate another cycle of this process. Meanwhile, the ubiquitinated target protein is recognized and degraded by the cellular proteasome machinery.

[0005] This PROTAC-mediated approach may be valuable as a way to treat certain diseases, such as cancer, where targeted degradation of specific bodily proteins may be beneficial. One such cancer-related target is the androgen receptor.

[0006] The androgen receptor (AR) belongs to the steroid hormone group of nuclear receptors and is a ligand-dependent transcription factor that controls the expression of various genes involved in the proliferation and survival of prostate cells. The AR is composed of four distinct domains: an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region that allows the N- and C-termini to interact, and a C-terminal ligand-binding domain (LBD). Androgens, such as testosterone and its derivative dihydrotestosterone (DHT), bind to the AR ligand-binding domain, which dimerizes the AR and releases AR chaperone proteins that translocate it from the cytoplasm to the nucleus. Within the nucleus, receptor dimers bind to androgen response elements (AREs) in the promoters of androgen-responsive genes, such as PSA and FKBP5. The AR signaling pathway is essential for normal prostate development; male sexual differentiation does not occur in the absence of androgens or when the AR is not functional.

[0007] The link between androgens and prostate cancer was first discovered in a seminal study by Huggins and Hodges in 1941, and subsequent studies have shown that androgen deprivation therapy is highly effective in treating recurrent prostate cancer. However, despite initial favorable responses, most tumor cells adapt to low androgen levels, and patients relapse within a few years, developing a condition known as castration-resistant prostate cancer (CRPC). Several second-generation antiandrogens have been approved by the US FDA for the treatment of CRPC. These include enzalutamide, apalutamide, and darolutamide, all of which compete with androgens for binding to the ligand-binding domain. In addition to antagonizing the AR and preventing its activation, they also inhibit nuclear translocation and DNA binding, thus effectively blocking AR signaling. In contrast, abiraterone acetate is an androgen biosynthesis inhibitor that targets the cytochrome P450 enzyme 17R-hydroxylase-17,20-lyase (CYP17). Testosterone is processed in the testes and adrenal glands by CYP17, and therefore inhibition of this enzyme inhibits prostate tumor growth by reducing circulating androgen levels.

[0008] While the aforementioned drugs significantly extend the survival of patients with late-stage prostate cancer, they are not curative, and resistance inevitably occurs. However, it is clear that the AR remains central to the progression of CRPC, meaning that the development of alternative AR inhibitors remains necessary. Several resistance mechanisms have been identified, including AR amplification, mutation, or the generation of splice variants lacking the ligand-binding domain. Mutations in the ligand-binding domain, such as F877L or L702H, can convert antagonists to agonists or cause the receptor to utilize alternative steroid hormones, such as glucocorticoids or progesterone. Therefore, drugs that degrade the AR and remove it from cells may be useful in addressing these forms of resistance. Therefore, AR PROTACs that bind to the ligand-binding domain of the androgen receptor and simultaneously recruit E3 ligases, such as cereblon, leading to AR ubiquitination and degradation via the proteasome may offer therapeutic benefits to patients with prostate cancer, particularly metastatic CRPC. AR PROTACs may also be useful for AR+ breast cancer.

[0009] Given the above-mentioned resistance mutations that may reside in the ligand-binding domain and limit the effectiveness of known CRPC treatments, it would be beneficial to develop AR-degrading PROTACs that not only target the "wild-type" AR but are also effective in degrading clinically relevant mutant forms of the AR.

[0010] Regardless of which target protein-binding unit (1) is used at one end of a PROTAC's linker unit, a fundamental element that must always be present at the other end of the PROTAC molecule is a unit (2) that helps direct tagging of the target protein, e.g., an E3 ubiquitin ligase cereblon conjugate unit, for degradation. Scientific efforts have already provided several such E3 ubiquitin ligase cereblon conjugate units, and further examples are demonstrated by the inventors herein below.

[0011] US Patent No. 6,299,949 describes certain PROTAC compounds that are said to be AR degraders.

[0012] As with "traditional small molecule" binders and PROTACs, there is always the issue of "off-target" activity in vivo, which can be important to avoid in the development of safe and effective drug therapeutics. In other words, a given binding unit may be very potent against its intended target, but if it is inadvertently potent against other, unintended biological targets in the human body, it may cause unacceptable toxicity, side effects, etc.

[0013] Therefore, developing potent molecules for pharmaceutical applications that are also suitably selective, i.e., avoid inhibiting / binding / degrading unintended biological targets in vivo, is an ongoing challenge.

[0014] For example, the inventors have surprisingly found that certain compounds herein exhibit advantageous selectivity that is expected to avoid or reduce the risk of mitochondrial toxicity in vivo.

[0015] As part of the development of existing and future PROTAC drug therapies for pharmaceutical applications (e.g., cancer), there remains a need to develop androgen receptor PROTAC compounds with a combination of advantageous / improved properties. As noted above, the development of a PROTAC that targets both wild-type AR and one or more clinically relevant mutant forms of AR is one example of such a combinatorial effect.

[0016] Additionally, although the E3 ubiquitin ligase cereblon conjugate unit is selected for use at the other end of the molecule, there is a need to develop an androgen receptor conjugate unit that can be incorporated into a PROTAC.

[0017] Other properties of interest during drug discovery and development of such PROTACs may relate to selectivity profile, absorption / bioavailability, distribution, metabolism, elimination, toxicity and side effect profile, stability, manufacturability, etc. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] International Publication No. 2018 / 071606 Brochure Summary of the Invention [Means for solving the problem]

[0019] The compounds herein provide, at a minimum, a potent AR-binding unit suitable for incorporation into a PROTAC compound, and a PROTAC compound containing such an AR-binding unit along with an E3 ubiquitin ligase cereblon conjugate unit at the other end of the PROTAC molecule. Certain AR-binding units are advantageously configured to degrade not only wild-type AR, but also one or more clinically relevant mutant forms of AR, such as L702H. Certain PROTAC compounds herein also possess a surprisingly advantageous combination of properties, for example, related to AR degradation and selectivity / safety profile in combination.

[0020] The present specification relates to the above-mentioned AR-binding units and PROTAC compounds (and pharmaceutically acceptable salts thereof) that incorporate such AR-binding units together with an E3 ubiquitin ligase cereblon conjugate unit, the two units being linked by a linker.

[0021] The present specification also relates to pharmaceutical compositions containing such PROTACs (and pharmaceutically acceptable salts thereof) and their use in methods of treatment of the human or animal body, for example in the treatment or prevention of cancer. The present specification also relates to processes and intermediate compounds (and salts thereof) involved in the preparation of said PROTACs.

[0022] According to a first aspect of the present specification, there is provided a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula, X 1 is C and X 2 , X 3 and X 4 0, 1 or 2 of are N and the rest are C; or X 3 and X 4 are both C and X 3 X bonded to 5 and X 5 X bonded to 8 With -X 5 =X 6 -X 7 =X 8 - is replaced by X 1 , X 2 , X 5 , X 6 , X 7 and X 8 one or two of are N and the others are C; X 3 and X 4 But -X 5 =X 6 -X 7 =X 8 When not substituted by -, p is 1 or 2, and X 1 is R 1 otherwise, p is 0, 1 or 2; During the ceremony, Each R 1 is X 1 , X 2 , X 3 and X 4 (or X 3 and X 4 But -X 5 =X 6 -X 7 =X 8 When replaced by -, X 1, X 2 , X 5 , X 6 , X 7 and X 8 ) are substituents on any C atom of the 1~3 Alkyl and C 1~3 alkoxy, wherein C 1~3 Alkyl and C 1~3 The alkoxy may be optionally substituted independently by one or more F; n is 0, 1 or 2; m is 0 or 1; When n and m are both other than 0, then Q is CH or N, otherwise Q is CH; R 2a and R 2b H, F and C 1~3 the same or different substituents on C atoms other than Q are each independently selected from alkyl, or R 2a and R 2b Combined, -(CH2) r - group, and r is 1, 2 or 3; Y 1 , Y 2 , Y 3 and Y 4 0, 1 or 2 of are N and the rest are C; Each R 3 is Y 1 , Y 2 , Y 3 and Y 4 and independently, F, Cl, C 1~3 Alkyl and C 1~3 alkoxy, wherein C 1~3 Alkyl and C 1~3 The alkoxy may be optionally substituted independently by one or more F; q is 0, 1 or 2; The linker is a saturated or partially or fully unsaturated backbone containing C and H atoms and at least one heteroatom, said backbone having bond endpoints 'a' and 'b' with a minimum length between 'a' and 'b' of 6 to 26 atoms; said backbone may contain one or more linear and / or branched chains and / or rings, optionally substituted by one or more F on any available C atom; W is the E3 ubiquitin ligase cereblon conjugation unit) is provided.

[0023] This specification also describes, in part, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0024] This specification also describes, in part, compounds of Formula (I), or pharmaceutically acceptable salts thereof, for use in therapy.

[0025] This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0026] This specification also describes, in part, a method for treating cancer in a warm-blooded animal in need of such treatment, comprising administering to the warm-blooded animal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0027] As shown in the experimental section herein below, the inventors have not only developed a variety of advantageous AR-binding units, but also gained an understanding of the positions at which such binding units can incorporate linkers (linked to E3 ubiquitin ligase cereblon conjugate units) without interfering with their AR-binding ability. Accordingly, the inventors have understood that when incorporating these AR-binding units into PROTACs, the linker of said PROTACs should not be attached at the left or middle ring in formula (I) shown herein above, but may suitably be attached at a designated position on the right-hand ring in compounds of formula (I) as shown herein.

[0028] Thus, in a further aspect herein, there is provided an E3 ubiquitin ligase cereblon conjugate unit and a compound of formula (Ia): [ka] (In the formula, R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, R 2a , R 2b , Q, Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q may each take any of the values ​​defined herein for each of these integers), or a pharmaceutically acceptable salt thereof.

[0029] For the avoidance of doubt, in formula (Ia) [ka] indicates the point of attachment to the remainder of the RROTAC compound via a single covalent bond.

[0030] In one embodiment, there is provided a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit linked to an AR binding unit of formula (Ia), as described herein, or a pharmaceutically acceptable salt thereof.

[0031] As described herein, the linkage between the E3 ubiquitin ligase cereblon conjugate unit and the AR binding unit of formula (Ia) as shown herein above preferably has a length corresponding to a linear chain length of 6 to 26 atoms, said atoms being linked by a single covalent bond, each selected from carbon or heteroatoms (i.e., O, N, or S).

[0032] As described herein, the linkage between the E3 ubiquitin ligase cereblon conjugate unit and the AR binding unit of formula (Ia) as shown herein above preferably has a length corresponding to a linear chain length of 7 to 14 atoms, said atoms being linked by a single covalent bond, each selected from carbon or heteroatoms (i.e., O, N, or S).

[0033] In one embodiment, the linkage between the E3 ubiquitin ligase cereblon conjugate unit and the AR binding unit of formula (Ia) as shown herein above preferably has a length corresponding to a linear chain length of 6 to 26 atoms, said atoms being linked by a single covalent bond, each selected from C, N or O.

[0034] In one embodiment, the linkage between the E3 ubiquitin ligase cereblon conjugate unit and the AR binding unit of formula (Ia) as shown herein above preferably has a length corresponding to a linear chain length of 7 to 14 atoms, said atoms being linked by a single covalent bond, each selected from C, N or O.

[0035] Despite the linkage length "corresponding to the length of [a particular atom in the chain]," it should be understood that this should not be construed as limiting the linkage to that atom; for example, a sulfur atom may also be present in the linkage even if the S atom is not included in the length descriptor.

[0036] As described herein, the linkage between the E3 ubiquitin ligase cereblon conjugate unit and the AR binding unit of formula (Ia) as shown herein above preferably has a length of 0.9 nm to 4 nm.

[0037] As described herein, the linkage between the E3 ubiquitin ligase cereblon conjugate unit and the AR binding unit of formula (Ia) as shown herein above preferably has a length of 1.0 nm to 2.2 nm.

[0038] In a further aspect herein, there is provided an androgen receptor binding unit of formula (Ia), as described herein, for use in a PROTAC compound (or a pharmaceutically acceptable salt thereof) that also contains an E3 ubiquitin ligase cereblon conjugate unit.

[0039] In a further aspect herein, there is provided an androgen receptor binding unit of formula (Ia), as described herein, for use in a PROTAC compound (or a pharmaceutically acceptable salt thereof) linked to an E3 ubiquitin ligase cereblon conjugate unit.

[0040] Thus, there is provided an androgen receptor binding unit of formula (Ia), as described herein, for use in a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein said PROTAC compound also contains an E3 ubiquitin ligase cereblon conjugate unit.

[0041] Thus, there is provided an androgen receptor binding unit of formula (Ia), as described herein, for use in a PROTAC compound (or a pharmaceutically acceptable salt thereof), said PROTAC compound also containing an E3 ubiquitin ligase cereblon conjugate unit linked to said androgen receptor binding unit.

[0042] Thus, there is provided an androgen receptor binding unit of formula (Ia), as described herein, for incorporation into a PROTAC compound (or a pharmaceutically acceptable salt thereof), said PROTAC compound also containing an E3 ubiquitin ligase cereblon conjugate unit.

[0043] Thus, there is provided an androgen receptor binding unit of formula (Ia), as described herein, for incorporation into a PROTAC compound (or a pharmaceutically acceptable salt thereof), said PROTAC compound also containing an E3 ubiquitin ligase cereblon conjugate unit linked to said androgen receptor binding unit.

[0044] Thus, there is provided an androgen receptor binding unit of formula (Ia), as described herein, contained within a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein said PROTAC compound also contains an E3 ubiquitin ligase cereblon conjugate unit.

[0045] Thus, there is provided an androgen receptor binding unit of formula (Ia), as described herein, contained within a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein said PROTAC compound also contains an E3 ubiquitin ligase cereblon conjugate unit linked to said androgen receptor binding unit.

[0046] In one embodiment, the link between the androgen receptor binding unit of formula (Ia) [as described above] and the E3 ubiquitin ligase cereblon conjugate unit is a linker as defined according to any embodiment or claim herein, and the attachment point shown in formula (Ia) above is attached to attachment point 'a' on any linker as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0047] Many embodiments of the present disclosure are detailed throughout this specification and will be apparent to those skilled in the art.

[0048] A pharmaceutically acceptable salt of a compound of formula (I) or a PROTAC compound described herein can be an acid addition salt, for example, if the compound contains a basic functional group such as an amine. The acid addition salt can be formed using an inorganic or organic acid. A pharmaceutically acceptable salt of a compound can be a base addition salt, for example, if the compound contains an acidic functional group such as a carboxylic acid. The acid addition salt can be formed using an inorganic or organic base. The term "pharmaceutically acceptable salt" is used to designate that the salt is suitable for use in the human or animal body. An exemplary list of pharmaceutically acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use," P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. A pharmaceutically acceptable salt of a compound of formula (I) or a PROTAC compound includes such salts that can be formed in the human or animal body after administration of the compound to the human or animal body.

[0049] As used herein, the term "alkyl" includes straight-chain, branched-chain, and cyclic alkyl groups having the specified number of carbon atoms, and combinations thereof. 1~3 Alkyl includes methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; C 1~9 Alkyl includes (4-isopropylcyclohexyl)methyl. The same principle applies to the term "alkoxy." Similarly, as used herein, the term "alkoxy" includes straight-chain, branched-chain, and / or cyclic alkoxy groups having the specified number of carbon atoms. Thus, C 1~3 Alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy and cyclopropoxy.

[0050] Chemical abbreviations familiar to those skilled in the art may be used herein, including, for example, "Me" = methyl, "Et" = ethyl, "Pr" = propyl, "Bu" = butyl, and "Ph" = phenyl.

[0051] When the term "optionally" is used, it is intended that the following feature may or may not be present. Thus, the use of the term "optionally" includes instances where the feature is present, as well as instances where the feature is not present. For example, "methyl optionally substituted with one or more F" includes -CH, -CHF, -CHF, and -CF.

[0052] The term "substituted" means that one or more hydrogens on the indicated atom or group are replaced by the specified substituents, provided that any atom having such a substituent maintains its allowed valence, as understood by those skilled in the art, with the standard valences of carbon, nitrogen, and oxygen being 4, 3, and 2, respectively. Thus, "substituted on any available C atom" should be understood to mean that the substituents are limited in their position (and / or potentially in their number) by whether there are any remaining hydrogen atoms on the specified atom or group that can be substituted with said substituent.

[0053] The dashed bond " [ka] " is X E , X F , X G , X H and X JAccording to the atom (or group of atoms) present at each of the positions, the possibility that the bond may in each case be a single or double covalent bond is indicated. Those skilled in the art will understand that the standard valences of carbon, nitrogen, and oxygen are as stated above, and will therefore be able to understand whether, in any given Z group of a compound of formula (I), each dashed bond should be interpreted as a single or double bond. This is because Z A X in E2 , X F2 , X G2 , X H2 and X J2 Applies to location.

[0054] The terms "adjacent" or "adjacent position" refer to, for example, X of Z. G , X H , and X J refers to the next closest position in the molecular chain / ring system with respect to Z. Thus, in the context of Z: X G and X H are adjacent to each other, and X H and X J are also adjacent to each other, but X G is X J is not adjacent to

[0055] The term "saturated" means that the atoms of the specified backbone or group are connected only by single covalent bonds. Accordingly, the term "unsaturated" means that the specified backbone or group contains double and / or triple covalent bonds. Examples of partially or fully unsaturated groups or unsaturated molecular fragments that may be present in the backbone are C=C, C=N, C=O, N=N, C≡C, or C≡N, where nitrogen and oxygen heteroatoms are permitted / present, and may also include S=O, where sulfur heteroatoms are permitted / present.

[0056] It should be understood that "heteroatom," unless expressly limited further in a given context, can refer to an oxygen, nitrogen, or sulfur atom.

[0057] The term "minimum length of atoms [...] between 'a' and 'b'" refers to the shortest chain of atoms in the chain between 'a' and 'b'. Thus, if the chain consists of -CH2CH2CH2-, the number of atoms in the chain is 3 (hydrogen atoms are considered not to be in the chain). Alternatively, if the chain consists of 1,3-phenylene, where the short route around the phenyl ring contains 3 C atoms and the long route around the phenyl ring contains 5 C atoms, the minimum length of such a chain is counted as 3 atoms.

[0058] It should be understood that attachment points 'a' and 'b' each represent a single covalent bond to the associated adjacent group / atom.

[0059] As used herein, a "ring" or "heterocyclic group" should be understood to include monocyclic, fused, spiro, and bridged rings.

[0060] With respect to linkers, as described herein, it should be understood that, if present, branches may be present on the chain (even a chain of one atom in length) and / or on the ring. While this is generally understood by those skilled in the art, for the avoidance of doubt, it should be understood that "branching" inherently occurring to form a ring is not considered "branching" in the context of the linker embodiments described herein. It should be understood that the branches may occur on the same atom or different atoms of the linker backbone. For example, it is possible to have two "=O" branches on a sulfur heteroatom to form an SO group within the linker backbone. Linker #22 described herein below is an example in which there is one branch (-Me) originating from the chain within the linker.

[0061] It should be further understood that "branch" (and the definition of branch provided herein) refers to a branch that branches off from the main chain of atoms between 'a' and 'b' that leads to the "ends" of the molecular structure.

[0062] It should be understood herein that the point of attachment (via a single covalent bond) of a given group to some other group may be represented by a line intersecting the bond at substantially right angles to said bond, for example, as shown on the distal right-hand side of formula (Ia) herein, and at the end of either of linkers 1-46 shown herein below.

[0063] In this specification, "X A , X B , X C , X D , X E and X F 0, 1 or 2 of the X E and X F are not both N and are otherwise C, it should be understood that a particular C atom implicitly has a hydrogen atom where necessary to satisfy the standard valence of the carbon atom (4). Those skilled in the art will appreciate that such H atoms may be present in the X when a substituent or linker is attached to said carbon. E or X F C on or X A , X B , X C or X D The same principle applies to X. 1 , X 2 , X 3 , X 4 (and X if present) 5 , X 6 , X 7 and X 8 together with Y 1 , Y 2 , Y 3 and Y 4 This also applies to X A2 , X B2 , X C2 , X D2 , X E2 , X F2 , X G2 , X H2 and X J2 applies to.

[0064] As used herein, references to secondary or tertiary amines are intended to have their ordinary meaning in the art; thus, for example, a nitrogen atom that is part of an amide or sulfonamide group is not considered to be a secondary or tertiary amine.

[0065] As used herein, a saturated heterocyclic group refers to at least one ring (including bridged rings, spiro rings, fused rings, and monocyclic rings) of atoms containing carbon atoms and at least one heteroatom, where each heteroatom is independently selected from N, O, and S, and each atom in the ring is linked to an adjacent atom by a single covalent bond. Thus, an example of a heterocyclic group is a spiro heterocyclic group having two rings and a total of one heteroatom, such as 9-azaspiro[5.5]undecane. Typically, saturated heterocyclic groups will have at least two carbon atoms separating each of the heteroatoms present in the group to ensure a suitable level of chemical stability for use in pharmaceutical contexts. When referring to a "nitrogen-containing saturated (or partially unsaturated) heterocyclic group," this requires the presence of at least one nitrogen heteroatom, but does not limit the possibility of one or more additional non-nitrogen heteroatoms (i.e., S, O). As used herein, a partially unsaturated heterocyclic group refers to at least one ring of atoms (including bridged, spiro, fused, and monocyclic rings) containing carbon atoms and at least one heteroatom, where each heteroatom is independently selected from N, O, and S, and where at least two atoms in the heterocyclic group are bonded to each other via a double covalent bond. Those skilled in the art will understand that partially unsaturated does not include fully unsaturated heterocyclic groups, i.e., the group contains the maximum number of double bonds possible for the backbone of atoms.

[0066] When referring to a cyclic group (e.g., a heterocyclic group) having a specified number of ring atoms, this includes the atoms that constitute the ring (including atoms participating in the bridging of bridged rings and all atoms of fused or spiro rings), but does not include any hydrogen atoms or other substituent atoms bonded to the ring atoms. Thus, for example, the cyclic group 1,4-piperazine-1,4-diyl has 6 ring atoms (4 C and 2 N).

[0067] As used herein, alkylene groups (e.g., C 1~5 Alkylenes are saturated groups consisting only of carbon and hydrogen atoms with two points of attachment to adjacent atoms / groups. They may contain straight chains, branched chains, and / or rings. Thus, a C alkylene represents -CH-, a C alkylene can represent -CHCH- or -CH(Me)-, and a C 1~5 Alkylene includes, for example, -CH2(cyclobuta-1,3-diyl)-. u1~u2 Alkylene is -(CH2) u - (wherein u is an integer from u1 to u2).

[0068] As used herein, a hydrocarbyl group means any group consisting only of C and H atoms. For example, C 1~7 Hydrocarbyl includes methyl, phenyl and p-tolyl.

[0069] The term "therapy" shall have its ordinary meaning of treating a disease in order to completely or partially alleviate one, some, or all of the symptoms of the disease, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" or "prophylactic," unless specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" shall be construed in a corresponding manner.

[0070] The term "prevention" is intended to have its ordinary meaning and includes primary prevention, to prevent the occurrence of a disease, and secondary prevention, where the disease has already occurred and the patient is temporarily or permanently protected against progression or worsening of the disease or the development of new symptoms associated with the disease.

[0071] The term "treatment" is used synonymously with "therapy." Similarly, the term "treating" can be considered as "applying therapy," where "therapy" is as defined herein.

[0072] Some values ​​of the variables are as follows: One, two or more of such values ​​may be used in any combination with other definitions, claims, aspects or embodiments herein (unless the context allows) to provide further embodiments / claims herein.

[0073] In one embodiment, X 1 is C and X 2 , X 3 and X 4 0 or 1 of the formulas is N and the rest are C; or X 3 and X 4 are both C and X 3 X bonded to 5 and X 5 X bonded to 8 With -X 5 =X 6 -X 7 =X 8 -(in the formula, X 1 , X 2 , X 5 , X 6 , X 7 and X 8 is replaced by N, and the other is C).

[0074] In one embodiment, X 1 is C and X 2 , X 3 and X 4 0, 1 or 2 of the following are N, and the rest are C.

[0075] In one embodiment, X 1 is C and X 2 , X 3 and X 4 0 or 1 of these is N, and the rest are C.

[0076] In one embodiment, X 1 is C and X 2 , X 3 and X 4 One or two of the groups are N, and the others are C.

[0077] In one embodiment, X 1 is C and X 2 , X 3 and X 4 One of them is N and the others are C.

[0078] In one embodiment, X 1 , X 2 , X 3 and X 4 are all C.

[0079] In one embodiment, X 1 and X 2 is C and X 3 and X 4 are both C and X 3 X bonded to 5 and X 5 X bonded to 8 With -X 5 =X 6 -X 7 =X 8 -(in the formula, X 5 , X 6 , X 7 and X 8 is replaced by (one of which is N and the other is C).

[0080] In one embodiment, X 3 and X 4 are both C and X 3 X bonded to 5 and X 5 X bonded to 8 With -X 5 =X 6 -X 7 =X 8 - replaced by ;X 6 and X 7 are all C and X 8 is N.

[0081] In one embodiment, each R 1 is X 1 When p is 2, X 2 , X3 and X 4 is a substituent on any other C atom of (or each R 1 is X 3 and X 4 But -X 5 =X 6 -X 7 =X 8 When replaced by -, X 1 , X 2 , X 5 , X 6 , X 7 or X 8 and R is a substituent at each occurrence independently selected from F, Cl, Me, cyclopropyl, CHF2, CF3, and OMe.

[0082] In one embodiment, each R 1 is X 1 When p is 2, X 2 , X 3 and X 4 and a substituent on any other C atom of 3 and X 4 -X 5 =X 6 -X 7 =X 8 - is not replaced by R otherwise 1 The value of is as defined herein.

[0083] In one embodiment, each R 1 are Cl, F, C 1~3 alkyl (optionally substituted with one or more F) and C 1~3 Alkoxy is selected from:

[0084] In one embodiment, X 3 and X 4 But -X 5 =X 6 -X 7 =X 8 When not substituted by -, p is 1 or 2, and X 1 is R 1 and p is C bonded to

[0085] In one embodiment, X 3 and X 4 but, -X 5 =X 6 -X 7 =X 8 When not substituted by -, p is 1 or 2, and X 1 is R 1 otherwise, p is 0 or 1.

[0086] In one embodiment, X 3 and X 4 but, -X 5 =X 6 -X 7 =X 8 When not substituted by -, p is 1 or 2, and X 1 is R 1 otherwise, p is 0.

[0087] In one embodiment, X 3 and X 4 but, -X 5 =X 6 -X 7 =X 8 -, p is 1, and X 1 is R 1 otherwise, p is 0, 1 or 2.

[0088] In one embodiment, X 3 and X 4 but, -X 5 =X 6 -X 7 =X 8 -, p is 2, and X 1 is R 1 otherwise, p is 0, 1 or 2.

[0089] In one embodiment, X 3and X 4 but, -X 5 =X 6 -X 7 =X 8 -, p is 2, and X 1 is R 1 otherwise, p is 0.

[0090] In one embodiment, p is 0 and X 3 and X 4 are both C and X 3 X bonded to 5 and X 5 X bonded to 8 With -X 5 =X 6 -X 7 =X 8 - is replaced by

[0091] In one embodiment, p is 1 or 2 and X 3 and X 4 -X 5 =X 6 -X 7 =X 8 - is not replaced by

[0092] In one embodiment, p is 1 or 2; X 3 and X 4 -X 5 =X 6 -X 7 =X 8 - is not replaced by X 1 is R 1 (-R 1 is a C bonded to a CF3.

[0093] In one embodiment, p is 1; 3 and X 4 -X 5 =X 6 -X 7 =X 8 - is not replaced by X 1 is R 1 is C bonded to

[0094] In one embodiment, p is 1; 3 and X 4 -X 5 =X 6 -X 7 =X 8 - is not replaced by X 1 is R 1 (R 1 is a C bonded to a CF3.

[0095] In one embodiment, p is 1 and R 1 are Cl, C 1~3 alkyl (optionally substituted with one or more F) and C 1~3 Alkoxy is selected from:

[0096] In one embodiment, p is 1 and R 1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.

[0097] In one embodiment, p is 1 and X 1 is R 1 (R 1 is a C bonded to a aryl group selected from Cl, Me, cyclopropyl, CHF2, CF3, and OMe.

[0098] In one embodiment, p is 1 and X 1 is R 1 C is bonded to X 3 and X 4 -X 5 =X 6 -X 7 =X 8 - is not replaced by R 1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.

[0099] In one embodiment, p is 1 or 2; X 3 and X 4 -X 5 =X 6 -X7 =X 8 - not replaced by;X 1 is R 1 (The above R 1 are Cl, C 1~3 alkyl (optionally substituted with one or more F) and C 1~3 alkoxy), and if present (i.e., when p is 2), other R 1 is F.

[0100] In one embodiment, p is 1 or 2; X 3 and X 4 -X 5 =X 6 -X 7 =X 8 - not replaced by;X 1 is R 1 (The above R 1 is a C bonded to a group selected from Cl, Me, cyclopropyl, CHF2, CF3, and OMe), and when present (i.e., when p is 2), other R 1 is F.

[0101] In one embodiment, p is 1 or 2; X 3 and X 4 -X 5 =X 6 -X 7 =X 8 - not replaced by;X 1 is R 1 (R 1 is a C bonded to a group selected from Cl, Me, cyclopropyl, CHF2, CF3, and OMe), and if present (i.e., when p is 2), an additional R 1 The substituent is X 2 (X 2 is F bonded to C).

[0102] In one embodiment, p is 1 and R 1 is C optionally replaced by one or more F 1~3 It is alkyl.

[0103] In one embodiment, p is 1 and R 1 is methyl, cyclopropyl, CF3 or CHF2.

[0104] In one embodiment, p is 1 and R 1 is CF3 or CHF2.

[0105] In one embodiment, p is 1 and R 1 is CHF2.

[0106] In one embodiment, p is 1 and R 1 is CF3.

[0107] In one embodiment, p is 1 and R 1 is methyl.

[0108] In one embodiment, p is 1 and R 1 is cyclopropyl.

[0109] In one embodiment, p is 1 and R 1 is methoxy.

[0110] The above eight embodiments can be implemented, for example, as follows: 3 and X 4 But -X 5 =X 6 -X 7 =X 8 - is not replaced by X 1 is C, and the above R 1 But X 1 may be present in the context of being a substituent on said C.

[0111] In one embodiment, p is 2; X 1 and X 2 are both C;X 3 and X 4 -X 5 =X 6 -X 7 =X 8 - not replaced by R 1The value of X 1 is replaced by CF3, and X 2 is replaced by F.

[0112] In one embodiment, p is 1; 3 and X 4 -X 5 =X 6 -X 7 =X 8 - not replaced by;X 1 , X 2 , X 3 and X 4 are all C and R 1 is X as defined herein 1 The above substituents.

[0113] In one embodiment, p is 1; 3 and X 4 -X 5 =X 6 -X 7 =X 8 - not replaced by;X 1 , X 2 , X 3 and X 4 are all C and R 1 is X 1 The above substituent is CF3.

[0114] In one embodiment, p is 2 and one R 1 is CF3, and the other R 1 is F or ethyl.

[0115] In one embodiment, p is 2 and one R 1 is CF3, and the other R 1 is F.

[0116] In one embodiment, p is 2 and one R 1 is CF3, and the other R 1 is ethyl.

[0117] In one embodiment, p is 2 and X1 is the first R 1 C is bonded to X 2 is the second R 1 is C bonded to

[0118] In one embodiment, p is 2 and X 1 is a C bonded to CF3, and X 2 is a C bonded to either F or ethyl.

[0119] In one embodiment, p is 2 and X 1 is a C bonded to CF3, and X 2 is a C bonded to an F.

[0120] In one embodiment, p is 2 and X 1 is a C bonded to CF3, and X 2 is a C bonded to ethyl.

[0121] The above seven embodiments are, for example, 3 and X 4 But -X 5 =X 6 -X 7 =X 8 - can occur in contexts where it is not replaced by

[0122] In one embodiment, n is 0.

[0123] In one embodiment, n is 1.

[0124] In one embodiment, n is 2.

[0125] In one embodiment, m is 0.

[0126] In one embodiment, m is 1.

[0127] In one embodiment, n is 0 and m is 1.

[0128] In one embodiment, n is 1 and m is 1.

[0129] In one embodiment, n is 0 and m is 0.

[0130] In one embodiment, n is 0, 1, or 2;

[0131] In one embodiment, n is 1, m is 1, and Q is CH.

[0132] In one embodiment, n is 1, m is 1, and Q is N.

[0133] In one embodiment, n is 1, m is 1, Q is CH or N, and R 2a is H and R 2b is H.

[0134] In one embodiment, n is 1, m is 1, Q is CH, and R 2a is H and R 2b is H.

[0135] In one embodiment, n is 0, m is 1, Q is CH, and R 2a is H and R 2b is H.

[0136] In one embodiment, n is 1, m is 0, and R 2a is H and R 2b is a C bonded to a C atom other than Q (the C atom has an (R)-stereochemical configuration) 1~3 It is alkyl.

[0137] In one embodiment, n is 1, m is 0, and R 2a is H and R 2b is a C bonded to a C atom other than Q (the C atom has an (S)-stereochemical configuration) 1~3 It is alkyl.

[0138] In one embodiment, n is 1, m is 1, and R 2ais H and R 2b is a C bonded to a C atom other than Q (the C atom has an (R)-stereochemical configuration) 1~3 It is alkyl.

[0139] In one embodiment, n is 1, m is 1, and R 2a is H and R 2b is a C bonded to a C atom other than Q (the C atom has an (S)-stereochemical configuration) 1~3 It is alkyl.

[0140] In one embodiment, n is 1, m is 1, Q is N, and R 2a is H and R 2b is H.

[0141] In one embodiment, Q is CH having the (R)-stereochemistry at said C atom.

[0142] In one embodiment, Q is CH having the (S)-stereochemistry at said C atom.

[0143] In one embodiment, n is 2; m is 1; and R 2a and R 2b are both H; Q is CH.

[0144] In one embodiment, n is 2; m is 1; and R 2a and R 2b are both H; Q is CH with the (R)-stereochemistry at said C atom.

[0145] In one embodiment, n is 2; m is 1; and R 2a and R 2b are both H; Q is CH with the (S)-stereochemistry at the C atom.

[0146] In one embodiment, R 2a and R 2b is H and C 1~3 are the same or different substituents on C atoms other than Q, each independently selected from alkyl.

[0147] In one embodiment, R 2a and R 2b are the same or different substituents on C atoms other than Q, each independently selected from H and Me.

[0148] In one embodiment, R 2a and R 2b are substituents on the same or different C atoms adjacent to Q, otherwise as defined herein.

[0149] In one embodiment, R 2a and R 2b is H and C 1~3 The substituents on the same or different C atoms adjacent to Q are each independently selected from alkyl (eg, Me).

[0150] In one embodiment, R 2a and R 2b are the same or different substituents on C atoms and are both H.

[0151] In one embodiment, R 2a and R 2b H, F and C 1~3 are the same or different substituents on C atoms other than Q, each independently selected from alkyl.

[0152] In one embodiment, R 2a and R 2b is H and C 1~3 the same or different substituents on C atoms other than Q are each independently selected from alkyl, or R 2a and R 2b Combined, -(CH2) r - group, and r is 1, 2 or 3.

[0153] In one embodiment, r is 1.

[0154] In one embodiment, r is 2.

[0155] In one embodiment, r is 3.

[0156] In one embodiment, R 2a and R 2b are the same or different substituents on C atoms other than Q, and R 2a is Me and R 2b is H.

[0157] In one embodiment, R 2a and R 2b is a substituent on the same C atom other than Q, and R 2a and R 2b Both are Me.

[0158] In one embodiment, R 2a and R 2b is a substituent on the same C atom adjacent to Q, and R 2a and R 2b Both are Me.

[0159] In one embodiment, Y 1 , Y 2 , Y 3 and Y 4 are selected from (C, C, C, C), (N, C, C, C), (C, N, C, C), and (N, C, N, C), respectively.

[0160] In one embodiment, Y 1 , Y 2 , Y 3 and Y 4 0 or 1 of these is N, and the rest are C.

[0161] In one embodiment, Y 1 , Y 2 , Y 3 and Y 4 One or two of the groups are N, and the others are C.

[0162] In one embodiment, Y 1 , Y 2 , Y 3 and Y 4are selected from (N, C, C, C), (C, N, C, C) and (N, C, N, C), respectively.

[0163] In one embodiment, Y 1 , Y 2 , Y 3 and Y 4 One of them is N and the others are C.

[0164] In one embodiment, Y 1 is N;Y 2 , Y 3 and Y 4 are all C.

[0165] In one embodiment, Y 2 is N;Y 1 , Y 3 and Y 4 are all C.

[0166] In one embodiment, Y 1 , Y 2 , Y 3 and Y 4 Two of them are N, and the others are C.

[0167] In one embodiment, Y 1 and Y 3 is N;Y 2 and Y 4 is C.

[0168] In one embodiment, Y 1 , Y 2 , Y 3 and Y 4 are all C.

[0169] In one embodiment, q is 0 or 1.

[0170] In one embodiment, q is 0.

[0171] In one embodiment, q is 1.

[0172] In one embodiment, q is 2.

[0173] In one embodiment, q is 0, 1, or 2, and R 3 F, CN and C (if present) 1~3 Y selected from alkyl 1 , Y 2 , Y 3 and Y 4 is a substituent on any C atom of

[0174] In one embodiment, q is 0, 1, or 2, and R 3 F and C (if present) 1~3 Y selected from alkyl 1 , Y 2 , Y 3 and Y 4 is a substituent on any C atom of

[0175] In one embodiment, q is 0 or 1 and R 3 If present, F or C 1~3 Y selected from alkyl 1 , Y 2 , Y 3 and Y 4 is a substituent on any C atom of

[0176] In one embodiment, q is 0 or 1 and R 3 Y (if present) is selected from F or Me 1 , Y 2 , Y 3 and Y 4 is a substituent on any C atom of

[0177] In one embodiment, R 3 (if present) C 1~3 It is alkyl.

[0178] In one embodiment, R 3 (if present) is Me.

[0179] In one embodiment, R 3 (if present) is F.

[0180] In one embodiment, R 3 (if present) is CN.

[0181] In one embodiment, q is 1 and R 3 is Y 1 is bonded to C of

[0182] In one embodiment, q is 1 and R 3 is Y 1 C is bonded to R 3 is selected from F, CN and Me.

[0183] In one embodiment, q is 2 and both R 3 The group is F.

[0184] In one embodiment, q is 2 and R 3 The group is Y 1 and Y 3 is bonded to C of

[0185] In one embodiment, q is 2 and each R 3 The group is F and Y 1 and Y 3 is bonded to C of

[0186] In one embodiment, the linker is a saturated or partially or fully unsaturated backbone comprising C and H atoms and at least one heteroatom, said backbone having bond endpoints 'a' and 'b' with a minimum length between 'a' and 'b' of 6 to 26 atoms; said backbone may comprise one or more linear and / or branched chains and / or rings, optionally substituted by one or more F on any available C atom.

[0187] In one embodiment, the backbone of the linker is a saturated or partially unsaturated backbone.

[0188] In one embodiment, the backbone of the linker is a saturated backbone.

[0189] In one embodiment, the backbone of the linker comprises C and H atoms and at least two heteroatoms.

[0190] In one embodiment, the backbone of the linker comprises at least two heteroatoms selected from C and H atoms and O and N.

[0191] In one embodiment, the backbone of the linker comprises C and H atoms and at least one nitrogen heteroatom.

[0192] In one embodiment, the backbone of the linker comprises at least two heteroatoms, including C and H atoms and at least one nitrogen heteroatom.

[0193] In one embodiment, the backbone of the linker comprises C and H atoms and at least one nitrogen heteroatom in the form of a secondary or tertiary amine.

[0194] In one embodiment, the backbone of the linker comprises C and H atoms and at least one nitrogen heteroatom in the form of a tertiary amine.

[0195] In one embodiment, the backbone of the linker comprises at least two heteroatoms, including C and H atoms and at least one nitrogen heteroatom in the form of a secondary or tertiary amine.

[0196] In one embodiment, the backbone of the linker comprises at least two heteroatoms, including C and H atoms and at least one nitrogen heteroatom in the form of a tertiary amine.

[0197] In one embodiment, the linker has a minimum length between 'a' and 'b' of 6 to 20 atoms.

[0198] In one embodiment, the linker has a minimum length between 'a' and 'b' of 6 to 15 atoms.

[0199] In one embodiment, the linker has a minimum length between 'a' and 'b' of 7 to 14 atoms.

[0200] In one embodiment, the total number of C and heteroatoms in the linker backbone is 6-26.

[0201] In one embodiment, the total number of C and heteroatoms in the linker backbone is 7-24.

[0202] In one embodiment, the total number of C and heteroatoms in the linker backbone is 8 to 22.

[0203] In one embodiment, the total number of C and heteroatoms in the linker backbone is 9-20.

[0204] In one embodiment, W is -ZR A When the linker is X of Z, B or X C is bonded at any available C atom of

[0205] In one embodiment, the backbone of the linker may comprise one or more linear chains and / or rings, optionally substituted on any available C atom by one or more F.

[0206] In one embodiment, the backbone of the linker consists of one or more straight chains and / or rings optionally substituted on any available C atom by one or more F.

[0207] In one embodiment, the backbone of the linker may comprise (or consist of) one or more linear and / or branched chains and / or rings (total number of branches is 0 to 5) optionally substituted on any available C atom by one or more F.

[0208] In one embodiment, the backbone of the linker may comprise (or consist of) one or more linear and / or branched chains and / or rings (total number of branches is 0 to 3) optionally substituted on any available C atom by one or more F.

[0209] In one embodiment, the backbone of the linker may comprise (or consist of) one or more straight and / or branched chains and / or rings (the total number of branches is 0 or 1) optionally substituted on any available C atom by one or more F.

[0210] In one embodiment, the total number of branches is zero.

[0211] In one embodiment, the total number of branches is one.

[0212] In one embodiment, the total number of branches is two.

[0213] In one embodiment, the total number of branches is three.

[0214] In one embodiment, any / each branch in the backbone of the linker has 1 to 5 C and / or heteroatoms.

[0215] In one embodiment, any / each branch in the backbone of the linker has 1 or 2 C and / or heteroatoms.

[0216] In one embodiment, any / each branch in the backbone of the linker has one C and / or heteroatom.

[0217] In one embodiment, any / each branch in the backbone of the linker has 1 C atom.

[0218] In one embodiment, the total number of C and / or heteroatoms in the backbone branches (if present) of the linker is 1-5.

[0219] In one embodiment, the total number of C and / or heteroatoms in the backbone branches (if present) of the linker is 1-3.

[0220] In one embodiment, the total number of C and / or heteroatoms in the backbone branches (if present) of the linker is one.

[0221] In one embodiment, either backbone of the linker is branched or has one branch that is Me.

[0222] In one embodiment, the backbone of the linker is optionally substituted on any available C atom by one or two F (e.g., two F, e.g., the two F are substituted on the same carbon atom).

[0223] In one embodiment, the backbone of the linker is not substituted with any F.

[0224] In one embodiment, the linker is a saturated or partially unsaturated backbone comprising C and H atoms and at least one heteroatom, said backbone having bond endpoints 'a' and 'b'; The minimum length between 'a' and 'b' is 7 to 14 atoms; the total number of C and heteroatoms in the linker skeleton is 9 to 20; the backbone comprises one or more straight and / or branched chains and / or rings optionally substituted on any available C atom by one or two F (e.g., two F); The total number of branches is 0 or 1, and if present, said branches are Me.

[0225] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 are each independently selected from N and O.

[0226] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 are each independently selected from N and O.

[0227] In one embodiment, the backbone of the linker is A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 are each independently selected from N and O.

[0228] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 One of them is N and the other is A 1 and A 2 the other of which is selected from N or O).

[0229] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 One of them is N and the other is A 1 and A 2 the other of which is selected from N or O).

[0230] In one embodiment, the backbone of the linker is A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 One of them is N and the other is A 1 and A 2 the other of which is selected from N or O).

[0231] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 One of the groups is N in the form of a secondary or tertiary amine, and A 1 and A2 the other of which is selected from N or O).

[0232] In one embodiment, the backbone of the linker is A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 One of the groups is N in the form of a secondary or tertiary amine, and A 1 and A 2 the other of which is selected from N or O).

[0233] In one embodiment, the backbone of the linker comprises at least one saturated or partially unsaturated heterocyclic group.

[0234] In one embodiment, the backbone of the linker comprises at least one saturated heterocyclic group.

[0235] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group.

[0236] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated heterocyclic group.

[0237] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group having 4 to 12 ring atoms.

[0238] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated heterocyclic group having 4 to 12 ring atoms.

[0239] In one embodiment, the backbone of the linker is: (1)A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 are each independently selected from N and O; and / or (2) Contains at least one nitrogen-containing saturated or partially unsaturated heterocyclic group selected from piperazine, azetidine, piperidine, 1,4-diazepane, 12-oxa-3,9-diazaspiro[5.6]dodecane, pyrrolidine, 3,9-diazaspiro-[5.5]undecane, 2,5-diazabicyclo[2.2.1]heptane, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole, 1,2,3,6-tetrahydropyridine, and 9-azaspiro[5.5]undecane.

[0240] In one embodiment, the backbone of the linker is: (1)A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 One of the groups is N in the form of a secondary or tertiary amine, and A 1 and A 2 the other is selected from N or O; and / or (2) Contains at least one nitrogen-containing saturated or partially unsaturated heterocyclic group selected from piperazine, azetidine, piperidine, 1,4-diazepane, 12-oxa-3,9-diazaspiro[5.6]dodecane, pyrrolidine, 3,9-diazaspiro-[5.5]undecane, 2,5-diazabicyclo[2.2.1]heptane, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole, 1,2,3,6-tetrahydropyridine, and 9-azaspiro[5.5]undecane.

[0241] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group selected from piperazine, azetidine, piperidine, 1,4-diazepane, 12-oxa-3,9-diazaspiro[5.6]dodecane, pyrrolidine, 3,9-diazaspiro-[5.5]undecane, 2,5-diazabicyclo[2.2.1]heptane, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole, 1,2,3,6-tetrahydropyridine, and 9-azaspiro[5.5]undecane.

[0242] In one embodiment, the backbone of the linker comprises O-CH2-CH2-N units.

[0243] In one embodiment, the backbone of the linker comprises O-CH2CH2-O-CH2CH2-N units.

[0244] In one embodiment, the backbone of the linker comprises a piperazine group.

[0245] In one embodiment, the backbone of the linker comprises an azetidine group.

[0246] In one embodiment, the backbone of the linker comprises a piperidine group.

[0247] In one embodiment, the backbone of the linker comprises a 1,4-diazepane group.

[0248] In one embodiment, the backbone of the linker comprises a 12-oxa-3,9-diazaspiro[5.6]dodecane group.

[0249] In one embodiment, the backbone of the linker comprises a pyrrolidine group.

[0250] In one embodiment, the backbone of the linker comprises a 3,9-diazaspiro[5.5]undecane group.

[0251] In one embodiment, the backbone of the linker comprises a 2,5-diazabicyclo[2.2.1]heptane group.

[0252] In one embodiment, the backbone of the linker comprises 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole groups.

[0253] In one embodiment, the backbone of the linker comprises 1,2,3,6-tetrahydropyridine groups.

[0254] In one embodiment, the backbone of the linker comprises a 9-azaspiro[5.5]undecane group.

[0255] In one embodiment, the backbone of the linker comprises at least two nitrogen-containing saturated or partially unsaturated heterocyclic groups.

[0256] In one embodiment, the backbone of the linker comprises at least two nitrogen-containing saturated heterocyclic groups.

[0257] In one embodiment, the backbone of the linker comprises a C, N or O atom at the 'a' point of attachment.

[0258] In one embodiment, the backbone of the linker comprises an N or O atom at the 'a' point of attachment.

[0259] In one embodiment, the backbone of the linker comprises an N or O atom at the 'b' point of attachment.

[0260] In one embodiment, the backbone of the linker comprises a C atom at the 'a' point of attachment.

[0261] In one embodiment, the backbone of the linker comprises an N atom at the 'a' point of attachment.

[0262] In one embodiment, the backbone of the linker comprises a C or N atom at the 'b' point of attachment.

[0263] In one embodiment, the backbone of the linker comprises an N atom at the 'b' point of attachment.

[0264] In one embodiment, the backbone of the linker comprises a C atom at the 'b' point of attachment.

[0265] In one embodiment, the backbone of the linker comprises an O atom at the 'a' point of attachment.

[0266] In one embodiment, the backbone of the linker comprises an O atom at the 'b' point of attachment.

[0267] In one embodiment, the backbone of the linker contains N or O atoms at both the 'a' and 'b' points of attachment.

[0268] In one embodiment, the backbone of the linker comprises a C, N or O atom at the 'a' point of attachment and a C or N atom at the 'b' point of attachment.

[0269] In one embodiment, the backbone of the linker is: (1)A 1 -CH2-CH2-A 2 Unit (A 1 and A 2 One of the groups is N in the form of a secondary or tertiary amine, and A 1 and A 2 the other is selected from N or O; and / or (2) Contains at least one nitrogen-containing saturated or partially saturated heterocyclic group selected from piperazine-1,4-diyl, azetidine-1,3-diyl, piperidine-1,4-diyl, 1,4-diazepane-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl, pyrrolidine-1,3-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, 3,6-dihydro-2H-pyridine-1,4-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0270] In one embodiment, the backbone of the linker comprises at least one nitrogen-containing saturated or partially saturated heterocyclic group selected from piperazine-1,4-diyl, azetidine-1,3-diyl, piperidine-1,4-diyl, 1,4-diazepane-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl, pyrrolidine-1,3-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, 3,6-dihydro-2H-pyridine-1,4-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0271] In one embodiment, the backbone of the linker comprises piperazine-1,4-diyl groups.

[0272] In one embodiment, the backbone of the linker comprises an azetidine-1,3-diyl group.

[0273] In one embodiment, the backbone of the linker comprises piperidine-1,4-diyl groups.

[0274] In one embodiment, the backbone of the linker comprises a 1,4-diazepane-1,4-diyl group.

[0275] In one embodiment, the backbone of the linker comprises a 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl group.

[0276] In one embodiment, the backbone of the linker comprises pyrrolidine-1,3-diyl groups.

[0277] In one embodiment, the backbone of the linker comprises a 3,9-diazaspiro[5.5]undecane-3,9-diyl group.

[0278] In one embodiment, the backbone of the linker comprises a 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl group.

[0279] In one embodiment, the backbone of the linker comprises 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl groups.

[0280] In one embodiment, the backbone of the linker comprises a 3,6-dihydro-2H-pyridine-1,4-diyl group.

[0281] In one embodiment, the backbone of the linker comprises a 9-azaspiro[5.5]undecane-3,9-diyl group.

[0282] In one embodiment, the linker has the formula: 'a'-Q A -Q B -Q C-'b' (In the formula, 'a' and 'b' represent the end points of the connection; Q A -GQ H -or-G-(C 1~5 alkylene)-; Q B is a direct bond, -Q B1 -Q B2 -Q B3 or C optionally substituted by one or more F (e.g., 1 or 2 F, e.g., 2 F) 1~3 is alkylene; Q B1 and Q B3 are each independently a direct bond or C 1~2 represents alkylene; Q B2 Q H , —O—CH2CH2—O—, —O— or —N(R J )-(wherein, R J is H or C 1~3 alkyl); Q C -Q H -G- or -(C 1~5 alkylene)-G-; Each G is independently a direct bond, —CH—, —O—, or —N(R G )-(in the formula, each R G are independently H or C 1~3 alkyl); Each Q H are independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; Q A , Q B and Q C The value of is selected so that the linker does not contain any N-N or N-O bonds.

[0283] In one embodiment, the linker has the formula: 'a'-Q A -Q B -Q C -'b' (In the formula, 'a' and 'b' represent the end points of the connection; Q A -GQ H -or-G-(C 1~5 alkylene)-; Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or C optionally substituted by one or more F (e.g., 1 or 2) 1~3 is alkylene; Q B1 and Q B3 are each independently a direct bond or C 1~2 represents alkylene; Q B2 Q H , —O—CH2CH2—O— or —N(R J )-(wherein, R J is C 1~3 alkyl); Q C -Q H -G- or -(C 1~5 alkylene)-G-; Each G is independently a direct bond, —CH—, —O—, or —N(R G )-(in the formula, each R G are independently H or C 1~3 alkyl); Each Q H are independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; Q A , Q B and Q C The value of is selected so that the linker does not contain any N-N or N-O bonds.

[0284] In one embodiment, the linker has the formula: 'a'-Q A -Q B -Q C -'b' (In the formula, 'a' and 'b' represent the end points of the connection; Q A -GA -Q HA -or-G A -(C 1~5 alkylene)-; G A is a direct bond, —CH—, —O—, —NH—, or —N(Me)—; Q HA is a 4- to 11-membered nitrogen-containing saturated heterocyclic group; Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or C optionally substituted by one or more F (e.g., 1 or 2) 1~3 is alkylene; Q B1 and Q B3 are each independently a direct bond or C 1~2 represents alkylene; Q B2 is piperazine-1,4-diyl, -O-CH2CH2-O- or -N(R J )-(wherein, R J is C 1~3 alkyl); Q C -Q HC -G C -or-(C 1~2 Alkylene)-G C -And;G C is a direct bond, —O— or —NH—; Q HC is a 6- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; Q A , Q B and Q C The value of is selected so that the linker does not contain any N-N or N-O bonds.

[0285] In one embodiment, Q A -G A -Q HA -or-G A -(C 1~5 alkylene)-, G A is a direct bond, -CH2-, -O- or -N(RG )-selected from; Each R G are independently H or C 1~3 is alkyl; Q HA is a 4- to 11-membered nitrogen-containing saturated heterocyclic group.

[0286] In one embodiment, Q A -G A -Q HA -or-G A -(C 1~5 alkylene)-, G A is a direct bond, -CH2-, -O- or -N(R G )-selected from; Each R G are independently H or C 1~3 is alkyl; Q HA is selected from azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl and 9-azaspiro[5.5]undecane-3,9-diyl.

[0287] In one embodiment, Q A -G A -Q HA -or-G A -(C 1~5 alkylene)-, G A is selected from a direct bond, —CH—, —O—, —NH—, or —N(Me)—; Q HA is selected from azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl and 9-azaspiro[5.5]undecane-3,9-diyl; -G A -(C 1~5 C in alkylene)- 1~5 Alkylene is -(CH2) f-(f is an integer from 1 to 5), cyclobuta-1,3-diyl, and -CH2(cyclobuta-1,3-diyl)-.

[0288] In one embodiment, Q A are azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, -O(piperidine-1,4-diyl)-, -CH2(piperidine-1,4-diyl)-, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, -O(9-azaspiro[5.5]undecane-3,9-diyl)-, -O(cyclobuta-1,3-diyl)-, -OCH2(cyclobuta-1,3-diyl)-, -(CH2) f -, -O-(CH2) f -, -NH-(CH2) f - and -N(Me)-(CH2) f -(f is an integer from 1 to 5).

[0289] In one embodiment, Q A is azetidine-1,3-diyl.

[0290] In one embodiment, Q A is pyrrolidine-1,3-diyl.

[0291] In one embodiment, Q A is piperidine-1,4-diyl.

[0292] In one embodiment, Q A is -O(piperidine-1,4-diyl)-.

[0293] In one embodiment, Q A is -CH2(piperidine-1,4-diyl)-.

[0294] In one embodiment, Q A is piperazine-1,4-diyl.

[0295] In one embodiment, Q Ais 3,9-diazaspiro[5.5]undecane-3,9-diyl.

[0296] In one embodiment, Q A is -O(9-azaspiro[5.5]undecane-3,9-diyl)-.

[0297] In one embodiment, Q A is -G-(C 1~5 alkylene).

[0298] In one embodiment, Q A are -O(cyclobuta-1,3-diyl)-, -OCH2(cyclobuta-1,3-diyl)-, -(CH2) f -, -O-(CH2) f -, -NH-(CH2) f - and -N(Me)-(CH2) f -(f is an integer from 1 to 5).

[0299] In one embodiment, Q A is -O(cyclobuta-1,3-diyl)-.

[0300] In one embodiment, Q A is -OCH2(cyclobuta-1,3-diyl)-.

[0301] In one embodiment, Q A is -(CH2) f -(f is an integer from 1 to 4 (for example, f is 4)).

[0302] In one embodiment, Q A is -O-(CH2) f -(f is an integer from 1 to 5 (for example, f is 1 or 2)).

[0303] In one embodiment, Q A is -NH-(CH2) f -(f is an integer from 1 to 5).

[0304] In one embodiment, QA is -N(Me)-(CH2) f -(f is an integer from 1 to 4).

[0305] In one embodiment, Q B is a direct bond, -Q B1 -Q B2 -Q B3 -or a straight chain C optionally substituted with one or more F (e.g., 1 or 2 F, e.g., 2 F) 1~3 It is alkylene.

[0306] In one embodiment, Q B is a direct bond.

[0307] In one embodiment, Q B -Q B1 -Q B2 -Q B3 -It is.

[0308] In one embodiment, Q B is C optionally replaced by one or more F 1~3 It is alkylene.

[0309] In one embodiment, Q B is C optionally substituted by 1 or 2 F (e.g., 2 F); 1~3 It is alkylene.

[0310] In one embodiment, Q B is a linear C optionally substituted with 1 or 2 F (e.g., 2 F) 1~3 It is alkylene.

[0311] In one embodiment, Q B is C 1~3 It is alkylene.

[0312] In one embodiment, Q B is a linear C 1~3 It is alkylene.

[0313] In one embodiment, QB is -CF2-CH2-CH2- or -(CH2) w (wherein w is 1 to 3).

[0314] In one embodiment, Q B1 and Q B3 each independently represents a direct bond, —CH2— or —CH2CH2—.

[0315] In one embodiment, Q B1 is a direct bond or -CH2-.

[0316] In one embodiment, Q B1 is a direct bond.

[0317] In one embodiment, Q B1 is -CH2-.

[0318] In one embodiment, Q B3 is a direct bond, -CH2- or -CH2CH2-.

[0319] In one embodiment, Q B3 is a direct bond.

[0320] In one embodiment, Q B3 is -CH2-.

[0321] In one embodiment, Q B3 is -CH2CH2-.

[0322] In one embodiment, Q B2 Q H , —O—CH2CH2—O— or —N(R J )-(wherein, R J is C 1~3 alkyl).

[0323] In one embodiment, Q B2 Q H , —O—CH2CH2—O— or —N(Me)—.

[0324] In one embodiment, Q B2 is piperazine-1,4-diyl, azetidine-1,3-diyl, —O—CH2CH2—O—, or —N(Me)—.

[0325] In one embodiment, Q B2 is piperazine-1,4-diyl, -O-CH2CH2-O- or -N(Me)-.

[0326] In one embodiment, Q B2 Q H is.

[0327] In one embodiment, Q B2 is piperazine-1,4-diyl.

[0328] In one embodiment, Q B2 is azetidine-1,3-diyl.

[0329] In one embodiment, Q B2 is -O-CH2CH2-O-.

[0330] In one embodiment, Q B2 is -N(R J )-(wherein, R J is C 1~3 alkyl).

[0331] In one embodiment, Q B2 is -N(Me)-.

[0332] In one embodiment, Q C -Q H -G- or -(C 1~4 alkylene)-G-.

[0333] In one embodiment, Q C -Q H -G- or -(C 1~3 alkylene)-G-.

[0334] In one embodiment, Q C -QH -G- or -(C 1~2 alkylene)-G-.

[0335] In one embodiment, Q C -Q HC -G C -or-(C 1~5 Alkylene)-G C - and G C is selected from a direct bond, —O—, or —NH—; Q HC is a 6- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.

[0336] In one embodiment, Q C -Q HC -G C -or-(C 1~2 Alkylene)-G C - and G C is selected from a direct bond, —O—, or —NH—; Q HC is a 6- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.

[0337] In one embodiment, Q C -Q HC -G C -or-(C 1~2 Alkylene)-G C - and G C is selected from a direct bond, —O—, or —NH—; Q HC is selected from piperazine-1,4-diyl, piperidine-1,4-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,4-diazepane-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 12-oxa-3,9-diazaspiro[5.6]-dodecane-3,9-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, and 3,6-dihydro-2H-pyridine-1,4-diyl.

[0338] In one embodiment, Q C are piperazine-1,4-diyl, piperidine-1,4-diyl, -(piperidine-1,4-diyl)O-, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,4-diazepane-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 12-oxa-3,9-diazaspiro[5.6]-dodecane-3,9-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, 3,6-dihydro-2H-pyridine-1,4-diyl, and -CHCH-NH- and -(CH) g -O- (wherein g is an integer of 1 to 4).

[0339] In one embodiment, Q C is piperazine-1,4-diyl.

[0340] In one embodiment, Q C is piperidine-1,4-diyl.

[0341] In one embodiment, Q C is -(piperidine-1,4-diyl)O-.

[0342] In one embodiment, Q C is 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl.

[0343] In one embodiment, Q C is 1,4-diazepan-1,4-diyl.

[0344] In one embodiment, Q C is 3,9-diazaspiro[5.5]undecane-3,9-diyl.

[0345] In one embodiment, Q C is 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl.

[0346] In one embodiment, QC is 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl.

[0347] In one embodiment, Q C is 3,6-dihydro-2H-pyridine-1,4-diyl.

[0348] In one embodiment, Q C is -(C 1~5 alkylene)-G-[e.g., -(CH2) g -O- (wherein g is an integer of 1 to 5).

[0349] In one embodiment, Q C is -(C 1~4 alkylene)-G-[e.g., -(CH2) g -O- (wherein g is an integer of 1 to 4).

[0350] In one embodiment, Q C is -(C 1~3 alkylene)-G-[e.g., -(CH2) g -O- (wherein g is 1, 2 or 3)].

[0351] In one embodiment, Q C is -(C 1~2 alkylene)-G-[e.g., -(CH2) g -O- (wherein g is 1 or 2)].

[0352] In one embodiment, Q C is -(CH2) g -G C -(g is an integer from 1 to 5, G C is —O— or —NH—).

[0353] In one embodiment, Q C is -(CH2) g -G C -(g is 1 or 2, G C is —O— or —NH—).

[0354] In one embodiment, Q C is -CH2CH2NH-.

[0355] In one embodiment, each Q H is independently selected from piperazine-1,4-diyl, azetidine-1,3-diyl, piperidine-1,4-diyl, 1,4-diazepane-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl, pyrrolidine-1,3-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, 3,6-dihydro-2H-pyridine-1,4-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0356] In one embodiment, each Q H are independently selected from piperazine-1,4-diyl, azetidine-1,3-diyl, piperidine-1,4-diyl, 1,4-diazepane-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl, pyrrolidine-1,3-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0357] In one embodiment, Q H is piperazine-1,4-diyl.

[0358] In one embodiment, Q H is azetidine-1,3-diyl.

[0359] In one embodiment, Q H is piperidine-1,4-diyl.

[0360] In one embodiment, Q H is 1,4-diazepan-1,4-diyl.

[0361] In one embodiment, Q H is 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl.

[0362] In one embodiment, Q H is pyrrolidine-1,3-diyl.

[0363] In one embodiment, Q H is 3,9-diazaspiro[5.5]undecane-3,9-diyl.

[0364] In one embodiment, Q H is 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl.

[0365] In one embodiment, Q H is 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl.

[0366] In one embodiment, Q H is 3,6-dihydro-2H-pyridine-1,4-diyl.

[0367] In one embodiment, Q H is 9-azaspiro[5.5]undecane-3,9-diyl.

[0368] In one embodiment, R J is C 1~3 It is alkyl.

[0369] In one embodiment, R J is Me.

[0370] In one embodiment, R G is C 1~3 It is alkyl.

[0371] In one embodiment, RG is H or Me.

[0372] In one embodiment, R G is Me.

[0373] In one embodiment, R G is H.

[0374] In one embodiment, the linker (e.g., 'a'-Q A -Q B -Q C -'b') is selected from any of the linkers 1-46 or 1-48 shown below: [ka] [ka] [ka]

[0375] In one embodiment, W is an E3 ubiquitin ligase cereblon conjugate unit attached to the 'b' end of the linker via an available C atom in the E3 ubiquitin ligase cereblon conjugate unit.

[0376] In one embodiment, W is W1, which is -Z-(R A ) h (Wherein Z is [ka] and [ka] represents a single or double covalent bond; X A , X B , X C , X D , X E and X F 0, 1 or 2 of the XE and X F are both not N, otherwise C; X G , X H and X J One of them is C(O); X G , X H and X J One of the groups is N-(2,6-dioxopiperidin-3-yl)(Y); X G , X H and X J One of them is C(R T )2, -CH2CH2-, C(O), N(C 1~3 alkyl), -O-, and -N=, and each R T is selected from H, F, Me or C(R T ) together with carbon 2 to form a cyclopropa-1,1-diyl group; X G , X H and X J does not have two C(O) groups at adjacent positions, and N-(2,6-dioxopiperidin-3-yl) is N(C 1~3 is selected so as not to be present adjacent to either an alkyl group or an O; Each R A are independently F, Cl, C 1~3 Alkyl, C 1~3 X selected from alkoxy A , X B , X C or X D is a substituent on any available C atom in 1~3 Alkyl and C 1~3 The alkoxy is independently optionally substituted with one or more F; h is 0, 1 or 2; The linker is X A , X B , X C or X D (bonded to any C atom in

[0377] In one embodiment, XA , X B , X C , X D , X E and X F 0 or 1 of these is N, and the rest are C.

[0378] In one embodiment, X A , X B , X C , X D , X E and X F One or two of the groups are N, and the others are C.

[0379] In one embodiment, X A , X B , X C , X D , X E and X F are all C.

[0380] In one embodiment, X A , X B , X C , X D , X E and X F One of them is N and the others are C.

[0381] In one embodiment, X A , X B , X C , X D , X E and X F Two of them are N (X E and X F are both not N), otherwise it is C.

[0382] In one embodiment, X B , X D and X F are all C and X A , X C and X E 0, 1 or 2 of the following are N, and the rest are C.

[0383] In one embodiment, X B , X D and X F are all C and X A , X C and X E 0, 1 or 2 of the X's are N, and the rest are C; A is C, the linker is X B or X A is combined with

[0384] In one embodiment, X B , X D and X F are all C and X A , X C and X E 0, 1 or 2 of are N and the rest are C; the linker is X B is combined with

[0385] In one embodiment, X G -X H -X J teeth, (i)X G -NY-C(O) (wherein X G is -CH2-, -CH2CH2-, ═N- or C(O); (ii) X G —C(O)—NY (wherein X G is -O- or N(C 1~3 alkyl) [e.g., N(Me)]; or (iii) C(O)-NY-CH is.

[0386] In one embodiment, the linker is X A or X B is bonded to the C atom of X G -X H -X J teeth, (i)X G -NY-C(O) (wherein X G is -CH2-, -CH2CH2-, ═N- or C(O); (ii) X G —C(O)—NY (wherein XG is -O- or N(C 1~3 alkyl) [e.g., N(Me)]; or (iii) C(O)-NY-CH is.

[0387] In one embodiment, the linker is X B is bonded to the C atom of X G -X H -X J teeth, (i)X G -NY-C(O) (wherein X G is -CH2-, -CH2CH2-, ═N- or C(O); (ii) X G —C(O)—NY (wherein X G is -O- or N(C 1~3 alkyl) [e.g., N(Me)]; or (iii) C(O)-NY-CH is.

[0388] In one embodiment, X G -X H -X J is CH2-NY-C(O).

[0389] In one embodiment, X G -X H -X J is CH2CH2-NY-C(O).

[0390] In one embodiment, X G -X H -X J is =N-NY-C(O).

[0391] In one embodiment, X G -X H -X J is C(O)-NY-C(O).

[0392] In one embodiment, X G -X H -X J is OC(O)-NY.

[0393] In one embodiment, X G -X H -X J is N(C 1~3 alkyl)-C(O)-NY [e.g., N(Me)-C(O)-NY].

[0394] In one embodiment, X G -X H -X J is C(O)-NY-CH2.

[0395] In one embodiment, each R A is F, Cl and C optionally substituted with one or more F 1~3 X selected from alkoxy A , X B , X C or X D is any available substituent on C.

[0396] In one embodiment, each R A is selected from F, Cl, OMe and -OCHF2 A , X B , X C or X D is any available substituent on C.

[0397] In one embodiment, h is 0.

[0398] In one embodiment, h is 1.

[0399] In one embodiment, h is 2.

[0400] In one embodiment, the linker is X C is combined with X C is C;X A is R A is bonded to R A is OMe, wherein said methyl is optionally substituted with one or more F (e.g., -OCHF2).

[0401] In one embodiment, the linker is X C is combined with X C is C;X A is R A is bonded to R A is OMe or -OCHF2.

[0402] In one embodiment, -Z-(R A ) h together represent any one of groups 1, 4, 16, 17 and 19 (the specific -Z-(R A ) h (Refers to groups 1 to 21).

[0403] In one embodiment, h is 1 and R A is C 1~3 Alkoxy [eg, OMe].

[0404] In one embodiment, h is 1 or 2 and one R A is OMe, and the other R A (if present, ie, when h is 2) is Cl.

[0405] In one embodiment, h is 1 or 2 and one R A is Cl, and the other R A (if present, i.e., when h is 2) is OMe.

[0406] In one embodiment, h is 1 and R A is F.

[0407] In one embodiment, h is 1 and R A is Cl.

[0408] In one embodiment, h is 1 and R A is -OCHF2.

[0409] In one embodiment, the linker is X A or X B is bonded to C, and h is 0.

[0410] In one embodiment, the linker is X A or X B C is bonded to R, h is 1 A is X C is the substituent on C is C and R A is F.

[0411] In one embodiment, the linker is X A or X B is bonded to C, h is 1, and R A is X D is the substituent on D is C and R A is OMe or -OCHF2.

[0412] In one embodiment, the linker is X B and h is 0, 1 or 2; A (if present, i.e., when h is 1 or 2), X D is a substituent on an available C of A (if it exists, i.e., h is 2), then X A Available on C.

[0413] In one embodiment, the linker is X B and h is 0, 1 or 2; A (if present, i.e., when h is 1 or 2), X is selected from Cl, OMe, and —OCHF D is a substituent on an available C of A (if it exists, i.e., h is 2), then X A is on an available C and is selected from Cl and OMe.

[0414] In one embodiment, -Z-(R A ) h together represent any of the groups 1 to 21 shown below: [ka]

[0415] In one embodiment, W is W2, which is [ka] and Z A teeth, [ka] where: [ka] represents a single or double covalent bond; X A2 , X B2 , X C2 and X D2 one of which is C and is covalently bonded to Y; X A2 , X B2 , X C2 , X D2 , X E2 and X F2 0, 1 or 2 of the E2 and X F2 are both not N), otherwise C; X G2 , X H2 and X J2 one or two of are N; the others are C; Each R AA is a substituent on any available C or N atom of Z, and in each case, one or more R AA2 R optionally replaced by AA1 are independently selected from R AA Z A When R is a substituent on an available C atom of AA Furthermore, R AA2 Selected from; Each R AA1 independently, C 1~4 Alkyl, C 2~3Alkenyl, C 2~3 Alkynyl, C 1~3 Alkoxy C 1~3 Alkyl, carboxy C 1~3 Alkyl, C 5~7 carbocyclyl or 4- to 6-membered heterocyclyl; Each R AA2 are independently F, Cl, Br, CN, NH2, C 1~3 Alkyl, O(C 1~3 alkyl), NH(C 1~3 alkyl), and N(C 1~3 alkyl)2; 1~3 The alkyl is optionally substituted with one or more F; v is 0, 1 or 2; Y is N-(2,6-dioxopiperidin-3-yl).

[0416] In one embodiment, Z A teeth, [ka] where: [ka] represents a single or double covalent bond; X A2 and X B2 One of the groups is C and is covalently bonded to Y, and X A2 and X B2 The other is C; X C2 and X D2 0 or 1 of these is N, and the rest are C; X G2 and X J2 One of them is N and the other is X G2 and X J2 The other is C; X H2 , X E2 and X F2 are all C.

[0417] In one embodiment, -Z A-Y together represent one or more of the groups A1 to A6 shown below, and in each case, A The group is -[R AA ] V is optionally substituted on available C and / or N atoms by [ka]

[0418] In one embodiment, each R AA is Z A and in each case one or more R AA2 R optionally replaced by AA1 are independently selected from R AA Furthermore, R AA is a substituent on an available C atom of Z, then R AA2 Each R is selected from AA1 independently, C 1~4 alkyl or 4- to 6-membered heterocyclyl; each R AA2 are independently F, Cl, CN and C 1~3 alkyl.

[0419] In one embodiment, each R AA is Z A and in each case one or more R AA2 R optionally replaced by AA1 are independently selected from R AA Z A When R is a substituent on an available C atom of AA Furthermore, R AA2 Each R is selected from AA1 is independently methyl, isopropyl, cyclopropyl, pyridinyl, or pyrazolyl; each R AA2 are independently F, Cl, CN or methyl.

[0420] In one embodiment, each R AA is ZA are substituents on available C atoms of each independently selected from methyl, isopropyl, cyclopropyl, pyridin-2-yl, 1-methylpyrazol-4-yl, -CHCN, F, Cl, CN; and / or Z A is a methyl substituent on an available N atom of

[0421] In one embodiment, v is 0.

[0422] In one embodiment, v is 1.

[0423] In one embodiment, v is 2.

[0424] In one embodiment, v is 1 or 2.

[0425] In one embodiment, v is 0 or 1.

[0426] In one embodiment, v is 1; A1 is a C atom; R AA is X A1 The above substituents.

[0427] In one embodiment, v is 1; A1 is a C atom; R AA is X A1 Upper C 1~4 It is an alkyl substituent.

[0428] In one embodiment, v is 1; B1 is a C atom; R AA is X B1 The above substituents.

[0429] In one embodiment, v is 1; B1 is a C atom; R AA is X B1 Upper C 1~4 Alkyl (eg, methyl) substituents.

[0430] In one embodiment, v is 1;C1 is a C atom; R AA is X C1 The above substituents.

[0431] In one embodiment, v is 1; C1 is a C atom; R AA is X C1 Upper C 1~4 Alkyl (eg, methyl) substituents.

[0432] In one embodiment, v is 1; D1 is a C atom; R AA is X D1 The above substituents.

[0433] In one embodiment, v is 1; D1 is a C atom; R AA is X D1 Upper C 1~4 It is an alkyl (eg, methyl) or F substituent.

[0434] In one embodiment, v is 1; G1 is a C atom; R AA is X G1 The above substituents.

[0435] In one embodiment, v is 1; G1 is a C atom; R AA is X G1 The above substituents are R AA is one or more R AA2 R optionally replaced by AA1 or R AA is R AA2 Selected from; R AA1 is C 1~4 alkyl or 4- to 6-membered heterocyclyl; R AA2 are F, Cl, CN and C 1~3 alkyl.

[0436] In one embodiment, v is 1; G1 is a C atom; RAA is X G1 The above substituents are R AA is selected from methyl, isopropyl, cyclopropyl, pyridin-2-yl, 1-methylpyrazol-4-yl, —CH 2 CN, F, Cl and CN.

[0437] In one embodiment, v is 1 or 2; X G1 is a C atom; R AA is X G1 The above substituents are R AA is one or more R AA2 R optionally replaced by AA1 or R AA is R AA2 Selected from; R AA1 is C 1~4 alkyl or 4- to 6-membered heterocyclyl; R AA2 are F, Cl, CN and C 1~3 alkyl; when v is 2, an additional R AA is Z A is a fluoro substituent on an available C atom of

[0438] In one embodiment, v is 1; G1 is an N atom; R AA is X G1 The above substituents.

[0439] In one embodiment, v is 1; G1 is an N atom; R AA is X G1 Upper C 1~4 Alkyl (eg, methyl) substituents.

[0440] In one embodiment, v is 1; H1 is a C atom; R AA is X H1 The above substituents.

[0441] In one embodiment, v is 1; H1 is a C atom; R AA is CN or C1~4 X is alkyl (e.g., methyl) H1 The above substituents.

[0442] In one embodiment, v is 1 or 2; X H1 and X G1 are both C atoms, and one or both of them are R AA Each R is replaced by AA are independently CN or C 1~4 alkyl (eg, methyl).

[0443] In one embodiment, the group: [ka] together represent one or more of the groups A1 to A29 shown below: [ka] [ka]

[0444] In some of these embodiments, W is W2-1 [ka] (In the formula, X K and X L are an N-linker and CH or NMe and a C-linker, respectively; X M and X O one of which is N-(2,6-dioxopiperidin-3-yl)(Y); X M and X N 0 or 1 of is CF; X N is X M If is not CF, it may be N; X N , X M and X OThe remainder is CH).

[0445] In one embodiment, W represents any of groups 22-26 shown below: [ka]

[0446] In a further aspect of the present specification, formula (Ia) is selected from any one or more of the following groups (1) to (28) or (1) to (39): (1) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl, (2) 4-[1-(4-cyano-3-cyclopropyl-phenyl)-4-piperidyl]phenyl, (3) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl, (4) 2-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyrimidin-5-yl, (5) 6-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyridin-3-yl, (6) 4-[1-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-4-piperidyl]phenyl, (7) 4-[1-(3-chloro-4-cyano-phenyl)-4-piperidyl]phenyl, (8) 4-[1-(4-cyano-3-methoxy-phenyl)-4-piperidyl]phenyl, (9) 4-[1-(5-cyano-6-methyl-2-pyridyl)-4-piperidyl]phenyl, (10) 4-[1-(5-cyano-8-quinolyl)-4-piperidyl]phenyl, (11) 4-[(4S)-1-[4-cyano-3-(trifluoromethyl)phenyl]-3,3-dimethyl-4-piperidyl]phenyl (12) 4-[(4R)-1-[4-cyano-3-(trifluoromethyl)phenyl]-3,3-dimethyl-4-piperidyl]phenyl (13) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-3,3-dimethyl-4-piperidyl]phenyl, (14) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-2-fluorophenyl, (15) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-fluorophenyl, (16) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-methylphenyl, (17) 4-[(2S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl, (18) 4-[(2R)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl, (19) 4-[4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl, (20) 5-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyridin-2-yl, (21) 4-[4-[4-cyano-3-(trifluoromethyl)phenyl]piperazin-1-yl]phenyl, (22) 4-[(3R)-1-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl, (23) 4-[(3S)-1-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl, (24) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl, (25) 4-[1-[4-cyano-3-(difluoromethyl)phenyl]-4-piperidyl]phenyl, (26) 4-[(4R)-1-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl, (27) 4-[(4R)-1-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl, (28) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl, (29) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-3,5-difluoro-phenyl, (30) 4-[(2S)-4-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl, (31) 4-[(3R)-4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methyl-piperazin-1-yl]phenyl, (32) 4-[(3S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methyl-piperazin-1-yl]phenyl, (33) (3S,4R)-1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-4-piperidyl, (34) (3R,4S)-1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-4-piperidyl, (35) 4-[1-[4-cyano-2-ethyl-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl, (36) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3,5-difluoro-phenyl, (37) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-fluoro-phenyl, (38) 4-[1-(4-cyano-3-cyclopropyl-phenyl)-4-piperidyl]-3-fluoro-phenyl and (39) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-methyl-phenyl.

[0447] In a further aspect herein, a compound comprising an E3 ubiquitin ligase cereblon conjugate unit and a compound of formula (Ia) or formula (Ib): [ka] (In the formula, Q A -GQ H -or-G-(C 1~5 alkylene)-; G is a direct bond, -CH2-, -O-, or -N(R G )-(in the formula, each R G are independently H or C 1~3 alkyl); Q H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, R 2a , R 2b , Q, Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q may each take any of the values ​​defined herein for each of these groups / variables), or a pharmaceutically acceptable salt thereof.

[0448] In one embodiment, Q H is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0449] For the avoidance of doubt, in formula (Ib) [ka] indicates the point of attachment to the remainder of the RROTAC compound via a single covalent bond.

[0450] In a further aspect herein, there is provided a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit of formula (Ib) linked to an AR binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof.

[0451] In a further embodiment herein, formula (Ib) is [ka] (In the formula, L X may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with formula (Ia); Q A Q A (which may take any value disclosed herein for

[0452] In a further aspect herein, there is provided a method for the preparation of an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) of formula (Ic): [ka] (In the formula, Q A -GQ H -or-G-(C 1~5 alkylene)-; G is a direct bond, -CH2-, -O-, or -N(R G )-(wherein, R G is H or C 1~3 alkyl); Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or C optionally substituted by one or more F (e.g., 1 or 2) 1~3 is alkylene; Q B1 and Q B3 are each independently a direct bond or C 1~2 represents alkylene; Q B2 Q H, —O—CH2CH2—O—, —O— or —N(R J )-(wherein, R J is H or C 1~3 alkyl); Each Q H are independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; Q A and Q B is selected such that formula (Ic) does not contain any N-N or N-O bonds; Other R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, R 2a , R 2b , Q, Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q may each take any of the values ​​defined herein for each of these groups / variables. or a pharmaceutically acceptable salt thereof.

[0453] In one embodiment, Q H is a 4- to 12-membered nitrogen-containing saturated heterocyclic group. [ka] indicates the point of attachment to the remainder of the RROTAC compound via a single covalent bond.

[0454] In a further aspect herein, there is provided a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit of formula (Ic) linked to an AR binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof.

[0455] In a further embodiment herein, formula (Ib) is [ka] (In the formula, L X may be any of the groups (1) to (28) listed hereinabove in connection with formula (Ia); Q A and Q B Q A and Q B may take any value disclosed herein for It could be.

[0456] In further embodiments, a compound or a pharmaceutically acceptable salt thereof is provided, wherein the compound is selected from one or more of the "Examples" listed herein below. Accordingly, these embodiments include Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 11 , 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142 , 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 153, 164, 165, 166, and 167.

[0457] The example compounds listed herein below are by title compound name and should be understood to be in no way limited by the method of preparation or whether a given compound was isolated in the form of a salt rather than as a neutral molecule.

[0458] In some embodiments, the compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof (In the formula, R Z1 is H or F; R Z2 is H or F; R Z3 is H or F; L Z is a linker selected from 1, 3, 45 and 47: [ka] and W Z are 1, 2, 3, 10, 16, 22, 23, 24 and 26: [ka] [ka] wherein Y is N-(2,6-dioxopiperidin-3-yl).

[0459] In some embodiments, the compound of formula (VI-1): [ka] or a pharmaceutically acceptable salt thereof (In the formula, R Z1 is H or F; L Z is a linker selected from 1 and 3: [ka] and W Z are 1, 2 and 10: [ka] wherein Y is N-(2,6-dioxopiperidin-3-yl).

[0460] In some embodiments, the compound of formula (VI-2): [ka] or a pharmaceutically acceptable salt thereof (In the formula, R Z1 is H or F; R Z2 is H or F; R Z3 is H or F; L Z is a linker selected from 3, 45 and 47: [ka] and W Z are 1, 3, 16, 22, 23, 24 and 26: [ka] [ka] wherein Y is N-(2,6-dioxopiperidin-3-yl).

[0461] Further embodiments are described in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, and 136 are individually disclaimed.

[0462] Further embodiments are described in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 09, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151 Any of the embodiments, claims, or aspects defined herein are provided, provided that one or more specific examples (e.g., one example, or two or three specific examples) selected from the group consisting of 1, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 153, 164, 165, 166, and 167 are individually disclaimed.

[0463] It will be appreciated that compounds of formula (I) and PROTAC compounds containing linking units of formula (Ia) may possess one or more chiral centers, and that such compounds may be prepared, isolated, and / or provided with or without the further presence of one or more other possible enantiomers and / or diastereoisomers of said compounds, or that such isomers may be provided in any relative ratio. The preparation of enantiomerically enriched / enantiopure and / or diastereoenriched / diastereopure compounds may be carried out by standard techniques of organic chemistry well known in the art, for example, by synthesis from enantiomerically enriched or enantiopure starting materials and / or by use of a suitable enantiomerically enriched or enantiopure catalyst during synthesis, and / or by resolution of a racemic or partially enriched mixture of stereoisomers, for example via chiral chromatography.

[0464] For use in a pharmaceutical context, it may be preferable to provide such compounds (or pharmaceutically acceptable salts thereof) in the absence of significant amounts of other stereoisomeric forms.

[0465] Thus, in one embodiment, there is provided a composition comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof is present in the composition in a diastereomeric excess (%de) of ≥ 90%.

[0466] In a further embodiment, the %de in the above composition is ≧95%.

[0467] In a further embodiment, the %de in the above composition is ≧98%.

[0468] In a further embodiment, the %de in the above composition is ≧99%.

[0469] In a further embodiment, there is provided a composition comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of ≥ 90%.

[0470] In a further embodiment, the %ee in the above composition is ≧95%.

[0471] In a further embodiment, the %ee in the above composition is ≧98%.

[0472] In a further embodiment, the %ee in the above composition is ≧99%.

[0473] In a further embodiment, there is provided a composition comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of ≥ 90% and a diastereomeric excess (%de) of ≥ 90%.

[0474] In further embodiments of the above composition, %ee and %de may take any combination of values ​​as listed below: · %ee is ≦ 5% and %de is ≧ 80%. · %ee is ≦ 5% and %de is ≧ 90%. · %ee is ≦ 5% and %de is ≧ 95%. · %ee is ≦ 5% and %de is ≧ 98%. ·%ee is ≧95% and %de is ≧95%. ·%ee is ≧98% and %de is ≧98%. ·%ee is ≧99% and %de is ≧99%.

[0475] In a further embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient.

[0476] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of ≥ 90%.

[0477] In a further embodiment, the %ee in the above composition is ≧95%.

[0478] In a further embodiment, the %ee in the above composition is ≧98%.

[0479] In a further embodiment, the %ee in the above composition is ≧99%.

[0480] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in a diastereomeric excess (% de) of ≥ 90%.

[0481] In a further embodiment, the %de in the above composition is ≧95%.

[0482] In a further embodiment, the %de in the above composition is ≧98%.

[0483] In a further embodiment, the %de in the above composition is ≧99%.

[0484] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of ≥ 90% and a diastereomeric excess (%de) of ≥ 90%.

[0485] In further embodiments of the above pharmaceutical composition, %ee and %de may take any combination of values ​​as listed below: ·%ee is ≧95% and %de is ≧95%. ·%ee is ≧98% and %de is ≧98%. ·%ee is ≧99% and %de is ≧99%.

[0486] Compounds of formula (I) [or PROTAC compounds containing a unit of formula (Ia) as defined herein], and pharmaceutically acceptable salts thereof, may be prepared, used, or supplied in amorphous, crystalline, or semi-crystalline form, and any given compound of formula (I) [or PROTAC compound containing a unit of formula (Ia) as defined herein] or pharmaceutically acceptable salt thereof may be capable of being formed into more than one crystalline / polymorphic form, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or hydrates of other stoichiometries) and / or solvated forms. It should be understood that the present specification encompasses all such solid forms of compounds of formula (I) [or PROTAC compounds containing a unit of formula (Ia) as defined herein], and pharmaceutically acceptable salts thereof.

[0487] In a further embodiment, there is provided a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia) as defined herein] obtainable by the methods described in the Examples section herein below.

[0488] intermediate compound As demonstrated in the experimental section herein below, compounds of formula (I) or PROTACs of formula (Ia) can be prepared, for example, by the following method.

[0489] The compound of formula (I) [or a salt thereof] or the PROTAC compound of formula (Ia) [or a salt thereof] may be prepared by reacting a compound of formula (II): [ka] or a salt thereof (wherein Q A -GQ H -or-G-(C 1~5 alkylene)-; G is a direct bond, -CH2-, -O-, or -N(R G )-(wherein, R G is H or C 1~3 alkyl); Q H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; Q D is a direct bond or C optionally substituted by one or more F 1~2 is alkylene; R L1 and R L2 together to form "=O" and R L3 is H; Q D is a direct bond, and Q A But, -GQ H -When Q H The value of Q D Q H is selected to be connected to the C atom of R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, Q, R 2a , R 2b , Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q can each take any of the values ​​disclosed herein for each of these groups / variables.

[0490] In one embodiment, Q H is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0491] Thus, such compounds of formula (II) as described above are aldehydes that can be reacted with a suitable molecule containing an amine group (e.g., a secondary amine group) to form a compound of formula (I) or a PROTAC compound of formula (Ia), either directly or after one or more additional reaction steps. Such reaction of the aldehyde with the amine can be carried out under reductive amination conditions, for example, using NaBH(OAc) or another reductive amination protocol known to those skilled in the art.

[0492] Such aldehydes may then be prepared from the corresponding acetals, e.g., compounds of formula (II), or salts thereof, as defined above, but with R L1 and R L2 are each independently 1~6 Alkoxy (e.g., C 1~3 alkoxy) or R L1 and R L2 Combined, -O-(CH2) k -O-, where k is 2 or 3. Such acetals can be converted to the corresponding aldehydes under acidic conditions, for example, using formic acid under conditions well known to those skilled in the art.

[0493] Alternatively, as shown in the experimental section herein below, the aldehyde may be prepared by reacting with R L1 is OH and R L2 can be prepared by oxidation of the corresponding primary alcohol, i.e., the compound of formula (II), or a salt thereof, as defined above except that is H. Such oxidation can be carried out using mild oxidation conditions, for example, Dess-Martin periodinane or some other mild oxidation protocol known to one skilled in the art.

[0494] As shown in the experimental section hereinbelow, the compounds of formula (I) [or salts thereof] or PROTAC compounds of formula (Ia) [or salts thereof] may be prepared by reacting R L1 is the leaving group and R L2

[0043] These compounds of formula (II) can be prepared from compounds of formula (II) or salts thereof as described above, except that R is H. Such compounds of formula (II) are therefore electrophiles that can react with molecules containing amine groups (e.g., secondary amine groups) via alkylation reactions to form compounds of formula (I) or PROTAC compounds of formula (Ia), either directly or after one or more additional reaction steps. Suitable leaving groups for alkylation reactions are well known to those skilled in the art and include Cl, Br, I, trifluoromethanesulfonate, mesylate, and tosylate. Alkylation reaction conditions are well known to those skilled in the art and generally involve a non-nucleophilic base (e.g., DIPEA) and a polar aprotic solvent (e.g., MeCN). As demonstrated in the experimental section herein below, when the leaving group is not I, a metal iodide salt can be used in the reaction mixture to form the corresponding iodide at that site (i.e., R L1 is I), facilitating the overall alkylation process. As shown in the experimental section hereinbelow, L1 Compounds of formula (II) in which R is a bromo leaving group can be prepared by cleaving the corresponding primary alcohol (i.e., as already described above, R L1 is OH and R L2 and R L3 and (where both are H).

[0495] The primary alcohol compounds of formula (II) above can then be prepared by reduction of the corresponding ester compounds, i.e., compounds of formula (II), as defined above, or salts thereof, where R L1 and R L2 together to form "=O" and R L3 But C 1~6 Alkoxy (e.g., C 1~3 Such reduction may be carried out using strong reducing conditions, for example, DIBAL or other stronger reducing conditions well known to those skilled in the art.

[0496] Alternatively, as demonstrated in the experimental section hereinbelow, it may be convenient to form the primary alcohol compound of formula (II) above via deprotection of a protected form of the alcohol. For example, deprotection of a compound in which the alcohol is protected by a silicon-based protecting group uses a source of fluorine, such as TBAF, to achieve deprotection, or other deprotection methods familiar to those skilled in the art.

[0497] Thus, as noted above, various compounds of formula (II), and salts thereof, may be useful as intermediates in the synthesis of compounds of formula (I) or PROTAC compounds of formula (Ia), and such intermediate compounds therefore provide a further aspect of the present specification.

[0498] Thus, in a further aspect, there is provided a compound of formula (II) as shown above, or a salt thereof, wherein: Q A -GQ H -or-G-(C 1~5 alkylene)-; G is a direct bond, -CH2-, -O-, or -N(R G )-(wherein, R G is H or C 1~3 alkyl); Q H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; Q D is a C optionally substituted by a direct bond or one or more F (e.g., 1 or 2 F); 1~2 is alkylene; (i)R L1 and R L2 together to form "=O" and R L3 is H or C 1~6 is alkoxy (e.g., OMe); (ii)R L1 and R L2 are each independently 1~6 alkoxy (e.g., OMe), and R L3 Is H; (iii)RL1 and R L2 Combined, -O-(CH2) k -O- (wherein k is 2 or 3), and R L3 is H; or (iv)R L1 OH, OPG 1 (In the formula, PG 1 is a protecting group), or LG 1 (In the formula, LG 1 is a leaving group), and R L2 and R L3 are both H; Q D is a direct bond, and Q A But, -GQ H -When Q H The value of Q D Q H is selected to be connected to the C atom of R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, Q, R 2a , R 2b , Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q can each take any of the values ​​disclosed herein for each of these groups / variables) are provided.

[0499] In one embodiment, Q H is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0500] Those skilled in the art will be aware of suitable protecting groups for alcohol groups, and therefore, PG 1 Know the preferred value of PG 1 is an alcohol protecting group.

[0501] In one embodiment, PG 1 is a silicon-based alcohol protecting group.

[0502] In one embodiment, PG 1 is Si(R Si )3(in the formula, each R Si independently, C 1~6 is a hydrocarbyl group).

[0503] In one embodiment, PG 1 is tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0504] In one embodiment, LG 1 are Cl, Br, I, trifluoromethanesulfonate and C 1~7 Hydrocarbyl sulfonates (e.g., mesylate or p-toluene sulfonate).

[0505] In one embodiment, LG 1 is Br or I.

[0506] In one embodiment, LG 1 is Br.

[0507] In one embodiment, LG 1 is Cl.

[0508] In one embodiment, LG 1 is I.

[0509] In one embodiment, LG 1 is trifluoromethanesulfonate.

[0510] In one embodiment, LG 1 is C 1~7 It is a hydrocarbyl sulfonate.

[0511] In one embodiment, LG 1 is the mesylate.

[0512] In one embodiment, LG 1 is p-toluenesulfonate.

[0513] In one embodiment, Q D is a direct bond, -CH2-, -CH2CH2- or -CF2CH2-.

[0514] In one embodiment, Q D is a direct bond.

[0515] In one embodiment, Q D is CH2.

[0516] In one embodiment, Q D is C optionally substituted by 1 or 2 F 1~2 It is alkylene.

[0517] In one embodiment, Q D is C 1~2 It is alkylene.

[0518] In one embodiment, Q D is -CH2CH2-.

[0519] In one embodiment, Q D is -CF2CH2-.

[0520] In a further embodiment herein, formula (II) is represented by formula (IIa): [ka] (In the formula, L X may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with formula (Ia); Q A , Q D , R L1 , R L2 and R L3 and may each take any of the values ​​disclosed herein for each of the groups.

[0521] As demonstrated in the experimental section herein below, certain compounds of formula (I) and certain PROTACs of formula (Ia) and certain intermediate compounds of formula (II) can be synthesized to give compounds of formula (III): [ka] or a salt thereof (wherein, G X is OH, and the oxygen atom of said OH can be alkylated with a suitable molecule to form a certain compound of formula (I) or PROTAC of formula (Ia) either directly or after one or more further reaction steps (e.g., via formula (II) as described hereinabove). Such alkylation reactions can be carried out under conditions well known to those skilled in the art, for example, using a primary alkyl bromide (or some other leaving group instead of Br) in a polar aprotic solvent such as MeCN, optionally in the presence of a metal iodide salt such as KI, using a non-nucleophilic base such as a metal carbonate (e.g., KCO).

[0522] Alternatively, as shown in the experimental section hereinbelow, a compound of formula (III) X is -NH(R G )[where R G is H or C 1~3 alkyl (e.g., Me)] may be used as an intermediate to prepare compounds of formula (I) or PROTACs of formula (Ia) via reductive amination chemistry with a suitable aldehyde-containing compound.

[0523] Alternatively, as shown in the experimental section hereinbelow, a compound of formula (III) X is bromo) may be coupled with a secondary compound to give a particular compound of formula (I) or PROTAC of formula (Ia), either directly or after one or more further reaction steps (e.g., via formula (II) as described hereinabove). Similarly, a compound of formula (III) (wherein G Xwhere G is chloro or trifluoromethanesulfonate) may also be used in coupling reactions with suitable secondary amines to give certain compounds of formula (I) or PROTACs of formula (Ia). Such couplings may be carried out under palladium-based coupling conditions (e.g., using "Ruphos Pd G3" and "Ruphos") by heating with CuI in the presence of a base and an anhydrous solvent such as 1,4-dioxane under an inert atmosphere, or in the presence of a base such as K3PO4 in a polar solvent such as DMSO. Alternatively, as also shown in the experimental section herein below, compounds of formula (III) (where G X is bromo) may be coupled with a suitable alcohol to form certain compounds of formula (I) or PROTACs of formula (Ia) either directly or after one or more further reaction steps (e.g., via formula (II) as described hereinabove). Such couplings may be carried out using a palladium-based reagent such as "Rockphos Pd G3" in the presence of a base such as Cs2CO3 in a solvent such as toluene.

[0524] Accordingly, compounds of formula (III), and salts thereof, may be useful as intermediates in the synthesis of certain compounds of formula (I) or PROTAC compounds of formula (Ia) or compounds of formula (II), and such intermediate compounds therefore provide a further aspect of the present specification.

[0525] Thus, in a further aspect, there is provided a compound of formula (III) as shown above, or a salt thereof, wherein: G X is OH, Cl, Br, trifluoromethanesulfonate or -NH(R G )(wherein, R G is H or C 1~3 alkyl); R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, Q, R 2a , R 2b, Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q can each take any of the values ​​disclosed herein for each of these groups / variables) are provided.

[0526] G X is OH, Cl, Br, trifluoromethanesulfonate or -NH(R G )(wherein, R G is C 1~3 alkyl (e.g., Me).

[0527] In one embodiment, G X is OH, Br, trifluoromethanesulfonate or -NH(R G )(wherein, R G is C 1~3 alkyl (e.g., Me).

[0528] In one embodiment, G X is OH, Br or -NH(R G )(wherein, R G is C 1~3 alkyl (e.g., Me).

[0529] In one embodiment, G X is OH or Br.

[0530] In one embodiment, G X is OH.

[0531] In one embodiment, G X is Br.

[0532] In one embodiment, G X is Cl.

[0533] In one embodiment, G X is trifluoromethanesulfonate.

[0534] In one embodiment, GX is -NH(R G )(wherein, R G is H or C 1~3 alkyl).

[0535] In one embodiment, G X is -NH(R G )(wherein, R G is C 1~3 alkyl).

[0536] In one embodiment, G X is -NH(Me).

[0537] In a further embodiment herein, formula (III) is X -G X (In the formula, L X may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with formula (Ia); G X is G X (which may take any value disclosed herein for

[0538] As demonstrated in the experimental section herein below, certain compounds of formula (I) and PROTACs of formula (Ia) can be synthesized by the synthesis of intermediate compounds of formula (IV): [ka] For example, a compound of formula (IV), or a salt thereof, where J is H (i.e., a secondary amine compound), may be coupled to further chemical fragments using chemical reactions well known to those skilled in the art and exemplified in the experimental section herein below, to obtain a compound of formula (I) or a PROTAC of formula (Ia), either directly or after one or more further reaction steps.

[0539] Such compounds of formula (IV) (where J is H) may then be conveniently prepared via deprotection of the N-protected form of the aforementioned amine compound. Thus, compounds of formula (IV) (where J is H) can be converted to compounds of formula (IV) (where J is PG 2 and PG 2 is a nitrogen protecting group (e.g., C-protecting group such as tert-butoxycarbonyl) 1~6 Thus, compounds of formula (IV) (wherein J is PG 2 ) are useful intermediates in the preparation of compounds of formula (I) and PROTACs of formula (Ia) and are provided as a further aspect herein.

[0540] Thus, in a further aspect herein, there is provided a compound of formula (IV) as shown above or a salt thereof, wherein: J is H or PG 2 (In the formula, PG 2 is a nitrogen protecting group (e.g., a tert-butoxycarbonyl group); Q A -GQ H -or-G-(C 1~5 alkylene)-; G is a direct bond, -CH2-, -O-, or -N(R G )-(wherein, R G is H or C 1~3 alkyl); Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or C optionally substituted by one or more F (e.g., 1 or 2) 1~3 is alkylene; Q B1 and Q B3 are each independently a direct bond or C 1~2 represents alkylene; Q B2 Q H , —O—CH2CH2—O—, —O— or —N(R J )-(wherein, R Jis H or C 1~3 alkyl); Each Q H ("Q" combined with J H ring) are independently 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic groups; Q A , Q B and Q H The ring values ​​are selected so that formula (IV) does not contain any N-N or N-O bonds; R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, R 2a , R 2b , Q, Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q may each take any of the values ​​defined herein for each of these groups / variables) are provided.

[0541] In one embodiment, each Q H ("Q" combined with J H The rings (including "rings") are independently 4- to 12-membered nitrogen-containing saturated heterocyclic groups.

[0542] In one embodiment, Q H The ring is piperidine-1,4-diyl or piperazine-1,4-diyl.

[0543] In one embodiment, J is H.

[0544] In one embodiment, J is PG 2 is.

[0545] In one embodiment, PG 2 is C 1~6 It is an alkoxycarbonyl.

[0546] In one embodiment, PG 2 is tert-butoxycarbonyl.

[0547] PG 2 C 1~6 In one embodiment, which is alkoxycarbonyl (eg, tert-butoxycarbonyl), the "and salts thereof" element of the claim is excluded.

[0548] In a further embodiment, the compound of formula (IV) may be any of Q in any other context, embodiment, aspect or claim found herein. A , Q B and Q H may take any combination of the alternative values ​​mentioned for

[0549] In a further embodiment herein, formula (IV) is represented by formula (IVa): [ka] (In the formula, L X may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with formula (Ia); Q A , Q B , Q H and J can each take any of the values ​​disclosed herein for each of the foregoing groups.

[0550] As also demonstrated in the experimental section herein below, certain compounds of formula (I) and PROTACs of formula (Ia) can be synthesized by the synthesis of intermediate compounds of formula (V): [ka] or a salt thereof (wherein X X is N replaced by J (J is H); G is a direct bond, -CH2-, -O-, or -N(R G )-(wherein, R G is H or C 1~3 alkyl); Q H The ring is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; G and QH The ring values ​​are selected so that formula (V) does not contain any N-N or N-O bonds; R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, R 2a , R 2b , Q, Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q can each take any of the values ​​defined herein for each of these groups / variables).

[0551] Such compounds of formula (V) may be converted to compounds of formula (I) or PROTACs of formula (Ia) via reductive amination or alkylation or other coupling chemistries known to those skilled in the art to obtain compounds of formula (I) or PROTACs of formula (Ia) directly or after one or more additional steps.

[0552] As shown in the experimental section herein below, such compounds of formula (V), or salts thereof, can then be conveniently prepared by deprotection of the corresponding N-protected compound. Such N-protected forms may be BOC-protected forms (i.e., tert-butoxycarbonyl), or alternative N-protecting groups known to those skilled in the art may be used. Thus, such N-protected compounds are also useful intermediates in the preparation of compounds of formula (I) and PROTACs of formula (Ia), providing a further aspect of the present invention.

[0553] Thus, one aspect of the present invention is X But J (J is PG 3 and PG 3 In one embodiment, a compound of formula (V), or a salt thereof, is provided, as described above, except that PG is N substituted with PG. 3 is C 1~6 In one embodiment, PG is an alkoxycarbonyl. 3is tert-butoxycarbonyl. PG 3 C 1~6 In one embodiment, which is alkoxycarbonyl (eg, tert-butoxycarbonyl), the "and salts thereof" element of the claim is excluded.

[0554] Other compounds of formula (I) and PROTACs of formula (Ia) (and salts thereof) may be X may be prepared from an intermediate compound of formula (V), or a salt thereof, as described above, except that is C=O. Such intermediates may be converted to compounds of formula (I) or PROTACs of formula (Ia) by reductive amination chemistry using an appropriate amine-containing compound, either directly or via one or more additional synthetic steps, using reductive amination conditions well known to those skilled in the art.

[0555] Then, as demonstrated in the experimental section hereinbelow, such compounds of formula (V) (wherein X X is C=O) can be conveniently prepared from the corresponding compound (wherein the ketone is protected / masked as a ketal). Such ketal compounds, and salts thereof, are therefore useful intermediates in the preparation of compounds of formula (I) or PROTACs of formula (Ia), and provide a further aspect herein.

[0556] Therefore, such ketal compounds are X But R U1 and R U2 (In the formula, R U1 and R U2 are respectively, C 1~6 Alkoxy; or R U1 and R U2 Combined, -O-(CH2) u

[0039] The compound may be represented as a compound of formula (V), as above, except that C is substituted by -O- (wherein u is 2 or 3), or a salt thereof.

[0557] Thus, in a further aspect herein, there is provided a compound of formula (V) as shown above, or a salt thereof, wherein: XX teeth, (i) J (J is H) or PG 3 (PG 3 is a protecting group); and (ii) by oxo or by R U1 and R U2 (In the formula, R U1 and R U2 are respectively, C 1~6 Alkoxy; or R U1 and R U2 Combined, -O-(CH2) u C substituted by -O- (wherein u is 2 or 3); G is a direct bond, -CH2-, -O-, or -N(R G )-(wherein, R G is H or C 1~3 alkyl); Q H The ring is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; G and Q H The ring values ​​are selected so that formula (V) does not contain any N-N or N-O bonds; R 1 ,p,X 1 , X 2 , X 3 , X 4 , n, m, R 2a , R 2b , Q, Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q may each take any of the values ​​defined herein for each of these groups / variables) are provided.

[0558] In one embodiment, J is H.

[0559] In one embodiment, J is PG 3 is.

[0560] In one embodiment, PG 3 is C 1~6It is an alkoxycarbonyl.

[0561] In one embodiment, PG 3 is tert-butoxycarbonyl.

[0562] In one embodiment, X X is C=O.

[0563] In one embodiment, X X is R U1 and R U2 (In the formula, R U1 and R U2 are respectively, C 1~6 is a C substituted by alkoxy.

[0564] In one embodiment, X X is R U1 and R U2 (In the formula, R U1 and R U2 Combined, -O-(CH2) u C substituted by —O— (wherein u is 2 or 3) (e.g., u=2).

[0565] In one embodiment, G is a direct bond or -O-.

[0566] In one embodiment, Q H The ring is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0567] Q H The value of the ring is Q H It can take any of the values ​​mentioned herein for

[0568] In one embodiment, Q H The ring is a piperidine ring, a piperazine ring, a 9-azaspiro[5.5]undecane ring, or a 3,9-diazaspiro[5.5]undecane ring.

[0569] In a further embodiment herein, formula (V) is represented by formula (Va): [ka] (In the formula, L X may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with formula (Ia); G, Q H Ring and X X and may each take any of the values ​​disclosed herein for each of the groups.

[0570] In addition to the methods described above, compounds of formula (I), (II), (III), (IV) and (V) and PROTAC compounds comprising formula (Ia) may be prepared using standard procedures and knowledge known to the skilled chemist, following the general procedures and chemical transformations demonstrated in the experimental section herein below.

[0571] In a further embodiment herein, there is provided a compound or a salt thereof, said compound being selected from one or more of the "intermediates" listed herein below in the Experimental section.

[0572] The intermediate compounds listed hereinafter refer to the title chemical names listed in the experimental section and are to be understood as in no way limited by the method of preparation or whether a given intermediate compound was isolated in the form of a salt rather than as a neutral molecule.

[0573] According to a further aspect herein, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient.

[0574] According to a further aspect herein, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0575] According to a further aspect herein, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of solid tumors.

[0576] According to a further aspect herein, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein, or a pharmaceutically acceptable salt thereof, for use in treating an AR-sensitive tumour type.

[0577] According to a further aspect herein, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for use in the treatment of tumor types harboring one or more mutated forms of the androgen receptor.

[0578] According to a further aspect herein, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer (e.g., CRPC, e.g., metastatic CRPC).

[0579] According to a further aspect herein, there is provided a pharmaceutical composition comprising a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of AR-mutated cancer.

[0580] In any embodiment, aspect, or claim herein that refers to "cancer" without further specificity, a further embodiment, aspect, or claim may be provided, wherein the cancer is (or includes) AR+ breast cancer.

[0581] The compositions may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or in a form suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular administration). The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0582] For further information on formulations, the reader is referred to Chapter 25.2 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990.

[0583] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.

[0584] The size of the dose of the compounds herein for therapeutic or prophylactic purposes will necessarily vary according to well-known principles of medicine, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0585] As described hereinabove, the compounds herein are useful as antitumor agents, particularly as selective inhibitors of mammalian cancer cell proliferation, survival, motility, dissemination, and invasion, and may inhibit tumor growth and survival, as well as inhibit metastatic tumor growth. In particular, the compounds herein may be useful as antiproliferative and anti-invasive agents in the containment and / or treatment of solid tumor disease.

[0586] Therefore, the compounds of the present invention may be useful in the prevention or treatment of tumors that are sensitive to androgen receptor degradation and are involved in signal transduction processes that lead to tumor cell proliferation and survival, as well as the migration and invasiveness of metastatic tumor cells. Furthermore, the compounds of the present invention may be useful in the prevention or treatment of tumors that can be treated by androgen receptor degradation. That is, the compounds may be used to produce the effect of androgen receptor degradation in warm-blooded animals in need of such treatment.

[0587] According to a further aspect of the present specification, there is provided a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0588] According to a further aspect herein, there is provided a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in therapy.

[0589] According to a further aspect of the present specification, there is provided a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

[0590] According to a further aspect of the present specification, there is provided a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for use in producing an antiproliferative effect (e.g. in a warm-blooded animal such as a human).

[0591] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the production of an antiproliferative effect (e.g. in a warm-blooded animal such as a human).

[0592] According to a further aspect herein, there is provided a method for producing an anti-proliferative effect in a warm-blooded animal, such as a human, in need of such effect, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof.

[0593] According to a further aspect of the present specification, there is provided a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for use as an anti-invasive agent in the containment and / or treatment of solid tumour disease (e.g. in a warm-blooded animal such as a human).

[0594] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as an anti-invasive agent in the containment and / or treatment of solid tumour disease (e.g. in a warm-blooded animal such as a human).

[0595] According to a further aspect herein, there is provided a method for producing an anti-invasive effect by containment and / or treatment of solid tumour disease in a warm-blooded animal, such as a human, in need of such effect, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof.

[0596] According to a further aspect of the present specification, there is provided a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer (e.g. in a warm-blooded animal such as a human).

[0597] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of cancer (e.g. in a warm-blooded animal such as a human).

[0598] According to a further aspect herein, there is provided a method for the prevention or treatment of cancer in a warm-blooded animal, such as a human, in need thereof, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof.

[0599] According to a further aspect of the present specification, there is provided a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of solid tumors (e.g. in a warm-blooded animal such as a human).

[0600] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of solid tumors (e.g. in a warm-blooded animal such as a human).

[0601] According to a further aspect herein, there is provided a method for the prevention or treatment of solid tumors in a warm-blooded animal, such as a human, in need thereof, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof.

[0602] According to a further aspect of the present specification, there is provided a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a tumour type that is sensitive to androgen receptor degradation.

[0603] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of those tumour types that are sensitive to androgen receptor degradation.

[0604] According to a further aspect herein, there is provided a method for the prevention or treatment of those tumor types that are sensitive to androgen receptor degradation in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof.

[0605] As explained hereinabove, tumor types that are sensitive to androgen receptor degradation include prostate cancer (eg, castration-resistant prostate cancer (CRPC), eg, metastatic CRPC).

[0606] According to a further aspect of the present specification, there is provided a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for use in producing a degrading effect on the androgen receptor (e.g. in a warm-blooded animal such as a human).

[0607] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) as defined herein [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing a degrading effect on the androgen receptor (e.g. in a warm-blooded animal such as a human).

[0608] According to a further aspect herein, there is provided a method for producing a degradative effect on the androgen receptor in a warm-blooded animal, such as a human, in need of such effect, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof.

[0609] According to a further aspect of the present specification, there is provided a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for use in producing a selective degradative effect on the androgen receptor (e.g. in a warm-blooded animal such as a human).

[0610] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) as defined herein [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing a selective degradative effect on the androgen receptor (e.g. in a warm-blooded animal such as a human).

[0611] According to a further aspect herein, there is provided a method for producing a selective degradative effect on the androgen receptor in a warm-blooded animal, such as a human, in need of such effect, comprising administering an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0612] According to a further aspect herein, there is provided a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of a tumour type having an androgen receptor mutation.

[0613] According to a further aspect of the present specification, there is provided the use of a compound of formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of those tumour types that have androgen receptor mutations.

[0614] According to a further aspect herein, there is provided a method for the prevention or treatment of those tumor types harboring an androgen receptor mutation in a warm-blooded animal, such as a human, in need thereof, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof.

[0615] As mentioned above, tumor types known to harbor androgen receptor mutations include prostate tumors, and thus prostate cancer, castration-resistant prostate cancer (CRPC), and metastatic (CRPC).

[0616] According to a further aspect herein, there is provided a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer (e.g. castration-resistant prostate cancer (CRPC), e.g. metastatic CRPC).

[0617] According to a further aspect herein, there is provided the use of a compound of formula (I) [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g. linked thereto)] as defined herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prostate cancer (e.g. castration-resistant prostate cancer (CRPC), e.g. metastatic CRPC).

[0618] According to a further aspect herein, there is provided a method for treating prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC) in a warm-blooded animal such as a human in need thereof, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon conjugate unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0619] In one embodiment where cancer is referred to herein, said cancer is prostate cancer.

[0620] In one embodiment, when cancer is referred to herein, the cancer is CRPC.

[0621] In one embodiment, where cancer is referred to herein, said cancer is metastatic CRPC. [Example]

[0622] General Experimental Conditions and Abbreviations The following abbreviations are used: AcOH = acetic acid; AIBN = 2,2'-azobis(2-methylpropinonitrile); aq. = aqueous; Boc = butoxycarbonyl; Brettphos = 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; Brettphos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate; CDI = 1,1'-carbonyldiimidazole; Dave-phos-Pd G3 = Methanesulfonato 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II); DCM = dichloromethane; DIAD = diisopropyl azodicarboxylate; DIPEA = N,N-diisopropylethylamine; Cbz = carboxybenzyl; Dess-Martin periodinane = 3-oxo-115-benzo[d][1,2]iodaoxol-1,1,1(3H)-triyl triacetate; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; Et2O = diethyl ether ethanol; EtOAc = ethyl acetate; EtOH = ethanol; FSC = flash silica chromatography; h = hours; HPLC = high performance liquid chromatography; IPA = isopropyl alcohol; MeCN = acetonitrile; MeOH = methanol; mins. = minutes; m / z = mass-to-charge ratio observed for the major mass spectrometry peak; MTBE = methyl tert-butyl ether; NBS = N-bromosuccinimide; NMP = N-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; Pd2dba3 = tris(dibenzylideneacetone)dipalladium; Pd-PEPPSI-IHept Cl= Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-yldiene(3-chloropyridyl)palladium(II); Pd-PEPPSI-IPent = Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Pd(dppf)2Cl2-DCM = 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex; RockPhos Pd G3 = methanesulfonate [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]-palladium(II); RT = room temperature (~17-25°C); RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G3 = methanesulfonato(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)-palladium(II); TFA = trifluoroacetic acid; THF = tetrahydrofuran; sat. = saturated; SFC = supercritical fluid chromatography; S Phos = 2-dicyclohexylphosphino-2,6-di-methyloxy-1,1-biphenyl; XPhos = 2-dicyclo-hexylphosphino-2',4',6'-triisopropylbiphenyl.

[0623] NMR was performed at 400 MHz in deuterated DMSO and at temperatures between 20 and 30° C. unless otherwise specified. The following standard abbreviations are used for NMR data: s = singlet, d = doublet, m = multiplet, br = broad, dd = doublet of doublets, q = quartet, dt = doublet of triplets, etc.

[0624] Preparative reverse phase HPLC (RP HPLC) using a mixture of decreasing polarity of eluents (e.g., water and MeCN) can typically involve a gradient from a 95:5 mixture to a 5:95 mixture of solvents at 40-50 mL per minute over 10-20 minutes. The following column and eluent conditions are used herein: Column A: Waters XSelect CSH C18 ODB column, 5 μm silica, 30 mm diameter, 100 mm length Column B: Waters XSelect CSH C18 ODB column, 5 μm silica, 19 mm diameter, 150 mm length Eluent A: decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN Eluent B: decreasingly polar mixtures of water (containing 0.3% formic acid aq) and MeCN Eluent C: decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN Eluent D: decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN

[0625] After HPLC (often with the presence of formic acid or trifluoroacetic acid in the eluent), fractions containing the desired product were in some cases treated with a suitable base as part of a further workup step to ensure delivery of the title compound as a neutral molecule rather than a salt. Thus, when "basic workup A" is referred to: fractions containing the desired compound were concentrated to remove MeCN. The resulting primarily aqueous fractions were basified with NaHCO solution (e.g., 50 mL) and extracted into DCM (e.g., 3 x 100 mL). The combined organic solutions were washed with brine (e.g., 100 mL), dried (e.g., with NaSO or MgSO), and concentrated to provide the title compound. Concentration: When a solution or mixture is described as being concentrated, this is generally done on a rotary evaporator under reduced pressure using a warm or hot water bath. Salts: When a particular compound is obtained as an acid addition salt, e.g., the monohydrochloride or dihydrochloride salt, the stoichiometry of the salt is assumed based on the number and nature of basic groups in the compound and may not have been determined experimentally, e.g., by elemental analysis data. Chemical Naming: In general, example and intermediate compounds were named using ACD Name, the "Structure to Name" part of ChemDraw Ultra (CambridgeSoft) or Biovia Draw 2016.

[0626] Intermediate 1a: Benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate [ka] 4-Formyl-N-Cbz-piperidine (5.00 g, 20.22 mmol) was dissolved in MeOH (11 mL) at 0 °C under N. A solution of TiCl (0.11 mL, 1.01 mmol) in DNC (1.1 mL) was then added, followed 15 min later by NEt (0.338 mL, 2.43 mmol), and the resulting solution was stirred at room temperature for 0.5 h. The mixture was then diluted with DCM (50 mL) and water (20 mL) and stirred at room temperature for 0.5 h. The layers were then separated, and the organic portion was dried on a hydrophobic frit and subsequently concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) afforded the title compound (5.16 g, 87%) as a colorless oil. 1 H NMR:(CDCl3)1.14-1.33(2H,m),1.63-1.82(3H,m),2.63-2.84(2H,m),3. 35(6H,s),4.02(1H,d),4.13-4.3(2H,m),5.12(2H,s),7.3-7.44(5H,m).

[0627] Intermediate 1b: 4-(dimethoxymethyl)piperidine [ka] Pd(OH) (10 wt%, 0.73 g, 0.52 mmol) was added to benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate (7.60 g, 25.9 mmol) in MeOH (60 mL) at room temperature under N in a steel pressure reactor. The resulting suspension was purged with N, followed by H, and stirred at room temperature for 2 days at 4 atmospheres of H. The mixture was then filtered through Celite and washed with MeOH (500 mL). The filtrate was concentrated to give the title compound (4.00 g, 97%) as a colorless oil. 1 H NMR: (CDCl3)1.19-1.41(2H,m),1.69-1.86(3H,m),2.61(2H,td),3.15(2H,d),3.35(6H,s),4.03(1H,d),4.47(1H,s).

[0628] Intermediate 1c: 4-bromo-2-methoxy-6-methylbenzoate methyl [ka] A solution of NaOMe (512 μL, 2.24 mmol) containing 25% methanol was added dropwise to a stirred solution of methyl 4-bromo-2-fluoro-6-methylbenzoate (527 mg, 2.13 mmol) in DMF (10 mL) at room temperature under N. The resulting mixture was stirred at room temperature for 18 hours (reaction complete within 1 hour). The mixture was then cooled to 0°C and quenched with EtOAc (20 mL) and 1N HCl (10 mL). The phases were separated, and the aqueous portion was extracted with EtOAc (2 × 30 mL). The combined organic solution was dried (MgSO) and concentrated. Purification by FSC (gradient 0-25% EtOAc in heptane) afforded the title compound (0.410 g, 74%) as a colorless oil, which solidified on standing. 1 H NMR: (CDCl3)2.25(3H,s),3.81(3H,s),3.90(3H,s),6.91(1H,d),6.98(1H,dd).

[0629] Intermediate 1d: 3-(5-bromo-7-methoxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione [ka] NBS (1.574 g, 8.84 mmol) was added to a stirred solution of methyl 4-bromo-2-methoxy-6-methylbenzoate (1.432 g, 5.53 mmol) and AIBN (0.182 g, 1.11 mmol) in tert-butyl acetate (20 mL), and the mixture was stirred at 100 °C for 3 h. The mixture was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water (50 mL). The organic layer was passed through a phase separation cartridge and concentrated. Purification by FSC (gradient: 0 to 15% EtOAc in heptane) gave 4-bromo-2-(bromomethyl)-6-methoxybenzoate (1.495 g, 80%) as a yellow gum that was 70% pure. DIPEA (1.654 mL, 9.29 mmol) was added in one portion to a stirred solution of methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate (1.495 g, 3.10 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.510 g, 3.10 mmol) in MeCN (20 mL) at room temperature under atmospheric pressure. The resulting solution was stirred at 80° C. for 16 hours. The mixture was then cooled to 0° C., and the solid was collected by filtration. The solid was washed with MeCN (50 mL) and EtO (50 mL) and dried under vacuum to give the title compound (0.761 g, 39% over two steps) as a mauve solid. 1 H NMR:1.97(1H,dtd),2.34(1H,qd),2.54-2.63(1H,m),2.90(1H,ddd),3.90(3H,s),4. 25(1H,d),4.38(1H,d),5.02(1H,dd),7.26(1H,d),7.39(1H,d),10.94(1H,s);m / z:ES + [M+H] + =355.0.

[0630] Intermediate 1e: tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate [ka] Pd-PEPPSI-IHept Cl (0.380 g, 0.39 mmol) was added to tert-butyl piperazine-1-carboxylate (2.183 g, 11.72 mmol), CsCO (3.82 g, 11.72 mmol), and 3-(5-bromo-7-methoxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-piperidine-2,6-dione (1.38 g, 3.91 mmol) in degassed 1,4-dioxane (39 mL) under N at room temperature. The resulting suspension was stirred at 100 °C for 6 h. The mixture was then diluted with DCM (100 mL) and washed successively with 5% AcOH in water (100 mL), water (100 mL), saturated NaHCO (100 mL), and saturated brine (100 mL). The organic layer was dried (MgSO) and concentrated. Trituration with EtOAc (40 mL) and washing with Et2O (50 mL) gave a solid which was collected by filtration and dried under vacuum to give the title compound (1.154 g, 64%) as a dark grey powder; 1 H NMR:1.43(9H,s),1.79-1.97(1H,m),2.28(1H,dd),2.53-2.62(1H,m),2.76-2.94(1H,m),3.32(4H,s),3.41-3. 54(4H,m),3.85(3H,s),4.12(1H,d),4.24(1H,d),4.95(1H,dd),6.51(1H,d),6.62(1H,s),10.87(1H,s);m / z:ES + [M+H] + =459.2.

[0631] Intermediate 1f: 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione [ka] 4M HCl (2 mL, 8.00 mmol) in 1,4-dioxane was added in one portion to tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (107 mg, 0.19 mmol) at room temperature under atmospheric pressure. The resulting mixture was stirred at room temperature for 1 day and then diluted with EtO (20 mL). The resulting mixture was filtered, and the solid was washed with EtO (20 mL) to give the title compound (0.080 g, 100%) as a white solid hydrochloride salt. 1 H NMR:1.93(1H,dd),2.25-2.4(1H,m),2.57(1H,d),2.89(1H,s),3.19(4H,s),3.59(4H,s),3.86(3H,s),4 .14(1H,d),4.26(1H,d),4.97(1H,dd),6.49-6.6(1H,m),6.68(1H,s),9.55(2H,s),10.89(1H,s);m / z:ES + [M+H] + =359.2.

[0632] Intermediate 1g: 4-(4-(4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] DIPEA (6.93 mL, 39.66 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (5.00 g, 26.44 mmol), and 4-(piperidin-4-yl)phenol (4.69 g, 26.44 mmol) were stirred in DMSO (10 mL) at 50° C. for 18 hours. The mixture was then cooled to room temperature, diluted with water (150 mL), and stirred for 18 hours. The resulting solid was collected by filtration, washed with EtO (50 mL), and dried under vacuum to give the title compound (5.65 g, 62%) as a yellow solid. 1H NMR:(CDCl3)1.75(2H,qd),1.88-2(2H,m),2.73(1H,tt),3.06(2H,td),3.98-4.1(2H,m),4.78 (1H,s),6.76-6.83(2H,m),6.99(1H,dd),7.06-7.12(2H,m),7.16(1H,d),7.62(1H,d);m / z:ES + [M+H] + =347.0.

[0633] Intermediate 1h: 4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] 2-(3-Chloropropyl)-1,3-dioxolane (2.57 mL, 19.49 mmol) was added in one portion to 4-(4-(4-hydroxy-phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.75 g, 10.83 mmol), K2CO3 (3.74 g, 27.07 mmol), and KI (4.49 g, 27.07 mmol) in MeCN (100 mL) at room temperature under air. The resulting suspension was stirred at 90 °C for 2 days. The mixture was then cooled to room temperature, filtered, and washed with DCM (100 mL). The filtrate was concentrated under reduced pressure. The crude residue was diluted with EtOAc (300 mL), washed with water (100 mL), followed by saturated brine (100 mL), dried (MgSO4), and concentrated. Purification by FSC (gradient 0-5% MeOH in DCM) gave the title compound (3.10 g, 62%) as a yellow solid; 1 H NMR:(CDCl3)1.56-1.67(2H,m),1.71(2H,ddd),1.74-1.82(2H,m),1.85(2H,d),2.77(1H,ddd),3-3.1(2H,m),3.75-3.82(2H,m), m / z:ES+ [M+H] + =461.3.

[0634] Example 1: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] 4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (178 mg, 0.39 mmol) and tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (177 mg, 0.39 mmol) were stirred in formic acid (0.5 mL) and 1,4-dioxane (0.5 mL) at 40° C. for 18 hours. The mixture was then concentrated, and the residue was redissolved in IPA (2 mL) and DCM (2 mL) at room temperature under air. NaBH(OAc) (164 mg, 0.77 mmol) was added in one portion after 10 minutes. The resulting dark suspension was stirred at room temperature for 1 hour and then concentrated. Purification by preparative HPLC (column A, eluent A) gave the title compound (70 mg, 23%) in the form of the formate salt as a dry film; 1H NMR:(CDCl3)1.54-1.68(4H,m),1.74(2H,q),1.84(2H,d),1.92(1H,dd),2.28(1H,dd),2.39(2H, t),2.54-2.62(2H,m),2.76(1H,td),2.89(1H,ddd),3.04(2H,t),3.2-3.38(6H,m),3.47(1H,s), 3.84(3H,s),3.97(2H,t),4.07-4.29(4H,m),4.96(1H,dd),6.48(1H,d),6.60(1H,s),6.81-6.94 (2H,m),7.16(2H,d),7.27(1H,dd),7.32(1H,d),7.81(1H,d),8.16(2H,s),10.88(1H,s);m / z:ES + [M+H] + =759.4.

[0635] Intermediate 2a: 3-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione [ka] DIPEA (25 mL, 143.52 mmol) was added to methyl 4-bromo-2-(bromomethyl)benzoate (14.65 g, 47.57 mmol) and 3-aminopiperidine-2,6-dione hydrochloride salt (11.74 g, 71.35 mmol) in MeCN (200 mL) under N. The resulting suspension was stirred at 80 °C for 4 h. The mixture was cooled to room temperature and filtered. The resulting solid was washed with MeCN (60 mL), MeCN:EtO (50 mL [2:3]), and EtO (2 × 50 mL) to give the title compound (13.10 g, 85%) as a dark blue solid. 1 H NMR:1.95-2.08(1H,m),2.34-2.46(1H,m),2.57-2.65(1H,m),2.91(1H,ddd),4.35(1H,d),4. 48(1H,d),5.11(1H,dd),7.67(1H,d),7.72(1H,dd),7.83-7.96(1H,m),10.98(1H,s).m / z:ES + [M+H] + =323.0.

[0636] Intermediate 2b: tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate [ka] CsCO (57.40 g, 176 mmol) and Pd-PEPPSI-IPent (2.33 g, 2.94 mmol) were added in one portion to a degassed solution of tert-butyl piperazine-1-carboxylate (14.22 g, 76.36 mmol) and 3-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (19.0 g, 58.74 mmol) in 1,4-dioxane (590 mL) under N. The resulting mixture was stirred at 90 °C for 24 h. The mixture was then cooled to room temperature, diluted with DCM (1 L), and washed successively with 5% AcOH in water (500 mL) and brine (500 mL). The organic solution was then dried (MgSO) and concentrated. Trituration with EtOAc (250 mL) gave a solid which was collected by filtration, washed with Et2O (100 mL) and dried under vacuum to give the title compound (22.10 g, 88%) as a grey solid; 1 H NMR:1.43(9H,s),1.96(1H,d),2.31-2.41(1H,m),2.59(1H,d),2.87(1H,s),3.29(4H,d),3.47( m / z:ES + [M+H] + =429.2.

[0637] Intermediate 2c: 3-[1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione [ka] A solution of 4M HCl in dioxane (8.75 mL, 35.0 mmol) was added to tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (1.50 g, 3.50 mmol) in 1,4-dioxane (2 mL) at room temperature, and the mixture was stirred for 1 hour. EtOAc (5 mL) was then added, and the mixture was stirred for 10 minutes. The resulting precipitate was collected by filtration, washed with EtOAc (2 × 5 mL), and dried under vacuum to give the title compound (1.08 g, 85%) in the form of its hydrochloride salt as a dark gray solid. 1 H NMR:1.97(1H,dd),2.36-2.44(1H,m),2.60(1H,d),2.84-2.99(1H,m),3.23(4H,s),3.5-3.57(4H,m),4. 27(1H,s),4.34(1H,s),5.06(1H,dd),7.11-7.18(2H,m),7.59(1H,d),9.17(2H,s),10.93(1H,s);m / z:ES + [M+H] + 329.0.

[0638] Intermediate 2d: 4-(4-(4-(4-oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] 4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Example 1h) (4.61 g, 10.01 mmol) was dissolved in 1,4-dioxane (100 mL) and formic acid (75 mL), and the mixture was warmed to 50° C. for 18 hours. The solvent was then removed under reduced pressure to give the title compound as a yellow oil (used directly in the next step, assumed 100% yield); m / z: ES + [M+H] + =417.0.

[0639] Example 2: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] 4-(4-(4-(4-oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (4.17 g, 8.71 mmol), 3-[1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (3.18 g, 8.71 mmol), and NaOAc (2.144 g, 26.13 mmol) were dissolved in DCM (150 mL) at room temperature. The resulting suspension was stirred at room temperature for 1 h, followed by the addition of NaBH(OAc) (3.69 g, 17.42 mmol), and the mixture was stirred for 0.5 h. The mixture was then diluted with DCM (200 mL) and washed with saturated NaHCO (2 × 200 mL) and saturated brine (200 mL). The organic solution was then dried (MgSO4) and concentrated. Purification by preparative HPLC (column A, eluent B, basic workup A) afforded the title compound (820 mg, 13%); 1 H NMR:1.52-1.69(4H,m),1.74(2H,p),1.84(2H,d),1.91-2.03(1H,m),2.34-2.42(3H,m),2 .52-2.54(4H,m),2.59(1H,d),2.76(1H,td),2.83-2.96(1H,m),2.96-3.1(2H,m),3.27-3. 29(4H,m),3.97(2H,t),4.1-4.28(3H,m),4.33(1H,d),5.05(1H,dd),6.78-6.9(2H,m),7. 05(2H,d),7.15(2H,d),7.23-7.36(2H,m),7.52(1H,d),7.81(1H,d),10.92(1H,s);m / z:ES + [M+H] + =729.5.

[0640] Intermediate 3a: 2-Cyclopropyl-4-fluorobenzonitrile [ka] Pd(OAc) (0.168 g, 0.75 mmol) was added to cyclopropylboronic acid (0.834 g, 9.71 mmol), 2-bromo-4-fluorobenzonitrile (1.50 g, 7.50 mmol), tricyclohexylphosphine (0.210 g, 0.75 mmol), and KPO (5.57 g, 26.25 mmol) in toluene (20 mL) at room temperature under N. The resulting mixture was stirred at 100 °C for 3 h. The mixture was then filtered through Celite and washed with EtOAc (30 mL). The filtrate was concentrated and purified by FSC (gradient: 0 to 5% EtOAc in petroleum ether) to give the title compound (0.950 g, 79%) as a green solid. 1 H NMR:0.85-0.94(2H,m),1.07-1.21(2H,m),2.13-2.25(1H,m),6.95-7.03(1H,m),7.15-7.25(1H,m),7.81-7.89(1H,m).

[0641] Intermediate 3b: 4-(4-(4-bromophenyl)piperidin-1-yl)-2-cyclopropylbenzonitrile [ka] 2-Cyclopropyl-4-fluorobenzonitrile (1.00 g, 6.20 mmol) was added to a mixture of 4-(4-bromophenyl)-piperidine (1.788 g, 7.45 mmol) and CsCO (6.06 g, 18.61 mmol) in DMSO (1.5 mL) at 80 °C. The resulting mixture was stirred at 80 °C for 16 h, then cooled to room temperature and diluted with water. The mixture was then filtered, diluted with EtOAc (1 L), and washed with water (500 mL) followed by saturated brine (500 mL). The organic layer was dried (NaSO) and concentrated. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) afforded the title compound (1.70 g, 72%) as a yellow solid. 1H NMR:0.79-0.93(2H,m),0.97-1.08(2H,m),1.54-1.69(2H,m),1.78-1.87(2H,m),2.02-2.13(1H,m),2.70-2.83(1H,m ),2.83-2.95(2H,m),4.00-4.08(2H,m),6.47(1H,d),6.82-6.90(1H,m),7.18-7.26(2H,m),7.45-7.52(3H,m);m / z:ES + [M+H] + =381.1.

[0642] Intermediate 3c: 2-cyclopropyl-4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)benzonitrile [ka] Ruphos Pd G3 (88 mg, 0.10 mmol) and Ruphos (46 mg, 0.10 mmol) were added to a mixture of Cs2CO3 (1.025 g, 3.15 mmol), 4-(dimethoxymethyl)piperidine (334 mg, 2.10 mmol), and 4-(4-(4-bromophenyl)-piperidin-1-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1,4-dioxane (6 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After cooling, the solvent was removed under reduced pressure. Purification by FSC (gradient: 0 to 30% EtOAc in petroleum ether) afforded the title compound (0.228 g, 47%) as a yellow solid. 1 H NMR:0.79-0.90(2H,m),0.97-1.10(2H,m),1.20-1.41(2H,m),1.50-1.74(5H,m),1.80(2H,d),1.97-2.15(1H,m),2.52-2.71(3H,m),2 m / z:ES + [M+H] +=460.3.

[0643] Example 3: 2-Cyclopropyl-4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)benzonitrile [ka] 2-Cyclopropyl-4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)benzonitrile (150 mg, 0.33 mmol) and 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (130 mg, 0.33 mmol) were stirred in formic acid (0.5 mL) and 1,4-dioxane (0.5 mL) at 40 °C for 7 days. The resulting mixture was then concentrated, and the residue was dissolved in IPA (2 mL) and DCM (2 mL) at room temperature under air. NaBH(OAc) (138 mg, 0.65 mmol) was then added in one portion after 10 min, and the resulting dark suspension was stirred at room temperature for 1 h. The mixture was then concentrated, dissolved in DMF (3 mL), and filtered. Purification by preparative HPLC (column A, eluent A) afforded the title compound (59 mg, 24%) as a white solid formate salt; 1H NMR:0.8-0.88(2H,m),0.98-1.07(2H,m),1.23(2H,q),1.51-1.64(2H,m),1.67(1H,d),1.79-1.83(4H,m),1. 88-1.96(1H,m),2.09(1H,s),2.23(2H,d),2.28-2.37(1H,m),2.52-2.53(4H,m),2.54-2.72(4H,m),2.82-2. 95(3H,m),3.30-3.32(4H,d),3.62(2H,d),3.84(3H,s),4.02(2H,d),4.11(1H,d),4.24(1H,d),4.96(1H,dd) m / z:ES + [M+H] + =756.7.

[0644] Intermediate 4a: 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] Cs2CO3 (73.6 g, 225.95 mmol) was added in portions to 4-fluoro-2-(trifluoromethyl)benzonitrile (20.51 g, 108.46 mmol) and 4-(4-bromophenyl)piperidine hydrochloride (25.0 g, 90.38 mmol) in DMSO (260 mL) at room temperature. The resulting cream suspension was stirred at room temperature for 18 hours and then slowly diluted with water (600 mL). The resulting cream suspension was stirred at room temperature for 0.5 hours and then filtered and washed with water (2 × 25 mL) and Et2O (50 mL). The solid was dried under vacuum to give the title compound (35.0 g, 95%) as a cream solid. 1 H NMR:1.65(2H,qd),1.87(2H,d),2.85(1H,tt),3.06(2H,td),4.19(2H,d),7.22 -7.26(2H,m),7.28(1H,dd),7.33(1H,d),7.43-7.59(2H,m),7.74-7.88(1H,m).

[0645] Intermediate 4b: 4-(4-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] Anhydrous 1,4-dioxane (160 mL) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (10.00 g, 24.43 mmol), 4-(1,3-dioxolan-2-yl)piperidine (4.17 g, 26.51 mmol), RuPhos Pd G3 (1.533 g, 1.83 mmol), RuPhos (0.855 g, 1.83 mmol), and sodium 2-methylpropan-2-olate (7.04 g, 73.30 mmol). The mixture was degassed by bubbling N through the mixture for 5 minutes and then stirred at 100 °C for 2 hours. The mixture was then cooled to room temperature, and water (320 mL) was added. The formed precipitate was collected by filtration to give an orange solid. The solid was slurried in MTBE (50 mL) and heated at 45° C. for 0.5 h, then cooled to room temperature and filtered. The solid was washed with MTBE (2×5 mL) and dried to give the title compound (12.0 g, 100%) as a pale orange solid; 1 H NMR:1.39(2H,qd),1.54-1.68(3H,m),1.72(2H,d),1.84(2H,d),2.58(2H,td),2.65-2.79(1H,m),2.99-3.12(2H,m),3.66(2H,d),3.7 m / z:ES + [M+H] + =486.3.

[0646] Intermediate 4c: 4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] 4-(4-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (10.00 g, 20.60 mmol) was dissolved in toluene (100 mL), formic acid (100 mL), and water (50 mL), followed by warming to 80° C. for 1 h. The mixture was then cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The layers were separated. The organic solution was washed with water (50 mL), saturated NaHCO (50 mL), and brine (50 mL), followed by drying (MgSO) and concentration. Purification by FSC (gradient: 0-100% EtOAc in heptane) afforded the title compound (4.60 g, 51%) as a white solid. 1 H NMR:1.53-1.68(4H,m),1.84(2H,d),1.92(2H,dd),2.45(1H,dd),2.73(1H,d),2.74-2.85(2H,m),2.97-3.11(2H, m / z:ES + [M+H] + 442.3.

[0647] Example 4: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] A mixture of 4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (4.60 g, 10.42 mmol) and 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (4.11 g, 10.42 mmol) and NaOAc (1.71 g, 20.84 mmol) was stirred in IPA (2 mL) and DCM (250 mL) at room temperature under air. NaBH(OAc) (4.42 g, 20.84 mmol) was added in small portions after 1 hour. The resulting dark suspension was stirred at room temperature for 1 hour. The mixture was then diluted with DCM (2 x 250 mL), washed (saturated NaHCO (250 mL), water (250 mL), followed by saturated brine (250 mL)), dried (NaSO), and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane, followed by 0-5% IPA in EtOAc) gave a solid that was slurried in MeCN (100 mL) at room temperature and collected by filtration to give the title compound (2.05 g, 31%) as a white solid; 1 H NMR:1.18-1.31(2H,m),1.55-1.74(3H,m),1.80-1.86(4H,m),1.88-1.97(1H,m),2.23(2H,d),2. 27-2.34(1H,m),2.52-2.53(4H,m),2.54-2.67(3H,m),2.73(1H,t),2.82-2.97(1H,m),3.04(2H,t ),3.32-3.35(4H,s),3.62(2H,d),3.84(3H,s),4.08-4.28(4H,m),4.96(1H,dd),6.49(1H,s),6.6 1(1H,s),6.87(2H,d),7.08(2H,d),7.27(1H,dd),7.32(1H,d),7.81(1H,d),10.88(1H,s);m / z:ES + [M+H] + =784.6.

[0648] Intermediate 5a: 2-(3-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-cyclobutyl)ethyl acetate [ka] RockPhos Pd G3 (0.103 g, 0.12 mmol) was added in one portion to a degassed mixture of ethyl 2-(3-hydroxycyclobutyl)acetate (0.387 g, 2.44 mmol), 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), and Cs2CO3 (2.79 g, 8.55 mmol) in toluene (20 mL) under N2 at room temperature. The resulting mixture was stirred at 90 °C for 18 h. The mixture was then cooled to room temperature and diluted with EtOAc (50 mL) and water (15 mL). The organic layer was separated, washed with saturated brine (20 mL), dried (MgSO4), and concentrated. Purification by FSC (gradient: 0 to 60% EtOAc in heptane) afforded the title compound (0.34 g, 29%) as a white solid. 1 H NMR: ( CDCl3)1.25(3H,td),1.75(2H,qd),1.81-1.91(1H,m),1.97(2H,d),2.25(1H,ddd),2.29-2.45(1H,m),2.50(2H,dd),2.71(3H,dddd),3.05 m / z:ES + [M+H] + 487.3.

[0649] Intermediates 5b and 5c: 4-(4-(4-((1r,3s)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile and 4-(4-(4-((1s,3r)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] Diisobutylaluminum hydride (1 M in toluene, 1.048 mL, 1.05 mmol) was added dropwise to a stirred solution of ethyl 2-(3-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)cyclobutyl)acetate (340 mg, 0.70 mmol) in THF (10 mL) under N2 at 0°C. The resulting mixture was stirred at 0°C for 10 minutes. The reaction was then quenched by the addition of Rochelle's salt (15 mL). EtOAc (25 mL) was added and the mixture was stirred at room temperature for 18 hours. The phases were then separated and the aqueous portion was extracted with EtOAc (3 x 50 mL). The combined organic solution was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave a ca. 2:1 mixture of cis / trans isomers (0.280 g, 90%). The sample was purified on a Sepiatec SFC system (column: YMC Chiral Art Cellulose-SJ, 20 x 250 mm, 5 μm, eluent: 70% CO, 30% MeOH + 0.1% NH) to give the title compounds: Intermediate 5b (cis, 0.142 g, 53%) and Intermediate 5c (trans, 0.054 g, 20%); Intermediate 5b (cis): 1H NMR:1.52-1.69(6H,m),1.85(2H,d),1.98(1H,ddd),2.53-2.61(2H,m),2.7-2.83(1H,m),2.97-3.1(2H,m),3.36(2H,td),4.17( 2H,d),4.31(1H,t),4.49(1H,p),6.65-6.83(2H,m),7.06-7.19(2H,m),7.27(1H,dd),7.32(1H,d),7.81(1H,d);Intermediate 5c(trans): 1 H NMR:1.55-1.72(4H,m),1.85(2H,d),2.14-2.16(4H,m),2.34-2.4(1H,m),2.7-2.82(1H,m),2.96-3.13(2H,m),3.34-3.4 4(2H,m),4.17(2H,d),4.33(1H,t),4.76(1H,p),6.64-6.78(2H,m),7.14(2H,d),7.27(1H,dd),7.32(1H,d),7.81(1H,d).

[0650] Intermediate 5d: 4-(4-(4-((1s,3s)-3-(2-bromoethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] A solution of PPh3 (142 mg, 0.54 mmol) in THF (2 mL) was added dropwise to a stirred mixture of 4-(4-(4-((1r,3s)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (120 mg, 0.27 mmol) and CBr4 (179 mg, 0.54 mmol) in THF (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h and then filtered. The solid was then washed with EtOAc (20 mL), and the filtrate was concentrated under reduced pressure. Purification by FSC (gradient: 0 to 30% EtOAc in heptane) afforded the title compound (0.140 g, 100%) as a colorless oil. 1H NMR:(500MHz,CDCl3)1.21-1.26(1H,m),1.63-1.78(4H,m),1.90(2H,d),1.95(1H,d),2.01-2.15(1H,m),2.49-2.73(3H,m),2.98(2H, m / z:ES + [M+H] + =507.1.

[0651] Example 5: 4-[4-(4-{[(1r,3s)-3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)cyclobutyl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] 4-(4-(4-((1s,3s)-3-(2-bromoethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (65.0 mg, 0.13 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (50.6 mg, 0.13 mmol), KI (63.8 mg, 0.38 mmol) and DIPEA (112 μL, 0.64 mmol) were dissolved in MeCN (2.5 mL) and stirred at 70° C. for 18 h. The mixture was then diluted with DCM (20 mL), washed (5% AcOH in water (20 mL), water (20 mL), followed by saturated NaHCO3 (20 mL)), dried (Na2SO4), and concentrated. Purification by preparative HPLC (Column A, Eluent A, Basic Workup A) afforded the title compound (8 mg, 8%) as a white solid; 1H NMR:1.66-1.75(3H,m),1.75-1.84(3H,m),1.92-1.99(3H,m),2.15(1H,dtd),2.28(1H,td),2.32-2.4(2H,m) ,2.54-2.61(4H,m),2.61-2.69(2H,m),2.69-2.78(1H,m),2.78-2.85(1H,m),2.85-2.91(1H,m),3.05(2H,td) ,3.27-3.36(4H,m),3.94(3H,s),4.02(2H,d),4.19(1H,d),4.35(1H,d),4.49(1H,p),5.12(1H,dd),6.36(1H, m / z:ES + [M+H] + =785.4.

[0652] Intermediate 6a: 3,4-Difluoro-2-(trifluoromethyl)benzonitrile [ka] 1-Bromo-3,4-difluoro-2-(trifluoromethyl)benzene (5.00 g, 19.16 mmol) and copper cyano (1.89 g, 21.07 mmol) were stirred in NMP (48 mL) at 150° C. for 3 h. The mixture was then cooled to room temperature, diluted with EtO (100 mL), washed with saturated brine (3×100 mL), followed by dilution with NH solution (50 mL), dried (MgSO), and concentrated to give the title compound (4.27 g), which was used in the next step without further purification; 1 H NMR:(500MHz,CDCl3)7.46(1H,q),7.59(1H,dddd).

[0653] Intermediate 6b: 4-(4-(4-bromophenyl)piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile [ka] 4-(4-Bromophenyl)piperidine (4.92 g, 20.49 mmol), 3,4-difluoro-2-(trifluoromethyl)benzonitrile (4.287 g, 18.63 mmol), and DIPEA (3.90 mL, 22.36 mmol) were dissolved in NMP (43 mL). The mixture was then heated to 100 °C for 0.5 h, then cooled to room temperature and diluted with EtO (100 mL). The mixture was washed with brine (2 × 100 mL), 2 M aqueous HCl (50 mL), followed by saturated NaHCO (50 mL) and brine (50 mL). The organic solution was dried (MgSO) and concentrated to give the title compound (6.16 g, 77%) as a light brown solid, which was used without further purification. 1 H NMR:(500MHz,CDCl3)1.82(2H,qd),1.87-1.94(2H,m),2.63(1H,tt),2.91(2H,t d),3.63-3.73(2H,m),7.01-7.08(3H,m),7.36-7.4(2H,m),7.42(1H,d);m / z:ES + [M+H] + =427.1.

[0654] Intermediate 6c: 3-fluoro-4-(4-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] CuI (44.6 mg, 0.23 mmol) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (500 mg, 1.17 mmol), piperidin-4-ylmethanol (202 mg, 1.76 mmol), 2-((2,6-dimethyl-phenyl)amino)-2-oxoacetic acid (45.2 mg, 0.23 mmol) and KPO (497 mg, 2.34 mmol) in DMSO (5 mL) under N. The mixture was stirred at 110 °C for 18 h. The mixture was then cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic solution was washed with NaHCO (50 mL) and brine (50 mL), dried (MgSO), and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) afforded the title compound (0.10 g, 19%) as a white solid; 1 H NMR: ( CDCl3)1.28(1H,d),1.41(2H,qd),1.53(1H,s),1.57-1.71(1H,m),1.82-1.91(3H,m),1.91-1.99(2H,m),2.53-2.7 9(3H,m),2.98(2H,td),3.55(2H,d),3.63-3.81(4H,m),6.88-6.95(2H,m),7.05-7.16(3H,m),7.48(1H,d);m / z:ES + [M+H] + =462.2.

[0655] Intermediate 6d: 3-fluoro-4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] Dess-Martin periodinane (101 mg, 0.24 mmol) was added to 3-fluoro-4-(4-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.22 mmol) in DCM (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (15 mL) and poured into a mixture of saturated NaHCO (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 min and the layers were separated. The organic layer was dried (NaSO) and concentrated to give the title compound as a dry yellow film, which was used in the next step without further purification (assumed 100% yield); m / z: ES + [M+H] + =460.3.

[0656] Example 6: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] 3-Fluoro-4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.100 g, 0.22 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (0.086 g, 0.22 mmol), and NaOAc (0.054 g, 0.65 mmol) were dissolved in DCM (3 mL) at room temperature and stirred for 10 minutes. NaBH(OAc) (0.092 g, 0.44 mmol) was added, and the mixture was stirred for 1 hour. The mixture was diluted with DCM (20 mL), washed (saturated NaHCO (20 mL), water (20 mL) followed by saturated brine (20 mL)), dried (NaSO), and concentrated. Purification by preparative HPLC (column A, eluent A) afforded the title compound (42 mg, 24%) as the formate salt as a white solid; 1 H NMR:1.23(2H,q),1.62-1.78(3H,m),1.82-1.84(4H,m),1.89-1.97(1H,m),2.23(2H,d),2 .26-2.38(2H,m),2.52-2.54(4H,m),2.56-2.67(3H,m),2.83-2.96(1H,m),3.04(2H,t),3 .31(4H,s),3.68(4H,dd),3.84(3H,s),4.12(1H,d),4.24(1H,d),4.96(1H,dd),6.49(1H, m / z:ES + [M+H] + =802.7.

[0657] Intermediate 7a: 3-fluoro-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] 4-(4-(4-bromophenyl)piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (0.500 g, 1.17 mmol), Cs2CO3 (1.335 g, 4.10 mmol), and butane-1,4-diol (0.501 mL, 5.85 mmol) were dissolved in toluene (15 mL) and degassed with N2. Rockphos Pd G3 (0.049 g, 0.06 mmol) was added, and the mixture was heated at 90 °C for 18 h. The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL), followed by saturated brine (100 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0 to 50% EtOAc in heptane) afforded the title compound (0.363 g, 71%) as a pale yellow solid. 1 H NMR: ( CDCl3)1.52(1H,s),1.69-1.8(2H,m),1.82-1.99(6H,m),2.67(1H,tt),2.98(2H,td),3.73 -3.74(4H,m),4.00(2H,t),6.82-6.92(2H,m),7.06-7.18(3H,m),7.44-7.53(1H,m);m / z:ES + [M+H] + =437.1.

[0658] Intermediate 7b: 3-fluoro-4-(4-(4-(4-oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] 3-Oxo-115-benzo[d][1,2]iodaoxol-1,1,1(3H)-triyl triacetate (192 mg, 0.45 mmol) was added to 3-fluoro-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.41 mmol) in DCM (2 mL) at 0 °C and allowed to warm to room temperature for 1 h. The mixture was then diluted with DCM (15 mL) and poured into a mixture of saturated NaHCO (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 min, followed by phase separation. The organic solution was dried (NaSO) and concentrated to give the title compound (0.120 g, 67%) as a yellow film, which was used in the next step without further purification; m / z: ES + [M+H] + =435.1.

[0659] Example 7: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-3-fluoro-2-(trifluoromethyl)benzonitrile [ka] 3-Fluoro-4-(4-(4-(4-oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.120 g, 0.28 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (0.109 g, 0.28 mmol), and NaOAc (0.068 g, 0.83 mmol) were dissolved in DCM (3 mL) at room temperature and stirred for 10 min. Then, NaBH(OAc) (0.117 g, 0.55 mmol) was added, and the mixture was stirred for 1 h. The mixture was then diluted with DCM (20 mL), washed (saturated NaHCO3 (20 mL), water (20 mL) followed by saturated brine (20 mL)), dried (Na2SO4) and concentrated. Purification by preparative HPLC (column A, eluent A) afforded the title compound (0.084 g, 39%) as a white solid; 1 H NMR:1.61(2H,p),1.75-1.76(4H,m),1.86(2H,d),1.89-1.98(1H,m),2.28(1H,dd),2.39(2H,t),2. 52-2.53(4H,m),2.54-2.62(1H,m),2.67-2.78(1H,m),2.89(1H,ddd),2.99-3.08(2H,m),3.27-3.32 (4H,m),3.72(2H,d),3.84(3H,s),3.98(2H,t),4.05-4.18(1H,m),4.24(1H,d),4.96(1H,dd),6.48 (1H,d),6.60(1H,s),6.8-6.92(2H,m),7.18(2H,d),7.46(1H,t),7.80(1H,d),10.88(1H,s);m / z:ES + [M+H] + =777.3.

[0660] Intermediate 8a: tert-butyl 4-(5-hydroxypyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Na2CO3 (1.211 g, 11.43 mmol) was added to a solution of 2-bromopyrimidin-5-ol (1.00 g, 5.71 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.65 g, 8.57 mmol) in toluene (8.0 mL), EtOH (2.0 mL), and water (4.0 mL). The mixture was degassed with N2 for 15 minutes. Next, Pd(dppf)2Cl2-DCM complex (0.467 g, 0.571 mmol) was added, and the resulting mixture was heated to 100 °C for 3 hours and then cooled to room temperature. The mixture was then diluted with water (150 mL) and extracted with EtOAc (2 × 200 mL). The combined organic solution was washed with brine (80 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-40% in heptane) gave the title compound (1.10 g, 65%) as a light brown viscous liquid; 1 H NMR:1.43(9H,s),2.56(2H,d),3.51(2H,t),4.04(2H,s),6.91(1H,s),8.34(2H,s),10.42(1H,br s);m / z:ES + [M-56] + =222.2.

[0661] Intermediate 8b: tert-butyl 4-(5-hydroxypyrimidin-2-yl)piperidine-1-carboxylate [ka] tert-Butyl 4-(5-hydroxypyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.10 g, 3.97 mmol) was dissolved in EtOH (30 mL) and the solution was bubbled with N for 15 minutes. Pd-on-C (0.55 g, 0.517 mmol) (10% w / w) was added under N, and the mixture was then stirred at room temperature under an atmosphere of H for 5 hours. The mixture was then filtered through Celite, and the filter cake was washed with MeOH (250 mL). The filtrate was concentrated to give the title compound (1.05 g, 70%) as a light brown viscous liquid, which was used in the next step without further purification. 1 H NMR:1.41(9H,s),1.48-1.65(2H,m),1.86(2H,d),2.76-2.95(3H,m),3.99(2H,d),8.23(2H,s);m / z:ES-[MH] - =278.3.

[0662] Intermediate 8c: 2-(piperidin-4-yl)pyrimidin-5-ol [ka] 4N HCl in 1,4-dioxane (5 mL, 20.00 mmol) was added to a solution of tert-butyl 4-(5-hydroxypyrimidin-2-yl)-piperidine-1-carboxylate (500 mg, 1.79 mmol) in DCM (10 mL) at 0° C. The mixture was stirred from 0° C. to room temperature for 2 hours and then concentrated. The resulting solid was triturated with hexane (10 mL) to give the title compound (460 mg, 99%) as the hydrochloride salt as an off-white solid. 1 H NMR:1.90-2.00(2H,m),2.03-2.15(2H,m),2.95-3.11(3H,m),3.29(2H,d),8.36(2H,s),8.89(1H,br s),9.14(1H,br s),10.60(1H,br s);m / z:ES + [M+H] + =180.2.

[0663] Intermediate 8d: 4-(4-(5-hydroxypyrimidin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] DIPEA (0.831 mL, 4.76 mmol) was added to a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (300 mg, 1.586 mmol) and 2-(piperidin-4-yl)pyrimidin-5-ol hydrochloride (513 mg, 2.380 mmol) in DMSO (5 mL) at room temperature under atmospheric pressure. The mixture was heated at 50° C. for 6 hours, then cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (2×150 mL). The combined organic solution was washed with ice water (2×80 mL), dried (NaSO), and concentrated. Purification by FSC (gradient: 0-6% in DCM) afforded the title compound (380 mg, 64%) as a pale yellow viscous liquid. 1 H NMR:(CDCl3)1.92-2.05(2H,m),2.14(2H,d),3.11-3.21(3H,m),4.03(2H,d),7.00(1H,dd),7.17(1H,d),7.62(1H,d),8.37(2H,s);m / z:ES + [M+H] + =349.2.

[0664] Intermediate 8e: 4-[4-[5-(4-bromobutoxy)pyrimidin-2-yl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile [ka] Cs2CO3 (711 mg, 2.182 mmol) and 1,4-dibromobutane (0.391 mL, 3.27 mmol) were added to a solution of 4-(4-(5-hydroxypyrimidin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (380 mg, 1.091 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours, then diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic solution was washed with brine (50 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-40% in heptane) afforded the title compound (390 mg, 71%) as an off-white solid. 1 H NMR:(CDCl3)1.96-2.21(8H,m),3.12-3.22(3H,m),3.51(2H,t),4.02(2H,d ),4.11(2H,t),7.01(1H,dd),7.17(1H,d),7.62(1H,d),8.39(2H,s);m / z:ES + [M+H] + =483.1.

[0665] Example 8: 4-[4-[5-[4-[4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazin-1-yl]-butoxy]pyrimidin-2-yl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile [ka] A mixture of DIPEA (0.216 mL, 1.241 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (137 mg, 0.348 mmol), 4-(4-(5-(4-bromobutoxy)pyrimidin-2-yl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (120 mg, 0.248 mmol), and KI (124 mg, 0.745 mmol) in DMSO (4 mL) was stirred at room temperature under N. The mixture was then heated to 80° C. for 16 hours, cooled to room temperature, and diluted with DCM (30 mL). The phases were separated and the organic solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO3 (20 mL), followed by saturated brine (20 mL)), dried (Na2SO4) and concentrated. The crude material was purified by preparative HPLC (column B, eluent C). Fractions containing the desired compound were combined, concentrated at low temperature to a minimum amount of solvent and basified with saturated NaHCO3 solution. The phases were separated and the aqueous phase was extracted with DCM (4 x 30 mL). The combined organic solution was washed with water (20 mL), dried on a phase separator and lyophilized to give the title compound (55 mg, 29%) as an off-white solid; 1 H NMR:1.57-1.67(2H,m),1.69-1.83(4H,m),1.92-2.04(3H,m),2.34-2.42( 3H,m),2.59(1H,d),2.85-2.97(1H,m),3.06-3.20(3H,m),3.26(4H,s),4.0 8-4.25(5H,m),4.30-4.38(1H,m),5.05(1H,dd),7.07(2H,s),7.27(1H,dd) ,7.32(1H,s),7.52(1H,d),7.82(1H,d),8.49(2H,s),10.95(1H,s);m / z:ES + [M+H] + =761.2.

[0666] Intermediate 9a: tert-butyl 5-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate [ka] Na2CO3 (1.218 g, 11.49 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-pyridine-1(2H)-carboxylate (2.67 g, 8.62 mmol) were added to a solution of 6-bromopyridin-3-ol (1.0 g, 5.75 mmol) in EtOH (4.0 mL), toluene (8.0 mL), and water (2.0 mL) at room temperature. The mixture was degassed with N2 for 15 min, followed by the addition of Pd(dppf)Cl2·DCM (0.079 g, 0.575 mmol), and the mixture was heated to 100 °C for 3 h. The mixture was then cooled to room temperature, diluted with water (120 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 150 mL) and the combined organic solution was washed with brine (100 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-35% in heptane) gave the title compound (1.52 g, 95%) as a pale yellow viscous liquid; 1 H NMR:(CDCl3)1.51(9H,s),2.61(2H,d),3.64(2H,t),4.11(2H,d),6.40(1H,s),7.18(1H,dd),7.30(1H,d),8.21(1H,d);m / z:ES + [M+H] + =277.2.

[0667] Intermediate 9b: tert-butyl 4-(5-hydroxypyridin-2-yl)piperidine-1-carboxylate [ka] 10% Pd-on-C (125 mg, 1.175 mmol) was added to a solution of tert-butyl 5-hydroxy-3',6'-dihydro-[2,4'-bi-pyridine]-1'(2'H)-carboxylate (500 mg, 1.809 mmol) in MeOH (10 mL) under N2. The resulting suspension was purged with H2 and stirred at room temperature under an atmosphere of H2 for 2 hours. The mixture was then filtered through Celite and washed with MeOH (150 mL). Concentration of the filtrate afforded the title compound (410 mg, 81%) as an off-white solid; 1 H NMR:1.41(9H,s),1.46-1.59(2H,m),1.76(2H,d),2.67-2.83(3H,m),4.03(2H,d),7.08(2H,d),8.05(1H,s),9.63(1H,br s);m / z:ES + [M+H] + =279.4.

[0668] Intermediate 9c: 6-(piperidin-4-yl)pyridin-3-ol. TFA salt [ka] TFA (0.886 mL, 11.50 mmol) was added to a solution of tert-butyl 4-(5-hydroxypyridin-2-yl)piperidine-1-carboxylate (400 mg, 1.437 mmol) in DCM (8.0 mL) at 0° C. The mixture was then warmed to room temperature over 2 hours and then concentrated. Trituration with MTBE (50 mL) afforded the title compound (430 mg, 99%) as the trifluoroacetic acid salt as an off-white solid. 1 H NMR:1.77-1.91(2H,m),1.94-2.03(2H,m),2.91-3.08(3H,m),3.37(2H,d),7.19-7.34(2H,m),8.13(1H,d),8.40(1H,br s),8.69(1H,br s),10.26(1H,br s);m / z:ES + [M+H] + =179.1.

[0669] Intermediate 9d: 4-(4-(5-hydroxypyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] DIPEA (0.831 mL, 4.76 mmol) and 6-(piperidin-4-yl)pyridin-3-ol (424 mg, 2.380 mmol) were added to a stirred solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (300 mg, 1.586 mmol) in DMSO (5.0 mL) at room temperature. The mixture was then heated to 50° C. for 5 hours, then cooled to room temperature and diluted with water (80 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2×120 mL). The combined organic solution was dried (NaSO) and concentrated. Trituration with hexane (100 mL) afforded the title compound (530 mg, 96%) as an off-white solid. 1 H NMR:1.69(2H,qd),1.88(2H,d),2.86-2.99(1H,m),3.09(2H,t),4.16(2H,d),7.08-7 .12(2H,m),7.27(1H,dd),7.32(1H,s),7.81(1H,d),8.04(1H,d),9.66(1H,s);m / z:ES + [M+H] + =348.1.

[0670] Intermediate 9e: 4-(4-(5-(4-bromobutoxy)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] K2CO3 (80 mg, 0.576 mmol) and 1,4-dibromobutane (186 mg, 0.864 mmol) were added to a stirred solution of 4-(4-(5-hydroxypyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.288 mmol) in acetone (3.0 mL) at room temperature. The mixture was then heated to 60 °C for 4 h, followed by cooling to room temperature and concentration. The mixture was then partitioned between water (80 mL) and EtOAc (100 mL). The aqueous portion was extracted with EtOAc (2 × 100 mL), and the combined organic solution was washed with saturated brine (50 mL), dried (Na2SO4), and concentrated to give the crude compound (170 mg). The same procedure was repeated with Cs2CO3 (188 mg, 0.576 mmol) instead of K2CO3, and the mixture was stirred at room temperature for 2 h. After the same workup as described previously, the crude products from both reactions were combined. Purification by FSC (gradient: 0-20% EtOAc in heptane) afforded the title compound (160 mg, 58%) as an off-white solid; 1 H NMR:(CDCl3)1.84-2.03(4H,m),2.05-2.14(4H,m),2.93-3.02(1H,m),3.13(2H,td),3.51(2H,t ),4.02-4.10(4H,m),7.01(1H,dd),7.12(1H,d),7.17(2H,dd),7.63(1H,d),8.25(1H,d);m / z:ES + [M+H] + =482.1.

[0671] Example 9: 4-(4-(5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] DIPEA (0.221 mL, 1.266 mmol), 4-(4-(5-(4-bromobutoxy)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (147 mg, 0.304 mmol), and KI (126 mg, 0.760 mmol) were added to a solution of 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (100 mg, 0.253 mmol) in DMSO (3.0 mL) at room temperature under N. The mixture was then heated to 80° C. for 12 h, then cooled to room temperature, and diluted with DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO3 (20 mL), followed by saturated brine (20 mL)), dried (Na2SO4), and concentrated. The crude material was purified by preparative HPLC (Column C, Eluent C). Fractions containing the desired compound were combined, concentrated at low temperature to a minimum amount of solvent, and basified with saturated NaHCO3 solution. The phases were separated, and the aqueous portion was extracted with DCM (4 x 30 mL). The combined organic solution was washed with water (20 mL), dried on a phase separator, and lyophilized to give the title compound (28 mg, 14%) as an off-white solid; 1 H NMR:1.62-1.95(10H,m),2.34-2.40(1H,m),2.59(2H,s),2.75-3.03(5H,m),3.10(4H,t),3.84(3H,s),4.03-4 .29(7H,m),4.97(1H,dd),6.52(1H,s),6.64(1H,s),7.21-7.38(4H,m),7.82(1H,d),8.21(1H,s),10.91(1H,br s);m / z:ES + [M+H] + =760.3.

[0672] Intermediate 10a: tert-butyl 3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)azetidine-1-carboxylate [ka] Imidazole (0.474 g, 6.96 mmol) and tert-butylchlorodiphenylsilane (1.48 g, 5.37 mmol) were added to a solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (1.00 g, 4.97 mmol) in DCM (8 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours and then partitioned between water (2 mL) and DCM (10 mL). The organic phase was dried (Na SO ) and concentrated to give the title compound (1.10 g, 90%), which was used in the next step without further purification. 1 H NMR:0.99(9H,s),1.21(9H,s),1.74-1.86(2H,m),2.61-2.79(1H,m),3.42-3.54(2 H,m),3.58-3.68(2H,m),3.81-3.94(2H,m),7.42-7.52(6H,m),7.58-7.65(4H,m).

[0673] Intermediate 10b: 3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)azetidine [ka] TFA (1.92 mL, 25.0 mmol) was carefully added to a solution of tert-butyl 3-(2-((tert-butyldiphenylsilyl)oxy)-ethyl)azetidine-1-carboxylate (1.10 g, 2.502 mmol) in DCM (8 mL) at 0 °C. The mixture was then stirred at 0 °C for 2 h, further diluted with DCM (5 mL), and washed with saturated NaHCO (20 mL). The organic solution was dried (NaSO) and concentrated to give the title compound (810 mg, 91%) as a viscous liquid, which was used in the next step without further purification; m / z: ES + [M+H] + =340.4.

[0674] Intermediate 10c: 4-(4-(4-(3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] 3-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)azetidine (809 mg, 2.382 mmol) and CsCO (1.04 g, 3.18 mmol) were added to a solution of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (650 mg, 1.588 mmol) in 1,4-dioxane (12 mL). The mixture was purged with N for 15 minutes, at which point Pddba (145 mg, 0.159 mmol) and SPhos (85 mg, 0.318 mmol) were added. The mixture was then stirred at 120 °C for 3 hours, cooled to room temperature, and diluted with DCM (25 mL). The mixture was then filtered through Celite. The filtrate was concentrated under reduced pressure and diluted with DCM (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated to give the title compound (1.20 g, 43%) as a grey solid, which was used in the next step without further purification; m / z: ES + [M+H] + =668.2.

[0675] Intermediate 10d: 4-(4-(4-(3-(2-hydroxyethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] Tetra n-butylammonium fluoride (1N solution in THF, 0.843 mL, 0.843 mmol) was added to a solution of 4-(4-(4-(3-(2-((tert-butyl-diphenylsilyl)oxy)ethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (512 mg, 0.767 mmol) in THF (4 mL) at 0 °C, and the resulting mixture was stirred for 3 h. The mixture was then concentrated and dissolved in DCM (25 mL). The resulting solution was washed with saturated NaHCO3 solution (25 mL), dried (Na2SO4), and concentrated to give the title compound (360 mg, 67%) as a viscous liquid; m / z: ES+ [M+H] + =430.2.

[0676] Intermediate 10e: 4-(4-(4-(3-(2-bromoethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] PPh3 (286 mg, 1.090 mmol) was added to a solution of 4-(4-(4-(3-(2-hydroxyethyl)azetidin-1-yl)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (360 mg, 0.838 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 5 min. CBr4 (361 mg, 1.090 mmol) was then added, and the mixture was stirred at room temperature for 2 h. The solvent was reduced to half its volume (2 mL) after concentration, followed by trituration of the product with pentane to give the title compound, which was used in the next step without further purification; m / z: ES + [M+H] + =492.0.

[0677] Example 10: 4-(4-(4-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] A mixture of DIPEA (0.25 mL, 1.422 mmol), 4-(4-(4-(3-(2-bromoethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (140 mg, 0.284 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (112 mg, 0.284 mmol), and KI (142 mg, 0.853 mmol) was stirred in DMSO (5 mL) at room temperature. The mixture was then heated to 80° C. for 12 hours, then concentrated and slowly poured into ice water. The resulting solid was collected by filtration, washed with water (10 mL), and dried under vacuum. Purification by preparative HPLC (column B, eluent C, basic workup A) afforded the title compound (34 mg, 15%) as an off-white solid; 1 H NMR:1.50-1.66(2H,m),1.66-1.77(1H,m),1.77-1.87(2H,m),1.87-1.99(1H,m),2.09-2.1 8(1H,m),2.24-2.43(4H,m),2.54-2.61(4H,m),2.65-2.75(2H,m),2.79-2.93(1H,m),2.93 -3.10(4H,m),3.17-3.26(2H,m),3.84(3H,s),4.04-4.30(4H,m),4.94(1H,dd),6.39-6.51 (3H,m),6.57-6.68(1H,m),6.96-7.11(2H,m),7.23-7.37(2H,m),7.81(1H,d),11.0(1H,br s);m / z:ES + [M+H] + =770.2.

[0678] Intermediate 11a: 5-(4-(4-hydroxyphenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile [ka] K2CO3 (826 mg, 5.98 mmol) was added to a solution of 5-bromo-3-(trifluoromethyl)picolinonitrile (500 mg, 1.992 mmol), 4-(piperidin-4-yl)phenol hydrobromide (771 mg, 2.99 mmol), and N1,N2-dimethylethane-1,2-diamine (35.1 mg, 0.398 mmol) in 1,4-dioxane (8 mL). The mixture was degassed with N2 for 15 minutes, followed by the addition of CuI (37.9 mg, 0.199 mmol). The mixture was heated to 120 °C for 16 hours, then cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (2 × 150 mL). The combined organic solution was washed with brine (80 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) afforded the title compound (310 mg, 43%) as a pale yellow solid; 1 H NMR:1.56-1.69(2H,m),1.84(2H,d),2.66-2.79(1H,m),3.06-3.15(2H,m),4.29 (2H,d),6.69(2H,d),7.05(2H,d),7.63(1H,d),8.65(1H,d),9.18(1H,s);m / z:ES + [M+H] + =348.0.

[0679] Intermediate 11b: 5-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile [ka] K2CO3 (119 mg, 0.864 mmol) was added to a solution of 5-(4-(4-hydroxyphenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile (150 mg, 0.432 mmol) and 1,4-dibromobutane (140 mg, 0.648 mmol) in DMF (3.0 mL) at room temperature. The mixture was heated to 70 °C for 6 h, then cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (2 × 80 mL). The combined organic solution was washed with saturated brine (30 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0 to 30% EtOAc in heptane) afforded the title compound (145 mg, 65%) as an off-white semisolid. 1 H NMR:1.23-1.32(4H,m),1.60-1.73(2H,m),1.91-2.04(2H,m),2.75-2.90(1H,m),3.11(2H,t),3.54 -3.67(2H,m),3.97(2H,t),4.30(2H,d),6.86(2H,d),7.17(2H,d),7.64(1H,d),8.66(1H,d);m / z:ES + [M+H] + =482.1.

[0680] Example 11: 5-(4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile [ka] DIPEA (0.332 mL, 1.899 mmol) was added to a solution of 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (150 mg, 0.380 mmol), 5-(4-(4-(4-bromobutoxy)-phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile (220 mg, 0.456 mmol), and KI (189 mg, 1.140 mmol) in DMSO (4 mL) at room temperature under N. The mixture was stirred at 80° C. for 16 hours, then cooled to room temperature and diluted with DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO3 (20 mL), followed by saturated brine (20 mL)), dried (Na2SO4), and concentrated. Purification by preparative HPLC (column B, eluent C, basic workup A) and trituration with pentane (10 mL) afforded the title compound (52 mg, 18%) as an off-white solid; 1 H NMR:1.58-1.78(6H,m),1.81-2.01(3H,m),2.27-2.38(3H,m),2.60-2.78(2H,m),2.80-2.98(2H,m),3.11(3H,t),3.83(3H,s),3.97(2H, m / z:ES + [M+H] + =760.4.

[0681] Intermediate 12a: 4-(4-(4-((3,3-difluoro-5-hydroxypentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile [ka] RockPhos Pd G3 (0.290 g, 0.34 mmol) was added to 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.39 g, 3.40 mmol), 3,3-difluoropentane-1,5-diol (1.19 g, 8.49 mmol), and Cs2CO3 (239 mg, 0.73 mmol) in 1,4-dioxane (50 mL) at room temperature. The resulting mixture was then stirred at 100 °C for 1 h. The mixture was then cooled to room temperature and concentrated. The resulting residue was dissolved in EtOAc (50 mL) and brine (50 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic solution was dried (MgSO4) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (0.60 g, 38%) as a yellow gum; 1 H NMR:(CDCl3)1.62(1H,t),1.7-1.89(2H,m),1.94-2.04(2H,m),2.25(2H,tt),2.43(2H,tt),2.66-2.82(1H,m),2.96- 3.16(2H,m),3.91(2H,q),4.02(2H,d),4.17(2H,t),6.76-6.92(2H,m),6.99(1H,dd),7.09-7.21(3H,m),7.61(1H,d).

[0682] Intermediate 12b: 5-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3-difluoropentyl methanesulfonate [ka] Methanesulfonic anhydride (167 mg, 0.96 mmol) was added in one portion to 4-(4-(4-((3,3-difluoro-5-hydroxy-pentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.38 mmol) and NEt (160 μL, 1.15 mmol) in DCM (2 mL) at room temperature, and the mixture was stirred for 18 h. The mixture was then diluted with DCM (25 mL) and washed successively with saturated NH Cl (10 mL), saturated NaHCO (10 mL), water (20 mL), and saturated brine (10 mL). The solution was then dried over a phase separation cartridge, filtered, and concentrated to give the title compound, which was used in the next step without further purification; m / z: ES + [M+H] + 547.2.

[0683] Example 12: 4-(4-(4-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)-3,3-difluoropentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] KI (200 mg, 1.21 mmol), 5-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3-difluoropentyl methanesulfonate (220 mg, 0.40 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (166 mg, 0.42 mmol), and DIPEA (0.247 mL, 1.41 mmol) were dissolved in MeCN (3 mL) and stirred at 80° C. for 18 hours. The mixture was then cooled to room temperature and concentrated. The resulting residue was dissolved in DCM (20 mL), washed with water (20 mL), separated through a phase separator, and concentrated. Purification by preparative HPLC (Column A, Eluent A, Basic Workup A) afforded the title compound (10.2 mg, 3%) as a yellow, dry film; 1 H NMR:(CDCl3)1.75(2H,qd),1.97(2H,d),2.13-2.34(4H,m),2.34-2.48(2H,m), 2.64-2.93(9H,m),3.06(2H,td),3.29-3.39(4H,m),3.94(3H,s),4.02(2H,d), 4.13-4.26(3H,m),4.36(1H,d),5.13(1H,dd),6.36(1H,d),6.46(1H,s),6.79- 6.9(2H,m),6.99(1H,dd),7.09-7.19(3H,m),7.61(1H,d),7.89(1H,s);m / z:ES - [MH] - 807.5.

[0684] Intermediate 13a: 4-(4-(4-(3-hydroxypropoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] Prepared from 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile according to the procedure described in Example 12 but using propane-1,3-diol.

[0685] Intermediate 13b: 4-(4-(4-(3-bromopropoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] A solution of PPh3 (419 mg, 1.60 mmol) in THF (10 mL) was added dropwise to a stirred mixture of 4-(4-(4-(3-hydroxypropoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (323 mg, 0.80 mmol) and CBr4 (530 mg, 1.60 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h, then filtered and washed with EtOAc (20 mL). The combined filtrate was concentrated. Purification by FSC (gradient: 0 to 50% EtOAc in heptane) afforded the title compound (346 mg, 93%) as a pale yellow solid. 1 H NMR:(CDCl3)1.76(2H,qd),1.98(2H,dd),2.31(2H,p),2.74(1H,tt),3.06(2H,td),3.60(2H,t),4 .02(2H,dd),4.09(2H,t),6.83-6.91(2H,m),6.99(1H,dd),7.09-7.19(3H,m),7.58-7.64(1H,m).

[0686] Example 13: 4-(4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] A mixture of 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (100 mg, 0.253 mmol), DIPEA (164 mg, 1.266 mmol), 4-(4-(4-(3-bromopropoxy)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (142 mg, 0.304 mmol), and KI (126 mg, 0.760 mmol) in DMSO (4 mL) was stirred at room temperature under N. The mixture was then heated at 80° C. for 12 h, then cooled to room temperature, and diluted with DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO3 (20 mL), followed by saturated brine (20 mL)), dried (Na2SO4), and concentrated. Purification by preparative HPLC (column B, eluent C, basic workup A) with lyophilization and washing with hexanes afforded the title compound (26 mg, 13%) as a brown solid; 1 H NMR:1.55-1.72(2H,m),1.80-1.97(5H,m),2.22-2.31(1H,m),2.58(2H,br s),2.75-2.82(1H,m),2.85-2.96(1H,m),3.05(2H,br t),3.44-3.59(4H,m),3.83(3H,s),4.00(2H,br t),4.07-4.29(5H,m),4.96(1H,br dd),6.49(1H,s),6.61(1H,s),6.87(2H,br d),7.16(2H,br d),7.27(1H,br d),7.33(1H,br s),7.81(1H,br d), 10.90 (1H, br s); m / z: ES + [M+H] + 745.4.

[0687] Intermediate 14a: 2-cyclopropyl-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)benzonitrile [ka] RockPhos Pd G3 (88 mg, 0.10 mmol) was added to a mixture of butane-1,4-diol (142 mg, 1.57 mmol), Cs2CO3 (1.03 g, 3.15 mmol), and 4-(4-(4-bromophenyl)piperidin-1-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1,4-dioxane (5 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0 to 50% EtOAc in petroleum ether) afforded the title compound (0.10 g, 25%) as a white solid. 1 H NMR:(300MHz)0.77-0.88(2H,m),0.93-1.08(2H,m),1.43-1.91(8H,m),1.98-2.13(1H,m),2.60-2.74(1H,m),2.79-2.93(2H,m),3.36-3.48 (2H,m),3.86-3.96(2H,m),3.99(1H,s),4.03(1H,s),4.36-4.46(1H,m ),6.44(1H,d),6.77-6.88(3H,m),7.07-7.17(2H,m),7.45(1H,d);m / z E.S. + [M+H] + =391.3.

[0688] Intermediate 14b 4-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)-2-cyclopropylbenzonitrile [ka] CBr4 (153 mg, 0.46 mmol) was added to a mixture of PPh3 (121 mg, 0.46 mmol) and 2-cyclopropyl-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)benzonitrile (90 mg, 0.23 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 2 h and then concentrated. Purification by FSC (gradient: 0-23% EtOAc in petroleum ether) afforded the title compound (81 mg, 78%) as a white solid; 1H NMR:0.79-0.90(2H,m),1.00-1.10(2H,m),1.60(2H,m),1.78-1.86(4H,m),1.91-2.03(2H,m),2.08(1H,m),2.65-2.75(1H, m / z E.S. + [M+H] + =453.2.

[0689] Example 14: 2-Cyclopropyl-4-(4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)benzonitrile [ka] DIPEA (57.8 μL, 0.33 mmol) was added to a mixture of KI (4 mg, 0.02 mmol), 4-(4-(4-(4-bromobutoxy)-phenyl)piperidin-1-yl)-2-cyclopropylbenzonitrile (50 mg, 0.11 mmol), and 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (43.5 mg, 0.12 mmol) in MeCN (2 mL) at room temperature. The resulting mixture was stirred at 80° C. for 16 hours and then concentrated. Purification by preparative TLC (DCM / MeOH=20 / 1) afforded the title compound (13 mg, 16%) as a white solid. 1H NMR:0.78-0.89(3H,m),0.97-1.08(2H,m),1.15(1H,s),1.24(4H,s),1.35(1H,s),1.45-1.67(4H,m) ,1.69-1.84(4H,m),1.91(1H,d),2.03-2.14(2H,m),2.14-2.21(1H,m),2.22-2.34(2H,m),2.37(2H, s),2.82-2.96(3H,m),3.83(3H,s),3.94-4.05(4H,m),4.10(1H,d),4.23(1H,d),4.91-5.01(1H,m), 6.43-6.50(2H,m),6.60(1H,s),6.81-6.89(3H,m),7.11-7.18(2H,m),7.47(1H,d),10.89(1H,s);m / z E.S. + [M+H] + =731.3.

[0690] Intermediate 15a: Benzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate [ka] To a solution of 2-(piperidin-4-yl)ethan-1-ol (5.00 g, 38.7 mmol) in DCM (100 mL) was added Na2CO3 (18.46 g, 174.1 mmol) in water (100 mL) at 0 °C, followed by the dropwise addition of benzyl carbonochloridate (6.08 mL, 42.6 mmol). The mixture was stirred at room temperature for 6 h, then diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic solution was washed with saturated brine (100 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-70% EtOAc in heptane) afforded the title compound (8.34 g, 82%) as a pale yellow solid. 1 H NMR: ( CDCl3)1.15(2H,qd),1.43(1H,t),1.52(2H,q),1.62(1H,dddd),1.69(2H,t),2 .78(2H,t),3.69(2H,q),4.14(2H,dd),5.12(2H,s),7.28-7.45(5H,m);m / z:ES +[M+H] + 264.3.

[0691] Intermediate 15b: Benzyl 4-(2-oxoethyl)piperidine-1-carboxylate [ka] To a solution of benzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (8.34 g, 31.7 mmol) in DCM (150 mL) was added Dess-Martin periodinane (14.78 g, 34.84 mmol) at 0 °C. The reaction was stirred at room temperature for 3 h, then quenched by the addition of saturated NaHCO3 solution (50 mL) and filtered to remove the solid residue. The solid residue was washed with DCM (50 mL). The phases were separated, and the organic solution was washed with saturated brine (20 mL × 2), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) afforded the title compound (5.20 g, 63%) as a colorless oil; 1 H NMR: ( CDCl3)1.20(2H,q),1.71(2H,d),2.07(1H,tq),2.38(2H,dd),2.82(2H,t),4.16(2H,s),5.12(2H,s),7.31-7.43(5H,m),9.77(1H,t);m / z:ES + [M+H] + 262.2.

[0692] Intermediate 15c: Benzyl 4-(2,2-dimethoxyethyl)piperidine-1-carboxylate [ka] To a solution of benzyl 4-(2-oxoethyl)piperidine-1-carboxylate (5.20 g, 19.9 mmol) in MeOH (60 mL) was added trimethoxymethane (10.9 mL, 99.5 mmol) and 4-methylbenzenesulfonic acid (0.17 g, 0.99 mmol) at 15 °C. The mixture was stirred at this temperature for 1 h. The reaction was then quenched by the addition of water (50 mL) and diluted with DCM (100 mL). The phases were separated, and the organic solution was washed with saturated brine (3 × 20 mL), dried (NaSO), and concentrated under reduced pressure to give the title compound (5.90 g, 96%) as a colorless oil. 1 H NMR: ( CDCl3)1.04-1.25(2H,m),1.5-1.57(2H,m),1.57-1.63(1H,m),1.68(2H,t),2.7 8(2H,t),3.31(6H,s),4.15(2H,d),4.46(1H,t),5.12(2H,s),7.27-7.37(5H,m).

[0693] Intermediate 15d: 4-(2,2-dimethoxyethyl)piperidine [ka] 10% Ph(OH)2 on carbon (0.54 g, 0.38 mmol) was added to benzyl 4-(2,2-dimethoxyethyl)piperidine-1-carboxylate (5.90 g, 19.2 mmol) in MeOH (60 mL) in a steel pressure reactor at room temperature under N2. The resulting suspension was purged with N2, followed by H2, and then stirred at room temperature for 3 days at 4 atmospheres of pressure. The mixture was then filtered through Celite and washed with MeOH (250 mL). The filtrate was concentrated to give the title compound (3.14 g, 94%) as a colorless oil; 1 H NMR: ( CDCl3)1.15-1.28(2H,m),1.53-1.56(2H,m),1.72(2H,d),2.63(2H,td),3.04-3.14(2H,m),3.31(8H,s),4.47(1H,t).

[0694] Intermediate 15e: 4-(4-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] RuPhos Pd G3 (0.205 g, 0.24 mmol) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), 4-(2,2-dimethoxyethyl)piperidine (0.64 g, 3.67 mmol), Cs2CO3 (2.388 g, 7.33 mmol), and RuPhos (0.114 g, 0.24 mmol) in 1,4-dioxane (20 mL) at room temperature under N2. The resulting solution was stirred at 100 °C for 10 h and then concentrated. Purification by flash C18-flash chromatography (gradient: 0 to 100% MeCN in water) afforded the title compound (1.20 g, 98%) as a yellow solid. 1 H NMR:1.21-1.31(2H,m),1.39-1.51(3H,m),1.52-1.67(2H,m),1.70-1.77(2H,m),1.79-1.87(2H,m),2.51-2.61(2H,m),2.71(1H,t),2.98-3 .08(2H,m),3.22(6H,s),3.58(2H,d),4.16(2H,d),4.43-4.50(1H,m) ,6.84(2H,d),7.07(2H,d),7.26(1H,d),7.32(1H,s),7.80(1H,d);m / z E.S. + [M+H] + =502.2.

[0695] Intermediate 15f: 4-(4-(4-(4-(2-oxoethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] A solution of 4-(4-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (200 mg, 0.40 mmol) in formic acid (2 mL) was stirred at room temperature for 5 hours. The mixture was then concentrated to give the title compound (0.17 g, 94%), which was used in the next step without further purification. 1 H NMR:1.23-1.33(2H,m),1.54-1.67(2H,m),1.67-1.76(2H,m),1.79-1.87(2H,m),1.95(1H,s),2.36-2.43(2H,m),2.57-2.69(2H,m),2.69-2 .76(1H,m),3.03(2H,t),3.58(2H,d),4.16(2H,d),6.85(2H,d),7.07 (2H,d),7.22-7.29(1H,m),7.31(1H,s),7.80(1H,d),9.70(1H,d);m / z E.S. + [M+H] + =456.1.

[0696] Example 15: 4-(4-(4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] tert-Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (50 mg, 0.11 mmol) was added to a solution of 4-(4-(4-(4-(2-oxoethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.11 mmol) in formic acid (2 mL) at room temperature. The resulting solution was stirred at 40° C. for 1 hour, then cooled to room temperature and concentrated. The resulting residue was dissolved in DCM (2 mL), followed by the addition of NaBH(OAc) (47 mg, 0.22 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was then diluted with DCM, washed (AcOH (5%, aq), water (20 mL), followed by saturated brine (20 mL)), dried (Na2SO4), and concentrated. Purification by preparative SFC (column: Torus 2-PIC; mobile phase A: CO2, mobile phase B: MeOH (0.5% 2M NH3-MeOH); flow rate: 50 mL / min; isocratic gradient: 30% B) afforded the title compound (6.1 mg, 7%) as a pale yellow solid; 1 H NMR: (300MHz) 1.15- 1.30(2H,m),1.30-1.50(3H,m),1.52-1.70(2H,m),1.71-1.97(5H,m),2.29 -2.43(3H,m),2.60(3H,d),2.75-3.10(4H,m),3.10-3.50(8H,m),3.61(2H,d ),3.84(3H,s),4.04-4.29(4H,m),4.97(1H,dd),6.49(1H,s),6.61(1H,s), 6.86(2H,d),7.08(2H,d),7.19-7.39(2H,m),7.82(1H,d),10.91(1H,s);m / z E.S. + [M+H]+=798.4.

[0697] Intermediate 16a: tert-butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate [ka] 4-(Piperidin-4-yl)phenol hydrobromide (5.14 g, 19.91 mmol) and di-tert-butyl dicarbonate (4.56 g, 20.91 mmol) were slurried in DCM (60 mL) at room temperature. NEt (5.53 mL, 39.82 mmol) was then added in one portion, and the mixture was stirred for 45 minutes. The mixture was then diluted with DCM (200 mL), washed with water (3×100 mL), dried over a phase separator, and concentrated to give the title compound (5.70 g, 100%) as a white solid. 1 H NMR:1.34-1.46(11H,m),1.70(2H,d),2.54-2.6(1H,m),2.77(2H,br s),4.05(2H,d),6.59-6.73(2H,m),6.94-7.06(2H,m),9.12(1H,s).m / z:ES-[MH] - =276.3.

[0698] Intermediate 16b: tert-butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate [ka] tert-Butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (2.20 g, 7.93 mmol), K2CO3 (1.32 g, 9.52 mmol), and 1,4-dibromobutane (2.37 mL, 19.83 mmol) were dissolved in anhydrous MeCN (80 mL) under N2. The mixture was stirred at 80 °C for 3 h and then cooled to room temperature. The mixture was then filtered and washed with DCM (200 mL). The filtrate was then concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) afforded the title compound (1.08 g, 33%) as a white oil, which solidified upon standing. 1H NMR:(CDCl3)1.48(9H,s),1.51-1.69(2H,m),1.75-1.86(2H,m),1.89-1.98(2H,m),2-2.13(2H,m),2.58(1H,t m / z:ES + [M-tBu] + 356.0.

[0699] Intermediate 16c: tert-butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate [ka] DIPEA (2.3 mL, 13.10 mmol) was added to 3-[1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]-piperidine-2,6-dione hydrochloride (1.05 g, 2.88 mmol) in DMSO (20 mL) at room temperature. The mixture was sonicated until a cloudy solution was obtained, followed by stirring at room temperature for 0.5 hours. KI (1.30 g, 7.86 mmol) was added, followed by a solution of tert-butyl 4-(4-(4-bromobutoxy)phenyl)piperidine-1-carboxylate (1.08 g, 2.62 mmol) in DMSO (7 mL), and the mixture was stirred at 70° C. for 18 hours. After cooling, the mixture was diluted with EtOAc (200 mL), washed with water (3 x 100 mL), followed by brine (2 x 100 mL), dried (MgSO4), and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) afforded the title compound (1.08 g, 63%) as a pale yellow gum; 1H NMR:1.48(9H,s),1.53-1.89(9H,m),2.14-2.25(1H,m),2.32(1H,qd),2.4 1-2.52(2H,m),2.53-2.65(5H,m),2.71-2.95(4H,m),3.26-3.39(3H,m),3. 98(2H,t),4.15-4.31(3H,m),4.41(1H,d),5.18(1H,dd),6.79-6.89(3H,m ),6.99(1H,dd),7.08-7.16(2H,m),7.73(1H,d),8.01-8.25(1H,m);m / z:ES + [M+H] + 660.3.

[0700] Intermediate 16d: 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione [ka] 4M HCl in dioxane (2 mL, 8.00 mmol) was added in one portion to tert-butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate (1.07 g, 1.62 mmol) in DCM (5 mL) at room temperature under air, and the mixture was stirred for 2 hours. The mixture was then concentrated, slurried in EtO (30 mL), and filtered to give the title compound as the hydrochloride salt as a beige solid, which was used in the next step without further purification; m / z: ES + [M+H] + 560.3.

[0701] Example 16: 2-chloro-4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}benzonitrile [ka] A mixture of 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.17 mmol), 2-chloro-4-fluorobenzonitrile (27.4 mg, 0.18 mmol), and K2CO3 (58.0 mg, 0.42 mmol) was suspended in DMSO (1 mL) and stirred at 90 °C for 1.5 h. Purification by preparative HPLC (column A, eluent A) afforded the title compound (65 mg, 56%) as a white solid; 1 H NMR:1.55-1.65(4H,m),1.68-1.77(2H,m),1.81(2H,d),1.89-2.02(1H,m),2.34-2. 43(3H,m),2.52-2.64(1H,m),2.7-2.94(2H,m),2.99(2H,t),3.21-3.4(8H,m),3.97( 2H,t),4.09(2H,d),4.21(1H,d),4.33(1H,d),5.04(1H,dd),6.85(2H,d),7.00(1H, m / z:ES + [M+H] + 695.5.

[0702] Example 17: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-methoxybenzonitrile [ka] A mixture of 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.17 mmol), 4-fluoro-2-methoxybenzonitrile (26.6 mg, 0.18 mmol), and KCO (58.0 mg, 0.42 mmol) was suspended in DMSO (1 mL) and stirred at 90 °C for 2.5 h. After cooling to room temperature, purification by preparative HPLC (column A, eluent A) afforded the title compound (40 mg, 35%) as a white solid. 1 H NMR:1.54-1.68(4H,m),1.74(2H,q),1.83(2H,d),1.92-2.02(1H,m),2.29-2.44(4 H,m),2.56-2.8(3H,m),2.82-3.02(3H,m),3.11-3.49(6H,m),3.88(3H,s),3.98(2 H,t),4.08(2H,d),4.21(1H,d),4.33(1H,d),5.05(1H,dd),6.53-6.67(2H,m),6.8 7(2H,d),7.06(2H,d),7.16(2H,d),7.41(1H,d),7.52(1H,d),10.92(1H,s);m / z:ES + [M+H] + 691.5.

[0703] Example 18: 6-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-methylpyridine-3-carbonitrile [ka] A mixture of 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (68 mg, 0.11 mmol), 6-fluoro-2-methylnicotinonitrile (16.3 mg, 0.12 mmol), and K2CO3 (39.4 mg, 0.29 mmol) was suspended in DMSO (1.5 mL) and then stirred in a microwave at 120 °C for 1 h. Purification by preparative HPLC (column A, eluent A) afforded the title compound (0.018 g, 23%) as a beige solid; 1 H NMR: ( CDCl3)1.62-1.77(4H,m),1.79-1.88(2H,m),1.93(2H,d),2.20(1H,ddq),2.32(1H,qd),2.42 -2.51(2H,m),2.56(3H,s),2.59-2.64(4H,m),2.71-2.9(3H,m),2.91-3.02(2H,m),3.24-3.4 1(4H,m),3.98(2H,t),4.25(1H,d),4.41(1H,d),4.60(2H,d),5.19(1H,dd),6.47(1H,d),6.8 1-6.9(3H,m),6.99(1H,dd),7.07-7.16(2H,m),7.54(1H,d),7.73(1H,d),7.91(1H,s);m / z:ES + [M+H] + =676.6.

[0704] Intermediate 19a: 8-Fluoroquinoline-5-carbonitrile [ka] KOAc (0.104 g, 1.062 mmol) and potassium hexacyanoferrate(II) trihydrate (1.869 g, 4.42 mmol) were added to 5-bromo-8-fluoroquinoline (2.00 g, 8.85 mmol) in 1,4-dioxane (30 mL) and water (30 mL). The mixture was degassed under N at room temperature for 5 minutes, after which XPhos (0.422 g, 0.885 mmol) and Xphos Pd G (0.374 g, 0.442 mmol) were added. The mixture was then stirred at 100 °C for 3 hours and then cooled to room temperature. The mixture was extracted with EtOAc (2 × 100 mL). The combined organic solution was washed with saturated brine (100 mL), dried (NaSO), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexanes) afforded the title compound (0.4 g, 26%) as an off-white solid; 1 H NMR:7.82(1H,dd),7.91(1H,dd),8.35(1H,dd),8.56(1H,dt),9.15(1H,dd);m / z:ES + [M+H] + =173.0.

[0705] Intermediate 19b: 8-(4-(4-hydroxyphenyl)piperidin-1-yl)quinoline-5-carbonitrile [ka] 4-(Piperidin-4-yl)phenol hydrobromide (0.900 g, 3.49 mmol) and DIPEA (1.217 mL, 6.97 mmol) were added to 8-fluoroquinoline-5-carbonitrile (0.400 g, 2.323 mmol) in DMSO (10 mL) at room temperature. The mixture was stirred at 50° C. for 6 hours, then cooled to room temperature and concentrated. The mixture was slowly poured into ice water. The solid was collected by filtration, washed with water (20 mL), and dried under vacuum to give the title compound (0.700 g, 89%) as a yellow solid. 1H NMR:1.81-1.98(4H,m),2.63-2.79(1H,m),2.95-3.16(2H,m),4.37(2H,d),6.63-6.78(2H,m),7.11(2 m / z:ES-[MH] - =328.0.

[0706] Intermediate 19c: 8-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)quinoline-5-carbonitrile [ka] 1,4-Dibromobutane (0.262 g, 1.214 mmol) and K2CO3 (0.252 g, 1.821 mmol) were added to 8-(4-(4-hydroxy-phenyl)piperidin-1-yl)quinoline-5-carbonitrile (0.200 g, 0.607 mmol) in MeCN (5 mL) at room temperature. The mixture was then stirred at 60 °C for 6 h. Water (40 mL) was then added, and the mixture was extracted with EtOAc (2 × 70 mL). The combined organic solution was washed with saturated brine (50 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexane) afforded the title compound (0.200 g, 68%) as a yellow solid; 1 H NMR:1.76-2.02(8H,m),2.70-2.82(1H,m),3.00-3.12(2H,m),3.62(2H,t),3.99(2H,t),4.3 7(2H,d),6.89(2H,d),7.23(3H,dd),7.74(1H,dd),8.05(1H,d),8.40(1H,dd),8.98(1H,dd).

[0707] Example 19: 8-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}quinoline-5-carbonitrile [ka] KI (0.205 g, 1.233 mmol) and DIPEA (0.359 mL, 2.056 mmol) were added to a mixture of 3-[1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (0.150 g, 0.411 mmol) and 8-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)quinoline-5-carbonitrile (0.115 g, 0.247 mmol) in DMSO (5 mL) at room temperature. The mixture was then stirred at 80° C. for 16 hours, then cooled to room temperature and concentrated. The residue was slowly poured into ice water. The solid was collected by filtration, washed with water (10 mL), and dried under vacuum. Preparative HPLC (Column C, Eluent C, Basic Workup A) afforded the title compound (0.090 g, 30%) as an off-white solid; 1 H NMR:1.57-1.67(2H,m),1.70-1.80(2H,m),1.84-2.00(5H,m),2.27-2.43(3H,m),2.51-2.64(5H ,m)2.69-2.82(1H,m),2.84-2.97(1H,m),3.00-3.11(2H,m),3.24-3.31(4H,m),3.99(2H,t),4. 17-4.25(1H,m),4.27-4.42(3H,m),5.05(1H,dd),6.89(2H,d),7.01-7.10(2H,m),7.22(3H,dd) ,7.52(1H,d),7.71-7.77(1H,m),8.05(1H,d),8.40(1H,dd),8.97(1H,dd),10.94(1H,s);m / z:ES + [M+H] + =712.4.

[0708] Intermediate 20a: 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione [ka] Potassium acetate (5.04 g, 51.37 mmol) was added in one portion to 3-aminopiperidine-2,6-dione hydrochloride (3 g, 18.23 mmol) and 4,5-difluorophthalic acid (3.35 g, 16.57 mmol) in AcOH (30 mL) at room temperature. The resulting solution was stirred at 90° C. for 18 hours. The mixture was then cooled to room temperature, and a solid formed. Water (30 mL) was added. The solid was collected by filtration, washed with water (2×5 mL), and dried under vacuum at 45° C. overnight to give the title compound (3.43 g, 70%) as a dark gray / purple solid. 1 H NMR:2.01-2.12(1H,m),2.53-2.7(2H,m),2.83-2.95(1H,m),5.17(1H,dd),8.15(2H,t),11.13(1H,s);m / z:ES-[MH] - 293.

[0709] Intermediate 20b: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate [ka] DMSO (0.5 mL) followed by DIPEA (118 μL, 0.68 mmol) was added to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (100 mg, 0.34 mmol) and tert-butyl piperazine-1-carboxylate (69.6 mg, 0.37 mmol). The mixture was then heated at 100° C. for 2 hours. Saturated NH4Cl solution (0.5 mL) and water (1.5 mL) were then added. The brown precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give the title compound (86 mg, 55%) as a dark brown / black solid. 1H NMR:1.44(9H,s),2.04(1H,dq),2.55-2.62(1H,m),2.89(1H,ddd),3.09(1H,d),3.16-3.26(4 H,m),3.45-3.55(4H,m),5.11(1H,dd),7.49(1H,d),7.75(1H,d),11.09(1H,s);m / z:ES-[MH] - 459.

[0710] Intermediates 20c and 20d: 3-(5-fluoro-1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione and 3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione [ka] Zinc powder (72.4 mg, 1.11 mmol) was added in one portion to tert-butyl-4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (170 mg, 0.37 mmol) in AcOH (3.4 mL) at room temperature. The resulting suspension was stirred at 60° C. for 48 h. Additional Zn powder (72.4 mg, 1.11 mmol) was added, and the mixture was stirred at 60° C. for 24 h. The mixture was then diluted with MeOH (25 mL), filtered, and the filtrate was concentrated. The resulting gum was dissolved in TFA (5 mL) at room temperature, and triethylsilane (587 μL, 3.68 mmol) was added in one portion. The resulting orange solution was stirred at room temperature for 1 h. The mixture was then concentrated. Trituration with Et2O and collection of the solid by filtration gave the title compound (trifluoroacetate salt form) (170 mg, 57%) as a mixture of isomers as a beige solid, which was used in the next step without further purification; m / z: ES + [M+H] + =347.

[0711] Example 20: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2d was reacted with intermediates 20c and 20d using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (column A, eluent A). 1 H NMR:(500MHz,CDCl3)1.85(2H,q),1.88-1.94(1H,m),1.94-2.01(3H,m),2.22(1H,dtd),2.35(1H ,qd),2.77(0H,s),2.82-2.88(1H,m),2.88-2.98(3H,m),3.06(2H,td),3.13(4H,s),3.32-3.44(4 H,m),3.98(2H,t),4.02(2H,dq),4.22-4.47(2H,m),5.18(1H,dd),6.81-6.88(2H,m),6.96-7.03( m / z E.S. + [M+H]+=747.4.

[0712] Example 21: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2d was reacted with intermediates 20c and 20d using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (column A, eluent A); 1H NMR:(500MHz,CDCl3)0.87-0.94(1H,m),1.76(2H,qd),1.8-1.94(1H,m),1.94-2.01(2H,m),2.22(1H,dtd) ,2.34(1H,qd),2.74(1H,tt),2.84-2.89(2H,m),2.93(1H,ddd),3.01-3.1(5H,m),3.32(3H,q),3.48-3.55 (1H,m),3.98(2H,t),4.02(2H,dt),4.28(1H,d),4.42(1H,d),5.19(1H,dd),6.65(0H,s),6.82-6.88(2H,m ),6.99(1H,dd),7.09-7.18(4H,m),7.48(1H,d),7.55(0H,dd),7.61(1H,d),7.98(1H,s),8.16(2H,s);m / z E.S. + [M+H]+=747.4.

[0713] Example 22: 4-{4-[5-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)pyrimidin-2-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 8e was reacted with intermediate 2c using the general synthetic method illustrated by Example 8 to give the title compound after purification by HPLC (column: Zorbax Eclipse Plus C18 50×2.1 mm, 1.8 μm, eluent C, basic workup A); 1H NMR:1.52-1.68(2H,m),1.66-1.84(4H,m),1.9-2.08(3H,m),2.26-2.49(6 H,m),2.59(2H,d),2.8-2.98(1H,m),3.05-3.2(3H,m),3.23-3.3(4H,m),4 .05-4.26(5H,m),4.33(1H,d),5.05(1H,dd),6.99-7.12(2H,m),7.27(1H, d),7.32(1H,s),7.52(1H,d),7.82(1H,d),8.49(2H,s),10.95(1H,s);m / z E.S. + [M+H]+=731.2.

[0714] Example 23: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 1h was reacted with intermediate 20b using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Workup A); 1 H NMR:(CDCl3)1.65-1.87(6H,m),1.92-2(2H,m),2.07-2.2(1H,m),2.41-2. 53(2H,m),2.56-2.67(4H,m),2.67-2.96(4H,m),3.06(2H,td),3.22-3.35 (4H,m),3.92-4.1(4H,m),4.93(1H,dd),6.78-6.92(2H,m),6.99(1H,dd), 7.07-7.21(3H,m),7.37(1H,d),7.47(1H,d),7.61(1H,d),7.97(1H,s);m / z E.S. + [M+H]+=761.5.

[0715] Intermediate 24a: tert-butyl 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Lithium bid(trimethylsilyl)amide (60.7 mL, 60.71 mmol) was slowly added to tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (9.2 g, 40.47 mmol) in THF (80 mL) at −78° C. over 20 minutes under N. The resulting mixture was stirred at −78° C. for 0.5 hours. N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (23.84 g, 60.71 mmol) was then added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was then quenched with saturated NH4Cl solution. The mixture was diluted with EtOAc, washed with water followed by saturated brine, dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-5% EtOAc in petroleum ether) afforded the title compound (11.00 g, 76%) as a yellow liquid; 1 H NMR(300MHz)5.82(s,1H),4.01(d,2H),3.35(s,2H),1.40(s,9H),1.05(s,6H).

[0716] Intermediate 24b: tert-butyl 4-(4-(benzyloxy)phenyl)-3,3-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate [ka] Pd(dppf)Cl-DCM (0.818 g, 1.00 mmol) was added to tert-butyl 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)-oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.600 g, 10.02 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetra-methyl-1,3,2-dioxaborolane (4.66 g, 15.03 mmol), and KCO (4.15 g, 30.05 mmol) in 1,4-dioxane (40 mL) and water (10 mL) at room temperature under N. The resulting mixture was stirred at 100 °C for 3 h. The mixture was then diluted with EtOAc, washed with water followed by saturated brine, dried (NaSO), and concentrated. Purification by C18-flash chromatography (gradient: 5-90% MeCN in water (0.1% NH4HCO3)) afforded the title compound (1.980 g, 50%) as a pale yellow solid; 1 H NMR:7.47-7.43(m,2H),7.42-7.37(m,2H),7.36-7.30(m,1H),7.12-7.05(m,2H),6.99-6.9 3(m,2H),5.40(s,1H),5.08(s,2H),3.94(d,2H),3.26(s,2H),1.43(s,9H),0.97(s,6H);m / z E.S. + [M-tBu+MeCN] + =379.

[0717] Intermediate 24c: tert-butyl 4-(4-hydroxyphenyl)-3,3-dimethyl-piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-(benzyloxy)phenyl)-3,3-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 2.54 mmol) and Pd-on-C (0.27 g, 0.25 mmol) in MeOH (10 mL) was stirred under an atmosphere of H at 20 atm and 80° C. for 1 h. Concentration of the mixture then afforded the title compound (0.844 g, 109%), which was used in the next step without further purification;1 H NMR(300MHz)0.68(s,6H),1.41(s,9H),1.80-2.10(m,1H),2.33-2.43(m,1H),2.73-2.75(m,1H) ,3.32 (s,2H),3.66-3.69(m,1H),4.10-4.12(m,1H),6.67(d,2H),6.93(d,2H),9.21(s,1H); E.S. + [M-tBu] + =250.

[0718] Intermediate 24d: 4-(3,3-dimethylpiperidin-4-yl)phenol [ka] 4M HCl in dioxane (7.00 mL, 28.00 mmol) was added to tert-butyl 4-(4-hydroxyphenyl)-3,3-dimethyl-piperidine-1-carboxylate (820 mg, 2.68 mmol) in DCM (7 mL) at room temperature, and the mixture was stirred for 16 hours. Concentration of the mixture then afforded the title compound (0.750 g, 116%) as the hydrochloride salt, which was used in the next step without further purification; 1 H NMR(300MHz)6.93(d,2H),6.71(d,2H),3.29(d,1H),3.04(d,1H),2.92(d,1H),2.78 (d,1H),2.60(m,1H),2.25-2.06(m,1H),1.61(d,1H),0.87(s,3H),0.76(s,3H);m / z E.S. + [M+H] + =206.

[0719] Intermediates 24e and 24f: rel-(S)-4-(4-(4-hydroxyphenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Isomer 1) and rel-(R)-4-(4-(4-hydroxyphenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Isomer 2) [ka] 4-Fluoro-2-(trifluoromethyl)benzonitrile (2017 mg, 10.67 mmol) was added to 4-(3,3-dimethylpiperidin-4-yl)phenol (730 mg, 3.56 mmol) and DIPEA (1863 μL, 10.67 mmol) in DMSO (10 mL) at room temperature. The resulting mixture was stirred at 60° C. for 16 hours. The mixture was then diluted with EtOAc, washed with water, followed by saturated brine, dried (NaSO), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave material which was further purified by preparative chiral HPLC (column: CHIRALPAK AD-3, 3.0 mm*100 mm, 3 μm; mobile phase A, mobile phase B: MeOH (0.1% diethylamine); flow rate: 2 mL / min; gradient: 10% B; 220 nm) to give the title compounds as pale yellow solids: Intermediate 24e (0.320 g, 24%); Intermediate 24f (0.289 g, 22%). Intermediate 24e (eluting first): 1 H NMR:0.69(3H,s),0.78(3H,s),1.53(1H,d),2.12(1H,qd),2.55(1H,d),2.82(1H,d),2.91-3.03(1H,m),3.90 (1H,dd),4.19(1H,d),6.65-6.70(2H,m),6.92-6.98(2H,m),7.24-7.31(2H,m),7.77(1H,d),9.21(1H,s);m / z E.S. + [M+H] + =375. Intermediate 24f: 1 H NMR:0.69(3H,s),0.78(3H,s),1.53(1H,d),2.12(1H,m),2.55(1H,d),2.82(1H,d),2.91-3.03(1H,m),3.85-3.93 (1H,m),4.14-4.25(1H,m),6.56-6.78(2H,m),6.81-7.06(2H,m),7.16-7.35(2H,m),7.77(1H,d),9.21(1H,s);m / z E.S. + [M+H] + =375.

[0720] Intermediate 24g: rel-(S)-4-(4-(4-(4-bromobutoxy)phenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] rel-(S)-4-(4-(4-hydroxyphenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 24e, Isomer 1, 100 mg, 0.27 mmol), KCO (44.3 mg, 0.32 mmol), and 1,4-dibromobutane (80 μL, 0.67 mmol) were dissolved in anhydrous MeCN (2.59 mL) under N. The mixture was stirred at 60° C. for 5 h, followed by 40° C. for 2 days. The mixture was then cooled to room temperature, filtered, and washed with DCM (20 mL). The filtrate was then concentrated to give the title compound as a colorless oil, which was used in the next step without further purification.

[0721] Example 24: rel-(S)-4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]-3,3-dimethylpiperidin-1-yl}-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet confirmed) [ka] Intermediate 2c was reacted with intermediate 24g using the general synthetic method illustrated by Example 5 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A). 1H NMR:(CDCl3)0.84(3H,s),0.86(3H,s),1.65-1.79(1H,m),1.77-1.95(4H,m),2.14-2.4 2(3H,m),2.54(1H,dd),2.7-3.05(10H,m),3.46(4H,q),3.63(1H,dd),3.93-4.14(3H,m) ,4.26(1H,d),4.42(1H,d),5.19(1H,dd),6.8-6.86(2H,m),6.89(1H,d),6.98(2H,ddd), 7.02-7.08(2H,m),7.12(1H,d),7.58(1H,d),7.75(1H,d),8.07(1H,s),8.23(1H,s);m / z E.S. + [M+H]+=757.4.

[0722] Intermediate 25a: rel-(R)-4-(4-(4-(4-bromobutoxy)phenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] rel-(R)-4-(4-(4-hydroxyphenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 24f, Isomer 2, 250 mg, 0.67 mmol), KCO (346 mg, 0.80 mmol), and 1,4-dibromobutane (0.199 mL, 1.67 mmol) were dissolved in anhydrous MeCN (4 mL) under N. The mixture was stirred at 70 °C for 2 h and then cooled to room temperature. The mixture was filtered and washed with DCM (20 mL). The filtrate was concentrated to give the title compound as a colorless oil, which was used in the next step without further purification.

[0723] Example 25: rel-(R)-4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]-3,3-dimethylpiperidin-1-yl}-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet confirmed) [ka] Intermediate 2c was reacted with intermediate 25a using the general synthetic method illustrated by Example 5 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A); 1 H NMR:(CDCl3)0.84(3H,s),0.86(3H,s),1.66-1.78(1H,m),1.81-2(4H,m),2.13-2.26(2H,m), 2.33(1H,qd),2.54(1H,dd),2.76-2.91(5H,m),2.92-3.05(5H,m),3.49-3.59(4H,m),3.63(1 H,dd),3.95-4.1(3H,m),4.27(1H,d),4.42(1H,d),5.19(1H,dd),6.8-6.86(2H,m),6.90(1H, m / z E.S. + [M+H]+=757.4.

[0724] Intermediate 26a: tert-butyl 4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate [ka] 6-Bromobenzo[d]oxazol-2(3H)-one (0.321 g, 1.5 mmol) and Dave-phos-Pd G3 (0.114 g, 0.15 mmol) were added to an oven-dried microwave vial containing a stir bar. The vial was sealed with a rubber septum and subsequently degassed with N2. THF (3 mL), lithium bis(trimethylsilyl)amide (3.30 mL, 3.30 mmol), and tert-butyl piperazine-1-carboxylate (0.335 g, 1.80 mmol) were then added. The reaction was again degassed with N2. The resulting solution was stirred at 70 °C for 16 h. AcOH was then added, and the mixture was concentrated. Purification by FSC (gradient: 0-80% EtOAc in hexanes) afforded the title compound (0.250 g, 52%) as a gray solid. 1 H NMR(500MHz)1.41(11H,s),2.35(1H,br s),2.51-2.53(1H,m),2.94-3.04(5H,m),3.26-3.32(3H,m),3.44(5H,br m / z(ES-)[MH] - =318.2.

[0725] Intermediate 26b: tert-butyl-4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate (0.048 g, 0.15 mmol), 3-bromopiperidine-2,6-dione (1.1 eq), and CsCO (0.147 g, 0.45 mmol) were added to an oven-dried microwave vial with a stir bar. The vial was then purged with N. DMF (1 mL) was then added. The resulting slurry was stirred at 90 °C for 16 h and then concentrated. Purification by FSC (gradient: 0 to 100% EtOAc in hexane) afforded the title compound (0.027 g, 41.8%) as a white solid. 1 H NMR(500MHz,CDCl3)1.49-1.54(9H,m),2.28-2.41(1H,m),2.64-2.78(1H,m),2.79-2.90(1H,m),2.95-3.02(1H,m),3.05-3.23 m / z E.S. + [M+H] + =431.

[0726] Intermediate 26c: 3-(2-oxo-6-(piperazin-1-yl)benzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione [ka] 4M HCl in dioxane (2.3 mL, 9.3 mmol) was added to a solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.46 mmol) in 1,4-dioxane (2.3 mL) at room temperature, and the mixture was stirred at 40° C. for 3 hours. Concentration of the mixture then afforded the title compound (0.170 g, 100%) as the hydrochloride salt as an off-white solid, which was used without further purification; 1H NMR(500MHz)2.09-2.20(1H,m),2.60-2.74(2H,m),2.84-2.97(1H,m),3.22(4H,br s),3.33(4H,br d),5.33(1H,br dd),6.85(1H,br d),7.10-7.28(2H,m),9.13(2H,br s),11.18(1H,s);m / z ES + [M+H] + =331.

[0727] Example 26: 4-{4-[4-(4-{4-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2d was reacted with intermediate 26c using the general synthetic method illustrated by Example 2 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A). 1 H NMR:1.56-1.69(4H,m),1.74(2H,p),1.85(2H,d),2.13(1H,dt),2.38(2H,t),2.53(4H,d),2 .59-2.71(2H,m),2.71-2.83(1H,m),2.83-2.94(1H,m),2.99-3.06(2H,m),3.09(4H,d),3.31 (1H,s),3.97(2H,t),4.17(2H,d),5.29(1H,dd),6.77(1H,dd),6.82-6.89(2H,m),7.03-7.12 (2H,m),7.16(2H,d),7.27(1H,dd),7.32(1H,d),7.81(1H,d),8.18(1H,s),11.15(1H,s);m / z E.S. + [M+H]+=731.6.

[0728] Intermediate 27a: tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate [ka] NaBH(OAc)3 (6.80 g, 32.08 mmol) was added in one portion to 1-Boc-piperazine (4.00 g, 21.48 mmol), 4-formyl-N-Cbz-piperidine (6.40 g, 25.88 mmol), and AcOH (1.50 mL, 26.23 mmol) in DCM (50 mL) at room temperature under atmospheric pressure, and the mixture was stirred at room temperature for 2 h. The mixture was then diluted with saturated NaHCO3 solution (60 mL), and the phases were separated. The aqueous layer was extracted with DCM (3 × 40 mL). The combined organic solution was dried (MgSO4) and concentrated. Purification by FSC (gradient: 50–70% EtOAc in heptane) afforded the title compound (8.83 g, 98%) as a colorless oil. 1 H NMR:0.91-1.05(2H,m),1.40(9H,s),1.6-1.77(3H,m),2.12(2H,d),2.22-2.32(4H,m) ,2.79(2H,s),3.26-3.33(4H,m),3.99(2H,d),5.07(2H,s),7.28-7.44(5H,m);m / z:ES + [M+H] + 418.3.

[0729] Intermediate 27b: tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (9.50 g, 22.75 mmol) and 10% Pd(OH) on activated carbon (3.20 g, 2.28 mmol) in EtOH (40 mL) was stirred under an atmosphere of H at 1 atm and room temperature for 18 h. The mixture was then filtered through Celite and washed with EtOH. The filtrate was concentrated. The residue was dissolved in EtOH (40 mL) and 10% Pd(OH) on activated carbon (3.20 g, 2.28 mmol) was added. The suspension was stirred under H at 1 atm and room temperature for 3 days. The mixture was then filtered through Celite and washed with EtOH (100 mL). The filtrate was concentrated to dryness to give the crude product (5.61 g, 87%) as a gray solid. A portion of the crude product (2.32 g) was purified by ion exchange chromatography (SCX column, eluting with 1M NH3 / MeOH) to give the title compound (1.84 g, 79%) as a grey oil; 1 H NMR:0.83-0.99(2H,m),1.37(9H,s),1.45-1.54(1H,m),1.58(2H,d),2.07(2 m / z:ES + [M+H]+ 284.2.

[0730] Intermediate 27c: tert-butyl 4-((1-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)-piperidin-4-yl)methyl)piperazine-1-carboxylate [ka] A mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (350 mg, 0.86 mmol), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (242 mg, 0.86 mmol), RuPhos G3 (53.6 mg, 0.06 mmol), RuPhos (29.9 mg, 0.06 mmol), sodium tert-butoxide (247 mg, 2.57 mmol) and anhydrous 1,4-dioxane (50 mL) was degassed and filled with N, and the mixture was stirred at 100 °C for 1 h. The mixture was then cooled and concentrated to dryness. Water (10 mL) was added and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic solution was dried (NaSO) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) afforded the title compound (0.360 g, 69%) as a pale yellow solid; 1 H NMR:1.20(2H,tt),1.40(9H,s),1.53-1.67(3H,m),1.77(2H,d),1.84(2H,d),2.16(2H,d),2.26-2.31(4H,m),2.54-2.64(2H,m),2.68-2.7 m / z E.S. + [M+H] + =611.9.

[0731] Intermediate 27d: Benzyl 4-(dibutoxymethyl)piperidine-1-carboxylate [ka] 4-Methylbenzenesulfonic acid hydrate (0.100 g, 0.53 mmol) was added to 4-formyl-N-Cbz-piperidine (20.0 g, 80.88 mmol) in n-butanol (40 mL) at room temperature under air. The resulting solution was stirred at 50 °C for 1 h. (Incomplete reaction). MgSO (10.6 g, 88.07 mmol) was added, and the suspension was stirred at 50 °C for an additional 1 h. Due to incomplete reaction, the temperature was increased to 70 °C, and the mixture was stirred for an additional 1 day. The mixture was then filtered, washed with EtOAc (200 mL), and the filtrate was collected in a vessel containing 2 M aq. KCO (40 mL). The phases were separated. The organic solution was washed with 2 M aq. KCO (2 × 40 mL), followed by saturated brine (2 × 20 mL), dried (MgSO), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) afforded the title compound (20.5 g, 67%) as a colorless liquid; 1 H NMR:0.88(6H,t),1.11(2H,qd),1.27-1.4(4H,m),1.47(4H,dq),1.65(2H,d),1.73(1H,dtt),2.75( 2H,s),3.37(2H,dt),3.54(2H,dt),3.95-4.06(2H,m),4.16(1H,d),5.07(2H,s),7.25-7.44(5H,m).

[0732] Intermediate 27e: 4-(dibutoxymethyl)piperidine [ka] A mixture of benzyl 4-(dibutoxymethyl)piperidine-1-carboxylate (20.5 g, 54.30 mmol) and 10% Pd(OH) on activated carbon (3.8 g, 2.71 mmol) in EtOH (120 mL) was stirred under H (1 atm) at room temperature for 3 days. The mixture was then filtered through Celite and washed with EtOH (200 mL). The filtrate was concentrated to dryness to give the title compound (13.10 g, 99%) as a colorless oil. 1H NMR:0.88(6H,t),1.07(2H,qd),1.26-1.4(4H,m),1.41-1.51(4H,m),1.51-1.65(3H,m) ,2.05(1H,s),2.31-2.46(2H,m),2.90(2H,d),3.36(2H,dt),3.52(2H,dt),4.10(1H,d).

[0733] Intermediate 27f: 3-(5-(4-(dibutoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Pd-PEPPSI-IHeptCl (0.23 g, 0.24 mmol) was added to a degassed mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.5 g, 4.64 mmol), 4-(dibutoxymethyl)piperidine (1.5 g, 6.16 mmol), and CsCO (4.54 g, 13.93 mmol) in 1,4-dioxane (45 mL) at room temperature under N. The resulting mixture was degassed in vacuo, refilled with N, and then stirred at 100 °C for 3 h. After cooling, the mixture was diluted with DCM (75 mL) and 10% aq. AcOH (50 mL), and the phases were separated. The aqueous portion was extracted with DCM (75 mL). The combined organic layers were washed with saturated NaHCO3 (50 mL), dried (MgSO4), and concentrated. The residue was partitioned between DCM (50 mL) and water (20 mL), and the aqueous portion was extracted with DCM (50 mL). The combined organic solution was then dried (MgSO4) and concentrated. Trituration with EtOAc (15 mL) gave a solid that was collected by filtration and washed successively with EtOAc (2 x 5 mL), EtOAc:Et2O (1:1; 5 mL), and Et2O (5 mL), followed by drying under vacuum to give the title compound (1.659 g, 74%) as a white solid; 1H NMR:0.89(6H,t),1.23-1.42(6H,m),1.43-1.56(4H,m),1.67-1.85(3H,m) ,1.96(1H,ddd),2.28-2.44(1H,m),2.55-2.64(1H,m),2.72-2.84(2H,m), 2.90(1H,ddd),3.40(2H,dt),3.56(2H,dt),3.89(2H,d),4.09-4.25(2H,m ),4.32(1H,d),5.04(1H,dd),7.04(2H,d),7.50(1H,d),10.91(1H,s);m / z E.S. + [M+H] + =486.0.

[0734] Example 27: 4-{4-[4-(4-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]methyl}piperidin-1-yl)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 27c was reacted with intermediate 27f using the general synthetic method illustrated by Example 1 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A). 1 H NMR:1.09-1.27(4H,m),1.53-1.69(3H,m),1.77(5H,d),1.84(2H,d),1.92-2.01(1H,m),2.15(4 H,d),2.28-2.42(9H,m),2.56-2.64(3H,m),2.74(1H,d),2.82(2H,t),2.86-2.95(1H,m),3.04( 2H,t),3.60(2H,d),3.86(2H,d),4.11-4.26(3H,m),4.32(1H,d),5.04(1H,dd),6.85(2H,d),7. 05(4H,q),7.27(1H,dd),7.32(1H,d),7.50(1H,d),7.81(1H,d),8.17(1H,s),10.91(1H,s);m / z E.S. +[M+H]+=851.6.

[0735] Intermediate 28a: 5-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3-difluoropentyl 4-methylbenzenesulfonate [ka] 4-Methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) was added in one portion to 4-(4-(4-((3,3-difluoro-5-hydroxypentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (190 mg, 0.41 mmol) and EtN (113 μL, 0.81 mmol) in DCM (2 mL) at room temperature, and the solution was stirred for 2 h. The reaction was incomplete, and additional 4-methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) and EtN (113 μL, 0.81 mmol) were added in one portion, and the solution was stirred at room temperature for an additional 18 h. The reaction was incomplete, and additional 4-methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) and EtN (113 μL, 0.81 mmol) were added in one portion, and the solution was stirred at room temperature for an additional 3 h. The mixture was then diluted with DCM (25 mL), washed (saturated NH4Cl (10 mL), saturated NaHCO3 (10 mL), water (20 mL), followed by saturated brine (10 mL)), dried through a phase separation cartridge, and concentrated. Purification by FSC (gradient: 0-60% EtOAc in heptane) afforded the title compound (0.147 g, 58%) as a yellow gum; m / z: ES + [M+H] + 623.3

[0736] Example 28: 4-(4-{4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3,3-difluoropentyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2c was reacted with intermediate 28a using the general synthetic method illustrated by Example 12 to give the title compound after purification by HPLC (column A, eluent A). 1 H NMR:(CDCl3)1.69-1.83(2H,m),1.97(2H,d),2.15-2.52(6H,m),2.65-2.96(9H,m),3.05(2H,td),3.32-3.46(4H,m),4.02(2H,d),4.16(2H, m / z E.S. + [M+H]+=779.4.

[0737] Intermediate 29a: (4-bromo-2-nitrophenyl)-L-glutamic acid di-tert-butyl ester [ka] 4-Bromo-1-fluoro-2-nitrobenzene (11.69 mL, 93.91 mmol) was added to a stirred, milky suspension of di-tert-butyl L-glutamate hydrochloride (50.00 g, 169.03 mmol) and EtN (52.4 mL, 375.62 mmol) in THF (500 mL) at room temperature. The mixture was then stirred at 70 °C for 72 h. Water (500 mL) was then added, and the mixture was extracted with EtOAc (2 × 500 mL). The combined organic solution was then washed with brine (500 mL), passed through a phase separation cartridge, and concentrated. Purification by FSC (gradient: 0-20% EtOAc in heptane) afforded the title compound (49.50 g, 115%) as a yellow gum. 1 H NMR(CDCl3)1.44(9H,s),1.48(9H,s),2.16(2H,q),2.38(2H,t),4.22(1H,q),6.77(1H,d),7.50(1H,dd),8.34(2H,d).

[0738] Intermediate 29b: (2-amino-4-bromophenyl)-L-glutamic acid di-tert-butyl ester [ka] Iron powder (26.20 g, 469.15 mmol) was added in one portion to a solution of di-tert-butyl (4-bromo-2-nitrophenyl)-L-glutamate (43.10 g, 93.83 mmol) and NH₄Cl (25.09 g, 469.15 mmol) in IPA (400 mL) and water (80 mL) at room temperature. The resulting mixture was stirred at 80°C for 16 h. After cooling, the mixture was filtered through Celite and washed with EtOAc (500 mL). The dark red filtrate was washed with water (250 mL), saturated brine (250 mL), dried (MgSO₄), and concentrated. Purification by FSC (gradient 0 to 30% EtOAc in heptane) afforded the title compound (36.1 g, 90%) as an orange gum. 1 H NMR(CDCl3)1.44(9H,s),1.44(9H,s),1.89-2.17(2H,m),2.27-2.53(2H,m ),3.53(2H,s),3.68-3.97(2H,m),6.48(1H,d),6.71-6.95(2H,m);m / z:ES + [M+H] + 429.

[0739] Intermediate 29c: (S)-2-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioate di-tert-butyl [ka] CDI (14.30 g, 88.19 mmol) was added in one portion to di-tert-butyl (2-amino-4-bromophenyl)-L-glutamate (36.1 g, 83.99 mmol) in THF (500 mL) at room temperature. The resulting dark red solution was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (500 mL). This solution was washed with water (500 mL) and brine (200 mL), dried (MgSO), and concentrated to give the title compound (41.0 g, 107%) as a beige solid. 1 H NMR(CDCl3)1.40(18H,d),2.13-2.43(3H,m),2.46-2.64(1H,m),5.07(1H,dd),6.86(1H,d),7.17(1H,dd),7.23(1H,d),9.98(1H,s)

[0740] Intermediate 29d: (S)-2-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioate di-tert-butyl [ka] (S)-Di-tert-butyl 2-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioate (38.0 g, 83.45 mmol) was dissolved in DMF.DMA (333 mL) and the solution was stirred at 100° C. for 16 h, then concentrated. Purification by FSC (gradient: 0-25% EtOAc in heptane) afforded the title compound (35.0 g, 89%) as a pale yellow gum, which solidified on standing. 1 H NMR(CDCl3)1.39(9H,s),1.40(9H,s),2.09-2.41(3H,m),2.43-2.63(1H,m),3.39(3H,s),5.06(1H,dd),6.85(1H,d),7.11(1H,d),7.17(1H,dd).

[0741] Intermediate 29e: (S)-2-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioic acid [ka] TFA (200 mL) was added to a stirred solution of (S)-di-tert-butyl 2-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioate (35.0 g, 74.57 mmol) in DCM (200 mL) at 0° C. The mixture was stirred for 15 minutes, then warmed to room temperature and stirred for an additional 3 hours. The mixture was then concentrated, and the residue was azeotroped twice with toluene to give a yellow solid, which was then triturated overnight in 3:1 heptane:MTBE. The solid was collected by filtration and dried to give the title compound (25.2 g, 95%) as a pale yellow solid; 1 H NMR:2-2.44(4H,m),3.33(3H,s),5.04(1H,dd),7.05(1H,d),7.21(1H,dd),7.44(1H,d),12.16(1H,s),13.07(1H,s);

[0742] Intermediate 29f: 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] (S)-2-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioic acid (1.0 g, 2.48 mmol) was dissolved in DCM (30 mL). Next, DIPEA (2.163 mL, 12.42 mmol) and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (V) (1.889 g, 4.97 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Next, 2,2,2-trifluoroacetamide (0.281 g, 2.48 mmol) was added, and the mixture was stirred for 1 hour. Next, the mixture was poured into 5% AcOH in water (200 mL). The mixture was extracted with DCM (2 x 150 mL), and the combined organic solution was washed with saturated NaHCO3 solution (200 mL), then passed through a phase separation cartridge and concentrated in vacuo to near dryness (approximately 75 mL). Purification by FSC (gradient: 0-80% EtOAc in heptane) afforded the crude product. The crude solid (0.8 g) was suspended in 1:1 MTBE:heptane (10 mL) and triturated overnight. The resulting solid was collected by filtration and dried to afford the title compound (0.70 g, 83%) as a white solid. 1 H NMR(CDCl3)2.11-2.33(1H,m),2.6-3.03(3H,m),3.42(3H,s),5.18(1H,dd),6.68(1H,d),7.1-7.24(2H,m),8.05(1H,s);m / z:ES + [M+H] + 338. The material was racemized in this process.

[0743] Intermediate 29g: tert-butyl-4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate [ka] (DiMeIHept Cl)Pd(cinnamyl)Cl (commercially available from Total Synthesis Ltd., Toronto, Canada, 0.031 g, 0.03 mmol) was added to 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.100 g, 0.30 mmol), CsCO (0.289 g, 0.89 mmol), and tert-butyl piperazine-1-carboxylate (0.138 g, 0.74 mmol) in 1,4-dioxane (4.5 mL) at room temperature under N. The resulting suspension was stirred at 100 °C for 6 h. The mixture was then diluted with DCM (25 mL), washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO3 solution (20 mL), followed by saturated brine (20 mL)), dried (MgSO4), and concentrated. Trituration with EtOAc gave a solid that was collected by filtration, washed with Et2O, and dried under vacuum to give the title compound (0.107 g, 82%) as a cream solid; 1 H NMR:1.43(9H,s),1.91-1.99(1H,m),2.54-2.65(2H,m),2.74-2.88(1H,m),3-3.07(4H,m),3.3 1(3H,s),3.45-3.51(4H,m),5.11-5.26(1H,m),6.65(1H,dd),6.87(1H,d),6.92(1H,d);m / z:ES + [M+H] + 444.2.

[0744] Example 29: 4-{4-[4-(4-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 1h was reacted with intermediate 29g using the general synthetic method illustrated by Example 1 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A);1 H NMR:1.56-1.68(4H,m),1.69-1.79(2H,m),1.85(2H,d),1.94-2.04(1H,m),2.39(2H,t),2.52-2. 54(4H,m),2.58-2.65(1H,m),2.67-2.71(1H,m),2.72-2.82(1H,m),2.85-2.96(1H,m),3.00-3.12 (6H,m),3.31(5H,br),3.97(2H,t),4.17(2H,d),5.29(1H,dd),6.62(1H,dd),6.81-6.91(3H,m), 6.94(1H,d),7.16(2H,d),7.27(1H,dd),7.32(1H,d),7.81(1H,d),8.17(1H,s),11.04(1H,s);m / z E.S. + [M+H]+=743.9.

[0745] Intermediate 30a: trans-4-(4-(4-((1r,3r)-3-(2-bromoethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] A solution of PPh3 (63.7 mg, 0.24 mmol) in THF (1 mL) was added dropwise to a stirred mixture of trans-4-(4-(4-((1s,3r)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 5c) (54.0 mg, 0.12 mmol) and CBr4 (81.0 mg, 0.24 mmol) in THF (1.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 week. Then, the mixture was filtered, washed with EtOAc (20 mL), and the filtrate was concentrated. Purification by FSC (gradient: 0 to 30% EtOAc in heptane) afforded the title compound (0.034 g, 55%) as a colorless oil. 1H NMR(CDCl3)1.75(2H,qd),1.97(2H,d),2.07(2H,q),2.14-2.23(2H,m),2.36(2H,dddd),2.54(1H,ddq),2.72(1H,tt),3.05(2H, m / z:ES + [M+H] + =507.2.

[0746] Example 30: trans-4-[4-(4-{[(1s,3r)-3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}ethyl)cyclobutyl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2c was reacted with intermediate 30a using the general synthetic method illustrated by Example 5 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A). 1 H NMR:1.56-1.69(2H,m),1.76(2H,s),1.85(2H,d),1.91-2.03(1H,m),2.16-2.20(4H,m),2. 29(1H,d),2.36-2.44(2H,m),2.51-2.53(4H,m),2.60(2H,d),2.78(1H,d),2.86-2.96(1H,m ),3.04(2H,t),4.20(3H,dd),4.34(1H,d),4.79(1H,q),5.05(1H,dd),6.75(2H,d),7.09(2H ,d),7.15(2H,d),7.22-7.37(2H,m),7.54(1H,d),7.81(1H,d),10.92(1H,s);4H below solvent peak;m / z E.S. + [M+H]+=755.4.

[0747] Intermediate 31a: tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate [ka] Di-tert-butyl carbonate (8.86 mL, 38.15 mmol) was added to 4-(piperidin-4-yl)butan-1-ol (4.00 g, 25.44 mmol) in THF (50 mL) and saturated Na2CO3 solution (50 mL) at room temperature, and the mixture was stirred for 16 hours. The mixture was then diluted with EtOAc (300 mL), washed with saturated brine (200 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-50% petroleum ether in EtOAc) afforded the title compound (5.30 g, 81%) as a white liquid. 1 H NMR:0.86-1.00(2H,m),1.13-1.22(2H,m),1.25-1.33(2H,m),1.35-1.40(12H,m),1 .57-1.65(2H,m),2.65(2H,s),3.34-3.42(2H,m),3.91(2H,d),4.31(1H,t);m / z:ES + [M-tBu] + =202.

[0748] Intermediate 31b: tert-butyl 4-(4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-butyl)piperidine-1-carboxylate [ka] RockPhos Pd G3 (0.488 g, 0.58 mmol) was added to tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (1.50 g, 5.83 mmol), 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.58 g, 8.74 mmol), and CsCO3 (5.70 g, 17.48 mmol) in 1,4-dioxane (30 mL) over 10 minutes at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 hours. The mixture was then diluted with EtOAc (200 mL), washed with saturated brine (100 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0 to 15% EtOAc in petroleum ether) afforded the title compound (1.50 g, 44%) as a yellow liquid. 1 H NMR:0.88-0.99(2H,m),1.22-1.28(2H,m),1.33-1.45(14H,m),1.55-1.69(6H,m),1.79-1.88(2H,m),2.72-2.80(1H,m),2.98-3.08(2 m / z:ES + [M-tBu] + =530.

[0749] Intermediate 31c: 4-(4-(4-(4-(piperidin-4-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] tert-Butyl 4-(4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)butyl)piperidine-1-carboxylate (500 mg, 0.85 mmol) was added to HCl in DCM (2 mL) and dioxane (7 mL) at room temperature, and the mixture was stirred for 16 hours. It was then concentrated under reduced pressure to give the title compound, which was used in the next step without further purification; 1 H NMR(300MHz)1.19-1.31(4H,m),1.32-1.54(4H,m),1.54-1.70(3H,m),1.73-1.84(4H,m),2.68-2.88(3H,m),3.02(2H,t ),3.19(2H,d),3.90(2H,t),4.16(2H,d),6.82(2H,d),7.13(2H,d),7.21-7.29(1H,m),7.30(1H,d),7.79(1H,d);m / z:ES + [M+H] + =486.

[0750] Example 31: 4-{4-[4-(4-{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Pd-PEPPSI-IPent (40.8 mg, 0.05 mmol) was added to 4-(4-(4-(4-(piperidin-4-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (250 mg, 0.51 mmol), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (166 mg, 0.51 mmol), and CsCO (503 mg, 1.54 mmol) in 1,4-dioxane (5 mL) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. The mixture was then diluted with DCM, washed (5% AcOH(aq), water, followed by saturated brine), dried (NaSO), and concentrated. Purification by flash C18-flash chromatography (gradient: 5-85% MeCN in water (0.1% NH4HCO3)) gave material which was further purified by preparative SFC (column: Viridis BEH 2-ethylpyridine Prep OBD, 30*150 mm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.5% 2M NH3-MeOH)-HPLC; flow rate: 50 mL / min; gradient: 28% B; 254 nm; RT1: 4.25; injection volume: 1 mL; number of runs: 5) to give the title compound (7 mg, 2%) as a white solid; 1 H NMR:1.13-1.33(5H,m),1.40-1.55(3H,m),1.55-1.77(6H,m),1.81-1.91(2H,m),1.92-2.04(1 H,m),2.30-2.42(1H,m),2.55-2.64(1H,m),2.71-2.96(4H,m),2.99-3.10(2H,m),3.86(2H,d), 3.93(2H,t),4.13-4.26(3H,m),4.31(1H,d),4.98-5.07(1H,m),6.82-6.88(2H,m),7.00-7.07 (2H,m),7.13-7.18(2H,m),7.24-7.30(1H,m),7.32(1H,d),7.47-7.52(1H,m),7.81(1H,d);m / z E.S. + [M+H]+=728.4.

[0751] Example 32: 4-[4-(4-{[(1r,3s)-3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}ethyl)cyclobutyl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2c was reacted with intermediate 5d using the general synthetic method illustrated by Example 5 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A); 1 H NMR:1.55-1.7(6H,m),1.85(2H,d),1.9-2.02(2H,m),2.25-2.31(2H,m),2.39(2H,dd), 2.56-2.64(3H,m),2.75(1H,d),2.82-2.95(1H,m),3.04(2H,t),3.29(8H,br),4.11-4. 27(3H,m),4.33(1H,d),4.51(1H,p),5.04(1H,dd),6.77(2H,d),7.06(2H,d),7.14(2H, m / z E.S. + [M+H]+=755.7.

[0752] Intermediate 33a: tert-butyl-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-oxa-3,10-diazaspiro[5.6]dodecane-10-carboxylate [ka] Pd-PEPPSI-IHept.Cl (0.083 g, 0.09 mmol) was added to tert-butyl 7-oxa-3,10-diazaspiro[5.6]dodecane-10-carboxylate (0.603 g, 2.23 mmol), CsCO (1.66 g, 5.11 mmol), and 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.550 g, 1.70 mmol) in 1,4-dioxane (12 mL) at room temperature under N. The resulting suspension was stirred at 100 °C for 20 h. The mixture was then diluted with DCM (25 mL), washed (5% AcOH in water (10 mL), water (10 mL), followed by saturated brine (10 mL)), dried (MgSO), and concentrated. Purification by FSC (gradient 0-5% MeOH in DCM) afforded the title compound (0.490 g, 56%) as a yellow solid. 1 H NMR:1.41(9H,s),1.49-1.6(2H,m),1.7-1.85(4H,m),1.91-2.02(1H,m), 2.33-2.44(1H,m),2.55-2.64(1H,m),2.84-2.96(1H,m),3.09-3.17(2H,m ),3.38-3.47(4H,m),3.49-3.61(2H,m),3.62-3.69(2H,m),4.20(1H,d), 4.32(1H,d),5.04(1H,dd),7-7.11(2H,m),7.50(1H,d),10.91(1H,s);m / z E.S. + [M+H]+=513.3.

[0753] Example 33: 4-{4-[4-(4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-7-oxa-3,10-diazaspiro[5.6]dodecan-10-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 1h was reacted with intermediate 33a using the general synthetic method illustrated by Example 1 to give the title compound (as the formate salt) after purification by HPLC (column A, eluent A). 1 H NMR:1.43-1.53(2H,m),1.53-1.67(4H,m),1.67-1.81(6H,m),1.85(2H,d),1.91-2(1H,m),2.35-2.4(1H, m),2.41-2.47(2H,m),2.54-2.63(4H,m),2.77(1H,t),2.85-2.95(1H,m),3.05(2H,t),3.16(2H,t),3.30( 2H,s),3.54(2H,d),3.62(2H,d),3.95(2H,t),4.18(3H,dd),4.32(1H,d),5.04(1H,dd),6.85(2H,d),7.04 (2H,d),7.15(2H,d),7.27(1H,dd),7.33(1H,d),7.50(1H,d),7.81(1H,d),8.16(1H,s),10.91(1H,s);m / z E.S. + [M+H]+=813.4.

[0754] Intermediate 34a: tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate [ka] Methanesulfonyl chloride (1.38 mL, 17.89 mmol) was added dropwise to a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.00 g, 14.91 mmol) and DIPEA (3.89 mL, 22.36 mmol) in DCM (55 mL) at 0° C. The mixture was then stirred at room temperature for 2 hours before being diluted with DCM (125 mL). This solution was washed with water (75 mL), citric acid solution (50 mL), brine (50 mL), and then dried (MgSO4) and concentrated to give the title compound (4.69 g, 113%) as a brown solid; 1H NMR(CDCl3)1.46(9H,s),1.81(2H,dtd),1.96(2H,ddt),3.03(3H,s),3.30(2H,ddd),3.64-3.76(2H,m),4.88(1H,tt).

[0755] Intermediate 34b: 2-(bromomethyl)-4-((tert-butyldimethylsilyl)oxy)benzoate methyl [ka] AIBN (0.094 g, 0.57 mmol) was added to methyl 4-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (8 g, 28.53 mmol) and NBS (6.60 g, 37.08 mmol) in EtOAc (71 mL) at 80° C. under N. The resulting mixture was stirred at 80° C. for 3 h. The mixture was then poured into water (100 mL). This mixture was then extracted with EtOAc (3×50 mL). The combined organic solution was washed with brine (50 mL), dried (MgSO), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) afforded the title compound (6.90 g, 67%) as a colorless liquid; 1 H NMR(CDCl3)0.22(6H,s),0.99(9H,s),2.15-2.24(1H,m),2.33(1H,qd),2.75-2.95(2H,m),4.2 2-4.46(2H,m),5.18(1H,dd),6.88(1H,s),6.89-6.96(1H,m),7.74(1H,d),8.02-8.19(1H,m).

[0756] Intermediate 34c: 3-(5-((tert-butyldimethylsilyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] DIPEA (9.89 mL, 56.77 mmol) was added to a stirred solution of methyl 2-(bromomethyl)-4-((tert-butyl-dimethylsilyl)oxy)benzoate (6.80 g, 18.92 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (3.11 g, 18.92 mmol) in MeCN (60 mL) at room temperature under N2, and the mixture was stirred for 25 hours. The mixture was then diluted with water (50 mL). The mixture was then extracted with EtOAc (25 mL x 3), and the combined organic solution was dried (MgSO4) and concentrated to give the title compound (2.00 g, 28%); 1 H NMR(CDCl3)0.22-0.25(6H,m),0.98-0.99(9H,m),3.87-3.92(3H,m),4.93(2H,s),6.76-6.82(1H,m),6.93(1H,d),7.91(1H,d).

[0757] Intermediate 34d: 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] A stirred solution of 3-(5-((tert-butyldimethylsilyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.50 g, 4.01 mmol) in 1,4-dioxane (10 mL) was treated with 4 M HCl (5.56 mL, 160.21 mmol) under N2. The resulting slurry was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure. The residue was then dissolved with hot MeCN and cooled to room temperature and then to 0 °C. The solid was collected by filtration, washed with cold MeCN, and dried in a vacuum desiccator for 18 hours to give the title compound (1.16 g, 111%) as a black solid; m / z (ES-)[MH] - =259.

[0758] Intermediate 34e: tert-butyl-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate [ka] K2CO3 (0.320 g, 2.31 mmol) was added in one portion to a stirred solution of tert-butyl 4-((methylsulfonyl)-oxy)piperidine-1-carboxylate (0.644 g, 2.31 mmol) and 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.500 g, 1.92 mmol) in DMF (10 mL) at room temperature under N2. The resulting solution was stirred at 100 °C for 18 h. The mixture was then diluted with water (50 mL). This mixture was then extracted with EtOAc (3 × 30 mL), and the combined organic solution was washed with brine (75 mL), dried (MgSO4), and concentrated. The residue (500 mg) was dissolved in 4.5 mL 7:2 DMSO:MeOH (111 mg / mL) and subsequently purified by preparative HPLC (column A, eluent A) to afford the title compound (0.461 g, 54%) as a white solid; 1 H NMR:1.42(9H,s),1.56(2H,d),1.91-2.02(3H,m),2.40(1H,td),2.55-2.65(1H,m),2.8-2.98(1H,m),3.20(2H,t),3.68(2H,dt ),4.27(1H,d),4.39(1H,d),4.70(1H,dt),5.07(1H,dd),7.09(1H,dd),7.22(1H,d),7.63(1H,d),10.94(1H,s);m / z(ES-)[MH] - =442.2.

[0759] Example 34: 4-(4-{4-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}piperidin-1-yl)butoxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] Intermediate 1h was reacted with intermediate 34e using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (column A, eluent A).1 H NMR:1.54-1.75(8H,m),1.85(2H,d),1.92-2.05(3H,m),2.21-2.32(2H,m),2.35-2.41(3H,m),2 .56-2.65(1H,m),2.7-2.82(3H,m),2.84-2.95(1H,m),3.05(3H,t),3.96(2H,t),4.17(2H,d),4 .26(1H,d),4.38(1H,d),4.51(1H,dt),5.07(1H,dd),6.81-6.91(2H,m),7.06(1H,dd),7.13-7. 22(3H,m),7.27(1H,dd),7.32(1H,d),7.61(1H,d),7.81(1H,d),8.15(1H,s),10.94(1H,s);m / z E.S. + [M+H]+=744.4.

[0760] Intermediate 35a: Benzyl 4-(3-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Pd(dppf)Cl-DCM (0.824 g, 1.01 mmol) was added to 2-fluoro-4-iodophenol (2.40 g, 10.08 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.19 g, 15.13 mmol), and KCO (4.18 g, 30.25 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) under N at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The mixture was then diluted with EtOAc, washed with water followed by saturated brine, dried (NaSO), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) afforded the title compound (2.20 g, 67%) as a yellow solid; 1H NMR(300MHz)2.45(2H,s),3.58(2H,d),4.05(2H,d),5.11(2H,s),6.06(1H,s) ,6.90(1H,t),7.07(1H,dd),7.21(1H,dd),7.29-7.42(5H,m),9.85(1H,s);m / z E.S. + [M+H] + =328.

[0761] Intermediate 35b: tert-butyl 4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate [ka] 10% Pd-on-C (1.365 g, 1.28 mmol) was added to di-tert-butyl carbonate (1.520 g, 7.06 mmol) and benzyl 4-(3-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.100 g, 6.42 mmol) in MeOH (10 mL) under H2 at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The mixture was then filtered through Celite, and the filtrate was concentrated. Purification by FSC (gradient: 0 to 30% EtOAc in petroleum ether) afforded the title compound (1.00 g, 53%) as a white solid. 1 H NMR:1.35-1.48(11H,m),1.70(2H,d),2.57(1H,tt),2.76(2H,s),3.99-4.10(2H,m),6.83-6.86(2H,m),6.97-7.02(1H,m),9.56(1H,s);m / z E.S. + [MH-tBu] + =240.1.

[0762] Intermediate 35c: 2-fluoro-4-(piperidin-4-yl)phenol [ka] tert-Butyl 4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (500 mg, 1.69 mmol) was added to 4 M HCl in 1,4-dioxane (8 mL, 32.00 mmol) at room temperature, and the mixture was stirred for 2 hours. Concentration under reduced pressure gave the title compound (0.430 g, 130%) as a white solid hydrochloride salt. 1 M / z E.S. + [M+H] + =196.0.

[0763] Intermediate 35d: 4-(4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] DIPEA (1.923 mL, 11.01 mmol) was added to 2-fluoro-4-(piperidin-4-yl)phenol (430 mg, 2.20 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (417 mg, 2.20 mmol) in DMSO (2 mL) at room temperature. The resulting solution was stirred at 60° C. for 2 hours. The mixture was then poured into water (20 mL). The mixture was then extracted with EtOAc (3×250 mL), and the combined organic solution was dried (NaSO) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) afforded the title compound (0.507 g, 63%) as a white solid. 1 H NMR:1.59(2H,qd),1.78-1.87(2H,m),2.73(1H,tt),3.02(2H,td),4.16(2H,dt),6.84 -6.89(2H,m),7.02(1H,dd),7.26(1H,dd),7.31(1H,d),7.80(1H,d),9.58(1H,s);m / z E.S. + [M+H] +=365.

[0764] Intermediate 35e: 4-(4-(4-(4-bromobutoxy)-3-fluorophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] K2CO3 (228 mg, 1.65 mmol) was added to 4-(4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (200 mg, 0.55 mmol) and 1,4-dibromobutane (593 mg, 2.74 mmol) in DMF (2 mL) at room temperature under air, and the mixture was stirred for 2 hours. The mixture was then poured into water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL), and the combined organic solution was dried (Na2SO4) and concentrated. Purification by flash C18-flash chromatography (gradient: 0-100% MeCN in water) afforded the title compound (0.210 g, 77%) as a white solid; 1 H NMR(300MHz)1.62(2H,qd),1.78-1.92(4H,m),1.92-2.04(2H,m),2.79(1H,t),3.03(2H,dd),3.61(2H,t),4. 05(2H,t),4.18(2H,d),7.01(1H,dd),7.07(1H,d),7.13(1H,dd),7.27(1H,dd),7.33(1H,d),7.82(1H,d);m / z E.S. + [M+H] + =499.

[0765] Example 35: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)-3-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2c was reacted with intermediate 35e using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH; 10:1); 1 H NMR:(300MHz)1.23-1.28(2H,m),1.54-1.89(8H,m),1.89-2.02(1H,m),2.30-2. 48(4H,m),2.53-2.65(2H,m),2.70-2.83(1H,m),2.81-2.97(1H,m),3.03(2H,t), 3.10-3.29(4H,m),4.06(2H,t),4.13-4.27(3H,m),4.34(1H,d),5.06(1H,dd),6 .97-7.18(5H,m),7.23-7.35(2H,m),7.54(1H,d),7.82(1H,d),10.95(1H,s);m / z E.S. + [M+H]+=747.4.

[0766] Intermediate 36a: methyl 3-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)methyl)-cyclobutane-1-carboxylate [ka] RockPhos Pd G3 (291 mg, 0.35 mmol) was added to methyl 3-(hydroxymethyl)cyclobutane-1-carboxylate (500 mg, 3.47 mmol), Cs2CO3 (3.39 g, 10.40 mmol), and 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.42 g, 3.47 mmol) in 1,4-dioxane (5 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) afforded the title compound (1.20 g, 73%) as a pale yellow solid. 1H NMR(300MHz)1.51-1.68(2H,m),1.82(2H,d),1.95-2.10(2H,m),2.20-2.37(2H,m),2.56-2.82(2H,m),2.94-3.10(2H,m),3.37-3.52 m / z E.S. + ,[M+H]+=473.4.

[0767] Intermediates 36b and 36c: 4-(4-(4-(((1r,3r)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile and 4-(4-(4-(((1s,3s)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] Methyl 3-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)methyl)cyclobutane-1-carboxylate (1.10 g, 2.33 mmol) was added to NaBH (0.264 g, 6.98 mmol) in MeOH (10 mL) at room temperature, and the mixture was stirred for 16 h. After concentration under reduced pressure, the mixture was poured into water (100 mL). The mixture was extracted with EtOAc (250 mL × 3), dried (NaSO), and concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) afforded the title compound (700 mg) as a mixture of cis / trans isomers. Purification by preparative Prep-SFC (column: CHIRAL ART Amylose-SA S, 3*25 cm, 5 μm; mobile phase A: CO, mobile phase B: MeOH (0.5% 2M NH-MeOH)—HPLC; flow rate: 6.1 mL / min; gradient: 40% B; 220 nm; 36b RT1: 9.47; 36c RT2: 10.97; injection volume: 1.5 mL; number of runs: 33) gave 36b (0.123 g, 12%) and 36c (0.154 g, 15%) as pale yellow solids. Intermediate 36b: 1 H NMR(CDCl3,300MHz)1.76(2H,qd),1.90-2.06(6H,m),2.54(1H,dt),2.67-2.81(2H,m),3.06(2H,td),3.6 9(2H,d),3.97(2H,d),4.03(2H,d),6.84-6.92(2H,m),6.99(1H,dd),7.08-7.20(3H,m),7.62(1H,d);m / z E.S. + ,[M+H]+=445.2. Intermediate 36c: 1 H NMR(CDCl3,300MHz)1.59-1.86(4H,m),1.93-2.08(2H,m),2.14-2.29(2H,m),2.37-2.56(1H,m),2.60-2.80(2H,m),2.98-3. 13(2H, m),3.60(2H,d),3.87(2H,d),4.02(2H,d),6.80-6.91(2H,m),6.94-7.04(1H,m),7.07-7.21(3H,m),7.61(1H,d); E.S.+ ,[M+H]+=445.2

[0768] Intermediate 36d: 4-(4-(4-(((1r,3r)-3-(bromomethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] CBr4 (74.6 mg, 0.22 mmol) was added to PPh3 (59.0 mg, 0.22 mmol) and 4-(4-(4-(((1r,3r)-3-(hydroxymethyl)-cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.11 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 2 h. After concentration under reduced pressure, purification by preparative TLC (eluent: petroleum ether: EtOAc = 5:1) afforded the title compound (0.050 g, 88%) as a colorless gum; 1 H NMR(300MHz)1.60(2H,qd),1.77-2.01(6H,m),2.56-2.80(3H,m),2.98-3.13(2H,m),3.63(2H,d),3.95 (2H,d),4.16(2H,d),6.81-6.89(2H,m),7.09-7.18(2H,m),7.25(1H,dd),7.31(1H,d),7.80(1H,d);m / z E.S. + ,[M+H]+=507.

[0769] Example 36: 4-[4-(4-{[(1r,3r)-3-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}methyl)cyclobutyl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2c was reacted with intermediate 36d using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 20:1); 1 H NMR:(300MHz)1.53-1.71(2H,m),1.79-2.09(7H,m),2.24-2.48(5H,m),2.53 -2.98(5H,m),3.05(2H,t),3.29(6H,d),3.51(1H,s),3.99(2H,d),4.12-4.2 4(2H,m),4.27-4.38(1H,m),5.05(1H,dd),6.87(2H,d),7.05(2H,d),7.16(2 m / z E.S. + [M+H]+=755.4.

[0770] Intermediate 37a: 4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] 4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), 4-(dimethoxymethyl)piperidine (0.467 g, 2.93 mmol), RuPhos G3 (0.153 g, 0.18 mmol), RuPhos (0.086 g, 0.18 mmol), sodium tert-butoxide (0.704 g, 7.33 mmol), and anhydrous 1,4-dioxane (24.4 mL) were added to a flask. The mixture was degassed, and the flask was filled with N. The mixture was then stirred at 100 °C overnight and then cooled to room temperature before being concentrated. Water (10 mL) was added, and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic solution was dried (NaSO) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) afforded the title compound (0.393 g, 33%) as a pale yellow solid; 1H NMR(CDCl3)1.45(2H,qd),1.67-1.8(3H,m),1.8-1.89(2H,m),1.97(2H,d),2.55-2.77(3H,m),3.05(2H,td),3.37(6H,s),3 m / z:ES + [M+H] + 488.8.

[0771] Example 37: 4-[4-(4-{4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}-piperidin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] Intermediate 34e was reacted with intermediate 37a using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (column A, eluent A); 1 H NMR:(CDCl3)1.42-1.59(2H,m),1.75(2H,qd),1.97(5H,dd),2.09-2.19(2H,m),2.22(1H,ddq),2.28-2 .4(1H,m),2.4-2.5(2H,m),2.71(3H,td),2.77-2.86(1H,m),2.92(3H,dd),2.99-3.16(4H,m),3.41(2H, d),3.65(2H,d),4.01(2H,d),4.30(1H,d),4.45(1H,d),4.72(1H,s),5.20(1H,dd),6.89(2H,dd),6.96 (2H,dd),6.98-7.04(2H,m),7.10(2H,d),7.15(1H,d),7.57-7.63(1H,m),7.82(1H,d),8.30(2H,s);m / z E.S. + [M+H]+=769.0.

[0772] Intermediate 38a: tert-butyl 4-(2-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] PdCl2(dppf) (118 mg, 0.16 mmol) was added to tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.62 mmol), 4-bromo-2-fluorophenol (340 mg, 1.78 mmol), and K2CO3 (670 mg, 4.85 mmol) in 1,4-dioxane (8 mL) and water (2 mL) at room temperature under N2. The resulting solution was stirred at 80 °C for 4 h. The mixture was then filtered through Celite, and the filtrate was concentrated. Purification by FCC (gradient: 0 to 10% EtOAc in petroleum ether) afforded the title compound (0.40 g, 84%) as a colorless oil. 1 M / z:ES + [M-tBu] + 238.

[0773] Intermediate 38b: tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate [ka] 10% Pd-on-C (1.451 g, 1.36 mmol) was added to tert-butyl 4-(2-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.00 g, 6.82 mmol) in MeOH (10 mL) at room temperature under H2. The resulting mixture was stirred at 80 °C for 16 h. The mixture was then filtered through Celite, and the filtrate was concentrated. Purification by flash C18-flash chromatography (gradient: 0 to 70% MeCN in water (0.1% formic acid)) afforded the title compound (1.20 g, 60%) as a white solid. 1 H NMR:1.42(9H,s),1.40-1.55(2H,m),1.63-1.72(2H,m),2.71-2.92(3H,m),3. 99-4.13(2H,m),6.51(1H,dd),6.56(1H,dd),7.08(1H,t),9.65(1H,s);m / z:ES + [M-tBu]+ 240.

[0774] Intermediate 38c: 3-fluoro-4-(piperidin-4-yl)phenol [ka] A mixture of HCl (18.8 mL, 8.00 mmol) and tert-butyl 4-(2-fluoro-4-hydroxyphenyl)-piperidine-1-carboxylate (600 mg, 2.05 mmol) in 1,4-dioxane was stirred at room temperature for 2 hours, followed by concentration under reduced pressure to give the title compound (0.580 g, 145%) as a white solid hydrochloride salt. 1 H NMR(300MHz)1.72-1.97(4H,m),2.97(3H,dq),3.29(2H,d),6.49-6.62(2H,m),7.02(1H,t),8.92(1H,br),9.83(1H,s);m / z:ES + [M+H]+ 196.

[0775] Intermediate 38d: 4-[4-(2-fluoro-4-hydroxyphenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] DIPEA (3.81 mL, 21.80 mmol) was added to 3-fluoro-4-(piperidin-4-yl)phenol hydrochloride (1.01 g, 4.36 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (0.989 g, 5.23 mmol) in DMSO (10 mL) at room temperature under atmospheric pressure, and the mixture was stirred for 18 hours and poured into water (20 mL). The mixture was stirred at room temperature for 0.5 hours and then filtered. The collected solid was washed with water (20 mL) and 5% AcOH / water (20 mL) and dried under vacuum to obtain the title compound (1.51 g, 95%) as a yellow solid; 1 H NMR:1.67(2H,qd),1.80(2H,d),2.94-3.01(1H,m),3.03-3.18(2H,m),4.17(2H,d), 6.45-6.63(2H,m),7.08(1H,t),7.19-7.38(2H,m),7.81(1H,d),9.65(1H,s);m / z:ES + [M+H]+ 365.2.

[0776] Intermediate 38e: 4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)-2-fluorophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] 2-(3-Bromopropyl)-1,3-dioxolane (0.613 mL, 4.53 mmol) was added in one portion to 4-(4-(2-fluoro-4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.50 g, 4.12 mmol) and K2CO3 (1.707 g, 12.35 mmol) in MeCN (10 mL) at room temperature under N2. The resulting suspension was stirred at 80 °C for 5 h. After cooling, the mixture was filtered, and water (150 mL) was added to the filtrate. The white precipitate was then collected by filtration to give the title compound (1.85 g, 94%) as a yellow solid. 1H NMR:1.62-1.84(8H,m),3.03-3.12(3H,m),3.75-3.8(2H,m),3.86-3.9(2H,m),3.98(2H,t),4.18( m / z:ES + [M+H]+ 479.4.

[0777] Example 38: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2b was reacted with intermediate 38e using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Workup A); 1 H NMR:(300MHz)1.21-1.32(1H,m),1.56-1.86(8H,m),1.91-2.03(1H,m),2.26-2.49( 4H,m),2.52-2.65(3H,m),2.84-2.98(1H,m),3.07(3H,t),3.20-3.33(4H,m),4.00(2 H,t),4.12-4.28(3H,m),4.34(1H,d),5.05(1H,dd),6.70-6.84(2H,m),7.07(2H,d) ,7.20(1H,t),7.27(1H,d),7.33(1H,d),7.53(1H,d),7.82(1H,d),10.95(1H,s); E.S. + [M+H]+=747.5.

[0778] Intermediate 39a: 4-(4-(4-(((1r,3r)-3-(bromomethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] CBr4 (74.6 mg, 0.22 mmol) was added to PPh3 (59.0 mg, 0.22 mmol) and 4-(4-(4-(((1s,3s)-3-(hydroxyl-methyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.11 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 2 h and then concentrated. Purification by preparative TLC (eluent EtOAc:petroleum ether = 1:5) afforded the title compound (0.050 g, 88%) as a colorless gum. 1 H NMR:1.51-1.70(4H,m),1.85(2H,d),2.13-2.24(2H,m),2.53-2.64(2H,m),2.71-2.83(1H,m),3.05(2H,dd), 3.56(2H,d),3.88(2H,d),4.18(2H,d),6.85(2H,d),7.15(2H,d),7.27(1H,dd),7.33(1H,d),7.82(1H,d);m / z E.S. + ,[M+H] + =507.

[0779] Example 39: 4-[4-(4-{[(1s,3s)-3-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperazin-1-yl}methyl)cyclobutyl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] Intermediate 2c was reacted with intermediate 39a using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 20:1); 1H NMR:(300MHz)1.43-1.75(4H,m),1.85(2H,d),1.91-2.10(1H,m),2.12-2.27(2H,m),2.31- 2.44(3H,m),2.50(4H,q),2.52-2.67(3H,m),2.77-2.98(2H,m),2.99-3.11(2H,m),3.22-3 .31(4H,m),3.86(2H,d),4.12-4.25(3H,m),4.33(1H,d),5.05(1H,dd),6.84(2H,d),7.05( m / z E.S. + [M+H]+=755.4.

[0780] Intermediate 40a: tert-butyl 4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-piperidine-1-carboxylate [ka] DIAD (337 μL, 1.73 mmol) was added to 4-(4-(4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (Example 1g) (300 mg, 0.87 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (209 mg, 1.04 mmol), and PPh3 (454 mg, 1.73 mmol) in DCM (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 hours and then concentrated. Purification by flash C18-flash chromatography (gradient: 0-100% MeCN in water (0.1% formic acid)) afforded the title compound (0.100 g, 22%) as a white solid; 1H NMR:1.40(9H,s),1.50(2H,ddt),1.62(2H,qd),1.78-1.93(4H,m),2.76(1H,tt),3.04(2H,td),3.13-3.21(2H,m) ,3.57-3.71(2H,m),4.17(2H,d),4.49(1H,tt),6.89(2H,d),7.15(2H,d),7.26(1H,dd),7.32(1H,d),7.81(1H,d).

[0781] Intermediate 40b: 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Pd-PEPPSI-IPent (0.355 g, 0.45 mmol) was added to 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.45 g, 4.49 mmol), 4-(dimethoxymethyl)piperidine (1.00 g, 6.28 mmol), and CsCO (4.38 g, 13.46 mmol) in 1,4-dioxane (45 mL) at room temperature under N. The resulting suspension was degassed in vacuo, refilled with N, and stirred at 90 °C for 4.5 h. The mixture was then allowed to stand at room temperature for 16 h. The mixture was then diluted with DCM (75 mL) and 10% aq. AcOH (150 mL), and the layers were separated. The aqueous layer was extracted with DCM (75 mL × 2). The combined organic solution was washed with saturated brine (60 mL), dried (MgSO4), and concentrated. Purification by FSC (gradient: 0-8% EtOH in EtOAc) afforded the title compound (0.800 g, 44%) as an off-white solid; 1H NMR:1.24-1.39(2H,m),1.71(2H,d),1.76-1.9(1H,m),1.9-2.04(1H,m),2.26-2.43(1H,m),2.58(1H,td),2.73-3.02(3H,m) m / z E.S. + ,[M+H] + =402.

[0782] Example 40: 4-[4-(4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile [ka] Intermediate 40a was reacted with intermediate 40b using the general synthesis method illustrated by Example 1 to give the title compound after purification by preparative SFC (column: DAICEL DCpak P4VP, 20 mm*250 mm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH--HPLC; flow rate: 50 mL / min; gradient: 45% B; 254 nm; RT1: 5.67; injection volume: 1 mL; number of runs: 5); 1 H NMR:(300MHz)1.09-1.21(2H,m),1.52-1.68(4H,m),1.70-2.02(8H,m), 2.10-2.44(5H,m),2.54-3.14(9H,m),3.87(2H,d),4.12-4.25(3H,m),4. 26-4.39(2H,m),5.05(1H,dd),6.82-6.93(2H,m),7.04(2H,d),7.12-7.1 8(2H,m),7.25-7.35(2H,m),7.50(1H,d),7.82(1H,d),10.94(1H,s);m / z E.S. + [M+H]+=769.4.

[0783] Intermediate 41a: Benzyl 4-(4-bromo-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] PdCl(dppf) (7.39 g, 10.10 mmol) was added to 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (3.47 g, 10.10 mmol), 4-bromo-1-iodo-2-methylbenzene (3.00 g, 10.10 mmol), and KCO (4.19 g, 30.31 mmol) in 1,4-dioxane (20 mL) and water (5 mL) at room temperature under N. The resulting solution was stirred at 80 °C for 4 h. The mixture was then diluted with EtOAc (50 mL). The solution was washed with water (20 mL × 3), followed by saturated brine (20 mL × 2), dried (NaSO), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) afforded the title compound (2.00 g, 51%) as a pale yellow solid; 1 H NMR(300MHz)2.21(3H,s),2.21-2.33(2H,m),3.59(2H,d),4.01(2H,d),5.11 (2H,s),5.58(1H,s),7.02(1H,d),7.25-7.36(2H,m),7.33-7.43(5H,m);m / z E.S. + [M+H]+=388.

[0784] Intermediate 41b: benzyl 4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Rockphos Pd G3 (0.217 g, 0.26 mmol) was added to benzyl 4-(4-bromo-2-methylphenyl)-3,6-dihydro-pyridine-1(2H)-carboxylate (1.00 g, 2.59 mmol), 4-((tert-butyldimethylsilyl)oxy)butan-1-ol (0.794 g, 3.88 mmol), and Cs2CO3 (2.53 g, 7.77 mmol) in 1,4-dioxane (1 mL) at room temperature under N2. The resulting solution was stirred at 100 °C for 12 h and then concentrated. Purification by flash C18-flash chromatography (gradient: 0 to 100% MeCN in water) afforded the title compound (0.700 g, 53%) as a yellow solid. 1 H NMR(300MHz)0.02(6H,s),0.84(9H,d),1.49-1.64(2H,m),1.66-1.78(2H,m),2.17(3H,s),2.22-2.36(2H,m),3.31(2H,s),3. 62(2H,t),3.92(2H,t),4.01(2H,q),5.11(2H,s),5.50(1H,s),6.67(1H,dd),6.72(1H,d),6.95(1H,d),7.35-7.39(5H,m);m / z E.S. + [M+H]+=510.

[0785] Intermediate 41c: 4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)piperidine [ka] A mixture of benzyl 4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (600 mg, 1.18 mmol) and platinum(IV) oxide hydrate (60 mg, 0.24 mmol) in EtOAc (10 mL) was stirred at 80 °C under H (20 atm) for 10 h. The mixture was then filtered through a Celite pad and the filtrate was concentrated to give the title compound (460 mg, 103%); m / z ES + [M+H]+=378.

[0786] Intermediate 41d: 4-(4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile [ka] Cs2CO3 (518 mg, 1.59 mmol) was added to 4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)-piperidine (200 mg, 0.53 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (150 mg, 0.79 mmol) in DMSO (5 mL) at room temperature under air. The resulting solution was stirred at 60 °C for 2 h and then concentrated. Purification by flash C18-flash chromatography (gradient: 10 to 100% MeCN in water) afforded the title compound (0.125 g, 43%) as a white solid; 1 H NMR(CD3OD,300MHz)0.82(6H,s),1.65(9H,s),2.30-2.45(4H,m),2.44-2.60(4H,m),3.09(3H,s),3.74(1H,t),3.87(2H,t), 4.42(2H,t),4.71(2H,t),4.98(2H,d),7.47(1H,dd),7.51(1H,d),7.84(1H,d),8.06(1H,dd),8.12(1H,d),8.61(1H,d);m / z E.S. + [M+H]+=547.

[0787] Intermediate 41e: 4-(4-(4-(4-hydroxybutoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] 4-(4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (90 mg, 0.16 mmol) was added to tetra-n-butylammonium fluoride (86 mg, 0.33 mmol) in THF (2 mL) at room temperature, and the mixture was stirred for 16 hours and then concentrated. The residue was diluted with DCM (250 mL). The solution was washed with water (30 mL), followed by saturated brine (50 mL), dried (Na2SO4), and concentrated to give the title compound (0.085 g, 119%); 1 H NMR:1.51-1.58(2H,m),1.61(2H,dd),1.71(2H,dd),1.77(2H,d),2.31(3H,s),2.95(1H,ddd),3.08(2H,t),3.40-3.50(2H,m) m / z E.S. + [M+H] + =433.2.

[0788] Intermediate 41f: 4-(4-(4-(4-bromobutoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile [ka] 4-(4-(4-(4-hydroxybutoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (80.0 mg, 0.18 mmol) was added to PPh3 (97.0 mg, 0.37 mmol) and CBr4 (123 mg, 0.37 mmol) in DCM (2 mL) at room temperature, and the mixture was stirred for 3 h and then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) afforded the title compound (0.075 g, 82%) as a colorless gum; 1H NMR(300MHz)1.59(2H,qd),1.68-1.85(4H,m),1.93(2H,dtd),2.29(3H,s),2.88-2.99(1H,m),3.06(2H,t),3.58(2H m / z E.S. + [M+H]+=495.2.

[0789] Example 41: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, X １ is C and X ２ , X ３ and X ４ are N and the rest are C; or X ３ and X ４ are both C and X ３ X bonded to ５ and X ５ X bonded to ８ -X ５ =X ６ -X ７ =X ８ - is replaced by X １ , X ２ , X ５ , X ６ , X ７ and X ８ one or two of are N and the others are C; X ３ and X ４ But, -X ５ =X ６ -X ７ =X ８ When not substituted by -, p is 1 or 2; X １ is R １ otherwise, p is 0, 1 or 2; During the ceremony, Each R １ , X １ , X ２ , X ３ and X ４ (or X ３ and X ４ But, -X ５ =X ６ -X ７ =X ８ When substituted by -, X １ , X ２ , X ５ , X ６ , X ７ and X ８ ) is a substituent on any C atom of １～３ Alkyl and C １～３ alkoxy, １～３ Alkyl and C １～３ The alkoxy may be optionally substituted independently by one or more F; n is 0, 1 or 2; m is 0 or 1; When n and m are both other than 0, Q is CH or N, otherwise Q is CH; R ２ａ and R ２ｂ H, F and C １～３ the same or different substituents on C atoms other than Q are each independently selected from alkyl, or R ２ａ and R ２ｂ Combined together, -(CH ２ ) ｒ - group, and r is 1, 2 or 3; Y １ , Y ２ , Y ３ and Y ４ 0, 1 or 2 of are N and the rest are C; Each R ３ Is Y １ , Y ２ , Y ３ and Y ４ is a substituent on any C atom of １～３ Alkyl and C １～３ alkoxy, １～３ Alkyl and C １～３ The alkoxy may be optionally substituted independently by one or more F; q is 0, 1 or 2; A linker is a saturated or partially or fully unsaturated backbone comprising C and H atoms and at least one heteroatom, said backbone having bond endpoints 'a' and 'b' with a minimum length between 'a' and 'b' of 6 to 26 atoms; said backbone may comprise one or more straight and / or branched chains and / or rings, optionally substituted by one or more F on any available C atom; W is the E3 ubiquitin ligase cereblon conjugation unit).

2. The linker has the formula: ‘a’-Q Ａ -Q Ｂ -Q Ｃ -‘b’ (In the formula, 'a' and 'b' represent the connection endpoints; Q Ａ H-G-Q Ｈ -or-G-(C １～５ alkylene)-; Q Ｂ is a direct bond, -Q Ｂ１ -Q Ｂ２ -Q Ｂ３ - or C optionally substituted by one or more F (e.g., 1 or 2) １～３ is alkylene; Q Ｂ１ and Q. Ｂ３ are each independently a direct bond or C １～２ represents alkylene; Q Ｂ２ Is, Q Ｈ , —O—CH ２ CH ２ -O-, -O- or -N(R Ｊ )-(wherein, R Ｊ is H or C １～３ alkyl); Q Ｃ , -Q Ｈ -G- or -(C １～５ alkylene)-G-; Each G is independently a direct bond, -CH ２ -, -O-, or -N(R Ｇ )-(wherein, R Ｇ is H or C １～３ alkyl); Each Q Ｈ is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; Q Ａ , Q Ｂ and Q. Ｃ is selected such that said linker does not contain any N-N or N-O bonds, or a pharma- ceutically acceptable salt thereof.

3. Q Ｂ２ But, Q Ｈ , —O—CH ２ CH ２ -O- or -N(R Ｊ )-(wherein, R Ｊ is C １～３ 3. The compound of formula (I) according to claim 2, wherein R is alkyl; or a pharma- ceutically acceptable salt thereof.

4. Q Ｃ But, -Q Ｈ -G- or -(C １～２ 4. The compound of formula (I) according to claim 2 or claim 3, wherein G is alkylene)-G-, or a pharma- ceutically acceptable salt thereof.

5. Each Q Ｈ are independently selected from the group consisting of piperazine-1,4-diyl, azetidine-1,3-diyl, piperidine-1,4-diyl, 1,4-diazepane-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl, pyrrolidine-1,3-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2,5-diazabicyclo[2. 2.1]heptane-2,5-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, 3,6-dihydro-2H-pyridine-1,4-diyl and 9-azaspiro[5.5]undecane-3,9-diyl, or a pharma- ceutically acceptable salt thereof.

6. The linker is Linker 1 to 46 or 1 to 48: 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 2. The compound of formula (I) according to claim 1, selected from any one of:

7. W is W1, which is -Z-(R Ａ ) ｈ (Wherein, Z is 【Chemistry 5】 and 【Chemistry 6】 represents a single or double covalent bond; X Ａ , X Ｂ , X Ｃ , X Ｄ , X Ｅ and X Ｆ 0, 1 or 2 of X are N; Ｅ and X Ｆ are both not N, otherwise C; X Ｇ , X Ｈ and X Ｊ is C(O); X Ｇ , X Ｈ and X Ｊ one of which is N-(2,6-dioxopiperidin-3-yl)(Y); X Ｇ , X Ｈ and X Ｊ One of them is C(R Ｔ ) ２ , -CH ２ CH ２ -, C(O), N(C １～３ alkyl), -O-, and -N=; Ｔ is selected from H, F, Me or C(R Ｔ ) ２ together with the carbon atom of to form a cyclopropa-1,1-diyl group; X Ｇ , X Ｈ and X Ｊ does not have two C(O) groups at adjacent positions, and N-(2,6-dioxopiperidin-3-yl) is N(C １～３ is selected so as not to be present adjacent to either alkyl (alkyl) or O; Each R Ａ are independently F, Cl, C １～３ Alkyl, C １～３ X selected from alkoxy Ａ , X Ｂ , X Ｃ Or X Ｄ is a substituent on any available C atom in １～３ Alkyl and C １～３ The alkoxy is optionally substituted independently by one or more F; h is 0, 1 or 2; The linker is X Ａ , X Ｂ , X Ｃ Or X Ｄ 7. The compound of formula (I) according to any one of claims 1 to 6, wherein:

8. Each R Ａ is optionally substituted by F, Cl and one or more F １～３ X selected from alkoxy Ａ , X Ｂ , X Ｃ Or X Ｄ or a pharma- ceutically acceptable salt thereof.

8. The compound of formula (I) according to claim 7, wherein any available substituent on C is:

9. X Ｇ -X Ｈ -X Ｊ but, (i) X Ｇ -NY-C(O) (wherein, X Ｇ is -CH ２ --, --CH ２ CH ２ -, ═N- or C(O); (ii) X Ｇ -C(O)-NY (wherein, X Ｇ is -O- or N(C １～３ alkyl); or ()) ２ 23. A compound of formula (I) according to claim 7 or claim 22, which is: or a pharma- ceutically acceptable salt thereof.

10. W is a group 1 to 21: 【Chemistry 7】 7. The compound of formula (I) according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, which is any one of:

11. W is W2, which is 【Chemistry 8】 and Z Ａ but, 【Chemistry 9】 (In the formula, 【Chemistry 10】 represents a single or double covalent bond; X Ａ２ , X Ｂ２ , X Ｃ２ and X Ｄ２ is C and is covalently bonded to Y; X Ａ２ , X Ｂ２ , X Ｃ２ , X Ｄ２ , X Ｅ２ and X Ｆ２ 0, 1, or 2 of N(X Ｅ２ and X Ｆ２ are not both N), otherwise C; X Ｇ２ , X Ｈ２ and X Ｊ２ one or two of are N; the others are C; Each R ＡＡ is a substituent on any available C or N atom of Z, in each case one or more R ＡＡ２ R optionally substituted by ＡＡ１ independently selected from ＡＡ Z Ａ When R is a substituent on an available C atom of ＡＡ Further, R ＡＡ２ Selected from: Each R ＡＡ１ is independently １～４ Alkyl, C ２～３ Alkenyl, C ２～３ Alkynyl, C １～３ Alkoxy C １～３ Alkyl, Carboxy C １～３ Alkyl, C ５～７ carbocyclyl, or 4- to 6-membered heterocyclyl; Each R ＡＡ２ are independently F, Cl, Br, CN, NH ２ , C １～３ Alkyl, O(C １～３ alkyl), NH(C １～３ alkyl), and N(C １～３ Alkyl) ２ C is selected from １～３ The alkyl is optionally substituted with one or more F; v is 0, 1 or 2; 7. The compound of formula (I) according to any one of claims 1 to 6, wherein Y is N-(2,6-dioxopiperidin-3-yl), or a pharma- ceutically acceptable salt thereof.

12. X Ａ２ and X Ｂ２ is C, covalently bonded to Y; Ａ２ and X Ｂ２ the other is C; X Ｃ２ and X Ｄ２ 0 or 1 of the formula (I) is N, and the rest are C; X Ｇ２ and X Ｊ２ One of the groups is N, and the other is X Ｇ２ and X Ｊ２ the other is C; X Ｈ２ , X Ｅ２ and X Ｆ２ The compound or salt thereof according to claim 11, wherein all of are C.

13. W is W2-1 【Chemistry 11】 (In the formula, X Ｋ and X Ｌ are an N-linker and CH or NMe and a C-linker, respectively; X Ｍ and X Ｏ one of which is N-(2,6-dioxopiperidin-3-yl)(Y); X Ｍ and X Ｎ 0 or 1 of is C—F; X Ｎ , X Ｍ if is not C-F, it may be N; X Ｎ , X Ｍ and X Ｏ The remainder is CH.

12. The compound according to claim 11, or a salt thereof,

14. W is a group 22 to 26 shown below: 【Chemistry 12】 The compound or salt thereof according to any one of claims 1 to 6, wherein

15. R ２ａ and R ２ｂ The compound or salt thereof according to any one of claims 1 to 14, wherein are substituents on the same or different C atoms adjacent to Q.

16. R ２ａ and R ２ｂ are the same or different substituents on a C atom, each independently being H and C １～３ The compound or salt thereof according to any one of claims 1 to 15, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl and alkyl.

17. p is 1; X ３ and X ４ But, -X ５ =X ６ -X ７ =X ８ is not substituted by -; １ , X ２ , X ３ and X ４ are all C and R １ But, X １ is the above substituent, CF ３ The compound or salt thereof according to any one of claims 1 to 16,

18. p is 2; X ３ and X ４ But, -X ５ =X ６ -X ７ =X ８ is not substituted by -; １ , X ２ , X ３ and X ４ are all C; one R １ The substituent is X １ Above, CF ３ and the other R １ The substituent is X ２ and is F or ethyl, or a salt thereof, according to any one of claims 1 to 16.

19. n is 1, m is 1, Q is CH, and R ２ａ is H, and R ２ｂ The compound of any one of claims 1 to 18, wherein is H, or a salt thereof.

20. Y １ , Y ２ , Y ３ and Y ４ are all C, or a salt thereof, of any one of claims 1 to 19.

21. The compound of any one of claims 1 to 20, wherein q is 0, or a salt thereof.

22. q is 1, R ３ But Y １ is bonded to C of R ３ The compound of any one of claims 1 to 20, wherein is selected from F, CN and Me, or a salt thereof.

23. q is 2, and each R ３ The group is F, which is Y １ and Y ３ 22. The compound of any one of claims 1 to 21, wherein the compound is attached to C of the salt thereof.

24. Formula (VI): 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof (In the formula, R Ｚ１ is H or F; R Ｚ２ is H or F; R Ｚ３ is H or F; L Ｚ is a linker selected from 1, 3, 45 and 47: 【Chemistry 14】 【Chemistry 15】 and W Ｚ are 1, 2, 3, 10, 16, 22, 23, 24 and 26: 【Chemistry 16】 【Chemistry 17】 2. The compound according to claim 1, wherein Y is selected from the group consisting of N-(2,6-dioxopiperidin-3-yl) and N-(2,6-dioxopiperidin-3-yl).

25. Formula (VI-1): 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof (In the formula, R Ｚ１ is H or F; L Ｚ is a linker selected from 1 and 3: 【Chemistry 19】 and W Ｚ are 1, 2 and 10: 【Chemistry 20】 2. The compound according to claim 1, wherein Y is selected from the group consisting of N-(2,6-dioxopiperidin-3-yl) and N-(2,6-dioxopiperidin-3-yl).

26. Formula (VI-2): 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof (In the formula, R Ｚ１ is H or F; R Ｚ２ is H or F; R Ｚ３ is H or F; L Ｚ is a linker selected from 3, 45 and 47: 【Chemical 22】 and W Ｚ are 1, 3, 16, 22, 23, 24 and 26: 【Chemistry 23】 【Chemistry 24】 2. The compound according to claim 1, wherein Y is selected from the group consisting of N-(2,6-dioxopiperidin-3-yl) and N-(2,6-dioxopiperidin-3-yl).

27. A pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 26 in association with a pharma- ceutically acceptable excipient.

28. A compound of formula (I) as defined in any one of claims 1 to 26 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 24 for use in the prophylaxis or treatment of tumor types that are sensitive to degradation of the androgen receptor or for use in the treatment of prostate cancer (e.g. castration-resistant prostate cancer (CRPC), e.g. metastatic CRPC).

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