A bifunctional compound that can degrade androgen receptors

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 is CH or N, p is 0, 1, or 2, where each R 1 is a substituent on any C atom and is independently selected from F, Cl, C 1~3 alkyl, and C 1~3 alkoxy, and the C 1~3 alkyl and C 1~3 alkoxy may each be optionally substituted by one or more Fs, R N is selected from H and Me, n is 0, 1, or 2, m is 0 or 1, Q 1 is CH or N, and when both n and m are other than 0, Q 2 is CH or N, and when both n and m are 0, Q 2 is CH, and when n is 0 or 1, Q 3 is CH, and when n is 2 and Q 2 is N, Q 3 is CH, and when n is 2 and Q 2 is CH, Q 3 is CH or O, and R 2a and R 2b are substituents on the same or different C atoms other than Q 1 or Q 2 and are each independently selected from H, F, and C 1~3 alkyl, or R 2a and R 2b together form a -(CH2) r - group, where r is 1, 2, or 3, Q 4 is a single bond or -NR 4 C(=O), R 4 is H or Me, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 of which 0, 1, or 2 are N and otherwise C, and each R 3 is Y1, Y 2 , Y 3 , Y 4 , and Y 5A substituent on any C atom, independently of F, Cl, CN, C 1~3 Alkyl and C 1~3 Selected from alkoxy, the C 1~3 Alkyl and C 1~3 The alkoxy can be independently and optionally substituted by one or more Fs, where q is 0, 1, or 2, and the linker is Y. 4 and Y 5 A compound of formula (I) or a pharmaceutically acceptable salt thereof, bonded at any available C atom, the linker being a saturated, partially or fully unsaturated skeleton comprising C and H atoms and at least one heteroatom, the skeleton having bond endpoints "a" and "b" and having a length of 5 to 26 atoms between "a" and "b", the skeleton may contain one or more linear and / or branched and / or ring chains, optionally substituted on any available C atom with one or more F, and W being an E3 ubiquitin ligase cereblon binding unit. [Formula 1] JPEG2026510359000635.jpg38128

Description

[Technical Field]

[0001] (Related applications) This application claims priority from U.S. Provisional Patent Application No. 63 / 489,528, filed on 10 March 2023, the disclosure thereof being incorporated in its entirety herein.

[0002] (Field of Invention) This specification relates to specific proteolysis-targeting chimera (PROTAC) compounds and their ability to degrade at least androgen receptors (ARs), and therefore their use for the treatment of androgen receptor-dependent diseases or disorders in mammals. Degradation of androgen receptors can, for example, provide antitumor effects, and therefore this specification relates, in part, to the use of such compounds for the treatment of cancer and to pharmaceutical compositions containing them. The present invention also relates to intermediate compounds that may be useful in the preparation of such PROTACs. [Background technology]

[0003] Conventional small molecule drugs reversibly (or sometimes irreversibly) bind to target proteins as a means of modulating a given biological activity. In contrast, PROTACs bind to their target proteins but then lead to the degradation of those target proteins. Once this effect is achieved, PROTACs can theoretically repeat this process with another target protein. Therefore, unlike "conventional small molecule" inhibitors, the PROTAC-driven degradation mechanism can theoretically act in a substoichiometric manner. This means that even with less exposure to PROTAC compounds, the desired level of efficacy can still be achieved in vivo. In practice, this is due to the degradation power of PROTACs (DC 50 and D max This could mean that it may have an improved effect than what would be reflected solely by its binding affinity.

[0004] At a simplified level, a PROTAC molecule is often described as having three parts: (1) a part that can bind to the 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.

[0005] Upon use, PROTAC simultaneously binds to both the target protein and the E3 ubiquitin ligase to form a ternary complex. The E3 ligase then recruits an E2-conjugating enzyme into the ternary complex, which ubiquitizes the target protein. This effectively labels the target protein for degradation by the cell's proteasome mechanism. PROTAC can then dissociate from the target protein, initiating another cycle of this process in a catalytic manner. Meanwhile, the ubiquitinated target protein is recognized and degraded by the cell's proteasome mechanism.

[0006] This PROTAC-mediated approach may be valuable as a way to treat specific diseases, for example, when the targeted degradation of certain bodily proteins can be beneficial in the treatment of cancer. One such cancer-related target is the androgen receptor.

[0007] The androgen receptor (AR) is a ligand-dependent transcription factor belonging to the nuclear receptor steroid hormone group, which regulates the expression of a series of genes involved in the proliferation and survival of prostate cells. AR consists of four distinct domains: the N-terminal domain (NTD), the DNA-binding domain (DBD), a hinge region that allows the N-terminus and C-terminus to interact, and the C-terminal ligand-binding domain (LBD). Androgens such as testosterone and its derivative dihydrotestosterone (DHT) bind to the AR ligand-binding domain, which releases the AR chaperone protein, allowing the AR to dimerize and translocate from the cytoplasm to the nucleus. In the nucleus, the receptor dimer binds to the androgen response element (ARE) in the promoters of androgen-responsive genes such as PSA and FKBP5. The AR signaling pathway plays a role in normal prostate development, and male sexual differentiation cannot occur in the absence of androgens or without a functioning AR.

[0008] The relationship between androgens and prostate cancer was first discovered in the groundbreaking research 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 an initial good response, most tumor cells adapt to low androgen levels, and patients relapse within a few years, developing a disease state known as castrate-resistant prostate cancer (CRPC). Several second-generation anti-androgen agents 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 their ligand-binding domains. In addition to antagonizing ARs and preventing their activation, they also inhibit nuclear translocation and DNA binding, thus effectively shutting down 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.

[0009] While the aforementioned drugs significantly extend survival in patients with advanced prostate cancer, they are not curative and inevitably lead to resistance. However, it is clear that AR remains central to the progression of CRPC, meaning that the need to develop alternative AR inhibitors still exists. Several resistance mechanisms have been identified, including amplification, mutation, or generation of splice variants lacking the ligand-binding domain of AR. Mutations in the ligand-binding domain (e.g., F877L or L702H) can convert antagonists into agonists or allow the receptor to utilize alternative steroid hormones such as glucocorticoids or progesterone. Therefore, drugs that degrade and remove AR from cells may help address these forms of resistance. Thus, AR PROTACs can bind to the ligand-binding domain of the androgen receptor and simultaneously recruit E3 ligases such as cereblon to result in proteasome-mediated ubiquitination and degradation of AR, providing therapeutic benefits to patients with prostate cancer, particularly those with metastatic CRPC. AR PROTAC may also be useful for AR+ breast cancer.

[0010] Given that the aforementioned resistance mutations can occur in the ligand-binding domain and may limit the effectiveness of known CRPC treatments, it would be beneficial to develop AR degradation protacs that are effective not only in targeting "wild-type" AR but also in degrading clinically relevant variants of AR.

[0011] Whatever the target protein binding unit (1) used at one end of the PROTAC 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 the tagging of the target protein for degradation, such as an E3 ubiquitin ligase cereblon binding unit. Scientific efforts have already provided several such E3 ubiquitin ligase cereblon binding units, and further examples are shown below by the present researchers.

[0012] International Publication No. 2018 / 071606 describes certain PROTAC compounds known as AR degrading agents.

[0013] As with conventional small molecule conjugates and proteacs, there is always the issue of in vivo "off-target" activity, which can be crucial to avoid in the development of safe and effective drug therapies. In other words, a given binding unit may be highly potent against its intended target, but if it is incidentally potent against other unintended biological targets in the human body, it can cause unacceptable toxicity, side effects, etc.

[0014] Therefore, the ongoing challenge is to develop potent molecules for pharmaceutical use that are also suitably selective, i.e., that avoid unintended inhibition / binding / degradation of biological targets in vivo.

[0015] For example, these researchers have surprisingly found that certain compounds described herein exhibit beneficial selectivity that is expected to avoid or reduce the risk of mitochondrial toxicity in vivo.

[0016] As part of developing current and future PROTAC drug therapies for pharmaceutical applications (e.g., cancer), there remains a need to develop androgen receptor PROTAC compounds with beneficial / improved combinations of properties. As mentioned above, the development of PROTACs targeting both wild-type ARs and one or more clinically relevant AR variants is one example of such a combination effect.

[0017] Furthermore, regardless of which E3 ubiquitin ligase cereblon binding unit is selected for use at the other end of the molecule, there is a need to develop androgen receptor binding units that can be incorporated into PROTAC.

[0018] Other properties of such PROTACs for pharmaceutical discovery and development may relate to selectivity profile, absorption / bioavailability, distribution, metabolism, elimination, toxicity and side effect profile, stability, and manufacturability. [Overview of the project]

[0019] The compounds herein provide at least a potent AR-binding unit suitable for incorporation into PROTAC compounds, and also provide PROTAC compounds comprising such an AR-binding unit together with an E3 ubiquitin ligase cereblon binding 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 variant forms of AR (e.g., L702H). Certain PROTAC compounds herein also possess a remarkably beneficial combination of properties (e.g., a combination of properties related to AR degradation and selectivity / safety profiles).

[0020] This specification relates to the aforementioned AR binding units, and to PROTAC compounds (and pharmaceutically acceptable salts thereof) that incorporate such AR binding units together with E3 ubiquitin ligase cereblon binding units (the two units linked by a linker).

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

[0022] According to a first aspect of this specification, formula (I):

[0023] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, X 1is CH or N, p is 0, 1, or 2, wherein each R 1 is a substituent on any C atom and is independently selected from F, Cl, C 1~3 alkyl, and C 1~3 alkoxy, and the C 1~3 alkyl and C 1~3 alkoxy may each independently be optionally substituted by one or more Fs, R N is selected from H and Me, n is 0, 1, or 2, m is 0 or 1, Q 1 is CH or N, when both n and m are other than 0, Q 2 is CH or N, when both n and m are 0, Q 2 is CH, when n is 0 or 1, Q 3 is CH, when n is 2 and Q 2 is N, Q 3 is CH, when n is 2 and Q 2 is CH, Q 3 is CH or O, R 2a and R 2b are substituents on the same or different C atoms other than Q 1 or Q 2 and are each independently selected from H, F, and C 1~3 alkyl, or R​​​​​​​​​​​​​​​​​​​​​, Y 3 , Y 4 , and Y 5 If 0, 1, or 2 of these is N, otherwise it is C. Each R 3 Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 A substituent on any C atom, independently of F, Cl, CN, C 1~3 Alkyl and C 1~3 Selected from alkoxy, the C 1~3 Alkyl and C 1~3 The alkoxy can be independently and optionally substituted with one or more Fs. q is 0, 1, or 2. Linker is Y 4 and Y 5 Bonded with any available C atom, The linker is a saturated, partially, or fully unsaturated skeleton comprising C and H atoms and at least one heteroatom, the skeleton having bond endpoints "a" and "b" and a minimum length of 5 to 26 atoms between "a" and "b", the skeleton may contain one or more linear and / or branched and / or rings, and is arbitrarily substituted on any available C atoms by one or more F atoms. W is provided as a compound of formula (I) or a pharmaceutically acceptable salt thereof, where W is an E3 ubiquitin ligase cereblon binding unit.

[0024] This specification also describes pharmaceutical compositions comprising, in part, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0025] This specification also describes, in part, compounds of formula (I) or pharmaceutically acceptable salts thereof for use in therapy.

[0026] This specification also describes, in part, compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of cancer.

[0027] This specification also describes, in part, a method for treating cancer in warm-blooded animals requiring cancer treatment, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the warm-blooded animals.

[0028] As shown in the experimental section below, the researchers not only developed a series of useful AR binding units but also gained an understanding of where such binding units can incorporate linkers (resulting in E3 ubiquitin ligase cereblon binding units) without impairing their AR binding ability. Thus, the researchers understand that when incorporating AR binding units into a PROTAC, the linker of the PROTAC should not be bound to the left-hand or central ring of formula (I) shown above, but rather can be suitably bound to the specified position on the right-hand ring of the compound of formula (I) shown herein.

[0029] Therefore, in further aspects of this specification, a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) or a pharmaceutically acceptable salt thereof,

[0030] [ka] Here, R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 A PROTAC compound or a pharmaceutically acceptable salt thereof is provided, wherein q and q can each take any of the values ​​defined herein for each of these integers.

[0031] To avoid any doubt, in equation (Ia)

[0032] [ka] This indicates a connection point to the rest of the PROTAC compound via a monocovalent bond.

[0033] In one embodiment, a PROTAC compound or a pharmaceutically acceptable salt thereof is provided, comprising an E3 ubiquitin ligase cereblon binding unit linked to an AR binding unit of formula (Ia) described herein.

[0034] As described herein, the linkage between the E3 ubiquitin ligase cereblon binding unit and the AR binding unit of formula (Ia) shown above may have a length corresponding to the length of a linear chain of 5 to 26 atoms, which are linked by monocovalent bonds and each selected from carbon or heteroatoms (i.e., O, N, or S).

[0035] As described herein, the linkage between the E3 ubiquitin ligase cereblon binding unit and the AR binding unit of formula (Ia) shown above may have a length corresponding to the length of a linear chain of 5 to 14 atoms, which are linked by monocovalent bonds and each selected from carbon or heteroatoms (i.e., O, N, or S).

[0036] In one embodiment, the linkage between the E3 ubiquitin ligase cereblon binding unit and the AR binding unit of formula (Ia) shown above may have a length corresponding to the length of a linear chain of 5 to 26 atoms, where the atoms are linked by single covalent bonds and each is selected from C, N, or O.

[0037] In one embodiment, the linkage between the E3 ubiquitin ligase cereblon binding unit and the AR binding unit of formula (Ia) shown above may have a length corresponding to the length of a linear chain of 5 to 14 atoms, where the atoms are linked by single covalent bonds and each is selected from C, N, or O.

[0038] The length of a linkage corresponds to the length of a specific atom in the chain, but this should not be interpreted as meaning that the linkage is limited to that atom. For example, a sulfur atom can be present in a linkage even if the S atom is not included in the length descriptor.

[0039] Further embodiments of this specification provide androgen receptor binding units of formula (Ia) described herein for use in PROTAC compounds (or pharmaceutically acceptable salts thereof), including E3 ubiquitin ligase cereblon binding units.

[0040] In further aspects of this specification, an androgen receptor binding unit of formula (Ia) described herein is provided for use with a PROTAC compound (or a pharmaceutically acceptable salt thereof) linked to an E3 ubiquitin ligase cereblon binding unit.

[0041] Accordingly, an androgen receptor binding unit of formula (Ia) described herein is provided for use with a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also includes an E3 ubiquitin ligase cereblon binding unit.

[0042] Accordingly, an androgen receptor binding unit of formula (Ia) described herein is provided for use with a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also includes an E3 ubiquitin ligase cerebron binding unit linked to the androgen receptor binding unit.

[0043] Accordingly, an androgen receptor binding unit of formula (Ia) described herein is provided for incorporation into a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also includes an E3 ubiquitin ligase cereblon binding unit.

[0044] Accordingly, an androgen receptor binding unit of formula (Ia) described herein is provided for incorporation into a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also includes an E3 ubiquitin ligase cerebron binding unit linked to the androgen receptor binding unit.

[0045] Accordingly, an androgen receptor binding unit of formula (Ia) as described herein is provided, contained within a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also includes an E3 ubiquitin ligase cereblon binding unit.

[0046] Accordingly, an androgen receptor binding unit of formula (Ia) as described herein is provided, contained within a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also includes an E3 ubiquitin ligase cerebron binding unit linked to the androgen receptor binding unit.

[0047] In one embodiment, the linkage between the androgen receptor binding unit of formula (Ia) [as described above] and the E3 ubiquitin ligase cereblon binding unit is a linker as defined in any embodiment or claim herein, where the binding point shown in formula (Ia) above is connected to the "a" connection point on any linker as defined herein. [Modes for carrying out the invention]

[0048] Many embodiments of this disclosure are described in detail throughout this specification and will be apparent to those skilled in the art.

[0049] A pharmaceutically acceptable salt of a compound of formula (I) or a PROTAC compound described herein may be an acid addition salt, for example, if the compound contains a basic functional group such as an amine. Acid addition salts may be formed using an inorganic or organic acid. A pharmaceutically acceptable salt of a compound may be a base addition salt, for example, if the compound contains an acidic functional group such as a carboxylic acid. Acid addition salts may be formed using an inorganic or organic base. “pharmaceutically acceptable salt” is used to specify that the salt is suitable for use in the body of a human or animal. An exemplary list of pharmaceutically acceptable salts can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use,” PHStahl and CGWermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. A pharmaceutically acceptable salt of a compound of formula (I) or a PROTAC compound includes salts that may be formed in the body of a human or animal after administration of the compound to the body of a human or animal.

[0050] As used herein, the term "alkyl" includes linear, branched, and cyclic alkyl groups having a specified number of carbon atoms, as well as combinations thereof. Therefore, C 1~3 Alkyl includes methyl, ethyl, n-propyl, isopropyl, and cyclopropyl, C 1~9 Alkyl groups include (4-isopropylcyclohexyl)methyl. The same principle applies to the term “alkoxy.” Similarly, as used herein, the term “alkoxy” includes linear, branched, and / or cyclic alkoxy groups having a specified number of carbon atoms. Therefore, C 1~3 Alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropoxy.

[0051] In this specification, chemical abbreviations well known to those skilled in the art may be used, including, for example, "Me" = methyl, "Et" = ethyl, "Pr" = propyl, "Bu" = butyl, and "Ph" = phenyl.

[0052] When the term "arbitrarily" is used, it is intended that subsequent features may or may not occur. Therefore, the use of the term "arbitrarily" includes cases where features are present and cases where they are not. For example, "methyl molecules arbitrarily substituted with one or more F molecules" include -CH3, -CH2F, -CHF2, and -CF3.

[0053] The term “substituted” means that one or more hydrogen atoms on a given atom or group are replaced by the indicated substituent. However, any atom having such substituents maintains its permissible valency, and it is assumed that those skilled in the art understand that the standard valencies of carbon, nitrogen, and oxygen are 4, 3, and 2, respectively. Thus, “substituted on any available C atom” should be understood to mean that the substituents are limited in their positions (and / or potentially their number) depending on whether there are any hydrogen atoms remaining on the given atom or group that can be replaced by the substituent.

[0054] The dashed lines included in Z are joined together.

[0055] [ka] In each case, the combination is X E , X F , X G , X H , and X J The possibility of a single covalent bond or a double covalent bond is shown according to the atoms (or groups of atoms) present at each position. A person skilled in the art will understand that the standard valencies of carbon, nitrogen, and oxygen are as described above, and therefore will be able to understand whether each dashed bond should be interpreted as a single bond or a double bond in any given Z group in the compound of formula (I). The same applies to Z A X in E2 , X F2 , X G2 , X H2 , and XJ2 This also applies to its position.

[0056] For example, Z's X G , X H , and X J In this context, the terms "adjacent" or "adjacent position" refer to the next closest position in the molecular chain / ring system. Therefore, in the context of Z, X G and X H They are adjacent to each other, X H and X J Although they are adjacent to each other, X G is X J It is not adjacent to it.

[0057] The term "saturated" means that the atoms of a given skeleton or group are linked only by single covalent bonds. Therefore, the term "unsaturated" means that the given skeleton or group contains double and / or triple covalent bonds. Examples of unsaturated molecular fragments that may be present in a partially or fully unsaturated group or skeleton include C=C, C=N, C=O, N=N, where nitrogen and oxygen heteroatoms are permitted / present.

[0058] [ka] And if sulfur heteroatoms are also allowed / present, then S=O may also be included.

[0059] It should be understood that "heteroatom" can refer to an oxygen, nitrogen, or sulfur atom unless explicitly limited further in a given context.

[0060] The term "minimum length of atoms between 'a' and 'b'" refers to the shortest chain of atoms in the chain between 'a' and 'b'. Therefore, if the chain consists of -CH2CH2CH2-, the number of atoms in the chain is 3 (assuming there are no hydrogen atoms in the chain). Alternatively, if the chain consists of 1,3-phenylene, with a short path around the phenyl ring containing 3 carbon atoms and a long path around the phenyl ring containing 5 carbon atoms, the minimum length of such a chain would be counted as 3 atoms.

[0061] Please understand that bond points "a" and "b" each represent a monocovalent bond to the corresponding adjacent group / atom.

[0062] Please understand that "direct bonding" is interchangeable with "single bonding."

[0063] In this specification, the terms "ring" or "heterocyclic group" may include monorings, fused rings, spirorings, and bridging rings.

[0064] With respect to the linkers described herein, it should be understood that, if present, branches may exist on chains (even if they are one-atom length chains) and / or on rings. While those skilled in the art generally interpret it this way, to avoid doubt, it should be understood that “branching” that arises essentially to form a ring is not considered “branching” in the context of the embodiments of linkers described herein. Such branching may occur on the same or different atoms of the linker framework. For example, it is possible to have two “=O” branches on a sulfur heteroatom to form an SO2 group within the linker framework. Linker #22 described below is an example with one branch (-Me) coming from a chain within the linker.

[0065] Furthermore, it should be understood that “branching” (and the definition of branching provided herein) refers to a branching that occurs from the main chain of atoms between “a” and “b” and leads to a “dead end” in the molecular structure.

[0066] In this specification, it should be understood that a bond point of a given group to another group may be represented by a line that intersects substantially perpendicularly with the bond, for example, at the end of any of the linkers 1 to 46 shown below, as shown on the far right of formula (Ia) of this specification.

[0067] In this specification, "X A , X B , X C , X D , X E , and XF Of these, zero, one, or two are N, and X E and X F are both not N, and otherwise are C. In cases where some C atoms are understood to implicitly have hydrogen atoms as necessary to satisfy the standard valence of carbon atoms (4). One of ordinary skill in the art will understand that when a substituent or linker is attached to such a carbon, such H atoms cannot be on the C of X E or X F or on the C of X A , X B , X C , or X D . The same principle applies to X 1 , X 2 , X 3 , X 4 (and when present, X 5 , X 6 , X 7 , and X 8 ), as well as Y 1 , Y 2 [[ID=, Y 3 , and Y 4 . The same principle applies to X A2 , X B2 , X C2 , X D2 , X E2 , X F2 , X G2 , X H2 , and X J2 .

[0068] As used herein, references to secondary or tertiary amines are intended to have their ordinary meaning in the art, and thus, for example, a nitrogen atom that is part of an amide group or a sulfonamide group shall not be considered a secondary or tertiary amine.

[0069] In this specification, a saturated heterocyclic group means at least one ring of atoms (including bridging rings, spiro rings, fused rings, and monorings) containing a carbon atom and at least one heteroatom, where the heteroatom is independently selected from N, O, and S, and each atom in the ring is linked to its adjacent atom by a single covalent bond. Thus, an example of a heterocyclic group is a spiroheterocyclic group having two rings and a total of one heteroatom, e.g., 9-azaspiro[5.5]undecane. Typically, a saturated heterocyclic group will have at least two carbon atoms separating each of the heteroatoms present in the group to ensure a level of chemical stability suitable for use in a pharmaceutical context. 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 the presence of one or more additional non-nitrogen heteroatoms (i.e., S, O). In this specification, a partially unsaturated heterocyclic group means at least one ring of an atom (including bridging rings, spiro rings, fused rings, and monorings) containing a carbon atom and at least one heteroatom, where the heteroatom is independently selected from N, O, and S, and at least two atoms in the heterocyclic group are connected to each other via double covalent bonds. As those skilled in the art will understand, a partially unsaturated heterocyclic group does not include a fully unsaturated heterocyclic group (i.e., the group contains the maximum possible number of double bonds for the atomic skeleton in question).

[0070] When referring to a cyclic group having a specified number of ring atoms (e.g., a heterocyclic group), this includes the atoms constituting the ring (including the atoms involved in bridging the bridging ring, and all the atoms of the fused or spiro ring), but not the hydrogen atoms or other substituent atoms bonded to the ring atoms. For example, the cyclic group 1,4-piperazine-1,4-diyl has six ring atoms (four carbon and two nitrogen).

[0071] In this specification, alkylene groups (e.g., C 1~5Alkylenes are saturated groups consisting only of carbon and hydrogen atoms with two bonding sites to adjacent atoms / groups. They can be linear, branched, and / or cyclic. Thus, C1 alkylenes represent -CH2-, and C2 alkylenes can represent -CH2CH2- or -CH(Me)-, and C- 1~5 -Alkylenes include, for example, -CH2(cyclobuta-1,3-diyl)-. "Linear C u1~u2 Alkilen is -(CH2) u - corresponds to, where u is an integer between u1 and u2.

[0072] In this specification, a hydrocarbyl group means any group consisting only of C and H atoms. For example, C 1~7 Hydrocarbyl contains methyl, phenyl, and p-tolyl.

[0073] The term “therapy” is intended to have its usual meaning of addressing a disease in order to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for an underlying medical condition. The terms “therapeutic” and “therapeutically” should be interpreted in the context of the corresponding means.

[0074] The term “treatment” is used synonymously with “therapy.” Similarly, the term “to treat” can be considered as “to apply therapy,” where “therapy” is as defined herein.

[0075] Some of the values ​​for the variable group are as follows. One, two, or more of these values ​​may be used in any combination with any other definitions, claims, aspects, or embodiments herein to provide further embodiments / claims herein (unless the context allows).

[0076] In one embodiment, X 1 It is CH.

[0077] In one embodiment, X 1 It is N.

[0078] In one embodiment, R N H is H.

[0079] In one embodiment, R N This is Me.

[0080] In one embodiment, X 1 CH is, R N H is H.

[0081] In one embodiment, X 1 CH is, R N This is Me.

[0082] In one embodiment, X 1 N is R N H is H.

[0083] In one embodiment, X 1 N is R N This is Me.

[0084] In one embodiment, p is 0.

[0085] In one embodiment, p is 0 or 1.

[0086] In one embodiment, p is 1 or 2.

[0087] In one embodiment, p is 1.

[0088] In one embodiment, p is 2.

[0089] If p is 1, R 1 Q 1 It can be coupled in the para position relative to this.

[0090] If p is 2, then one of R 1 Q 1 The other R is obtained by coupling in the para position with respect to 1 Q 1It can be bonded to the ortho or meta position.

[0091] One embodiment, each R 1 This is selected from F, Cl, methyl, CF3, methoxy, and OCF3.

[0092] One embodiment, each R 1 This is selected from F, Cl, and methyl.

[0093] In one embodiment, p is 1, and R 1 This is selected from F, Cl, and methyl.

[0094] In one embodiment, p is 1, and R 1 This is selected from F and Cl.

[0095] In one embodiment, n is 0.

[0096] In one embodiment, n is 1.

[0097] In one embodiment, n is 2.

[0098] In one embodiment, m is 0.

[0099] In one embodiment, m is 1.

[0100] In one embodiment, n is 0 and m is 1.

[0101] In one embodiment, n is 1 and m is 1.

[0102] In one embodiment, n is 2 and m is 0.

[0103] In one embodiment, n is 0, m is 1, and Q 1 N is Q 2 It is CH.

[0104] In one embodiment, n is 1, m is 1, and Q 1 CH and Q 2 It is CH.

[0105] In one embodiment, n is 1, m is 1, and Q 1 N is Q 2 It is either CH or N.

[0106] In one embodiment, n is 2, m is 0, and Q 1 N is Q 2 It is CH.

[0107] In one embodiment, n is 2, m is 0, and Q 1 N is Q 2 CH and Q 3 It is CH.

[0108] In one embodiment, n is 2, m is 0, and Q 1 N is Q 2 CH and Q 3 It is O.

[0109] In one embodiment, Q 1 N is Q 2 CH and Q 3 It is CH.

[0110] In one embodiment, Q 1 N is Q 2 CH and Q 3 is CH, and n and m are 1 and 1, or 2 and 0, respectively.

[0111] In one embodiment, R 2a H is R 2b H is H.

[0112] In one embodiment, n is 1, m is 0, and R 2a H is R 2b Q 1 and Q2 C bonded to other C atoms 1~3 It is an alkyl group, and the C atom has a (R)-stereochemical configuration.

[0113] In one embodiment, n is 1, m is 0, and R 2a H is R 2b Q 1 and Q 2 C bonded to other C atoms 1~3 It is an alkyl group, and the C atom has a (S)-stereochemical configuration.

[0114] In one embodiment, n is 1, m is 1, and R 2a H is R 2b Q 1 and Q 2 C bonded to other C atoms 1~3 It is an alkyl group, and the C atom has a (R)-stereochemical configuration.

[0115] In one embodiment, n is 1, m is 1, and R 2a H is R 2b Q 1 and Q 2 C bonded to other C atoms 1~3 It is an alkyl group, and the C atom has a (S)-stereochemical configuration.

[0116] In one embodiment, Q 1 It is CH, and the C atom has a (R)-stereochemical configuration.

[0117] In one embodiment, Q 1 It is CH, and the C atom has a (S)-stereochemical configuration.

[0118] In one embodiment, n is 2, m is 0, and R 2a and R 2b Both are H, and Q 1 CH and Q 2 It is N.

[0119] In one embodiment, n is 2, m is 0, and R 2a and R 2b Both are H, and Q 2 N is Q 1 It is CH, and the C atom has a (R)-stereochemical configuration.

[0120] In one embodiment, n is 2, m is 0, and R 2a and R 2b Both are H, and Q 2 N is Q 1 It is CH, and the C atom has a (S)-stereochemical configuration.

[0121] In one embodiment, Q 2 It is CH, and the C atom has a (R)-stereochemical configuration.

[0122] In one embodiment, Q 2 It is CH, and the C atom has a (S)-stereochemical configuration.

[0123] In one embodiment, n is 2, m is 0, and R 2a and R 2b Both are H, and Q 1 N is Q 2 It is CH.

[0124] In one embodiment, n is 2, m is 0, and R 2a and R 2b Both are H, and Q 1 N is Q 2 It is CH, and the C atom has a (R)-stereochemical configuration.

[0125] In one embodiment, n is 2, m is 0, and R 2a and R 2b Both are H, and Q 1 N is Q 2 It is CH, and the C atom has a (S)-stereochemical configuration.

[0126] In one embodiment, R 2a and R 2b These are substituents on the same or different C atoms other than Q, and each is independently H and C 1~3 Selected from alkyl groups.

[0127] In one embodiment, R 2a and R 2b is a substituent on the same or different C atom other than Q, each independently selected from H and Me.

[0128] In one embodiment, R 2a and R 2b is a substituent on the same or different carbon atom adjacent to Q, otherwise as defined herein.

[0129] In one embodiment, R 2a and R 2b These are substituents on the same or different C atoms adjacent to Q, and each is independently H and C 1~3 Selected from alkyl groups (e.g., Me).

[0130] In one embodiment, R 2a and R 2b These are substituents on the same or different carbon atoms, both of which are hydrogen atoms.

[0131] In one embodiment, R 2a and R 2b These are substituents on the same or different C atoms other than Q, and each is independently H, F, and C 1~3 Selected from alkyl groups.

[0132] In one embodiment, R 2a and R 2b These are substituents on the same or different C atoms other than Q, and each is independently H and C 1~3 Selected from alkyl groups, or R 2a and R 2b Together - (CH2) r - Forms a group (where r is 1, 2, or 3).

[0133] In one embodiment, R 2a and R 2b R is a substituent on the same or different C atom other than Q, where R 2a Me is R 2b H is H.

[0134] In one embodiment, R 2a and R 2b R is a substituent on the same C atom other than Q, where R 2a and R 2b Both are Me.

[0135] In one embodiment, R 2a and R 2b R is a substituent on the same C atom adjacent to Q, where R 2a and R 2b Both are Me.

[0136] In one embodiment, Q 4 It is a single bond.

[0137] In one embodiment, Q 4 , NR 4 C (=O), R 4 H is H.

[0138] In one embodiment, Q 4 , NR 4 C (=O), R 4 It is methyl.

[0139] In one embodiment, Q 4 , NR 4 C (=O), R 4 H is Q 2 It is CH.

[0140] In one embodiment, Q 4 , NR 4 C (=O), R 4 is methyl, Q 2 It is CH.

[0141] In one embodiment, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each is selected from (C, C, C, C, C), (N, C, C, C, C), (C, N, C, C, C), (N, C, C, N, C), (N, N, C, C, C), (N, C, N, C, C), (C, N, C, N, C), and C(C, N, N, C, C).

[0142] In one embodiment, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 These are selected from (C, C, C, C, C), (N, C, C, C, C), and (N, N, C, C, C).

[0143] In one embodiment, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 One of these is N, and if not, it is C.

[0144] In one embodiment, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 One or two of them are N, otherwise they are C.

[0145] In one embodiment, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 One of them is N, and the other is C.

[0146] In one embodiment, Y 1 N is Y 2 , Y 3 , Y 4 , and Y 5 All of them are C.

[0147] In one embodiment, Y 2 N is Y 2 , Y 3 , Y 4 , and Y 5 All of them are C.

[0148] In one embodiment, Y 2 , Y 3 , Y 4 , and Y 5 Two of them are N, and the other two are C.

[0149] In one embodiment, Y 1 and Y 3 N is Y 2 , Y 4 , and Y 5 It is C.

[0150] In one embodiment, Y 1 and Y 2 N is Y 3 , Y 4 , and Y 5 It is C.

[0151] In one embodiment, Y 1 and Y 4 N is Y 2 , Y 3 , and Y 5 It is C.

[0152] In one embodiment, Y 2 and Y 3 N is Y 1 , Y 4 , and Y 5 It is C.

[0153] In one embodiment, Y 2 and Y 4 N is Y 1 , Y 3 , and Y 5 It is C.

[0154] In one embodiment, Y 1 , Y 2 , Y3 , Y 4 , and Y 5 All of them are C.

[0155] In one embodiment, q is 0 or 1.

[0156] In one embodiment, q is 0.

[0157] In one embodiment, q is 1.

[0158] In one embodiment, q is 2.

[0159] In one embodiment, q is 0, 1, or 2, and R 3 If present, F, CN, and C 1~3 Selected from alkyl, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 It is a substituent on any C atom.

[0160] In one embodiment, q is 0, 1, or 2, and R 3 If present, Y is selected from F, CN, and methyl. 1 , Y 2 , Y 3 , Y 4 , and Y 5 It is a substituent on any C atom.

[0161] In one embodiment, q is 0 or 1, and R 3 If Y exists, 1 , Y 2 , Y 3 , Y 4 , and Y 5 A substituent on any C atom, which is F.

[0162] In one embodiment, R 3 If it exists, C 1~3 It is alkyl.

[0163] In one embodiment, R3 If it exists, it is Me.

[0164] In one embodiment, R 3 If it exists, then it is F.

[0165] In one embodiment, R 3 If present, it is CN.

[0166] In one embodiment, q is 1, and R 3 Y 1 It is bonded to C.

[0167] In one embodiment, q is 1, and R 3 Y 1 It is coupled to C, and R 3 This is selected from F, CN, and Me.

[0168] In one embodiment, q is 1, and R 3 Y 2 It is coupled to C, and R 3 The language is selected from CN and Me.

[0169] In one embodiment, q is 2, and both R 3 Either one of the groups is F, or one of the groups is F and the other is Me.

[0170] In one embodiment, q is 2, and R 3 The base is Y 1 and Y 3 It is bonded to C.

[0171] In one embodiment, q is 2, and each R 3 The base is F, and these are Y 1 and Y 3 It is bonded to C.

[0172] In one embodiment, q is 2, and one R 3 The base is F, which is Y 1 It is bonded to C, and one R 3The base is Me, which is Y 3 It is bonded to C.

[0173] In one embodiment, the linker is Y 5 They are joined together.

[0174] In one embodiment, the linker is Y 4 They are joined together.

[0175] In one embodiment, the base of equation (Ia) is equation (Ia-1):

[0176] [ka] It is the basis of, and here, R 1 and Q 1 This is as defined above. Q 1 It is either CH or N.

[0177] In one embodiment, the base of formula (Ia) is formula (Ia-2):

[0178] [ka] It is the basis of, and here, R 1 Q 1 Q 2 , and Q 3 This is as defined above. Q 1 is CH or N, Q 2 is CH or N, Q 2 If Q is N, 3 CH and Q 2 If Q is CH, 3 It is either CH or O.

[0179] In one embodiment, the base of equation (Ia) is equation (Ia-3):

[0180] [ka] It is the basis of, and here, R 1This is as defined above.

[0181] In one embodiment, the linker is a saturated, partially or fully unsaturated skeleton comprising C and H atoms and at least one heteroatom, the skeleton having bond endpoints "a" and "b" and a minimum length of 5 to 26 atoms between "a" and "b", the skeleton may comprise one or more linear and / or branched and / or rings, and is optionally substituted on any available C atoms by one or more F atoms.

[0182] In one embodiment, the linker skeleton is saturated or partially unsaturated.

[0183] In one embodiment, the linker skeleton is a saturated skeleton.

[0184] In one embodiment, the linker skeleton includes C and H atoms and at least two heteroatoms.

[0185] In one embodiment, the linker skeleton includes C and H atoms and at least two heteroatoms selected from O and N.

[0186] In one embodiment, the linker skeleton includes C and H atoms and at least one nitrogen heteroatom.

[0187] In one embodiment, the linker skeleton includes C and H atoms and at least two heteroatoms, including at least one nitrogen heteroatom.

[0188] In one embodiment, the linker skeleton comprises C and H atoms and at least one nitrogen heteroatom in the form of a secondary or tertiary amine.

[0189] In one embodiment, the linker skeleton comprises C and H atoms and at least one nitrogen heteroatom in the form of a tertiary amine.

[0190] In one embodiment, the linker skeleton comprises C and H atoms and at least two heteroatoms, each containing at least one nitrogen heteroatom in the form of a secondary or tertiary amine.

[0191] In one embodiment, the linker skeleton comprises C and H atoms and at least two heteroatoms, including at least one nitrogen heteroatom in the form of a tertiary amine.

[0192] In one embodiment, the linker has a minimum length of 5 to 20 atoms between "a" and "b".

[0193] In one embodiment, the linker has a minimum length of 5 to 15 atoms between "a" and "b".

[0194] In one embodiment, the linker has a minimum length of 5 to 14 atoms between "a" and "b".

[0195] In one embodiment, the total number of carbon atoms and heteroatoms in the linker skeleton is 6 to 26.

[0196] In one embodiment, the total number of carbon atoms and heteroatoms in the linker skeleton is 7 to 24.

[0197] In one embodiment, the total number of carbon atoms and heteroatoms in the linker skeleton is 7 to 22.

[0198] In one embodiment, the total number of carbon atoms and heteroatoms in the linker skeleton is 7 to 20.

[0199] In one embodiment, the total number of carbon atoms and heteroatoms in the linker skeleton is 7 to 18.

[0200] In one embodiment, W is -ZR A If so, the linker is Z's X B or X C It is bonded with any available carbon atom.

[0201] In one embodiment, the linker skeleton may comprise one or more linear chains and / or rings, which are optionally substituted on any available carbon atoms by one or more F atoms.

[0202] In one embodiment, the linker skeleton consists of one or more linear and / or ring chains in which one or more F atoms are optionally substituted on any available C atoms.

[0203] In one embodiment, the linker skeleton may (or may consist of) one or more linear and / or branched chains and / or rings (where the total number of branches is 0 to 5) in which one or more F atoms are optionally substituted on any available C atoms.

[0204] In one embodiment, the linker skeleton may (or may consist of) one or more linear and / or branched chains and / or rings (where the total number of branches is 0 to 3) in which one or more F atoms are optionally substituted on any available C atoms.

[0205] In one embodiment, the linker skeleton may (or may consist of) one or more linear and / or branched chains and / or rings (where the total number of branches is 0 or 1) in which one or more F atoms are optionally substituted on any available C atoms.

[0206] In one embodiment, the total number of branches is 0.

[0207] In one embodiment, the total number of branches is 1.

[0208] In one embodiment, the total number of branches is 2.

[0209] In one embodiment, the total number of branches is 3.

[0210] In one embodiment, each branch in the linker skeleton has 1 to 5 carbon and / or heteroatoms.

[0211] In one embodiment, any / each branch in the linker skeleton has one or two C and / or heteroatoms.

[0212] In one embodiment, each branch in the linker skeleton has one carbon and / or heteroatom.

[0213] In one embodiment, any / each branch in the linker skeleton has one C atom.

[0214] In one embodiment, if present, the total number of carbon and / or heteroatoms in the linker skeleton branching is 1 to 5.

[0215] In one embodiment, if present, the total number of carbon and / or heteroatoms in the linker skeleton branching is 1 to 3.

[0216] In one embodiment, if present, the total number of carbon and / or heteroatoms in the linker skeleton branching is 1.

[0217] In one embodiment, the linker skeleton is either unbranched or has one branch that is Me.

[0218] In one embodiment, the linker's skeleton is unbranched.

[0219] In one embodiment, the linker skeleton is optionally substituted on any available carbon atom with one or two F atoms (for example, two F atoms) (for example, the two F atoms are substituted on the same carbon atom).

[0220] In one embodiment, the linker's skeleton is not replaced by any of the Fs.

[0221] In one embodiment, the linker is a saturated or partially unsaturated skeleton containing C and H atoms and at least one heteroatom, and the skeleton has bond endpoints "a" and "b". It has a minimum length of 5 to 14 atoms between "a" and "b", The total number of carbon atoms and heteroatoms in the linker skeleton is 7 to 18. Here, the skeleton comprises one or more linear and / or rings in which any available carbon atom is optionally substituted with one or two F atoms (e.g., two F atoms).

[0222] In one embodiment, the linker skeleton is 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 Includes units, where A 1 and A 2 Each of these is independently selected from N and O.

[0223] In one embodiment, the linker skeleton is at least one nitrogen-containing saturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A 1 -CH2-CH2-A 2 Includes units, where A 1 and A 2 Each of these is independently selected from N and O.

[0224] In one embodiment, the linker skeleton is A 1 -CH2-CH2-A 2 Includes units, where A 1 and A 2 Each of these is independently selected from N and O.

[0225] In one embodiment, the linker skeleton is 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 Includes units, where A 1 and A 2 One of them is N, and A 1 and A 2 The other is selected from N or O.

[0226] In one embodiment, the linker skeleton is at least one nitrogen-containing saturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A 1 -CH2-CH2-A 2 Includes units, where A 1 and A 2 One of them is N, and A 1 and A 2 The other is selected from N or O.

[0227] In one embodiment, the linker skeleton is A 1 -CH2-CH2-A 2 Includes units, where A 1 and A 2 One of them is N, and A 1 and A 2 The other is selected from N or O.

[0228] In one embodiment, the linker skeleton is 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 Includes units, where A 1 and A 2 One of them 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.

[0229] In one embodiment, the linker skeleton is A 1 -CH2-CH2-A 2 Includes units, where A 1 and A 2 One of them 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.

[0230] In one embodiment, the linker skeleton includes at least one saturated or partially unsaturated heterocyclic group.

[0231] In one embodiment, the linker skeleton includes at least one saturated heterocyclic group.

[0232] In one embodiment, the linker skeleton includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group.

[0233] In one embodiment, the linker skeleton includes at least one nitrogen-containing saturated heterocyclic group.

[0234] In one embodiment, the linker skeleton includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group having 4 to 12 ring atoms.

[0235] In one embodiment, the linker skeleton includes at least one nitrogen-containing saturated heterocyclic group having 4 to 12 ring atoms.

[0236] In one embodiment, the linker skeleton is (1)A 1 -CH2-CH2-A 2 Unit (here, A 1 and A 2 (Each is independently selected from N and O), and / or (2) comprising 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, morpholine, 2-azaspiro[3.5]nonane, and 9-azaspiro[5.5]undecane.

[0237] In one embodiment, the linker skeleton is (1)A 1 -CH2-CH2-A 2 Unit (here, A 1 and A 2 One of them 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) comprising 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, morpholine, 2-azaspiro[3.5]nonane, and 9-azaspiro[5.5]undecane.

[0238] In one embodiment, the linker skeleton 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, morpholine, 2-azaspiro[3.5]nonane, and 9-azaspiro[5.5]undecane.

[0239] In one embodiment, the linker skeleton includes O-CH2-CH2-N units.

[0240] In one embodiment, the linker skeleton includes O-CH2CH2-O-CH2CH2-N units.

[0241] In one embodiment, the linker skeleton includes a piperazine group.

[0242] In one embodiment, the linker skeleton includes an azetidine group.

[0243] In one embodiment, the linker skeleton includes a piperidine group.

[0244] In one embodiment, the linker skeleton includes a 1,4-diazepane group.

[0245] In one embodiment, the linker skeleton includes a 12-oxa-3,9-diazaspiro[5.6]dodecane group.

[0246] In one embodiment, the linker skeleton includes a pyrrolidine group.

[0247] In one embodiment, the linker skeleton includes a 3,9-diazaspiro[5.5]undecane group.

[0248] In one embodiment, the linker skeleton includes a 2,5-diazabicyclo[2.2.1]heptane group.

[0249] In one embodiment, the linker skeleton includes a 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole group.

[0250] In one embodiment, the linker skeleton includes a 1,2,3,6-tetrahydropyridine group.

[0251] In one embodiment, the linker skeleton includes a morpholine group.

[0252] In one embodiment, the linker skeleton includes a 2-azaspiro[3.5]nonane group.

[0253] In one embodiment, the linker skeleton includes a 9-azaspiro[5.5]undecane group.

[0254] In one embodiment, the linker skeleton includes at least two nitrogen-containing saturated or partially unsaturated heterocyclic groups.

[0255] In one embodiment, the linker skeleton includes at least two nitrogen-containing saturated heterocyclic groups.

[0256] In one embodiment, the linker skeleton includes a C, N, or O atom at the "a" bond point.

[0257] In one embodiment, the linker skeleton includes an N or O atom at the "a" bond point.

[0258] In one embodiment, the linker skeleton includes an N or O atom at the "b" bond site.

[0259] In one embodiment, the linker skeleton includes a C atom at the "a" bond point.

[0260] In one embodiment, the linker skeleton includes an N atom at the "a" bond point.

[0261] In one embodiment, the linker skeleton includes a C or N atom at the "b" bond site.

[0262] In one embodiment, the linker skeleton includes an N atom at the "b" bond site.

[0263] In one embodiment, the linker skeleton includes a C atom at the "b" bond point.

[0264] In one embodiment, the linker skeleton includes an O atom at the "a" bond point.

[0265] In one embodiment, the linker skeleton includes an O atom at the "b" bond site.

[0266] In one embodiment, the linker skeleton contains N or O atoms at both the "a" and "b" bond points.

[0267] In one embodiment, the linker skeleton includes a C, N, or O atom at the "a" bond point and a C or N atom at the "b" bond point.

[0268] In one embodiment, the linker skeleton is (1)A 1 -CH2-CH2-A 2 Unit (here, A 1 and A 2 One of them is N in the form of a secondary or tertiary amine, and A 1 and A 2The other is selected from N or O), and / or (2) 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 It comprises at least one nitrogen-containing saturated or partially saturated heterocyclic group selected from 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl, 3,6-dihydro-2H-pyridine-1,4-diyl, morpholine-2,3-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0269] In one embodiment, the linker skeleton consists 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, and 2,5-diazabicyclo[2.2.1]heptane. It comprises at least one nitrogen-containing saturated or partially saturated heterocyclic group selected from -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, morpholine-2,3-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0270] In one embodiment, the linker skeleton includes a piperazine-1,4-diyl group.

[0271] In one embodiment, the linker skeleton includes an azetidine-1,3-diyl group.

[0272] In one embodiment, the linker skeleton includes a piperidine-1,4-diyl group.

[0273] In one embodiment, the linker skeleton includes a 1,4-diazepane-1,4-diyl group.

[0274] In one embodiment, the linker skeleton includes a 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl group.

[0275] In one embodiment, the linker skeleton includes a pyrrolidine-1,3-diyl group.

[0276] In one embodiment, the linker skeleton includes a 3,9-diazaspiro[5.5]undecane-3,9-diyl group.

[0277] In one embodiment, the linker skeleton includes a 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl group.

[0278] In one embodiment, the linker skeleton contains a 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl group.

[0279] In one embodiment, the linker skeleton includes a 3,6-dihydro-2H-pyridine-1,4-diyl group.

[0280] In one embodiment, the linker skeleton includes a morpholine-2,3-diyl group.

[0281] In one embodiment, the linker skeleton includes a 2-azaspiro[3.5]nonane-2,7-diyl group.

[0282] In one embodiment, the linker skeleton includes a 9-azaspiro[5.5]undecane-3,9-diyl group.

[0283] In one embodiment, the linker is given by formula: "a" - Q A -Q B -Q C -Having "b", During the ceremony, "a" and "b" represent the endpoints of the connection. Q A -GQ H -or-G-(C 1~5 Alkylene)- Q B This is a direct bond, -Q B1 -Q B2 -Q B3 - or C optionally replaced by one or more Fs (e.g., one or two Fs, e.g., two Fs) 1~3 It is alkylene, and here, Q B1 and Q B3 Each can be directly joined or C 1~2 Represents alkylene, Q B2 Q H -O-CH2CH2-O-, -O-, or -N(R J )- and here, R J is H or C 1~3 It is alkyl, Q C is, -Q H -G- or -(C 1~5 It is alkylene-G-. Each G can independently form a direct bond, -CH2-, -O-, -C(=O)-, or -N(R) G )- and here, each R G H or C 1~3 It is alkyl, Each Q H These are independently 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic groups, Here, Q A Q B , and Q C The value is selected so that the linker does not include any NN or NO links.

[0284] In one embodiment, the linker is given by formula: "a" - Q A -Q B -Q C -Having "b", During the ceremony, "a" and "b" represent the endpoints of the connection. Q A -GQ H -or-G-(C 1~5 Alkylene)- Q B This is a direct bond, -Q B1 -Q B2 -Q B3 - Or C optionally replaced with one or more Fs (e.g., one or two). 1~3 It is alkylene, and here, Q B1 and Q B3 Each can be directly joined or C 1~2 Represents alkylene, Q B2 Q H -O-CH2CH2-O-, or -N(R J )- and here, R J C 1~3 It is alkyl, Q C is, -Q H -G- or -(C 1~5 It is alkylene-G-. Each G can independently form a direct bond, -CH2-, -C(=O)-, -O-, or -N(R) G )- and here, each R G H or C 1~3 It is alkyl, Each Q H These are independently 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic groups, Here, Q A Q B , and Q C The value is selected so that the linker does not include any NN or NO links.

[0285] In one embodiment, the linker is given by formula: "a" - Q A -Q B -Q C -Having "b", During the ceremony, "a" and "b" represent the endpoints of the connection. Q Ais, -G A -Q HA -or-G A -(C 1~5 Alkylene)-, and here G A These are direct bonds, -CH2-, -C(=O)-, -O-, -NH-, or -N(Me)-, Q HA This is a 4-11 member nitrogen-containing saturated heterocyclic group, Q B This is a direct bond, -Q B1 -Q B2 -Q B3 - Or C optionally replaced with one or more Fs (e.g., one or two). 1~3 It is alkylene, and here, Q B1 and Q B3 Each can be directly joined or C 1~2 Represents alkylene, Q B2 This is piperazine-1,4-diyl, -O-CH2CH2-O-, or -N(R J )- and here, R J C 1~3 It is alkyl, Q C is, -Q HC -G C -or-(C 1~2 Alkilen)-G C - and G C These are direct bonds, -O- or -NH-, Q HC This is a 6-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group, Here, Q A Q B , and Q C The value is selected so that the linker does not include any NN or NO links.

[0286] In one embodiment, Q A is, -G A -Q HA -or-G A -(C 1~5 Alkylene)-, and here, G AThese are direct bonds, -CH2-, -C(=O)-, -O-, or -N(R G )- Selected from, Each R G H or C 1~3 It is alkyl, Q HA It is a 4- to 11-membered nitrogen-containing saturated heterocyclic group.

[0287] In one embodiment, Q A is, -G A -Q HA -or-G A -(C 1~5 Alkylene)-, and here, G A These are direct bonds, -CH2-, -C(=O)-, -O-, or -N(R G )- Selected from, Each R G H or C 1~3 It is alkyl, Q HA The following are selected from azetidine-1,3-diyl, morpholine-2,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0288] In one embodiment, Q A is, -G A -Q HA -or-G A -(C 1~5 Alkylene)-, and here, G A The bond is selected from a direct bond, -CH2-, -C(=O)-, -O-, or -NH- or -N(Me)-. Q HA These are 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. The relevant G A -(C 1~5 Alkylene)-C inside 1~5 Alkylene is -(CH2) f -(where f is an integer from 1 to 5), selected from cyclobuta-1,3-diyl and -CH2(cyclobuta-1,3-diyl).

[0289] In one embodiment, Q A These are azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, -O(piperidine-1,4-diyl)-, -C(O)-piperidine-1,4-diyl, -CH2(piperidine-1,4-diyl)-, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, morpholine-2,3-diyl, 2-azaspiro[3.5]nonane-2,7-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 - is selected from (where f is an integer between 1 and 5).

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

[0291] In one embodiment, Q A It is pyrrolidine-1,3-diyl.

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

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

[0294] In one embodiment, Q AIt is -O(piperidine-1,4-diyl)-.

[0295] In one embodiment, Q A It is -CH2(piperidine-1,4-diyl)-.

[0296] In one embodiment, Q A It is piperazine-1,4-diyl.

[0297] In one embodiment, Q A It is -CH2(piperazine-1,4-diyl)-.

[0298] In one embodiment, Q A This is morpholine-2,3-diyl.

[0299] In one embodiment, Q A is 2-azaspiro[3.5]nonan-2,7-ziel.

[0300] In one embodiment, Q A This is 3,9-diazaspiro[5.5]undecane-3,9-zyil.

[0301] In one embodiment, Q A It is -O(9-azaspiro[5.5]undecane-3,9-zyyl)-.

[0302] In one embodiment, Q A is -G-(C 1~5 Alkylene)-

[0303] In one embodiment, Q A -O(cyclobuta-1,3-diyl)-, -OCH2(cyclobuta-1,3-diyl)-, -(CH2) f -, -O(CH2) f -, -NH-(CH2) f -, and -N(Me)-(CH2) f - is selected from (where f is an integer between 1 and 5).

[0304] In one embodiment, Q A It is -O(cyclobuta-1,3-diyl)-.

[0305] In one embodiment, Q A It is -OCH2(cyclobuta-1,3-diyl)-.

[0306] In one embodiment, Q A is, -(CH2) f - (where f is an integer between 1 and 4. For example, f is 4).

[0307] In one embodiment, Q A is -O-(CH2) f - (where f is an integer between 1 and 5. For example, f is 4).

[0308] In one embodiment, Q A is -NH-(CH2) f - (where f is an integer between 1 and 5).

[0309] In one embodiment, Q A is -N(Me)-(CH2) f - (where f is an integer between 1 and 4).

[0310] In one embodiment, Q B This is a direct bond, -Q B1 -Q B2 -Q B3 - or linear C, optionally substituted with one or more F (e.g., one or two F, e.g., two F) 1~3 It is alkylene.

[0311] In one embodiment, Q B This is a direct bond.

[0312] In one embodiment, Q B is, -Q B1 -Q B2 -Q B3 - is

[0313] In one embodiment, Q B C is a C that is optionally replaced by one or more Fs. 1~3 It is alkylene.

[0314] In one embodiment, Q B C is optionally replaced by one or two Fs (for example, by two Fs). 1~3 It is alkylene.

[0315] In one embodiment, Q B This is a linear C molecule that is optionally substituted with one or two F molecules (for example, two F molecules). 1~3 It is alkylene.

[0316] In one embodiment, Q B C 1~3 It is alkylene.

[0317] In one embodiment, Q B is a linear C 1~3 It is alkylene.

[0318] In one embodiment, Q B is -CF2-CH2-CH2- or -(CH2) w - (where w is 1 to 3).

[0319] In one embodiment, Q B1 and Q B3 Each of these independently represents a direct bond, -CH2-, or -CH2CH2-.

[0320] In one embodiment, Q B1 These are either direct bonds or -CH2- groups.

[0321] In one embodiment, Q B1 This is a direct bond.

[0322] In one embodiment, Q B1 It is -CH2-.

[0323] In one embodiment, Q B3These are direct bonds, -CH2-, or -CH2CH2-.

[0324] In one embodiment, Q B3 This is a direct bond.

[0325] In one embodiment, Q B3 It is -CH2-.

[0326] In one embodiment, Q B3 It is -CH2CH2-.

[0327] In one embodiment, Q B2 Q H -O-CH2CH2-O-, or -N(R J )- is (where R J C 1~3 (It is alkyl.)

[0328] In one embodiment, Q B2 Q H It is -O-CH2CH2-O- or -N(Me)-.

[0329] In one embodiment, Q B2 These are piperazine-1,4-diyl, azetidine-1,3-diyl, -O-CH2CH2-O-, or -N(Me)-.

[0330] In one embodiment, Q B2 This is piperazine-1,4-diyl, -O-CH2CH2-O-, or -N(Me)-.

[0331] In one embodiment, Q B2 Q H That is the case.

[0332] In one embodiment, Q B2 It is piperazine-1,4-diyl.

[0333] In one embodiment, Q B2 This is azetidine-1,3-diyl.

[0334] In one embodiment, Q B2 It is -O-CH2CH2-O-.

[0335] In one embodiment, Q B2 is -N(R J )- is (where R J C 1~3 (It is alkyl.)

[0336] In one embodiment, Q B2 It is -N(Me)-.

[0337] In one embodiment, Q C is, -Q H -G- or -(C 1~4 It is alkylene-G-.

[0338] In one embodiment, Q C is, -Q H -G- or -(C 1~3 It is alkylene-G-.

[0339] In one embodiment, Q C is, -Q H -G- or -(C 1~2 It is alkylene-G-.

[0340] In one embodiment, Q C is, -Q HC -G C -or-(C 1~5 Alkilen)-G C -and (here, G C (Selected from direct bonding, -O-, or -NH-), Q HC This is a 6-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group.

[0341] In one embodiment, Q C is, -Q HC -G C -or-(C 1~2 Alkilen)-G C -and (here, GC (Selected from direct bonding, -O-, or -NH-), Q HC This is a 6-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group.

[0342] In one embodiment, Q C is, -Q HC -G C -or-(C 1~2 Alkilen)-G C -and (here, G C (Selected from direct bonding, -O-, or -NH-), Q HC The following are 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.

[0343] In one embodiment, Q C These include 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 -CH2CH2-NH-, and -(CH2) g It is selected from -O- (where g is an integer from 1 to 4).

[0344] In one embodiment, Q C It is piperazine-1,4-diyl.

[0345] In one embodiment, Q C It is piperidine-1,4-diyl.

[0346] In one embodiment, Q C It is -(piperidine-1,4-diyl)O-.

[0347] In one embodiment, Q C This is 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl.

[0348] In one embodiment, Q C This is 1,4-diazepane-1,4-diyl.

[0349] In one embodiment, Q C This is 3,9-diazaspiro[5.5]undecane-3,9-zyil.

[0350] In one embodiment, Q C It is 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl.

[0351] In one embodiment, Q C This is 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl.

[0352] In one embodiment, Q C It is 3,6-dihydro-2H-pyridine-1,4-diyl.

[0353] In one embodiment, Q C is, -(C 1~5 It is an alkylene-G- [for example, -(CH2) g -O-, where g is an integer between 1 and 5.

[0354] In one embodiment, Q C is, -(C 1~4 It is an alkylene-G- [for example, -(CH2) g -O-, where g is an integer between 1 and 4.

[0355] In one embodiment, Q C is, -(C 1~3 It is an alkylene-G- [for example, -(CH2) g -O-, where g is 1, 2, or 3].

[0356] In one embodiment, Q C is, -(C 1~2 It is an alkylene-G- [for example, -(CH2) g -O-, where g is 1 or 2].

[0357] In one embodiment, Q C is, -(CH2) g -G C - (where g is an integer from 1 to 5, G C (It is -O- or -NH-).

[0358] In one embodiment, Q C is, -(CH2) g -G C - (where g is 1 or 2, G C (It is -O- or -NH-).

[0359] In one embodiment, Q C It is -CH2CH2NH-.

[0360] In one embodiment, Q C It is -CH2-.

[0361] In one embodiment, each Q HThe following 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, 3,6-dihydro-2H-pyridine-1,4-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl.

[0362] In one embodiment, each Q H The following 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, morpholine-2,3-diyl, 2-azaspiro[3.5]nonane-2,7-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.

[0363] In one embodiment, Q H It is piperazine-1,4-diyl.

[0364] In one embodiment, Q H This is azetidine-1,3-diyl.

[0365] In one embodiment, Q H It is piperidine-1,4-diyl.

[0366] In one embodiment, Q H This is 1,4-diazepane-1,4-diyl.

[0367] In one embodiment, Q H It is 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl.

[0368] In one embodiment, Q H It is pyrrolidine-1,3-diyl.

[0369] In one embodiment, Q H This is 3,9-diazaspiro[5.5]undecane-3,9-zyil.

[0370] In one embodiment, Q H This is 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl.

[0371] In one embodiment, Q H This is 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2,5-diyl.

[0372] In one embodiment, Q H It is 3,6-dihydro-2H-pyridine-1,4-diyl.

[0373] In one embodiment, Q H This is 9-azaspiro[5.5]undecane-3,9-ziyl.

[0374] In one embodiment, Q H is 2-azaspiro[3.5]nonan-2,7-ziel.

[0375] In one embodiment, Q H This is morpholine-2,3-diyl.

[0376] In one embodiment, R J C 1~3 It is alkyl.

[0377] In one embodiment, R J This is Me.

[0378] In one embodiment, RG C 1~3 It is alkyl.

[0379] In one embodiment, R G is either H or Me.

[0380] In one embodiment, R G This is Me.

[0381] In one embodiment, R G H is H.

[0382] In one embodiment, a linker (e.g., "a"-Q) is used. A -Q B -Q C - "b)" is selected from one of the linkers 1 to 58 shown below.

[0383] [ka]

[0384] [ka]

[0385] [ka]

[0386] [ka]

[0387] In one embodiment, a linker (e.g., "a"-Q) is used. A -Q B -Q C - "b)" is selected from any of the following linkers: 1, 3, 6, 9, 19, 28, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, and 58.

[0388] In some embodiments, linker 54 is 54a:

[0389] [ka] That is the case.

[0390] In one embodiment, W is an E3 ubiquitin ligase cereblon binding unit bonded to the "b" end of the linker via an available C atom within the E3 ubiquitin ligase cereblon binding unit.

[0391] In one embodiment, W is W1, which is -Z-(R A ) h And, Here, Z is as follows:

[0392] [ka] During the ceremony,

[0393] [ka] This represents a single covalent bond or a double covalent bond. X A , X B , X C , X D , X E , and X F Of these, 0, 1, or 2 are N, where X E and X F Both are not N, otherwise they are C. X G , X H , and X J One of them is C(O), X G , X H , and X J One of them is N-(2,6-dioxopiperidine-3-yl)(Y), X G , X H , and X J One of them is C(RT )2, -CH2CH2-, C(O), N(C 1~3 Selected from alkyl), -O-, and -N=, where each R T It is selected from H, F, Me, or C(R T ) Together with the carbon of 2, it forms a cyclopropane-1,1-diyl group, Here, X G , X H , and X J In this case, there are no two C(O) groups in adjacent positions, and N-(2,6-dioxopiperidine-3-yl) is N(C 1~3 Selected so as not to be adjacent to either an alkyl group or an O group, Each R A These are F, Cl, and C, independently. 1~3 Alkyl, C 1~3 X selected from alkoxy A , X B , X C , or X D A substituent on any available C atom, and said C 1~3 Alkyl and C 1~3 The alkoxy is independently and optionally substituted by one or more Fs. h is 0, 1, or 2. Linker is X A , X B , X C , or X D It is then bonded to any carbon atom.

[0394] Y is as follows:

[0395] [ka]

[0396] In one embodiment, X A , X B , X C , X D , X E , and X F One of these is N, and if not, it is C.

[0397] In one embodiment, X A , X B , X C , X D , X E , and X F One or two of them are N, otherwise they are C.

[0398] In one embodiment, X A , X B , X C , X D , X E , and X F All of them are C.

[0399] In one embodiment, X A , X B , X C , X D , X E , and X F One of them is N, and the other is C.

[0400] In one embodiment, X A , X B , X C , X D , X E , and X F Two of them are N, where X E and X F Both are not N, otherwise they are C.

[0401] In one embodiment, X B , X D , and X F All are C, and X A , X C , and X E If 0, 1, or 2 of these values ​​are present, then it is N; otherwise, it is C.

[0402] In one embodiment, X B , X D , and X F All are C, and X A , X C , and X EOf these, 0, 1, or 2 are N, otherwise C, where the linker is X A If C, then X B or X A It will be joined to

[0403] In one embodiment, X B , X D , and X F All are C, and X A , X C , and X E Of these, 0, 1, or 2 are N, otherwise C, where the linker is X B It is connected.

[0404] In one embodiment, X G -X H -X J teeth, (i)X G -NY-C(O)(Here, X G (is -CH2-, -CH2CH2-, =N-, or C(O)), (ii)X G -C(O)-NY(where X G is -O- or N(C 1~3 Alkyl) [for example, N(Me)], or (iii) C(O)-NY-CH2

[0405] In one embodiment, the linker is X A or X B Bonded to the C atom, X G -X H -X J teeth, (i)X G -NY-C(O)(Here, X G (is -CH2-, -CH2CH2-, =N-, or C(O)), (ii)X G -C(O)-NY(where X G is -O- or N(C 1~3 Alkyl) [for example, N(Me)], or (iii) C(O)-NY-CH2

[0406] In one embodiment, the linker is X B Bonded to the C atom, X G -X H -X J teeth, (i)X G -NY-C(O)(Here, X G (is -CH2-, -CH2CH2-, =N-, or C(O)), (ii)X G -C(O)-NY(where X G is -O- or N(C 1~3 Alkyl) [for example, N(Me)], or (iii) C(O)-NY-CH2

[0407] In one embodiment, X G -X H -X J It is CH2-NY-C(O).

[0408] In one embodiment, X G -X H -X J It is CH2CH2-NY-C(O).

[0409] In one embodiment, X G -X H -X J The formula is =N-NY-C(O).

[0410] In one embodiment, X G -X H -X J It is C(O)-NY-C(O).

[0411] In one embodiment, X G -X H -X J This is OC(O)-NY.

[0412] In one embodiment, X G -X H -X J is, N(C 1~3is (alkyl)-C(O)-NY [for example, N(Me)-C(O)-NY].

[0413] In one embodiment, X G -X H -X J is C(O)-NY-CH2.

[0414] In one embodiment, each R A is selected from F, Cl, and C 1~3 alkoxy optionally substituted by one or more Fs, X A X B X C or X D is any available C-substituent on X

[0415] In one embodiment, each R A is selected from F, Cl, OMe, and -OCHF2, X A X B X C or X D is any available C-substituent on X

[0416] In one embodiment, h is 0.

[0417] In one embodiment, h is 1.

[0418] In one embodiment, h is 2.

[0419] In one embodiment, the linker is attached to X C where X C is C, X A is C attached to R A R A is OMe, where the methyl is optionally substituted by one or more Fs (for example, -OCHF2).

[0420] In one embodiment, the linker is attached to X C where X C is C, X A is RA A C bonded to R, where R A This is OMe or -OCHF2.

[0421] In one embodiment, -Z-(R A ) h Together, these represent one of the bases 1, 4, 16, 17, and 19 (specifically -Z-(R A ) h This refers to bases 1-21, whose structures are shown below.

[0422] In one embodiment, h is 1, and R A C 1~3 It is an alkoxy [for example, OMe].

[0423] In one embodiment, h is 1 or 2, and one of R A OMe is the other R A Cl is (if it exists, i.e., when h is 2).

[0424] In one embodiment, h is 1 or 2, and one of R A Cl is the other R A OMe is (if it exists, i.e., when h is 2).

[0425] In one embodiment, h is 1, and R A It is F.

[0426] In one embodiment, h is 1, and R A It is Cl.

[0427] In one embodiment, h is 1, and R A It is -OCHF2.

[0428] In one embodiment, the linker is X A or X B It is joined to C, and h is 0.

[0429] In one embodiment, the linker is X A or XB It is bonded to C, and h is 1, R A X C The substituents above, where X C C is R A It is F.

[0430] In one embodiment, the linker is X A or X B It is bonded to C, and h is 1, R A X D The substituents above, where X D C is R A This is OMe or -OCHF2.

[0431] In one embodiment, the linker is X B It is bonded to C, where h is 0, 1, or 2, and the first R A (If it exists, i.e., when h is 1 or 2), X D Substituents on C available in the second R A (If it exists, i.e., if h is 2) then X A It is available on C.

[0432] In one embodiment, the linker is X B It is bonded to C, where h is 0, 1, or 2, and the first R A (If present, i.e., when h is 1 or 2) X is selected from Cl, OMe, and -OCHF2. D Substituents on C available in the second R A (If present, i.e., when h is 2) X is selected from Cl and OMe. A It is available on C.

[0433] In one embodiment, -Z-(R A ) h Together, these represent one of the bases 1-21, 27, and 32 shown below.

[0434] [ka]

[0435]

Chem.

[0436] In one embodiment, W is W2, which is

[0437]

Chem.

[0438]

Chem.

[0439]

Chem.

[0440] Y N The following applies:

[0441] [ka] In one embodiment, Z A The following is true:

[0442] [ka] During the ceremony,

[0443] [ka] This represents a single covalent bond or a double covalent bond. X A2and X B2 One of them is C, and Y N Covalently bonded to X A2 and X B2 The other is C, X C2 and X D2 0 or one of them is N, otherwise it is C. X G2 and X J2 One of them is N, and X G2 and X J2 The other is C, X H2 , X E2 , and X F2 All of them are C.

[0444] In one embodiment, -Z A -Y N Together, they represent one or more of the bases A1 to A5 shown below, and in each case, the Z A The base is further defined herein -[R AA ] V This is used to selectively substitute on available C and / or N atoms.

[0445] [ka]

[0446] One embodiment, each R AA is, Z A A substituent on any available C or N atom, in each case independently, one or more R AA2 R is optionally replaced by AA1 Selected from, R AA If is a substituent on an available C atom of Z, then R AA R AA2 Further selections are made from each R AA1 Independently, C 1~4 Alkyl or 4-6 member heterocyclyl, each R AA2 These are independently F, Cl, CN, and C 1~3 Selected from alkyl groups.

[0447] One embodiment, each R AA is, Z A A substituent on any available C or N atom, in each case independently, one or more R AA2 R is optionally replaced by AA1 Selected from, where R AA is Z A If R is a substituent on an available C atom, AA R AA2 Further selections are made from each R AA1 These are independently methyl, isopropyl, cyclopropyl, pyridinyl, or pyrazolyl, and each R AA2 These are independently F, Cl, CN, or methyl.

[0448] One embodiment, each R AA Each is independently selected from methyl, isopropyl, cyclopropyl, pyridine-2-yl, 1-methylpyrazole-4-yl, -CH2CN, F, Cl, CN, Z A A substituent on an available C atom, and / or Z A The available methyl substituents on the N atom are...

[0449] In one embodiment, v is 0.

[0450] In one embodiment, v is 1.

[0451] In one embodiment, v is 2.

[0452] In one embodiment, v is 1 or 2.

[0453] In one embodiment, v is 0 or 1.

[0454] In one embodiment, v is 1, and X A1 is a C atom, and R AA X A1 The substituent shown above.

[0455] In one embodiment, v is 1, and X A1 is a C atom, and R AA X A1 Upper C 1~4 It is an alkyl substituent.

[0456] In one embodiment, v is 1, and X B1 is a C atom, and R AA X B1 The substituent shown above.

[0457] In one embodiment, v is 1, and X B1 is a C atom, and R AA X B1 Upper C 1~4 It is an alkyl (e.g., methyl) substituent.

[0458] In one embodiment, v is 1, and X C1 is a C atom, and R AA X C1 The substituent shown above.

[0459] In one embodiment, v is 1, and X C1 is a C atom, and R AA X C1 Upper C 1~4 It is an alkyl (e.g., methyl) substituent.

[0460] In one embodiment, v is 1, and X D1 is a C atom, and R AA X D1 The substituent shown above.

[0461] In one embodiment, v is 1, and X D1 is a C atom, and R AA X D1 Upper C 1~4 It is an alkyl (e.g., methyl) or F substituent.

[0462] In one embodiment, v is 1, and X G1 is a C atom, and R AA X G1 The substituent shown above.

[0463] In one embodiment, v is 1, and X G1 is a C atom, and R AA X G1 The substituents above, where R AA is one or more R AA2 R is optionally replaced by AA1 Selected from or R AA R AA2 Selected from, in the formula, R AA1 C 1~4 Alkyl or 4-6 membered heterocyclyl, R AA2 These are F, Cl, CN, and C 1~3 Selected from alkyl groups.

[0464] In one embodiment, v is 1, and X G1 is a C atom, and R AA X G1 The substituent above, R AA The is selected from methyl, isopropyl, cyclopropyl, pyridine-2-yl, 1-methylpyrazole-4-yl, -CH2CN, F, Cl, and CN.

[0465] In one embodiment, v is 1 or 2, and X G1 It is a C atom, and one / its R AA X G1 The substituents above, where R AA is one or more R AA2 R is optionally replaced by AA1 Selected from or R AA R AA2 Selected from, in the formula, R AA1 C 1~4 Alkyl or 4-6 membered heterocyclyl, R AA2 These are F, Cl, CN, and C 1~3 Selected from alkyl, if v is 2, an additional R AA is, Z A It is a fluorocarbon substituted on an available C atom.

[0466] In one embodiment, v is 1, and X G1 It is an N atom, and R AA X G1 The substituent shown above.

[0467] In one embodiment, v is 1, and X G1 It is an N atom, and R AA X G1 Upper C 1~4 It is an alkyl (e.g., methyl) substituent.

[0468] In one embodiment, v is 1, and X H1 is a C atom, and R AA X H1 The substituent shown above.

[0469] In one embodiment, v is 1, and X H1 is a C atom, and R AA is CN or C 1~4 X is alkyl (for example, methyl). H1 The substituent shown above.

[0470] In one embodiment, v is 1 or 2, and X H1 and X G1 Both are C atoms, and one or both of them are R AA It is replaced by, where each R AA Independently, CN or C 1~4 Selected from alkyl groups (e.g., methyl).

[0471] In one embodiment, the base is

[0472] [ka] Together, they represent one or more of the bases A1 to A9 shown below.

[0473] [ka]

[0474] In some of these embodiments, W is W2-1,

[0475] [ka] During the ceremony, X K and X L These are, respectively, N-linker and CH, N-linker and CMe, or NMe and C-linker. X M and X O One of them is C-2,4-dioxohexahydropyrimidine-1-yl(Y N ) and X M and X N 0 or 1 of them is CF, X M If it is not CF, then X N It can be N, X N , X M , and X O The remainder is CH, X P It is either CH or CMe.

[0476] In one embodiment, W represents one of the bases 22-26, 29, and 31 shown below.

[0477] [ka]

[0478] In one embodiment, W is W3, which is -Z B And, Here, Z B The following is true:

[0479] [ka] X E3 C(=O) and CR E1 R E2 Selected from, where RE1 and R E2 H and C are independent of each other. 1~3 Selected from the group consisting of alkyl groups, or R E1 and R E2 They become C together with the carbon they are bonded to. 3~6 Forming a cycloalkane ring, Y is N-(2,6-dioxopiperidine-3-yl), X A3 , X B3 , X C3 , and X D3 All of them are C, X A3 and X B3 , X B3 and X C3 , and X C3 and X D3 One pair of these forms a 5 or 6-membered fully unsaturated or partially unsaturated nitrogen-containing heterocycle, which is bonded to the "b" end of the linker via the nitrogen atom. X A3 , X B3 , X C3 , and X D3 Other things are based on R B It has, and here each R B These are H, F, Cl, C 1~3 Alkyl and C 1~3 Selected from alkoxy.

[0480] In one embodiment, X E3 C (=O) is the result.

[0481] In one embodiment, X E3 CR E1 R E2 And here, R E1 and R E2 H and C are independent of each other. 1~3 Selected from the group consisting of alkyl groups, or R E1 and R E2 They become C together with the carbon they are bonded to. 3~6 It forms a cycloalkane ring.

[0482] In one embodiment, XE3 CR E1 R E2 And here, R E1 and R E2 H and C are independent of each other. 1~3 It is selected from the group consisting of alkyl (e.g., methyl).

[0483] In one embodiment, X A3 and X B3 This forms a 5- or 6-membered fully unsaturated or partially unsaturated nitrogen-containing heterocycle, which is bonded to the "b" end of the linker via the nitrogen atom.

[0484] In one embodiment, X B3 and X C3 It forms a 5 or 6-membered fully unsaturated or partially unsaturated nitrogen-containing heterocycle, which is bonded to the "b" end of the linker via the nitrogen atom.

[0485] In one embodiment, X C3 and X D3 It forms a 5 or 6-membered fully unsaturated or partially unsaturated nitrogen-containing heterocycle, which is bonded to the "b" end of the linker via the nitrogen atom.

[0486] In one embodiment, the 5- or 6-membered fully unsaturated or partially unsaturated N-containing heterocycle is a 5-membered ring, which is in the absence of further unsaturation.

[0487] One embodiment, each R B This is selected from H, F, Cl, methyl, and methoxy.

[0488] One embodiment, each R B H is H.

[0489] In one embodiment, W is base 28:

[0490] [ka] That is the case.

[0491] In one embodiment, W is W4, which is -Z C And, Here, Z C The following is true:

[0492] [ka] X B4 and X C4 One of them is CC(=O)-NH-Y, X A4 , X B4 , X C4 , X D4 , and X E4 One of them could be CF, or X A4 , X B4 , X C4 , X D4 , and X E4 One or two of them can be N, X A4 , X B4 , X C4 , X D4 , and X E4 The remainder is CH.

[0493] In one embodiment, X A4 , X B4 , X C4 , X D4 , and X E4 One of them is CF.

[0494] In one embodiment, X B4 This is CF.

[0495] In one embodiment, X B4 One of them is CF, and X C4 This is CC(=O)-NH-Y.

[0496] In one embodiment, X A4 , X B4 , X C4 , X D4 , and X E4 Two of them are N.

[0497] In one embodiment, X A4 , X B4 , X C4 , X D4 , and X E4 One of them is N.

[0498] In one embodiment, X A4 , X B4 , X C4 , X D4 , and X E4 None of them are N.

[0499] In one embodiment, X A4 , X B4 , X C4 , X D4 , and X E4 In all of these cases, it is X, not N. A4 , X B4 , X C4 , X D4 , and X E4 One of them is CF.

[0500] In one embodiment, X B4 is CF, X C4 CC(=O)-NH-Y, and X A4 , X D4 , and X E4 It is CH.

[0501] In one embodiment, W is base 30:

[0502] [ka] That is the case.

[0503] In further aspects of this specification, formula (Ia) is selected from one or more of the following groups (1) to (43): (1) 4-[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]phenyl, (2) 4-[1-(3-cyano-4-fluoro-1H-indole-7-yl)-4-piperidyl]phenyl, (3) 4-[1-(3-cyano-4-methyl-1H-indole-7-yl)-4-piperidyl]phenyl, (4) 4-[1-(4-chloro-3-cyano-1H-indazole-7-yl)-3-piperidyl]phenyl, (5) 4-[1-(4-chloro-3-cyano-1H-indole-7-yl)-3-piperidyl]phenyl, (6) 4-[1-(3-cyano-4-fluoro-1H-indole-7-yl)-3-piperidyl]phenyl, (7) 4-[1-(3-cyano-4-methyl-1H-indole-7-yl)-4-piperidyl]-3-fluorophenyl, (8) 4-[1-(3-cyano-1H-indole-7-yl)-4-piperidyl]phenyl, (9)6-[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]-3-pyridyl, (10) 5-[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]pyrazine-2-yl, (11) 4-[3-(3-cyano-4-methyl-1H-indole-7-yl)-1-piperidyl]phenyl, (12)3-[3-(3-cyano-4-methyl-1H-indole-7-yl)-1-piperidyl]phenyl, (13) 4-[3-(4-chloro-3-cyano-1H-indole-7-yl)-1-piperidyl]phenyl, (14) 4-[4-(3-cyano-4-methyl-1H-indole-7-yl)piperazine-1-yl]phenyl, (15) 5-[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]-2-pyridyl, (16) 4-[1-(4-chloro-3-cyano-1-methyl-indole-7-yl)-4-piperidyl]phenyl, (17)3-[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]phenyl, (18) 5-[1-(4-chloro-3-cyano-1H-indole-7-yl)-3-piperidyl]-2-pyridyl, (19) 4-[4-(4-chloro-3-cyano-1H-indole-7-yl)morpholin-2-yl]phenyl, (20) 4-[4-(4-chloro-3-cyano-1H-indazole-7-yl)morpholin-2-yl]phenyl, (21)6-[1-(4-chloro-3-cyano-1H-indole-7-yl)-3-piperidyl]pyridazine-3-yl, (22)4-[1-(3-cyano-4-fluoro-1H-indazole-7-yl)-3-piperidyl]phenyl, (23) 4-[1-(4-chloro-3-cyano-1H-indazole-7-yl)-4-piperidyl]phenyl, (24)4-[1-(3-cyano-4-fluoro-1H-indazole-7-yl)-4-piperidyl]phenyl, (25) 4-[1-(3-cyano-4-methyl-1H-indazole-7-yl)-4-piperidyl]phenyl, (26) 4-[1-(3-cyano-4-methyl-1H-indole-7-yl)pyrrolidine-3-yl]phenyl, (27) 4-[[1-(4-chloro-3-cyano-1H-indazole-7-yl)-4-piperidyl]carbamoyl]-3-fluorophenyl, (28) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-3-fluorophenyl, (29) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-3-cyanophenyl, (30) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-3-fluoro-5-methylphenyl, (31) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-2-methylphenyl, (32) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-2-cyanophenyl, (33)6-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-3-pyridyl, (34)6-[[1-(4-chloro-3-cyano-1H-indazole-7-yl)-4-piperidyl]carbamoyl]-3-pyridyl, (35)6-[[1-(3-cyano-4-methyl-1H-indole-7-yl)-4-piperidyl]carbamoyl]-3-pyridyl, (36) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]phenyl, (37) 4-[[4-(4-chloro-3-cyano-1H-indole-7-yl)cyclohexyl]carbamoyl]-3-fluorophenyl, (38) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-3,5-difluorophenyl, (39) 5-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]pyrazine-2-yl, (40)2-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]pyrimidine-5-yl, (41) 4-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]-3-methylphenyl, (42)6-[[1-(4-chloro-3-cyano-1H-indole-7-yl)-4-piperidyl]carbamoyl]pyridazine-3-yl, (43)6-[[(3R)-1-(4-chloro-3-cyano-1H-indole-7-yl)-3-piperidyl]carbamoyl]-3-pyridyl.

[0504] Further embodiments of this specification provide a PROTAC compound or a pharmaceutically acceptable salt thereof comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) or formula (Ib).

[0505] [ka] Here, Q A -GQ H -or-G-(C 1~5 Alkylene)- G is a direct bond, -CH2-, -C(=O)-, -O-, or -N(R G )- and here, each R G H or C 1~3 It is alkyl, Q H This is a 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group. Here, R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 , and q can each take any of the values ​​defined herein for each of these bases / variables.

[0506] In one embodiment, Q H It is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0507] To avoid any ambiguity, in formula (Ib)

[0508] [ka] This indicates a connection point to the rest of the PROTAC compound via a monocovalent bond.

[0509] Further embodiments of this specification provide a PROTAC compound or a pharmaceutically acceptable salt thereof comprising an E3 ubiquitin ligase cereblon binding unit linked to the AR binding unit of formula (Ia) of formula (Ib) as defined herein.

[0510] In further embodiments of this specification, formula (Ib) may be:

[0511] [ka] Here, L X Q can be any of the bases (1) to (43) listed above in relation to equation (Ia), and A Q A It can take any of the values ​​disclosed herein.

[0512] Further embodiments of this specification provide a PROTAC compound or a pharmaceutically acceptable salt thereof comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) of formula (Ic),

[0513] [ka] Here, Q A -GQ H -or-G-(C 1~5 Alkylene)- G is a direct bond, -CH2-, -C(=O)-, -O-, or -N(R G )- and here, R G is H or C 1~3 It is alkyl, Q B This is a direct bond, -Q B1 -Q B2 -Q B3 - Or C optionally replaced with one or more Fs (e.g., one or two). 1~3 It is alkylene, and here, Q B1 and Q B3 Each can be directly joined or C 1~2 Represents alkylene, Q B2 Q H -O-CH2CH2-O-, -O-, or -N(R J )- and here, R J is H or C 1~3 It is alkyl, Each Q H These are independently 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic groups, Here, Q A and Q B The value of is selected such that expression (Ic) does not contain any NN or NO bonds. Here, R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 , and q may otherwise take any of the values ​​defined herein for each of these bases / variables.

[0514] In one embodiment, Q H is a 4-12 member nitrogen-containing saturated heterocyclic group. To avoid ambiguity, in formula (Ic)

[0515] [ka] This indicates a connection point to the rest of the PROTAC compound via a monocovalent bond.

[0516] Further embodiments of this specification provide a PROTAC compound or a pharmaceutically acceptable salt thereof comprising an E3 ubiquitin ligase cereblon binding unit linked to an AR binding unit of formula (Ia) or formula (Ic) as defined herein.

[0517] In further embodiments of this specification, formula (Ib) may be:

[0518] [ka] Here, L X Q can be any of the bases (1) to (43) listed above in relation to equation (Ia), where Q A and Q B Q A and Q B It can take any of the values ​​disclosed herein.

[0519] In further embodiments, a compound or a pharmaceutically acceptable salt thereof is provided, the compound selected from one or more of the “Examples” listed below. Thus, these embodiments are 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, 10 9, 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 This includes one or more specific embodiments (for example, one embodiment or two or three specific embodiments) selected from the group consisting of 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 153, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, and 181.

[0520] Please understand that the compounds in the examples listed below relate to the title compound names and are not limited by the preparation method or whether a given compound was isolated in salt form rather than as a neutral molecule.

[0521] In some embodiments, formula (VI):

[0522] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, X 11 is CH or N, R 11 is F, Cl, or Me, Q 11 and Q 12 These are either N and CH, or CH and N, respectively. n and m are either 1 and 1, or 2 and 0, respectively. Q 14 It is a single bond or -NHC (=O), Y 11 and Y 12 These are selected from CH and CH, CF and CH, N and CH, and N and N, respectively. Linkers are Linkers 3, 47, 49, 54, and 58:

[0523] [ka] Selected from, W is from groups 1, 2, 3, 15, 16, 22, 24, 25, 26, 28, 31, and 32:

[0524] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y N The compound of formula (VI) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is 2,4-dioxohexahydropyrimidine-1-yl.

[0525] In some embodiments, formula (VI-1):

[0526] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, X 21 is CH or N, R 21 These are F and Cl, n and m are either 1 and 1, or 2 and 0, respectively. Linkers are Linker 3 and 47:

[0527] [ka] Selected from, W is from groups 2, 22, and 24:

[0528] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y N The compound of formula (VI-1) or a pharmaceutically acceptable salt thereof is provided, which is 2,4-dioxohexahydropyrimidine-1-yl.

[0529] In some embodiments, formula (VI-2):

[0530] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, X 31 is CH or N, R 31 These are F, Cl, and methyl, n and m are either 1 and 1, or 2 and 0, respectively. Q 31 and Q 32 These are either N and CH, or CH and N, respectively. Q 34 It is a single bond or -NHC (=O), Y 31 and Y 32These are selected from CH and CH, CF and CH, N and CH, and N and N, respectively. Linkers are Linkers 3, 47, 49, 54, and 58:

[0531] [ka] Selected from, W is from groups 1, 2, 3, 15, 16, 22, 24, 25, 26, 28, 31, and 32:

[0532] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y N The compound of formula (VI-2) or a pharmaceutically acceptable salt thereof is provided, which is 2,4-dioxohexahydropyrimidine-1-yl.

[0533] In some embodiments, formula (VII):

[0534] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, The linker is a saturated, partially, or fully unsaturated skeleton comprising C and H atoms and at least one heteroatom, the skeleton having bond endpoints "a" and "b" and a minimum length of 5 to 26 atoms between "a" and "b", the skeleton may contain one or more linear and / or branched and / or rings, and is arbitrarily substituted on any available C atoms by one or more F atoms. W is provided as a compound of formula (VII) or a pharmaceutically acceptable salt thereof, which is an E3 ubiquitin ligase cereblon binding unit.

[0535] In some embodiments, equation (VII-I):

[0536] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Linkers are Linkers 3, 47, 49, 54, and 58:

[0537] [ka] Selected from, W is from groups 1, 2, 3, 15, 16, 22, 24, 25, 26, 28, 31, and 32:

[0538] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y N The compound of formula (VII-I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is 2,4-dioxohexahydropyrimidine-1-yl.

[0539] In some embodiments, formula (VII-II):

[0540] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Linkers are Linker 3 and 47:

[0541] [ka] Selected from, W is from groups 2, 22, and 24:

[0542] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y NThe compound of formula (VII-II) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is 2,4-dioxohexahydropyrimidine-1-yl.

[0543] In some embodiments, equations (VII-III):

[0544] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Linkers are Linkers 3, 47, 49, 54, and 58:

[0545] [ka] Selected from, W is from groups 1, 2, 3, 15, 16, 22, 24, 25, 26, 28, 31, and 32:

[0546] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y N The compound of formula (VII-III) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is 2,4-dioxohexahydropyrimidine-1-yl.

[0547] In some embodiments, formula (VIII):

[0548] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, W is provided as a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, which is an E3 ubiquitin ligase cereblon binding unit.

[0549] In some embodiments, formula (VIII-I):

[0550] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, W is from groups 1, 2, 3, 15, 16, 22, 24, 25, 26, 28, 31, and 32:

[0551] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y N The compound of formula (VIII-I) or a pharmaceutically acceptable salt thereof is provided, which is 2,4-dioxohexahydropyrimidine-1-yl.

[0552] In some embodiments, formula (VIII-II):

[0553] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, W is from groups 2, 22, and 24:

[0554] [ka] Selected from, where Y is 2,6-dioxopiperidine-3-yl, Y N The compound of formula (VIII-II) or a pharmaceutically acceptable salt thereof is provided, which is 2,4-dioxohexahydropyrimidine-1-yl.

[0555] The specific compounds described herein include: 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonilicate, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R * )-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R * )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitride, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitride, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R * )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonilicate, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonilicate, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-(4-{4-[(4-{2-[(3R * )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonilicate, 4-Chloro-7-[(3S)-3-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonilicate, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorophenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorophenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorophenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitride, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{6-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridazin-3-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-[(3R * )-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S *)-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrazine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyrazine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-methyl-1H-indole-3-carbonil, 4-Chloro-7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonil, 7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonilicate, 4-Chloro-7-(4-{4-[4-({4-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitride, 7-[(3S)-3-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-{4-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indazole-3-carbonitrile, 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-{(3R *)-1-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{(3S * )-1-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{(3R * )-1-[3-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{(3S * )-1-[3-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-[(3R * )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-4-methyl-1H-indole-3-carbonitrile, 7-[(3S * )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-carbonyl]phenyl}piperidine-1-yl)-1H-indole-3-carbonil, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-(2-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}ethyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-(3-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}propyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-[(3R * )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S * )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3R * )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S * )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperazine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R* )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S * )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3R * )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S * )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-carbonyl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-[4-(4-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]oxy}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diadinan-1-yl)-7-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-{4-[(1-{4-[(3S)-1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-3-yl]phenyl}piperidine-4-yl)methyl]piperazine-1-yl}-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, 4-{4-[(1-{4-[1-(3-cyano-4-fluoro-1H-indole-7-yl)piperidine-4-yl]phenyl}piperidine-4-yl)methyl]piperazine-1-yl}-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, 4-{4-[(1-{4-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]phenyl}piperidine-4-yl)methyl]piperazine-1-yl}-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, 7-[4-(4-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]methyl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-(4-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{6-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl][1,4'-bipiperidine]-1'-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{3-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-2-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S * )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3R * )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(2S * )-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}morpholine-4-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(2R * )-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl }methyl)piperidine-1-yl]phenyl}morpholine-4-yl]-1H-indole-3-carbonilicate, 4-Chloro-7-[(2S * )-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}morpholine-4-yl]-1H-indazole-3-carbonilicate, 4-Chloro-7-[(2R *)-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}morpholine-4-yl]-1H-indazole-3-carbonilicate, 4-Chloro-7-[(3R * )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S * )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-2-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyrimidine-5-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{2-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrimidine-5-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 7-(4-{4-[(2R)-2-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)morpholine-4-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[(2R)-2-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)morpholine-4-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[7-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[7-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)-2-azaspiro[3.5]nonan-2-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[7-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[7-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indazole-3-carbonitride, 7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indazole-3-carbonitride, 7-(4-{4-[7-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonilicate, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-2-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[7-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indazole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonilicate, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indazole-3-carbonitride, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonilicate, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indazole-3-carbonilicate, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indazole-3-carbonilicate, 7-{(3S *)-3-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]pyrrolidine-1-yl}-4-methyl-1H-indole-3-carbonitride, 7-{(3R * )-3-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]pyrrolidine-1-yl}-4-methyl-1H-indole-3-carbonitride, N-[1-(4-chloro-3-cyano-1H-indazole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[5-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1~{H}-indole-7-yl)-4-piperidyl]-4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)carbamoyl]-3-fluorophenyl]piperazine-1-yl]methyl]-1-piperidyl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-2-cyano-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]benzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluoro-6-methylbenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-3-methylbenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-3-cyano-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]benzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}piperidine-1-yl)pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indazole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(3-cyano-4-methyl-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(3-cyano-4-methyl-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]benzamide, N-[4-(4-chloro-3-cyano-1H-indole-7-yl)cyclohexyl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2,6-difluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrazine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrimidine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-methylbenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-6-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-carboxamide, N-[(3R *)-1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-3-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, and N-[(3S * )-1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-3-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0556] The specific compounds described herein include: 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonilicate, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R *)-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R * )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride, 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitride, or a pharmaceutically acceptable salt thereof.

[0557] Further specific compounds described herein include: 4-Chloro-7-(4-{4-[7-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indazole-3-carbonitride, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonilicate, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonitride, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indazole-3-carbonitride, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonilicate, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indazole-3-carbonilicate, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indazole-3-carbonilicate, 7-{(3S * )-3-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]pyrrolidine-1-yl}-4-methyl-1H-indole-3-carbonitride, 7-{(3R * )-3-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]pyrrolidine-1-yl}-4-methyl-1H-indole-3-carbonitride, N-[1-(4-chloro-3-cyano-1H-indazole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[5-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1~{H}-indole-7-yl)-4-piperidyl]-4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)carbamoyl]-3-fluorophenyl]piperazine-1-yl]methyl]-1-piperidyl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, and N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-2-cyano-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]benzamide, or a pharmaceutically acceptable salt thereof.

[0558] Further specific compounds described herein include: 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitride, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{6-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridazin-3-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-[(3R *)-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-[(3S * )-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl]-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrazine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyrazine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitride, 7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-methyl-1H-indole-3-carbonil, 4-Chloro-7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonil, 7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonilicate, 4-Chloro-7-(4-{4-[4-({4-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride, 4-Chloro-7-[(3S)-3-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitride, 7-[(3S)-3-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride, 4-Chloro-7-{4-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indazole-3-carbonitrile, and 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, or a pharmaceutically acceptable salt thereof.

[0559] In one embodiment, this specification refers to 4-chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile

[0560] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0561] In one embodiment, this specification refers to 7-4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile

[0562] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0563] In one embodiment, this specification refers to 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile

[0564] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0565] In one embodiment, this specification refers to 4-chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile

[0566] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0567] In one embodiment, this specification refers to 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile

[0568] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0569] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitrile

[0570] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0571] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitrile

[0572] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0573] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0574] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0575] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0576] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0577] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0578] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0579] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitrile

[0580] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0581] In another embodiment, this specification refers to 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile

[0582] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0583] In another embodiment, this specification refers to 7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile

[0584] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0585] In another embodiment, this specification refers to 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-fluoro-1H-indole-3-carbonitrile

[0586] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0587] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0588] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0589] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0590] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0591] In another embodiment, this specification refers to 4-chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-2-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0592] [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0593] Further embodiments provide any of the embodiments, claims, or aspects defined herein, except for 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 ,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,10 6, 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, One or more specific embodiments (for example, one embodiment or two or three specific embodiments) selected from the group consisting of 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 153, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, and 181 are individually discarded.

[0594] PROTAC compounds comprising the compound of formula (I) and the bonding unit of formula (Ia) may have one or more chiral centers, and it is recognized that such compounds may be prepared, isolated and / or supplied with or without the presence of one or more other possible enantiomers and / or diastereomer isomers of the compound, or that such isomers may be supplied in any relative proportion. The preparation of enantioenriched / 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 enantioenriched or enantiopure starting materials and / or by appropriately using an enantioenriched or enantiopure catalyst during synthesis and / or by dividing a racemic or partially enriched mixture of stereoisomers (e.g., via chiral chromatography).

[0595] Accordingly, in one embodiment, a composition is provided comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, optionally together 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 at a diastereomeric excess of ≥90% (%de(diastereomeric excess)).

[0596] In further embodiments, %de in the above-described composition is ≥95%.

[0597] In further embodiments, %de in the above-described composition is ≥98%.

[0598] In further embodiments, %de in the above-described composition is ≥99%.

[0599] In further embodiments, a composition is provided 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 together 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 at an enantiomeric excess of ≥90% (%ee).

[0600] In further embodiments, %ee in the above-described composition is ≥95%.

[0601] In further embodiments, %ee in the above-described composition is ≥98%.

[0602] In further embodiments, %ee in the above-described composition is ≥99%.

[0603] In further embodiments, a composition is provided 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 together 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 with an enantiomer excess of ≥90% (%ee) and a diastereomer excess of ≥90% (%de).

[0604] In further embodiments of the above-described composition, %ee and %de may take any combination of the values ​​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%.

[0605] In further embodiments, pharmaceutical compositions are provided comprising a compound of formula (I) [or a PROTAC compound comprising a unit of formula (Ia) as defined herein] or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

[0606] In one embodiment, a pharmaceutical composition is provided 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, together 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 at an enantiomer excess of ≥90% (%ee).

[0607] In further embodiments, %ee in the above-described composition is ≥95%.

[0608] In further embodiments, %ee in the above-described composition is ≥98%.

[0609] In further embodiments, %ee in the above-described composition is ≥99%.

[0610] In one embodiment, a pharmaceutical composition is provided 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, together 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 at a diastereomer excess of ≥90% (%de).

[0611] In further embodiments, %de in the above-described composition is ≥95%.

[0612] In further embodiments, %de in the above-described composition is ≥98%.

[0613] In further embodiments, %de in the above-described composition is ≥99%.

[0614] In one embodiment, a pharmaceutical composition is provided 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, together 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 enantiomer excess of ≥90% (%ee) and a diastereomer excess of ≥90% (%de).

[0615] In further embodiments of the pharmaceutical composition described above, %ee and %de may take any combination of the values ​​listed below: • %ee is ≥ 95% and %de is ≥ 95%. • %ee is ≥ 98% and %de is ≥ 98%. • %ee is ≥ 99% and %de is ≥ 99%.

[0616] Compounds of formula (I) [or PROTAC compounds containing the units of formula (Ia) as defined herein] and their pharmaceutically acceptable salts may be prepared, used, or supplied in amorphous, crystalline, or semicrystalline form. Any given compound of formula (I) [or PROTAC compounds containing the units of formula (Ia) as defined herein] or its pharmaceutically acceptable salt may be formed into multiple crystalline / polymorphic forms, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric forms of hydrate) and / or solvated forms. It should be understood that this specification encompasses any and all such solid forms of compounds of formula (I) [or PROTAC compounds containing the units of formula (Ia) as defined herein], as well as their pharmaceutically acceptable salts.

[0617] Further embodiments provide compounds of formula (I) [or PROTAC compounds comprising units of formula (Ia) as defined herein] which can be obtained by the methods described in the following “Examples” section.

[0618] intermediate compound As demonstrated in the following experimental section, the compound of formula (I) or the PROTAC of formula (Ia) can be prepared, for example, by the following method.

[0619] A compound of formula (I) [or a salt thereof] or a PROTAC compound of formula (Ia) [or a salt thereof] is a compound of formula (II):

[0620] [ka] A compound or salt thereof, wherein, Q A -GQ H -or-G-(C 1~5 Alkylene)- G is a direct bond, -CH2-, -C(=O)-, -O-, or -N(R G)- and here, R G is H or C 1~3 It is alkyl, Q H This is a 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group. Q D C is either directly bonded or optionally substituted by one or more Fs. 1~2 It is alkylene, R L1 and R L2 Together, they form "=O", R L3 H is, Q D It is a direct connection, and Q A GQ H -If Q H The value of is Q D Q H Selected to connect to the C atom, R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 , and q can each be prepared from a compound of formula (II) or a salt thereof, wherein each of these groups / variables may take any of the values ​​disclosed herein.

[0621] In one embodiment, Q H It is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0622] Therefore, as described above, such compounds of formula (II) are aldehydes that can react directly or after one or more additional reaction steps 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). Such reactions between the aldehyde and the amine can be carried out under reductive amination conditions, for example, using NaBH(OAc)3 or another reductive amination protocol known to those skilled in the art.

[0623] Next, such aldehydes can be prepared from the corresponding acetals, for example, the compound of formula (II) defined above or a salt thereof, but R L1 and R L2 Each of them operates independently, C- 1-6 Alkoxy (for example, C 1~3 (alkoxy) or R L1 and R L2 Together, -O-(CH2) k It forms an -O- group (where k is 2 or 3). Such an acetal can be converted to the corresponding aldehyde using formic acid under acidic conditions, for example, under conditions well known to those skilled in the art.

[0624] Alternatively, as shown in the experimental section below, the above aldehydes can be prepared by oxidation of the corresponding primary alcohol (i.e., the compound of formula (II) defined above or its salt), but R L1 OH and R L2 is H. Such oxidation can be carried out using mild oxidation conditions, for example, Dess-Martin periodinane or several other mild oxidation protocols known to those skilled in the art.

[0625] As shown in the experimental section below, the compound of formula (I) [or its salt] or the PROTAC compound of formula (Ia) [or its salt] can be prepared from the compound of formula (II) or its salt, as described above, but R L1 R is a leaving group, L2is H. Therefore, such compounds of formula (II) are electrophiles that can react with molecules containing an amine group (e.g., a secondary amine group) via alkylation reactions, either directly or after one or more additional reaction steps, to form compounds of formula (I) or PROTAC compounds of formula (Ia). Suitable leaving groups for alkylation reactions are well known to those skilled in the art and include Cl, Br, I, trifluoromethanesulfonates, mesylates, and tosylates. Alkylation reaction conditions are well known to those skilled in the art and generally include a non-nucleophilic base (e.g., DIPEA) and a polar aprotic solvent (e.g., MeCN). As demonstrated in the following experimental section, if the leaving group is not I, a metal iodide salt can be used in the reaction mixture to form the corresponding iodide at insights (i.e., R L1 If R is I, the entire alkylation process can be accelerated. As shown in the experimental section below, L1 Compounds of formula (II) in which is a bromo-leading group can be prepared from the corresponding primary alcohol (i.e., as already mentioned above, R L1 is OH, and R L2 and R L3 (If both are H).

[0626] Next, the primary alcohol compound of formula (II) described above can be prepared by reduction of the corresponding ester compound, i.e., the compound of formula (II) defined above or its salt, but R L1 and R L2 Together, they form "=O", R L3 C 1~6 Alkoxy (for example, C 1~3 Such reductions are alkoxys. Such reductions can be carried out using strong reducing conditions (for example, using DIBAL or other stronger reducing conditions well known to those skilled in the art).

[0627] Alternatively, it may be advantageous to form the primary alcohol compound of formula (II) above by deprotecting a protected form of the alcohol, as demonstrated in the experimental section below. For example, deprotection of a compound in which the alcohol is protected by a silicon-based protecting group, using a fluoride source (e.g., TBAF) or other deprotection methods well known to those skilled in the art to achieve deprotection.

[0628] Therefore, as described above, various compounds of formula (II) and their salts may be useful as intermediates in the synthesis of compounds of formula (I) or PROTAC compounds of formula (Ia), and thus such intermediate compounds provide further embodiments of this specification.

[0629] Therefore, in a further embodiment, a compound of formula (II) shown above or a salt thereof, wherein in the formula Q A -GQ H -or-G-(C 1~5 Alkylene)- G is a direct bond, -CH2-, -C(=O)-, -O-, or -N(R G )- and here, R G is H or C 1~3 It is alkyl, Q H This is a 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group. Q D C is either directly bonded or optionally substituted by one or more Fs (e.g., one or two Fs). 1~2 It is alkylene, (i)R L1 and R L2 Together, they form "=O", R L3 is H or C 1~6 Is it an alkoxy (for example, OMe)? (ii)R L1 and R L2 Each of them is independent of C 1~6 It is an alkoxy (e.g., OMe), and R L3 Is it H? (iii)R L1 and RL2 Together, -O-(CH2) k -O- is formed, where k is 2 or 3, R L3 is H, or (iv)R L1 OH, OPG 1 (Here, PG 1 (is a protective group), or LG 1 (Here, LG 1 (is a leaving group), and R L2 and R L3 Both are H, Q D It is a direct connection, and Q A GQ H -If Q H The value of is Q D Q H Selected to connect to the C atom, 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 A compound of formula (II) or a salt thereof is provided, wherein q and q can each take any of the values ​​disclosed herein for each of these groups / variables.

[0630] In one embodiment, Q H It is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0631] Those skilled in the art recognize suitable protecting groups for alcohol groups, and therefore, PG 1 It recognizes the optimal value for PG. For example, PG 1 This is an alcohol protecting group.

[0632] In one embodiment, PG 1 This is a silicon-based alcohol protecting group.

[0633] In one embodiment, PG 1 is Si(R Si )3, where each R Si Independently, C 1~6 It is a hydrocarbyl group.

[0634] In one embodiment, PG 1 These are tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0635] In one embodiment, LG 1 These are Cl, Br, I, trifluoromethanesulfonate, and C 1~7 Selected from hydrocarbyl sulfonates (e.g., mesylate or p-toluenesulfonate).

[0636] In one embodiment, LG 1 It is either Br or I.

[0637] In one embodiment, LG 1 It is Br.

[0638] In one embodiment, LG 1 It is Cl.

[0639] In one embodiment, LG 1 It is I.

[0640] In one embodiment, LG 1 It is trifluoromethanesulfonate.

[0641] In one embodiment, LG 1 C 1~7 It is a hydrocarbyl sulfonate.

[0642] In one embodiment, LG 1 It is a mesylate.

[0643] In one embodiment, LG 1 It is p-toluenesulfonate.

[0644] In one embodiment, Q D These are direct bonds, -CH2-, -CH2CH2-, or -CF2CH2-.

[0645] In one embodiment, Q D This is a direct bond.

[0646] In one embodiment, Q D This is CH2.

[0647] In one embodiment, Q D C is optionally replaced by one or two Fs. 1~2 It is alkylene.

[0648] In one embodiment, Q D C 1~2 It is alkylene.

[0649] In one embodiment, Q D It is -CH2CH2-.

[0650] In one embodiment, Q D It is -CF2CH2-.

[0651] In further embodiments of this specification, formula (II) may be formula (IIa),

[0652] [ka] Here, L X Q can be any of the bases (1) to (43) listed above in relation to equation (Ia), and A Q D , R L1 , R L2 and R L3 Each of these values ​​may take any of the values ​​disclosed herein for each of the groups.

[0653] As demonstrated in the following experimental section, certain compounds of formula (I), certain PROTACS of formula (Ia), and certain intermediate compounds of formula (II) are related to formula (III):

[0654] [ka] A compound or salt thereof, where G X The compound is OH, and the oxygen atom of the OH is alkylated by a suitable molecule to form a specific compound of formula (I) or a PROTAC of formula (Ia) (e.g., via formula (II) described above), which can be prepared using a compound of formula (III) or a salt thereof. Such alkylation reactions can be carried out under conditions well known to those skilled in the art, for example, 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., K2CO3), using a primary alkyl bromide (or using some other leaving group instead of Br).

[0655] Alternatively, as shown in the experimental section below, G X ga-NH(R G )[Here, R G is H or C 1~3 A compound of formula (III) which is alkyl (e.g., Me) may be used as an intermediate for preparing a compound of formula (I) or a PROTAC of formula (Ia) via reductive amination with a suitable aldehyde-containing compound.

[0656] Alternatively, as shown in the experimental section below, G X Compounds of formula (III) in which is bromo may be coupled with secondary amine compounds to give a specific compound of formula (I) or a PROTAC of formula (Ia) either directly or after one or more further reaction steps (e.g., via formula (II) described above). Similarly, G XCompounds of formula (III), where is chloro or trifluoromethanesulfonate, can also be used in coupling reactions with the relevant secondary amines to give specific compounds of formula (I) or PROTACs of formula (Ia). Such couplings can be carried out under palladium-based coupling conditions (e.g., using "Ruphos Pd G3" and "Ruphos") in an inert atmosphere, in the presence of a base and an anhydrous solvent such as 1,4-dioxane, or by heating with CuI in a polar solvent such as DMSO, in the presence of a base such as K3PO4. Alternatively, as shown in the experimental section herein, G X Compounds of formula (III) in which is brominated can be coupled with a suitable alcohol to form a specific compound of formula (I) or a PROTAC of formula (Ia) (e.g., via formula (II) described above) either directly or after one or more further reaction steps. Such coupling can be carried out in a solvent such as toluene, in the presence of a base such as Cs2CO3, using a palladium-based reagent such as "Rockphos Pd G3".

[0657] Therefore, compounds of formula (III) and salts thereof may be useful as intermediates in the synthesis of certain compounds of formula (I), PROTAC compounds of formula (Ia), or compounds of formula (II), and such intermediate compounds provide further embodiments of this specification.

[0658] Therefore, in a further embodiment, a compound of formula (III) shown above or a salt thereof, wherein in the formula G X is OH, Cl, Br, trifluoromethanesulfonate, or -NH(R G ) and here, R G is H or C 1~3 It is alkyl, R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 A compound of formula (III) or a salt thereof is provided, wherein q and q can each take any of the values ​​disclosed herein for each of these groups / variables.

[0659] G X is OH, Cl, Br, trifluoromethanesulfonate, or -NH(R G ) and here, R G C 1~3 It is an alkyl group (for example, Me).

[0660] In one embodiment, G X is OH, Br, trifluoromethanesulfonate, or -NH(R G ) and here, R G C 1~3 It is an alkyl group (for example, Me).

[0661] In one embodiment, G X is OH, Br, or -NH(R G ) and here, R G C 1~3 It is an alkyl group (for example, Me).

[0662] In one embodiment, G X It is either OH or Br.

[0663] In one embodiment, G X It is OH.

[0664] In one embodiment, G X It is Br.

[0665] In one embodiment, G X It is Cl.

[0666] In one embodiment, G X It is trifluoromethanesulfonate.

[0667] In one embodiment, G X is -NH(R G ) and here, R G is H or C 1~3 It is alkyl.

[0668] In one embodiment, G X is -NH(R G ) and here, R G C 1~3 It is alkyl.

[0669] In one embodiment, G X It is -NH(Me).

[0670] In further embodiments of this specification, formula (III) is L X -G X This is possible, and here, L X This can be any of the bases (1) to (43) listed above in relation to equation (Ia), and G X G X It can take any of the values ​​disclosed herein.

[0671] As demonstrated in the following experimental section, the compounds of specific formula (I) and PROTAC of formula (Ia) are defined as follows, as shown below, for formula (IV):

[0672] [ka] It can be prepared using intermediate compounds or salts thereof. For example, compounds of formula (IV) where J is H (i.e., secondary amine compounds) are well known to those skilled in the art and can be coupled to further chemical fragments using the chemistry exemplified in the experimental section below to provide compounds of formula (I) or PROTACs of formula (Ia), either directly or after one or more further reaction steps.

[0673] Next, such compounds of formula (IV) where J is H can be easily prepared by deprotecting the N-protected form of the aforementioned amine compound. Thus, compounds of formula (IV) where J is H can be prepared by deprotecting J is PG. 2 And, PG 2 is a nitrogen protecting group (e.g., C such as tert-butoxycarbonyl). 1~6 It can be easily prepared using a compound of formula (IV) which has an alkoxycarbonyl group. Therefore, if J is PG 2 The compound of formula (IV) is a useful intermediate in the preparation of the compound of formula (I) and the PROTAC of formula (Ia), providing further embodiments of this specification.

[0674] Therefore, in further embodiments of this specification, a compound of formula (IV) shown above or a salt thereof, wherein the formula comprises, J is H or PG 2 And here, PG 2 This 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-, -C(=O)-, -O-, or -N(R G )- and here, R G is H or C 1~3 It is alkyl, Q B This is a direct bond, -Q B1 -Q B2 -Q B3 - Or C optionally replaced with one or more Fs (e.g., one or two). 1~3 It is alkylene, and here, Q B1 and Q B3 Each can be directly joined or C 1~2 Represents alkylene, Q B2 Q H -O-CH2CH2-O-, -O-, or -N(R J )- and here, R J is H or C 1~3It is alkyl, Each Q H (J joined to "Q" H The group containing the "ring" is independently a 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group. Here, Q A Q B , and Q H The values ​​of the rings were selected such that equation (IV) does not contain any NN or NO bonds. Here, R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 A compound of formula (IV) or a salt thereof is provided, wherein q and q can each take any of the values ​​defined herein for each of these groups / variables.

[0675] In one embodiment, each Q H (J joined to "Q" H The group containing the 'ring' is independently a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0676] In one embodiment, Q H The ring is piperidine-1,4-diyl or piperazine-1,4-diyl.

[0677] In one embodiment, J is H.

[0678] In one embodiment, J is PG 2 That is the case.

[0679] In one embodiment, PG 2 C 1~6 It is an alkoxycarbonyl.

[0680] In one embodiment, PG2 It is tert-butoxycarbonyl.

[0681] PG 2 C 1~6 In one embodiment, which is an alkoxycarbonyl (e.g., tert-butoxycarbonyl), the “and salts thereof” element of the claim is omitted.

[0682] In further embodiments, the compound of formula (IV) is used in any other context, embodiment, aspect, or claim found herein, where Q A Q B , and Q H Any combination of the alternative values ​​mentioned can be taken.

[0683] In further embodiments of this specification, formula (IV) may be formula (IVa),

[0684] [ka] Here, L X Q can be any of the bases (1) to (43) listed above in relation to equation (Ia), and A Q B Q H , and J may each take any of the values ​​disclosed herein for each of the groups.

[0685] Furthermore, as demonstrated in the following experimental section, the compounds of specific formula (I) and the PROTAC of formula (Ia) are of formula (V):

[0686] [ka] An intermediate compound or salt thereof, wherein in the formula, X X is N substituted by J, where J is H, G is a direct bond, -CH2-, -C(=O)-, -O-, or -N(R G )- and here, R G is H or C1~3 It is alkyl, Q H The ring is a 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group. Here, G and Q H The values ​​of the rings were selected so that formula (V) does not contain any NN or NO bonds. R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 , and q can each be prepared using an intermediate compound of formula (V) or a salt thereof, wherein each of these groups / variables may take any of the values ​​defined herein.

[0687] Such a compound of formula (V) may be converted to a compound of formula (I) or a PROTAC of formula (Ia) via reductive amination or alkylation or other coupling chemistry known to those skilled in the art, thereby providing a compound of formula (I) or a PROTAC of formula (Ia), either directly or after one or more additional steps.

[0688] Next, as shown in the experimental section below, such compounds of formula (V) or salts thereof can be readily prepared by deprotection of the corresponding N-protected compound. Such N-protected forms may be BOC-protected forms (i.e., tert-butoxycarbonyl) or other 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 PROTAC of formula (Ia), providing further embodiments of this specification.

[0689] Therefore, one aspect of this specification provides a compound of formula (V) or a salt thereof as described above, but X Xis N substituted by J, and J is PG 3 And, PG 3 is a protecting group. In one embodiment, PG 3 C 1~6 It is an alkoxycarbonyl. In one embodiment, PG 3 It is tert-butoxycarbonyl. PG 3 C 1~6 In one embodiment, which is an alkoxycarbonyl (e.g., tert-butoxycarbonyl), the “and salts thereof” element of the claim is omitted.

[0690] Other compounds of formula (I) and PROTAC of formula (Ia) (and its salts) can be prepared from the intermediate compound of formula (V) or its salt, as described above, but X X The compound is C=O. Such intermediates can be converted to the compound of formula (I) or the PROTAC of formula (Ia) by reductive amination chemistry using a suitable amine-containing compound, either directly or through one or more additional synthesis steps, using reductive amination conditions well known to those skilled in the art.

[0691] Next, as demonstrated in the following experimental section, X X Compounds of formula (V) where C=O can be readily prepared from the corresponding compound in which the ketone is protected / masked as a ketal. Thus, such ketal compounds and their salts are useful intermediates in the preparation of compounds of formula (I) or PROTACs of formula (Ia), providing further embodiments of this specification.

[0692] Therefore, such ketal compounds can be represented as the compound of formula (V) or a salt thereof, as described above, but X X R U1 and R U2 C is substituted by R U1 and R U2 Each of them is C 1~6 It is alkoxy, or R U1 and R U2 Together, -O-(CH2) uThis represents -O-, where u is either 2 or 3.

[0693] Therefore, in further embodiments of this specification, a compound of formula (V) shown above or a salt thereof, wherein the formula includes, X X teeth, (i) N substituted by J, where J is H or PG 3 And, PG 3 However, the protecting group is N, and (ii) by oxo, or R U1 and R U2 C substituted by R U1 and R U2 Each of them is C 1~6 It is alkoxy, or R U1 and R U2 Together, -O-(CH2) u - Represents O, where u is selected from C, either 2 or 3. G is a direct bond, -CH2-, -C(=O)-, -O-, or -N(R G )- and here, R G is H or C 1~3 It is alkyl, Q H The ring is a 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic group. G and Q H The values ​​of the rings were selected so that formula (V) does not contain any NN or NO bonds. Here, R 1 , p, X 1 , R N n, m, R 2a , R 2b Q 1 Q 2 Q 3 Q 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 3 A compound of formula (V) or a salt thereof is provided, wherein q and q can each take any of the values ​​defined herein for each of these groups / variables.

[0694] In one embodiment, J is H.

[0695] In one embodiment, J is PG 3 That is the case.

[0696] In one embodiment, PG 3 C 1~6 It is an alkoxycarbonyl.

[0697] In one embodiment, PG 3 It is tert-butoxycarbonyl.

[0698] In one embodiment, X X Therefore, C=O.

[0699] In one embodiment, X X R U1 and R U2 C is substituted by, where R U1 and R U2 Each of them is C 1~6 It is an alkoxy.

[0700] In one embodiment, X X R U1 and R U2 C is substituted by R U1 and R U2 Together, -O-(CH2) u -O- represents -O-, where u is either 2 or 3 (for example, u=2).

[0701] In one embodiment, G is either a direct bond or an -O-.

[0702] In one embodiment, Q H The ring is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

[0703] Q H The value of the ring is Q H It can take any of the values ​​referred to herein.

[0704] 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.

[0705] In further embodiments of this specification, formula (V) may be formula (Va),

[0706] [ka] Here, L X This can be any of the bases (1) to (43) listed above in relation to equation (Ia), and G, Q H Ring, and X X Each of these values ​​may take any of the values ​​disclosed herein for each of the groups.

[0707] In addition to the methods described above, the compounds of formulas (I), (II), (III), (IV), and (V), as well as the PROTAC compounds including formula (Ia), can be prepared using standard procedures and knowledge known to those skilled in the art, according to the general procedures and chemical transformations demonstrated in the following experimental sections.

[0708] Further embodiments of this specification provide compounds or salts thereof, which are selected from one or more of the “intermediates” listed below in the Experimental Section.

[0709] It should be understood that the intermediate compounds listed below are not limited in any way by the method of preparation or by whether a given intermediate compound was isolated in salt form rather than as a neutral molecule, with respect to the title chemical name listed in the experimental section.

[0710] A further embodiment of this specification provides a pharmaceutical composition comprising a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

[0711] Further embodiments of this specification provide pharmaceutical compositions for use in the treatment of cancer, comprising a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0712] Further embodiments of this specification provide pharmaceutical compositions for use in the treatment of solid tumors, comprising a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0713] Further embodiments of this specification provide pharmaceutical compositions for use in the treatment of AR-sensitive tumor types, comprising a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0714] Further aspects of this specification provide pharmaceutical compositions comprising a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding 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 having one or more variant forms of the androgen receptor.

[0715] Further embodiments of this specification provide pharmaceutical compositions comprising a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding 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., CRPC, e.g., metastatic CRPC).

[0716] A further aspect of this specification provides a pharmaceutical composition for use in the treatment of AR-mutated cancers, comprising a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0717] Any embodiment, aspect, or claim of this specification that does not further specifically refer to "cancer" may provide further embodiments, aspects, or claims in which the cancer is (or includes) AR+ breast cancer.

[0718] The composition may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or parenteral administration (e.g., as sterile aqueous or oily liquids for intravenous, subcutaneous, or intramuscular administration). The composition may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Accordingly, a composition intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0719] For further information regarding the formulation, please refer to Chapter 25.2 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0720] The amount of active ingredient combined with one or more excipients to produce a single dosage form inevitably varies depending on the host being treated and the specific route of administration.

[0721] The size of the therapeutic doses of the compounds described herein naturally varies according to well-known medical principles, depending on the nature and severity of the disease state, the age and sex of the animal or patient, and the route of administration.

[0722] As described above, the compounds herein may have value as antitumor agents, particularly as selective inhibitors of the proliferation, survival, motility, dissemination, and invasiveness of mammalian cancer cells, resulting in inhibition of tumor growth and survival, as well as inhibition of metastatic tumor growth. In particular, the compounds herein may have value as antiproliferative and anti-invasive agents in the suppression and / or treatment of solid tumor diseases.

[0723] Therefore, the compounds described herein may be useful for the prevention or treatment of tumors that are sensitive to the degradation of androgen receptors and are involved in signaling steps that result in the proliferation and survival of tumor cells, as well as the migratory ability and invasiveness of metastatic tumor cells. Furthermore, the compounds described herein may be useful for the prevention or treatment of tumors that can be treated by the degradation of androgen receptors; that is, the compounds may be used to induce an androgen receptor degrading effect in warm-blooded animals that require such treatment.

[0724] Further embodiments of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use as pharmaceuticals.

[0725] Further embodiments of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in therapy.

[0726] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in methods of treating the body of a human or animal by therapy.

[0727] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in generating antiproliferative effects (e.g., in warm-blooded animals such as humans).

[0728] Further aspects of this specification provide the use of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia for generating an antiproliferative effect (e.g., in warm-blooded animals such as humans).

[0729] A further aspect of this specification provides a method for producing an antiproliferative effect in a warm-blooded animal such as a human requiring an antiproliferative effect, 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 cerebron binding unit and (e.g., a linked) AR binding unit of formula (Ia)] or a pharmaceutically acceptable salt thereof.

[0730] Further embodiments of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cerebron binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use as anti-invasive agents in the suppression and / or treatment of solid tumor diseases (e.g., in warm-blooded animals such as humans).

[0731] Further aspects of this specification provide for the use of compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for use as anti-invasive agents in the suppression and / or treatment of solid tumor diseases (e.g., in warm-blooded animals such as humans).

[0732] A further aspect of this specification provides a method for producing an anti-invasive effect in a warm-blooded animal such as a human that requires suppression and / or treatment of a solid tumor disease, 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 cerebron binding unit and (e.g., a linked) AR binding unit of formula (Ia)] or a pharmaceutically acceptable salt thereof.

[0733] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in the prevention or treatment of cancer (e.g., in warm-blooded animals such as humans).

[0734] Further aspects of this specification provide the use of compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for the prevention or treatment of cancer (e.g., in warm-blooded animals such as humans).

[0735] A further aspect of this specification provides a method for preventing or treating cancer in a warm-blooded animal such as a human, 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 cerebron binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0736] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in the prevention or treatment of solid tumors (e.g., in warm-blooded animals such as humans).

[0737] Further aspects of this specification provide the use of compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for the prevention or treatment of solid tumors (e.g., in warm-blooded animals such as humans).

[0738] A further aspect of this specification provides a method for preventing or treating solid tumors in a warm-blooded animal such as a human, 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 cerebron binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0739] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in the prevention or treatment of tumor types sensitive to androgen receptor degradation.

[0740] Further aspects of this specification provide the use of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding 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 the prevention or treatment of tumor types sensitive to androgen receptor degradation.

[0741] A further aspect of this specification provides a method for preventing or treating a tumor type sensitive to the degradation of androgen receptors in a warm-blooded animal such as a human, 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 cerebron binding unit and (e.g., a linked) AR binding unit of formula (Ia)] or a pharmaceutically acceptable salt thereof.

[0742] As explained above, tumor types that are sensitive to the degradation of androgen receptors include prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC).

[0743] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in providing a degrading effect on androgen receptors (e.g., in warm-blooded animals such as humans).

[0744] Further aspects of this specification provide the use of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding 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 to provide a degrading effect on androgen receptors (e.g., in warm-blooded animals such as humans).

[0745] A further aspect of this specification provides a method for providing an androgen receptor-degrading effect in a warm-blooded animal such as a human, 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 cerebron binding unit and (e.g., a linked) AR binding unit of formula (Ia)] or a pharmaceutically acceptable salt thereof.

[0746] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in providing a selective degrading effect on androgen receptors (e.g., in warm-blooded animals such as humans).

[0747] Further aspects of this specification provide the use of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia to provide a selective degradation effect on androgen receptors (in warm-blooded animals such as humans).

[0748] A further aspect of this specification provides a method for providing a selective degrading effect on an androgen receptor in a warm-blooded animal such as a human, the method comprising administering an effective amount of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cerebron binding unit and (e.g., an AR binding unit of formula (Ia) linked thereto] or a pharmaceutically acceptable salt thereof.

[0749] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in the treatment of tumor types having androgen receptor mutations.

[0750] Further aspects of this specification provide the use of a compound of formula (I) as defined herein [or a PROTAC compound comprising an E3 ubiquitin ligase cereblon binding 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 the prevention or treatment of tumor types having androgen receptor mutations.

[0751] A further aspect of this specification provides a method for preventing or treating a tumor type having an androgen receptor mutation in a warm-blooded animal such as a human, 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 cerebron binding unit and (e.g., a linked) AR binding unit of formula (Ia)] or a pharmaceutically acceptable salt thereof.

[0752] As mentioned above, tumor types known to have androgen receptor mutations include prostate tumors, and therefore prostate cancer, castration-resistant prostate cancer (CRPC), and metastatic prostate cancer (CRPC).

[0753] Further aspects of this specification provide compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for use in the treatment of prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC).

[0754] Further embodiments of this specification provide for the use of compounds of formula (I) as defined herein [or PROTAC compounds comprising an E3 ubiquitin ligase cereblon binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for the treatment of prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC).

[0755] A further aspect of this specification provides a method for treating a warm-blooded animal, such as a human, who is in need of treatment for prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC), 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 cerebron binding unit and an AR binding unit of formula (Ia) (e.g., linked thereto)] or a pharmaceutically acceptable salt thereof.

[0756] In one embodiment in which cancer is referred to herein, the cancer is prostate cancer.

[0757] In one embodiment where cancer is referred to herein, the cancer is CRPC.

[0758] In one embodiment in which cancer is referred to herein, the cancer is metastatic CRPC.

[0759] General experimental conditions and abbreviations Use the following abbreviations: AcOH = Acetic acid; AIBN = 2,2'-Azobis(2-methylpropionitrile); aq. = Aqueous solution; Boc = Butoxycarbonyl; Brettphos = 2-(Dicyclohexylphosphino)3,6-Dimethoxy-2',4',6'-Triisopropyl-1,1'-Biphenyl; Brettphos Pd G3 = [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate; tert-butyl BrettPhos = di-tert-butyl(2',4',6'-triisopropyl-3,6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine; tert-BuOH = tert-butanol; CDI = 1,1'-carbonyldiimidazole; CPhos = 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl; Dave-phos-Pd G3 = Methanesulfonato 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II); DCM = Dichloromethane; DEA = Diethylamine; DIAD = Diisopropyl azodicarboxylate; DIPEA = N,N-Diisopropylethylamine; Cbz = Carboxybenzyl; DMAP = 4-(dimethylamino)pyridine; Dess-Martin periodinane = 3-oxo-1l5-benzo[d][1,2]iodooxol-1,1,1(3H)-triyltriacetate; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EDC = (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride); Ephos = dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane; Et2O = diethyl ether; Depositphotos = ethyl acetate; EtOH = ethanol; FSC = flash silica chromatography; h = time; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt = hydroxybenzotriazole;HPLC = High-Performance Liquid Chromatography; IPA = Isopropyl Alcohol; LHMDS = Lithium Bis(Trimethylsilyl)amide; MeCN = Acetonitrile; MeOH = Methanol; mins. = Minutes; m / z = Mass-to-charge ratio observed for the main mass spectrometry peak; MTBE = Methyl-tert-butyl ether; 2-MeTHF = 2-Methyltetrahydrofuran; NBS = N-Bromosuccinimide; NMP = N-Methyl-2-Pyrrolidone; NMR = Nuclear Magnetic Field [Pd(cinnamyl)Cl]2 = di-chlorobis[(1,2,3-)-1-phenyl-2-propenyl]dipalladium(II); PdCl2(dtbpf) = [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium; PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; Pd-PEPPSI-IHept; Cl =Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazole-2-yldiene(3-chloropyridyl)palladium(II);Pd-PEPPSI-IPent=Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II), Pd(dppf)2Cl2-DCM=1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex; Pd(dppf)Cl2=[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(t-Bu3P)2=bis(tri-tert-butylphosphine)palladium(O); RockPhos=2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl; RockPhos Pd G3 = [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]-palladium(II) methanesulfonate; RT = room temperature (approx. 17~25℃); RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G3 = methanesulfonate (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-dimethyloxy-1,1-biphenyl; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0760] Unless otherwise specified, NMR was performed in deuterated DMSO at 300–500 MHz and 20–30°C. The following standard abbreviations are used in the NMR data: s = singleline, d = doubleline, m = multipleline, br = broad, dd = doubleline of doubleline, q = quadrupleline, dt = doubleline of tripleline, etc.

[0761] Preparative reverse-phase HPLC (RP HPLC) using a polarity-reducing eluent mixture (e.g., water and MeCN) typically involves a gradient of 40–50 mL / min over 10–20 minutes from a 95:5 solvent mixture to a 5:95 mixture. The following column and eluent conditions are used herein. Column A: Waters XSelect CSH C18 ODB column, 5μm silica, 30mm diameter, 100mm length Elution A: A mixture of water (containing 0.1% formic acid) with reduced polarity and MeCN. Elutate B: A mixture of water (containing 0.1% NH3) with reduced polarity and MeCN.

[0762] After HPLC (often with the presence of formic acid or trifluoroacetic acid in the eluate), the fraction containing the desired product was treated with a suitable base as part of a further workup step to ensure that the title compound was delivered as a neutral molecule rather than a salt, and thus, where indicated as "Basic Workup A," the fraction containing the desired compound was concentrated to remove MeCN. The resulting predominantly aqueous fraction was basicized with NaHCO3 solution (e.g., 50 mL) and extracted into DCM (e.g., 3 × 100 mL). The combined organic solution was washed with NaCl solution (e.g., 100 mL), dried (e.g., with Na2SO4 or MgSO4), concentrated to obtain the title compound.

[0763] Concentration / Evaporation: When it is stated that a solution or mixture is concentrated or evaporated, this is generally done in a rotary evaporator under reduced pressure using a warm water bath or hot water bath.

[0764] Salts: When a particular compound is obtained as an acid addition salt (e.g., monohydrochloride or dihydrochloride), the stoichiometric ratio of the salt is estimated based on the number and properties of basic groups in the compound and may not be determined experimentally, for example, by elemental analysis data.

[0765] Chemical nomenclature: Generally, examples and intermediate compounds were named using ACD names, the "Structure to Name" function of ChemDraw Ultra (CambridgeSoft), or Biovia Draw 2016.

[0766] Example 1: Intermediate 1a: 7-Bromo-4-chloro-1H-indole

[0767] [ka] 1-Bromo-4-chloro-2-nitrobenzene (7 × 100 g, 422.9 mmol) was added to THF (7 × 700 mL), followed by the dropwise addition of vinyl magnesium bromide (1 M, 7 × 1.69 L) at -60°C, and the mixture was stirred for 1 hour. NH4Cl (aqueous solution, 2.0 L) was added to the solution at 0°C, and the product mixture was combined and extracted with siRNA (2.0 L). The organic layer was washed with NaCl solution (1.0 L), and the solvent was evaporated to dryness to obtain the crude product, which was purified by column chromatography (elution gradient 10-25% Et2O: siRNA) to obtain the title compound (260 g, 34%) as a yellow solid. 1 H NMR(CDCl3)δ 6.64(1H,s),6.93(1H,m),7.18(2H,m),8.35(1H,s).

[0768] Intermediate 1b: 7-Bromo-4-chloro-1H-indole-3-carbonitride

[0769] [ka] 7-Bromo-4-chloro-1H-indole (4 × 70.0 g, 303.7 mmol) was added to MeCN (4 × 560 mL), followed by the dropwise addition of chlorosulfonyl isocyanate (4 × 51.6 g, 364.4 mmol, 4 × 31.6 mL) at 0°C, and the mixture was stirred for 2 hours. Then, DMF (4 × 266.0 g, 3.64 mol, 4 × 280.0 mL) was added dropwise, and the solution was stirred at 0°C for 2 hours, followed by 16 hours at room temperature. Water was added dropwise at 10°C until a solid was formed, and the solid was isolated by filtration. The batches of solids were combined and ground with Et2O:siRNA:DCM (4:1:1) to obtain the title compound (105.0 g, 33.3%) as a white solid. 1 H NMR δ 7.22-7.24(1H,d,J=8.4Hz),7.50-7.52(1H,d,J=8.4Hz),8.46(1H,s);m / z:ES + [M+H] + =255.1.

[0770] Intermediate 1c: Benzyl 4-(4-bromophenyl)piperidine-1-carboxylate

[0771] [ka] Benzylcarbonochloride (14.27 mL, 96.17 mmol) was added dropwise over 5 minutes at 0°C to a solution of 4-(4-bromophenyl)piperidine (25.0 g, 100.98 mmol) and DIPEA (42.0 mL, 240.43 mmol) in 2-MeTHF (250 mL). The resulting mixture was stirred at room temperature for 24 hours and then quenched with water (250 mL). The layers were separated, the organic layer was washed with water (250 mL) and NaCl solution (50 mL), dried using MgSO4, filtered, and evaporated to obtain the crude product as a colorless oil. The oil was diluted with IPA water (1:1, 200 mL) and stirred at room temperature for 1 hour. The obtained solid was recovered by filtration, washed with water (2 × 20 mL), and dried under vacuum at 50°C for 16 hours to obtain the title compound (32.9 g, 91%) as a white solid. 1H NMR δ 1.50(2H,qd),1.75(2H,d),2.72(1H,m),2.90(2H,s),4.14(2H,d),5.10(2H,s),7.18-7.26(2H,m),7.29-7.44(5H,m),7.45-7.53(2H,m).

[0772] Intermediate 1d: Benzyl 4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-carboxylate

[0773] [ka] 4-(1,3-dioxolan-2-yl)piperidine (15.02 g, 95.52 mmol), benzyl 4-(4-bromophenyl)piperidine-1-carboxylate (32.5 g, 86.83 mmol), and Cs2CO3 (56.6 g, 173.67 mmol) were added to 1,4-dioxane (325 ml) under nitrogen, to which tri-tert-butylphosphonium tetrafluoroborate (2.52 g, 8.68 mmol) was added. The mixture was degassed with nitrogen, and then Pd(t-Bu3P)2 (2.21 g, 4.34 mmol) was added. The resulting mixture was stirred at 100°C for 20 hours, cooled to room temperature, and the solid was filtered under vacuum. The solid was washed with 1,4-dioxane (3 × 65 ml), and the filtrate was evaporated to obtain a pale yellow solid. The solid was suspended in cyclopentyl methyl ether:heptane (1:10, 300 ml), stirred at 50°C for 30 minutes, and then cooled to room temperature for a further 2 hours. The solid was filtered to obtain the title compound (28.9 g, 73.9%) as a cream-colored solid. 1 H NMR δ 1.43(4H,m),1.57-1.67(1H,m),1.73(4H,m),2.54-2.63(3H,m),2.89(2H,s),3.65(2H,m),3.75-3.9 3(4H,m),4.13(2H,m),4.61(1H,d),5.09(2H,s),6.85(2H,m),7.06(2H,m),7.29-7.44(5H,m);m / z:ES + [M+H] + =451.5.

[0774] Intermediate 1e: 4-(1,3-dioxolan-2-yl)-1-[4-(piperidine-4-yl)phenyl]piperidine

[0775] [ka] Benzyl 4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-carboxylate (762 mg, 1.69 mmol) was dissolved in EtOH (20 mL), and Pd / C (10%, 180 mg, 0.17 mmol) was added under nitrogen. The reaction mixture was stirred under a hydrogen atmosphere at 4 bar for 16 hours. The catalyst was then filtered through a Celite® pad, the solvent was removed under reduced pressure, and the mixture was azeotropically reacted with excess MeCN. The product was dried in a vacuum oven for 2 hours to obtain the title compound (449 mg, 84%) as a waxy white solid. 1 H NMR δ 1.33-1.51(4H,m),1.54-1.68(3H,m),1.72(2H,d),2.4-2.46(1H,m),2.54-2.64(4H,m),3 .01(2H,d),3.64(2H,d),3.74-3.94(4H,m),4.61(1H,d),6.85(2H,d),7.04(2H,d);m / z:ES + [M+H] + =317.7.

[0776] Intermediate 1f: 4-Chloro-7-(4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride

[0777] [ka] [Pd(cinnamyl)Cl]2 (0.218 g, 0.42 mmol) and CPhos (0.735 g, 1.68 mmol) were added to a degassed mixture of 4-(1,3-dioxolan-2-yl)-1-[4-(4-piperidyl)phenyl]piperidine (11.72 g, 37.03 mmol) and 7-bromo-4-chloro-1H-indole-3-carbonitrile (intermediate 1b) (8.6 g, 33.66 mmol) in 2-MeTHF (86 mL). LHMDS (1 M in THF, 118 mL, 117.81 mmol) was added dropwise, and the reaction mixture was stirred at 50°C for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and stirred for 10 minutes. A precipitate formed between the two layers. This solid was collected by filtration, washed with water (25 mL), and dried overnight in a vacuum oven at 50°C to obtain the title compound (13.95 g, 84%) as a cream-colored solid. 1 H NMR δ 1.39(2H,m),1.56-1.67(1H,m),1.67-1.78(2H,m),1.83(2H,m),1.88-2.03(2H,m),2.58(3H,td),2.71-2.82(2H,m),3.42(2H,d),3.66(2 m / z:ES + [M+H] + =491.5.

[0778] Intermediate 1g: 4-Chloro-7-{4-[4-(4-formylpiperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile

[0779] [ka] HCl (2M, 274 mL, 547.83 mmol) was gradually added at room temperature to a suspension of 4-chloro-7-(4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile (13.45 g, 27.39 mmol) in THF (135 mL). The resulting solution was stirred at 60°C for 4 hours. The solution was pooled in an ice bath and neutralized with NaOH (2M, 180 mL) until the pH reached approximately 7. The product was filtered off, the solid was washed with water (20 mL), and dried under vacuum to obtain the title compound (12.85 g) as a cream-colored solid, which was used without further purification. 1 H NMR δ 1.64(2H,s),1.83(2H,d),1.88-2.06(4H,m),2.71-2.92(4H,m),3.40(3H,d),3.51-3.62(3H m / z:ES + [M+H] + =447.4.

[0780] Intermediate 1h: 3-(5-bromo-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione

[0781] [ka] DIPEA (25 mL, 143.52 mmol) was added under nitrogen to methyl 4-bromo-2-(bromomethyl)benzoate (14.65 g, 47.57 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (11.74 g, 71.35 mmol) in MeCN (200 mL). The resulting suspension was stirred at 80°C for 48 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with MeCN (60 mL), MeCN:Et2O (2:3, 50 mL), and Et2O (2 × 50 mL) to obtain the title compound as a dark blue solid (13.1 g, 85%). 1H NMR δ 1.95-2.08(1H,m),2.34-2.46(1H,m),2.57-2.65(1H,m),2.91(1H,m),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.

[0782] Intermediate 1i: tert-butyl4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-carboxylate

[0783] [ka] Cs2CO3 (57.4 g, 176 mmol) and Pd-PEPPSI-IPent (2.33 g, 2.94 mmol) were added in one go under nitrogen to a degassed solution of tert-butylpiperazine-1-carboxylate (14.22 g, 76.36 mmol) and 3-(5-bromo-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione (19.0 g, 58.74 mmol) in 1,4-dioxane (590 mL). The resulting mixture was stirred at 90°C for 24 hours. The reaction mixture was cooled to room temperature, diluted with DCM (1 L), and sequentially washed with 5% AcOH and NaCl solution in water (500 mL). The organic layer was dried over MgSO4, filtered, and evaporated to obtain the crude product. The crude product was pulverized with dimethyl sulfate (250 mL), the solid was recovered by filtration, washed with Et2O (100 mL), and dried under vacuum to obtain the title compound (22.1 g, 88%) as a gray solid. 1H NMR δ 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(4H ,d),4.22(1H,d),4.34(1H,d),5.05(1H,dd),7.07(2H,d),7.54(1H,d),10.92(1H,s);m / z:ES + [M+H] + =429.2.

[0784] Intermediate 1j: 3-[1-oxo-5-(piperazine-1-yl)-1,3-dihydro-2H-isoindole-2-yl]piperidine-2,6-dione hydrochloride

[0785] [ka] A solution of 4M HCl in 1,4-dioxane (8.75 mL, 35.0 mmol) was added at room temperature to tert-butyl 4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-carboxylate (1.50 g, 3.50 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. HCl (5 mL) was added, and the reaction mixture was stirred for 10 minutes. The resulting precipitate was collected by filtration, the solid was washed with HCl (2 × 5 mL), and then dried under vacuum to obtain the title compound (1.08 g, 85%) as a dark gray solid (HCl salt). 1 H NMR δ 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.

[0786] Example 1: 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile

[0787] [ka] 4-Chloro-7-{4-[4-(4-formylpiperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile (intermediate 1 g) (9.3 g, 20.81 mmol) and 3-[1-oxo-5-(piperazine-1-yl)-1,3-dihydro-2H-isoindole-2-yl]piperidine-2,6-dione hydrochloride (intermediate 1 j) (7.97 g, 21.85 mmol) were stirred in NMP (65.0 mL) at room temperature, followed by DIPEA (3.81 mL, 21.85 mmol). After stirring for 5 hours, sodium triacetoxyborohydride (5.29 g, 24.97 mmol) was added all at once, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (260 mL), stirred for 30 minutes, and then filtered under vacuum. The solid was washed with water (10 mL), dissolved in IPA:DCM (1:3, 720 mL), washed with NaHCO3 solution (180 mL) and NaCl solution (180 mL), dried over MgSO4, and filtered to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient of 50-100% toluene in heptane, followed by 0-7% MeOH in DCM) to obtain a cream-colored solid. The solid was suspended in MeCN (65 mL) and stirred at 80°C for 1 hour. The suspension was cooled to room temperature for 16 hours and filtered under vacuum to obtain the title compound (6.06 g, 38.4%) as a white solid. 1H NMR δ 1.17-1.29(2H,m),1.64-1.74(1H,m),1.83(4H,br t),1.91-2.02(3H,m),2.23(2H,br d),2.31-2.43(2H,m),2.51-2.54(4H,m),2.54-2.66(4H,m),2.78(2H,br t),2.85-2.95(1H,m),3.29-3.31(4H,m),3.42(2H,br d),3.64(2H,br d),4.21(1H,d),4.33(1H,d),5.05(1H,dd),6.86(1H,d),6.91(2H,d),7.05-7.08(1H,m),7.07(1H,s),7.13(2H,br d),7.16(1H,d),7.53(1H,d),8.32(1H,s),10.94(1H,s),12.26(1H,br s);m / z:ES + [M+H] + =759.8.

[0788] Example 2 Intermediate 2a: 7-bromo-4-fluoro-1H-indole

[0789] [ka] 1-Bromo-4-fluoro-2-nitrobenzene (6 × 100.0 g, 454 mmol) was dissolved in THF (6 × 700.0 mL) at -45°C, and then vinyl magnesium bromide (1 M, 6 × 1.82 L) was added dropwise under nitrogen, and the mixture was stirred for 30 minutes. NH4Cl (aqueous solution, 2.0 L) was added to the solution, and six batches were combined. The THF was evaporated, the product was extracted with siRNA (9.0 L), washed with NaCl solution (1.0 L), dried over Na2SO4, filtered, and the solvent was evaporated. The crude product was purified by column chromatography (elution gradient 0-20% Et2O:siRNA) to obtain the title compound (148.5 g, 24.3%) as a brown oily substance. 1 H NMR δ 6.64(1H,s),6.78(1H,m),7.27(1H,m),7.45(1H,s),11.65(1H,s).

[0790] Intermediate 2b: 7-Bromo-4-fluoro-1H-indole-3-carbonitrile

[0791] [ka] 7-Bromo-4-fluoro-1H-indole (140.0 g, 654 mmol) was added to MeCN (848 mL), followed by the dropwise addition of chlorosulfonyl isocyanate (111.1 g, 785 mmol, 68.2 mL) at 0°C, and the mixture was stirred for 2 hours. DMF (574.0 g, 7.85 mol, 604 mL) was added dropwise to the solution at 0°C, and the mixture was stirred for a further 2 hours. Water (1.6 L) was added, and the resulting solid was washed with water (100.0 mL) to obtain a yellow solid. The yellow solid was extracted with toluene (500.0 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was ground with Et₂O:toluene (4:1, 800.0 mL) to obtain the title compound (100.78 g, 62.9%) as a yellow solid. 1 H NMR δ 7.03(1H,m),7.50(1H,m),8.40(1H,m),12.77(1H,s);m / z:ES - [MH] - =237.0.

[0792] Intermediate 2c: 7-(4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride

[0793] [ka] [Pd(cinnamyl)Cl]2 (0.068 g, 0.13 mmol), CPhos (0.228 g, 0.52 mmol), 4-(1,3-dioxolan-2-yl)-1-[4-(piperidine-4-yl)phenyl]piperidine intermediate 1e (3.64 g, 11.50 mmol), and 7-bromo-4-fluoro-1H-indole-3-carbonitride intermediate 2b (2.5 g, 10.46 mmol) were degassed in 2-MeTHF (25 mL) for 10 minutes. LHMDS (1 M in THF, 36.6 mL, 36.60 mmol) was added all at once, and the reaction mixture was stirred at 50°C for 1.5 hours. The reaction mixture was then cooled to room temperature, diluted with water (65 mL), and stirred for 10 minutes. A precipitate formed between the two layers, which was collected by filtration, washed with water (25 mL), and vacuum-dried in a 50°C oven for 16 hours to obtain the title compound (3.41 g, 68.7%) as a cream-colored solid. 1 H NMR δ 1.39(2H,qd),1.56-1.67(1H,m),1.67-1.77(2H,m),1.77-1.86(2H,m),1.94(2H,qd),2.52-2.64(3H,m),2.68-2.8(2H,m),3.36(2H m / z:ES + [M+H] + =475.5.

[0794] Intermediate 2d: 4-Fluoro-7-{4-[4-(4-formylpiperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitride

[0795] [ka] To a stirred suspension of 7-(4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile (3.41 g, 7.19 mmol) in THF (34.0 mL), HCl (2 M, 71.9 mL, 143.71 mmol) was added at room temperature. The mixture was stirred at 60 °C for 2.5 hours, cooled in an ice bath, and neutralized with NaOH (2 M) until the pH reached 7. The mixture was extracted with 2-MeTHF (2 × 100 mL), the organic extract was then washed with NaCl solution:water (1:1, 50 mL), dried by passing through a phase separation cartridge, filtered, and evaporated to obtain the crude product. The crude product was slurryed in MeCN (50 mL) at 80 °C for 1 hour, and then cooled to room temperature over 16 hours. The solid was recovered by filtration, washed with excess MeCN, and dried under vacuum at 45°C to obtain the title compound (2.45 g, 79%) as a cream-colored solid. 1 H NMR δ 1.53-1.66(2H,m),1.78-1.88(2H,m),1.88-2.03(4H,m),2.43-2.48(1H,m),2.53-2.63(1H,m),2.7-2.85(4H,m),3.37(2 H,d),3.55(2H,dt),6.82(1H,dd),6.87-6.96(3H,m),7.14(2H,d),8.26(1H,d),9.64(1H,d),12.23(1H,s);m / z:ES-[MH] - =429.3.

[0796] Example 2: 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride

[0797] [ka] 4-Fluoro-7-{4-[4-(4-formylpiperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile (3.46 g, 8.04 mmol) and 3-[1-oxo-5-(piperazine-1-yl)-1,3-dihydro-2H-isoindole-2-yl]piperidine-2,6-dione HCl (intermediate 1j) (3.08 g, 8.44 mmol) were suspended in DCM (25.0 mL) and IPA (8.3 mL) at room temperature. DIPEA (1.47 mL, 8.44 mmol) was added, and the suspension was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (2.04 g, 9.64 mmol) was added, and the suspension was stirred at room temperature for 5 minutes. The reaction mixture was diluted with IPA:DCM (1:3, 135 mL), washed with water (70 mL), NaHCO3 solution (70 mL), and NaCl solution (75 mL), and dried by passing through a phase separation cartridge. The solvent was evaporated to obtain the crude product, which was purified by flash silica chromatography (elution gradient: 50-100% Â in heptane, followed by 0-10% MeOH in DCM). The fraction was evaporated, and the product was stirred in MeCN (35 mL) at 80°C for 1 hour, then cooled to room temperature for 16 hours. The solid was recovered by filtration, washed with MeCN (10 mL), and dried under vacuum at 45°C to obtain the title compound (3.5 g, 58.6%) as a cream-colored solid. 1 H NMR δ 1.16-1.3(2H,m),1.63-1.75(1H,m),1.76-1.88(4H,m),1.9-2.03(3H,m),2.23(2H,d),2.31-2 .42(1H,m),2.52(4H,d),2.54-2.68(4H,m),2.71-2.81(2H,m),2.85-2.96(1H,m),3.31(4H,s) ,3.37(2H,d),3.64(2H,d),4.21(1H,d),4.33(1H,d),5.05(1H,dd),6.82(1H,dd),6.86-6.97( m / z:ES + [M+H] + =743.5.

[0798] Examples 3 and 4 The enantiomer (30 mg, 0.04 mmol) of 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile (Example 2) was subjected to Sepiatec 100 under SFC conditions (Regis(R,R)Whelk-01, 21.1 × 250 mm, 5 microns, 50% MeOH / MeCN 3:7 / 50% scCO2, flow rate 60 mL / min, 40°C). The compounds were separated on an SFC (Steel Fibre Casting Cell), and in order of elution, Example 3 (isomer 1, 9.0 mg, 30.0%) and Example 4 (isomer 2, 7.2 mg, 24.0%) were obtained as white solids.

[0799] Example 3: 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride [Absolute stereochemistry is unconfirmed]

[0800] [ka] 1H NMR δ 1.17-1.31(2H,m),1.64-1.76(1H,m),1.78-1.88(4H,m),1.89-2.03(3H,m),2.23(2H,d),2.34-2.4(1H,m ),2.51-2.53(4H,m),2.53-2.55(1H,m),2.55-2.59(1H,m),2.61(2H,d),2.71-2.81(2H,m),2.84-2.96(1H ,m),3.25-3.31(4H,m),3.37(2H,d),3.64(2H,d),4.16-4.37(2H,m),5.04(1H,dd),6.82(1H,dd),6.87-6 .96(3H,m),7.02-7.09(2H,m),7.13(2H,d),7.52(1H,d),8.26(1H,d),10.93(1H,s),12.23(1H,s);m / z:ES + [M+H] + =743.5;>99%ee.

[0801] Example 4: 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride [Absolute stereochemistry is unconfirmed]

[0802] [ka] 1H NMR δ 1.24(3H,s),1.63-1.76(1H,m),1.77-1.88(4H,m),1.89-2.03(3H,m),2.23(2H,d),2.34-2.4(1H,m), 2.51-2.56(4H,m),2.55-2.59(1H,m),2.59-2.65(2H,m),2.71-2.81(2H,m),2.84-2.96(1H,m),3.30(4 H,s),3.34-3.41(2H,m),3.6-3.68(2H,m),4.16-4.38(2H,m),5.04(1H,dd),6.82(1H,dd),6.88-6.96 (3H,m),7.03-7.09(2H,m),7.13(2H,d),7.52(1H,d),8.26(1H,d),10.93(1H,s),12.24(1H,s);m / z:ES + [M+H] + =743.5;>99%ee.

[0803] Example 5 Intermediate 5a: tert-butyl 4-(4-nitro-1H-indole-1-yl)piperidine-1-carboxylate

[0804] [ka] 4-nitro-1H-indole (5 × 95.0 g, 585 mmol), tert-butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (5 × 409.0 g, 1.46 mol), and Cs2CO3 (5 × 573.0 g, 1.76 mol) were added to DMF (1.5 L). The solution was degassed with nitrogen and stirred at 80°C for 12 hours. Water (10.0 L) was added to each mixture, and the batches were combined by extraction with ELISA (6.0 L). The organic layer was washed with NaCl solution (10.0 L × 3) and dried over Na2SO4. The solvent was evaporated, and the crude product was purified by recrystallization from MTBE:Et2O (1:4, 500.0 mL) at room temperature for 20 minutes. The solid was filtered and dried under vacuum to obtain the title compound (910.0 g) as a brown solid. 1H NMR δ 1.39(s,9H),1.82-1.93(m,4H),2.85(s,2H),4.08-4.11(m,2H),4.69-4.75(m,1H),7.02(d,J=3.2 Hz,1H),7.32(t,J=8.4Hz,1H),7.92(d,J=3.6Hz,1H),8.05(d,J=7.6Hz,1H),8.13(d,J=8.4Hz,1H).

[0805] Intermediate 5b: tert-butyl 4-(4-amino-1H-indole-1-yl)piperidine-1-carboxylate

[0806] [ka] Tert-butyl 4-(4-nitro-1H-indole-1-yl)piperidine-1-carboxylate (7 × 140.0 g, 405 mmol) was added to seven separate solutions of Pd / C (20.0 g, 10% purity) in MeOH:THF (1:1, 1.0 L). The solutions were degassed with nitrogen and stirred under a hydrogen atmosphere (30 PSI) for 12 hours. The seven batches were combined by filtering off the Pd / C and evaporating the solvent. The resulting solid was used without further purification to obtain the title compound (770.0 g, 86%) as a brown solid. 1 H NMR δ 1.43(s,9H),1.86-1.98(m,4H),3.46-3.82(m,2H),4.12(d,J=10.4Hz,2H),4.59(t,J=3.6Hz,1H),5. 36(s,2H),6.34(d,J=3.2Hz,1H),6.89(d,J=7.2Hz,1H),7.16(t,J=7.6Hz,1H),7.56(t,J=3.6Hz,1H).

[0807] Intermediate 5c: tert-butyl4-{4-[(3-methoxy-3-oxopropyl)amino]-1H-indole-1-yl}piperidine-1-carboxylate

[0808] [ka] Tert-butyl 4-(4-amino-1H-indole-1-yl)piperidine-1-carboxylate (5 × 175.0 g, 555 mmol) was added to MeOH (1.2 L) in five separate additions. AcOH (5 × 499.0 g, 8.32 mol, 476 mL) was added to each mixture, followed by the addition of methyl acrylate (471.0 g, 5.47 mol, 4923 mL), and the mixture was stirred at 80°C for 18 hours. The batches were combined, the solvent evaporated to obtain the crude product, which was extracted with HCl (10.0 L) and washed with NaHCO3 (15.0 L). The aqueous layer was back-extracted with HCl (5.0 L × 3). The combined organic matter was washed with NaCl solution and dried over Na2SO4. The solvent was evaporated to obtain the title compound (1.08 kg, crude) as a black oily substance, which was used without further purification. 1 H NMR δ 1.79(s,9H),1.89-1.91(m,2H),1.98(s,1H),2.65(t,6.8Hz,1H),2.67(s,2H),3.32-3.42(m,1H),3.51(s,1H),3.61(s,2H),4.02-4.09 (m,2H),4.11-4.41(m,1H),6.10(d,7.2Hz,1H),6.39-6.54(m,1H),6.78(d,J=8.4Hz,1H),6.77-6.89(m,1H),7.23(s,1H),11.89(s,1H).

[0809] Intermediate 5d: tert-butyl4-{4-[carbamoyl(3-methoxy-3-oxopropyl)amino]-1H-indole-1-yl}piperidine-1-carboxylate

[0810] [ka] tert-butyl 4-{4-[(3-methoxy-3-oxopropyl)amino]-1H-indole-1-yl}piperidine-1-carboxylate (6 × 200 g, 498 mmol) was added to DCM (6 × 1.0 L). AcOH (6 × 2.1 kg, 34.97 mol, 2.0 L) from DCM (6 × 1.0 L) was added to the mixture, followed by potassium cyanate (6 × 40.4 g, 498 mmol), and the mixture was stirred at room temperature for 2 hours. Six batches were combined, and water (5.0 L) was added to the mixture. DCM (8 L × 2) was added to the extract and washed with NaCl solution. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (elution gradient 30:1~1:1 Et2O:ELISA) to obtain the title compound (260.0 g, 19.6%) as a brown solid. 1 H NMR δ 1.82(s,9H),1.93-1.98(m,4 H),2.44-2.50(m,2H),2.98(s,2H),3.46(s,3H),3.84(s,2H),4.66(d,J=8.4Hz,2H),4.66- 4.78(m,1H),5.36(s,2H),6.34(d,J=3.2Hz,1H),6.90(d,J=7.6Hz,1H),7.16(t,J=8.4Hz,1 H),7.56(t,J=4Hz,2H).

[0811] Intermediate 5e: tert-butyl4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-carboxylate

[0812] [ka] Tert-butyl 4-{4-[carbamoyl(3-methoxy-3-oxopropyl)amino]-1H-indole-1-yl}piperidine-1-carboxylate (3 × 105.0 g, 236 mmol) in MeOH (3 × 779.0 g, 24.3 mol, 3 × 984 mL) was added to three separate containers of MeOH (1.0 L), followed by the addition of MeONa / MeOH (42.5 g, 236 mmol, 30% purity). The reaction mixture was stirred at room temperature for 2 hours, and the combined solid was collected by filtration. The filtrate was evaporated and purified by column chromatography (elution gradient 10:1 DCM:MeOH) to obtain the title compound (180 g, 70.7%) as a white solid. 1 H NMR δ 1.43(s,9H),1.92-1.81(m,4H),2.75(t,J=6.8Hz,2H),2.7 5(s,2H),3.37-3.77(m,2H),4.12(d,J=5.6Hz,2H),4.59-4.60(m,1H),6.41(d,J=3.2 Hz,1H),6.96(d,J=7.6Hz,1H),7.15(t,J=7.6Hz,1H),7.52-7.54(m,2H),10.3(s,1H).

[0813] Intermediate 5f: 1-[1-(piperidine-4-yl)-1H-indole-4-yl]-1,3-diadinane-2,4-diotosylate

[0814] [ka] 140.0 g, 339.41 mmol of tert-butyl 4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-carboxylate (140.0 g, 339.41 mmol) in a solution of MeCN (300 mL) was added dropwise to 82.6 g, 434 mmol of p-toluenesulfonic acid hydrate (560 mL) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. 6.46 g, 33.9 mmol of p-toluenesulfonic acid hydrate was added to the mixture and stirred for another 1 hour at 60°C. The reaction mixture was then filtered and dried under vacuum to obtain the title compound (120.0 g, 70.8%) as a gray solid.1 H NMR δ 2.06-2.16(m,4H),2.29(s,3H),2.76(t,J=6.8Hz,2H),3.19-3.45(m,2H),3.45-3.48(m,3H),3.77(t,J=6.4Hz,2H),4.42-4.79(m,1H), 6.46(d,J=3.2Hz,1H),6.99(d,J=7.6Hz,1H),7.10(d,J=44.0Hz,2H),7.14(t,J=14.0Hz,1H),7.40(d,J=3.6Hz,1H),7.52(d,J=8.0Hz,1 m / z:ES + [M+H] + =313.1.

[0815] Example 5: 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitride

[0816] [ka] A suspension of 1 g (2.79 g, 6.24 mmol) of intermediate and 1-[1-(piperidine-4-yl)-1H-indole-4-yl]-1,3-diadinane-2,4-dione TsOH (intermediate 5f) (3.18 g, 6.55 mmol) in NMP (27.0 mL) was stirred at room temperature for 2.5 hours. Sodium triacetoxyborohydride (1.58 g, 7.49 mmol) was added, and the solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 mL), and the suspension was stirred at room temperature for 30 minutes. The solid was recovered by filtration, washed with water (100 mL), and extracted in DCM:IPA (3:1, 500 mL). The organic matter was washed with NaHCO3 solution (150 mL) and NaCl solution (100 mL), dried in a phase separation cartridge, and the solvent was evaporated to dryness. The crude product was purified by flash silica chromatography (elution gradient: 50-100% siRNA in heptane, followed by 100% siRNA for 15 minutes, 0-10% MeOH in DCM for 25 minutes, and 10% MeOH in DCM for 20 minutes) to obtain the product as a solid. The product was slurryed in MeCN (100 mL) at 80°C for 1 hour, and then stirred at room temperature for 18 hours. The solid was recovered by filtration, washed with MeCN, and dried under vacuum at 50°C to obtain the title compound (2.52 g, 54.3%) as an off-white solid. 1 H NMR δ 1.15-1.32(3H,m),1.61-1.74(1H,m),1.79-1.9(4H,m),1.89-2.04(6H,m),2.13-2.22(2H,m),2. 26(2H,d),2.51-2.53(1H,m),2.53-2.65(2H,m),2.73-2.82(3H,m),3.01(2H,d),3.42(2H,d),3. 65(2H,d),3.78(2H,t),4.32-4.43(1H,m),6.42(1H,d),6.86(1H,d),6.88-6.95(2H,m),6.96(1H m / z:ES + [M+H] + =743.4.

[0817] Example 6: 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile

[0818] [ka] The suspensions of intermediates 2d (2.34 g, 5.44 mmol) and 5f (2.77 g, 5.71 mmol) in NMP (23.0 mL) were stirred at room temperature for 2.5 hours. Sodium triacetoxyborohydride (1.38 g, 6.52 mmol) was added, and the solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 mL), and the suspension was stirred at room temperature for 30 minutes. The solid was recovered by filtration and washed with water. The solid was slurryed in MeCN (50 mL) at 80°C for 1 hour, and then cooled to room temperature for 18 hours. The suspension was filtered under vacuum and washed with MeCN to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient of 50-100% siRNA in heptane over 15 minutes, followed by 100% siRNA over 15 minutes, 0-10% MeOH in DCM over 25 minutes, and 10% MeOH in DCM over 20 minutes) to obtain the product as a solid. The product was slurryed in MeCN (100 mL) at 80°C for 1 hour, and then stirred at room temperature for 18 hours. The solid was recovered by filtration, washed with MeCN, and dried under vacuum at 50°C to obtain the title compound (2.22 g, 56.2%) as an off-white solid. 1H NMR δ 1.18-1.3(2H,m),1.6-1.73(1H,m),1.84(4H,d),1.9-2.06(6H,m),2.13-2.23(2H,m),2. 26(2H,d),2.55-2.58(1H,m),2.58-2.68(2H,m),2.71-2.82(4H,m),3.01(2H,d),3.38(2 H,d),3.65(2H,d),3.78(2H,t),4.3-4.46(1H,m),6.42(1H,d),6.82(1H,dd),6.86-7.04 (4H,m),7.14(3H,t),7.44-7.6(2H,m),8.26(1H,s),10.31(1H,s),12.24(1H,s);m / z:ES + [M+H] + =727.5.

[0819] Example 7 Intermediate 7a: Methyl 4-bromo-2-methoxy-6-methylbenzoate

[0820] [ka] A 25% methanol solution of sodium methanol (512 μL, 2.24 mmol) was added dropwise to a stirred solution of methyl 4-bromo-2-fluoro-6-methylbenzoate (527 mg, 2.13 mmol) in DMF (10 mL) under nitrogen at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0°C and quenched with HCl (20 mL) and HCl (1 M, 10 mL). The phases were separated, and the aqueous phase was extracted with HCl (2 × 30 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-25% HCl in heptane) to obtain the title compound (0.410 g, 74%) as a colorless oil, which solidified upon standing. 1 H NMR(CDCl3)δ 2.25(3H,s),3.81(3H,s),3.90(3H,s),6.91(1H,d),6.98(1H,dd);m / z:ES + [M+H] +=227.3.

[0821] Intermediate 7b: 3-(5-bromo-7-methoxy-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione

[0822] [ka] NBS (1.57 g, 8.84 mmol) was added to a stirred solution of methyl 4-bromo-2-methoxy-6-methylbenzoate (1.43 g, 5.53 mmol) and AIBN (0.182 g, 1.11 mmol) in t-butyl acetate (20 mL). The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with SiO4 (50 mL), and washed with water (50 mL). The organic layer was passed through a phase separation cartridge and concentrated. The crude product was purified by flash silica chromatography (elution gradient 0-15% SiO4 in heptane) to obtain 4-bromo-2-(bromomethyl)-6-methoxybenzoate (1.49 g, 80%) as a yellow gum-like substance, which was 70% pure. The solid was added to MeCN (20 mL), followed by the addition of DIPEA (1.65 mL, 9.29 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.510 g, 3.10 mmol) at room temperature. The resulting solution was stirred at 80°C for 16 hours. The reaction mixture was cooled to 0°C, and the solid was recovered by filtration. The solid was washed with MeCN (50 mL) and Et2O (50 mL), dried under vacuum, and the title compound (0.761 g, 39% in 2 steps) was obtained as a lilac solid. 1 H NMR δ 1.97(1H,dtd),2.34(1H,qd),2.54-2.63(1H,m),2.90(1H,m),3.90(3H,s),4.25( m / z:ES + [M+H] + =353.0.

[0823] Intermediate 7c: tert-butyl4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-carboxylate

[0824] [ka] Pd-PEPPSI-IHept Cl (0.380 g, 0.39 mmol) was added to tert-butylpiperazine-1-carboxylate (2.18 g, 11.72 mmol), Cs2CO3 (3.82 g, 11.72 mmol), and 3-(5-bromo-7-methoxy-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione (1.38 g, 3.91 mmol) in degassed 1,4-dioxane (39 mL) under nitrogen at room temperature. The resulting suspension was stirred at 100 °C for 6 hours. The reaction mixture was diluted with DCM (100 mL) and washed sequentially with 5% AcOH in water (100 mL), water (100 mL), NaHCO3 solution (100 mL), and NaCl solution (100 mL). The organic layer was dried over MgSO4, filtered, and evaporated to obtain the crude product. The crude product was ground with dimethylethanol (40 mL) and washed with Et2O (50 mL) to obtain a solid, which was recovered by filtration and dried under vacuum to obtain the title compound (1.15 g, 64%) as a dark gray solid. 1 H NMR δ 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.

[0825] Example 7: 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile

[0826] [ka] Intermediate 1f (780 mg, 1.59 mmol) and tert-butyl 4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-carboxylate (874 mg, 1.91 mmol) were heated in formic acid (5 mL, 132.54 mmol) at 60°C for 2 hours. The reaction mixture was concentrated, and the crude residue was suspended in NMP (5 mL) at room temperature. The mixture was stirred for 5 minutes, and sodium triacetoxyborohydride (673 mg, 3.18 mmol) was added. The resulting suspension was stirred at room temperature for 10 minutes. The reaction mixture was poured into NaHCO3 solution (20 mL), and the resulting solid was collected by filtration and washed with MeCN (20 mL) and siRNA (20 mL). The solid was purified by preparative HPLC (column A, eluate A). The fraction containing the product was evaporated, dissolved in DCM (250 mL), and washed with NaHCO3 solution (100 mL) and NaCl solution (100 mL). The organic layer was dried over MgSO4 and evaporated to dryness to obtain the title compound (350 mg, 27.9%) as a white solid. 1H NMR δ 1.19-1.3(2H,m),1.70(1H,s),1.79-1.88(4H,m),1.9-2.03(3H,m),2.24(2H,d),2. 31(1H,d),2.53(4H,d),2.60(4H,dd),2.79(2H,t),2.85-2.97(1H,m),3.43(2H,d),3 .65(2H,d),3.84(3H,s),4.11(1H,d),4.24(1H,d),4.97(1H,dd),6.50(1H,s),6.62( m / z:ES + [M+H] + =790.0.

[0827] Example 8 Intermediate 8a: 7-Bromo-4-methyl-1H-indole-3-carbonitrile

[0828] [ka] Chlorosulfonyl isocyanate (1.9 mL, 22.61 mmol) was added dropwise at 0°C to a cooled solution of 7-bromo-4-methyl-1H-indole (5.0 g, 23.8 mmol) in MeCN (94 mL) and DMF (23 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then quenched with NaHCO3 solution (50 mL) and diluted with DCM (100 mL). The organic layer was dried in a phase separation cartridge, and the solvent was evaporated to obtain the crude product, which was purified by column chromatography (elution gradient heptane with 0-30% Â) to obtain the title compound (3.93 g, 70.2%) as a cream-colored solid. 1 H NMR(CDCl3)δ 2.75(3H,d),6.92(1H,m),7.35(1H,m),7.78(1H,m),8.73(1H,s);m / z:ES + [M+H] + =235.0.

[0829] Intermediate 8b: 7-(4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride

[0830] [ka] A mixture of 7-bromo-4-methyl-1H-indole-3-carbonitride (459 mg, 1.95 mmol), intermediate 1e (1.23 g, 3.90 mmol), RuPhos (27.3 mg, 0.06 mmol), and RuPhos Pd G3 (49.0 mg, 0.06 mmol) in 1,4-dioxane (3 mL) was mixed with LHMDS (1 M in THF, 10.63 mL, 10.63 mmol) under nitrogen, and the reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with  (50 mL), and washed with water (2 × 50 mL) and NaCl solution (25 mL). The organic layer was dried in a phase separation cartridge and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient heptane with 0-100% siRNA) to obtain the title compound (0.388 g, 42.2%) as a yellow solid. 1 H NMR δ 1.37-1.48(3H,m),1.57-1.7(3H,m),1.7-1.79(3H,m),2.57-2.63(4H,m),2.69-2.79(2H,m),3.38(2H,d),3.68(2H,d) m / z:ES + [M+H] + =471.4.

[0831] Example 8: 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile

[0832] [ka] 7-(4-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile (424 mg, 0.76 mmol) was heated in formic acid (5 mL, 129.46 mmol) at 40°C for 2.5 hours. The reaction mixture was concentrated, and the crude residue was suspended in NMP (2 mL) at room temperature. Intermediate 5f (528 mg, 1.14 mmol) was added, and the reaction mixture was stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (565 mg, 2.67 mmol) was added, and the resulting suspension was stirred at room temperature for 10 minutes. The reaction mixture was quenched with water (10 mL), and the product was extracted with DCM:IPA (9:1, 25 mL). The organic layer was washed with NaHCO3 solution and NaCl solution (10 mL), and dried in a phase separation cartridge. The solvent was evaporated, and the crude product was purified by flash silica chromatography (elution gradient DCM with 0-25% IPA) to obtain the title compound (291 mg, 0.403 mmol, 52.9%) as a white solid. 1 H NMR δ 1.16-1.31(3H,m),1.61-1.75(1H,m),1.84(4H,d),1.89-2.09(6H,m),2.13-2.31(4H,m),2. 55-2.61(4H,m),2.61-2.7(1H,m),2.7-2.82(4H,m),3.02(2H,d),3.38(2H,d),3.65(2H,d),3 .72-3.83(2H,m),4.39(1H,s),6.42(1H,d),6.77(1H,d),6.84-6.94(3H,m),6.96(1H,dd),7 .11-7.18(3H,m),7.51(1H,d),7.54(1H,d),8.16(1H,d),10.31(1H,s),11.89(1H,s);m / z:ES + [M+H] + =723.5.

[0833] Example 9 Intermediate 9a: 7-bromo-4-chloro-1H-indazole

[0834] [ka] 3-Bromo-6-chloro-2-fluorobenzaldehyde (23.0 g, 96.86 mmol) was added to 1,2-dimethoxyethane (230 mL), and hydrazine hydrate (14.55 g, 290.58 mmol) was added. The mixture was stirred under reflux for 36 hours, cooled to room temperature, and then poured into rapidly stirred water (460 mL) for 30 minutes. The resulting solid was filtered, washed with water (2 × 200 mL), and dried in a vacuum oven at 50°C for 24 hours to obtain the title compound (21.80 g, 97%) as a white solid. 1 H NMR δ 7.16(1H,d),7.60(1H,d),8.30(1H,s),13.02(1H,s);m / z:ES + [M+H] + =231.1.

[0835] Intermediate 9b: 7-Bromo-4-chloro-3-iodo-1H-indazole

[0836] [ka] 7-Bromo-4-chloro-1H-indazole (21.0 g, 90.72 mmol) was added to DMF (100 mL) and potassium hydroxide (20.36 g, 362.89 mmol), and the mixture was cooled to 0°C. Iodine (29.9 g, 117.94 mmol) was added, and after 5 minutes, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with sodium thiosulfate (20% aqueous solution, 250 mL) and extracted with siRNA (250 mL). The organic layer was washed with lithium chloride (10% aqueous solution, 250 mL), water (2 × 250 mL), and NaCl solution (100 mL), dried in a phase separation cartridge, and the solvent was evaporated to obtain the title compound (31.2 g, 96%) as a cream-colored solid. 1 H NMR δ 7.15(1H,d),7.63(1H,d),14.23(1H,s);m / z:ES-[MH]- =355.0.

[0837] Intermediate 9c: 7-Bromo-4-chloro-1H-indazole-3-carbonitride

[0838] [ka] 7-Bromo-4-chloro-3-iodo-1H-indazole (10.0 g, 27.98 mmol) and potassium hexacyanoferrate(II) trihydrate (4.73 g, 11.19 mmol) were added to dimethylacetamide (80 mL) under nitrogen and stirred at 60°C for 10 minutes. Water (60 mL) was added, followed by Xantphos (0.810 g, 1.40 mmol) and allyl palladium(II) chloride dimer (0.256 g, 0.70 mmol), and the mixture was stirred at 95°C for 4.5 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and washed with 2-MeTHF (200 mL). The mother liquor was diluted with water (200 mL), washed with water (2 × 200 mL) and NaCl solution (100 mL), dried in a phase separation cartridge, and the solvent was evaporated. The crude product was suspended in MeCN (50 mL) and stirred under reflux. Water (50 mL) was added, followed by MeCN (20 mL). The solution was decanted while still hot through cotton wool and cooled to room temperature. The resulting solid was filtered, dried under vacuum, and slurryed in DCM (20 mL) for 5 minutes. The resulting solid was dried under vacuum to obtain the title compound (4.55 g, 63.4%) as an off-white solid. 1 H NMR δ 7.40(1H,d),7.79(1H,d),15.17(1H,s);m / z:ES - [MH] - =254.0.

[0839] Intermediate 9d: Benzyl(3S)-3-(4-bromophenyl)piperidine-1-carboxylate

[0840] [ka] K2CO3 (2M, 159.0 mL, 318.01 mmol) was gradually added at room temperature to a solution of (S)-3-(4-bromophenyl)piperidine oxalate (35.0 g, 106.00 mmol) in THF (250 mL) and water (100 mL). Then, 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (26.4 g, 106.00 mmol) was gradually added, and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with ELISA (500 mL) and water (250 mL), stirred for 10 minutes, and the layers were separated. The organic layer was washed with citric acid (1M, 250 mL) and NaCl solution (200 mL), dried in a phase separation cartridge, and evaporated to dryness to obtain the crude product. The crude product was dissolved in EtOH (100 mL) and water (300 mL), stirred at 60°C, and then cooled to room temperature. The resulting solid was filtered under vacuum and dried in a vacuum oven at 45°C to obtain the title compound (37.6 g, 94%) as a cream-colored solid. 1 H NMR δ 1.48(1H,m),1.63(1H,m),1.72(1H,m),1.83-1.93(1H,m),2.65(1H,tt),2.87(2H,s) ,3.96-4.08(2H,m),5.10(2H,s),7.24(2H,d),7.28-7.42(5H,m),7.50(2H,d);m / z:ES + [M+H] + =374.1.

[0841] Intermediate 9e: Benzyl(3S)-3-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-carboxylate

[0842] [ka] 4-(1,3-dioxolan-2-yl)piperidine (25.9 g, 164.74 mmol), benzyl(3S)-3-(4-bromophenyl)piperidine-1-carboxylate (56.1 g, 149.77 mmol), and Cs2CO3 (98.0 g, 299.54 mmol) were degassed under nitrogen for 10 minutes in 1,4-dioxane (500 mL). Then, Pd(t-Bu3P)2 (3.83 g, 7.49 mmol) and tri-tert-butylphosphonium tetrafluoroborate (4.35 g, 14.98 mmol) were added, and the mixture was stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature, and the solid was filtered through Celite®. The solid was washed with 1,4-dioxane (200 mL), and the filtrate was evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient of 10-50% siRNA in heptane) to obtain the title compound (28.5 g, 42.2%) as a cream-colored solid. 1 H NMR δ 1.33-1.52(3H,m),1.55-1.68(2H,m),1.68-1.78(3H,m),1.85(1H,d),2.54(1H,s),2.59(2H,td),2.84(2H,s),3.67(2H,d),3.74- m / z:ES + [M+H] + =451.3.

[0843] Intermediate 9f: 4-(1,3-dioxolan-2-yl)-1-{4-[(3S)-piperidine-3-yl]phenyl}piperidine

[0844] [ka] Benzyl(3S)-3-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-carboxylate (27.5 g, 61.03 mmol) was suspended in EtOH (100 mL) and DCM (20 mL). Pd / C (10%, 2.6 g, 2.44 mmol) was added, and the reaction mixture was hydrogenated at a pressure of 2 bar at room temperature for 16 hours. DCM (50 mL) was added to the reaction mixture, and it was filtered through Celite®. The filtrate was evaporated to dryness, stirred in MTBE (50 mL) for 16 hours, filtered, and dried under vacuum to obtain the title compound (14.95 g, 77%) as a cream-colored solid. 1 H NMR δ 1.33-1.44(2H,m),1.48(2H,d),1.62(2H,m),1.72(2H,d),1.82(1H,d),2.47(4H,d),2.58(2H,m),2.94( m / z:ES + [M+H] + =317.2.

[0845] Intermediate 9g: 4-Chloro-7-[(3S)-3-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitrile

[0846] [ka] Intermediate 9c (2.3 g, 8.98 mmol) and 4-(1,3-dioxolan-2-yl)-1-{4-[(3S)-piperidine-3-yl]phenyl}piperidine (2.90 g, 9.16 mmol) were suspended in 2-MeTHF (25 mL). The mixture was degassed under nitrogen for 10 minutes, followed by the addition of CPhos (0.39 g, 0.90 mmol) and [Pd(cinnamyl)Cl]2 (0.23 g, 0.45 mmol). LHMDS (1 M in THF, 31.4 mL, 31.45 mmol) was added, and the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was then cooled to room temperature and partitioned between water (25 mL) and 2-MeTHF (25 mL). The organic layer was washed with NaCl solution (25.0 mL), dried through a phase separation cartridge, and the solvent was evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient heptane 0-100% siRNA) to obtain the title compound (2.46 g, 55.6%) as a pale orange solid. 1 H NMR δ 1.39(2H,m),1.62(2H,m),1.72(2H,d),1.84-1.98(3H,m),2.59(2H,m),2.66-2.8(2H,m),3.00(1H,t),3.47(2H,t),3.67(2H,d ),3.75-3.83(2H,m),3.83-3.9(2H,m),4.61(1H,d),6.87(2H,d),6.94(1H,d),7.18(2H,d),7.28(1H,d),14.69(1H,s);m / z:ES + [M+H] + =492.3.

[0847] Intermediate 9h: 4-Chloro-7-{(3S)-3-[4-(4-formylpiperidine-1-yl)phenyl]piperidine-1-yl}-1H-indazole-3-carbonitrile

[0848] [ka] To a stirred solution of 4-chloro-7-[(3S)-3-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitrile (3.15 g, 6.40 mmol) in THF (32.0 mL), HCl (2 M, 64.0 mL, 128.04 mmol) was added. The reaction mixture was stirred at 60 °C for 4 hours and then cooled to 0 °C in an ice bath. The mixture was neutralized to pH 7 with NaOH (2 M), extracted with 2-MeTHF (100 mL), washed with water (100 mL) and NaCl solution (50 mL), dried in a phase separation cartridge, and the solvent was evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient heptane with 0-100% siRNA) to obtain the title compound (2.5 g, 87%) as a yellow solid. 1 H NMR δ 1.58(3H,m),1.83-1.98(5H,m),2.46(1H,m),2.66-2.82(4H,m),2.94-3.06(1H,m),3.4-3.6( m / z:ES + [M+H] + =448.3.

[0849] Example 9: 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride

[0850] [ka] A suspension of 4-chloro-7-{(3S)-3-[4-(4-formylpiperidine-1-yl)phenyl]piperidine-1-yl}-1H-indazole-3-carbonitrile (9.22 g, 20.58 mmol) and intermediate 5f (10.47 g, 21.61 mmol) in NMP (92 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (5.23 g, 24.70 mmol) was added, and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (250 mL), and the suspension was stirred at room temperature for 30 minutes. The solid was collected by filtration, washed with excess water, and extracted with DCM:IPA (3:1, 250 mL). The organic layer was washed with NaHCO3 solution (100 mL) and NaCl solution (100 mL) and dried on a phase separation cartridge. The solvent was evaporated, and the crude product was purified by flash silica chromatography (elution gradient of 0-100% siRNA in heptane, followed by 0-10% MeOH in siRNA). The product was then slurryed in MeCN (225 mL) at 80°C for 3 hours, and then cooled to room temperature for 16 hours. The solid was recovered by filtration, washed with excess MeCN, and dried under vacuum at 45°C to obtain the title compound (11.57 g, 76%) as a pale orange solid. 1 H NMR δ 1.17-1.29(2H,m),1.53-1.72(2H,m),1.79-1.85(2H,m),1.85-1.99(5H,m),1.98-2.06(2H,m),2. 15-2.24(2H,m),2.27(2H,d),2.57-2.65(2H,m),2.66-2.79(4H,m),2.95-3.05(3H,m),3.43-3.55( 2H,m),3.63(2H,d),3.78(2H,t),4.33-4.43(1H,m),6.41(1H,d),6.88(2H,d),6.92(1H,d),6.96(1 m / z:ES + [M+H] + =744.4.

[0851] Example 10: 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride

[0852] [ka] 9 g (2.0 g, 3.46 mmol) of intermediate and intermediate 1i (1.48 g, 3.46 mmol) were heated in formic acid (20 mL) at 40 °C for 2 hours. The reaction mixture was cooled and evaporated to dryness, and the residue was stirred in NMP (20 mL) at room temperature for 16 hours. The reaction mixture was poured into NaHCO3 solution (300 mL), the precipitate was collected by filtration, washed with water (100 mL), and dried under vacuum to obtain the crude product, which was purified by flash silica chromatography (elution gradient 0-6% DCM in EtOH). The pure fraction was evaporated to dryness to obtain the product, which was slurryed in MeCN (50 mL), filtered under vacuum, and the title compound (1.17 g, 44.5%) was obtained as a yellow solid. 1 H NMR δ 1.12-1.27(2H,m),1.49-1.59(1H,m),1.59-1.71(1H,m),1.73-2.01(6H,m),2.19(2 H,d),2.28-2.43(1H,m),2.49(4H,dd),2.54-2.78(5H,m),2.83-3.04(2H,m),3.27(4 H,t),3.46(2H,t),3.60(2H,d),4.16-4.37(2H,m),5.05(1H,dd),6.88(3H,dd),7.0 4(2H,d),7.15(2H,d),7.25(1H,d),7.52(1H,d),10.95(1H,s),14.62(1H,s);m / z:ES + [M+H] + =760.0.

[0853] Example 11 Intermediate 11a: Benzyl(3S)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-carboxylate

[0854] [ka] Pd(t-Bu3P)2 (0.55 g, 1.07 mmol) was added under nitrogen to intermediate 9d (4.0 g, 10.69 mmol), 4-(dibutoxymethyl)piperidine (2.6 g, 10.69 mmol), Cs2CO3 (6.96 g, 21.37 mmol), and tri-tert-butylphosphonium tetrafluoroborate (0.310 g, 1.07 mmol) in 1,4-dioxane (50 mL). The resulting mixture was stirred at 100 °C for 2 hours. The mixture was then cooled to room temperature, and the solvent was evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-40% siRNA in Et2O) to obtain the title compound (2.3 g, 40.1%) as a yellow oil. 1 H NMR δ 0.89(6H,t),1.24-1.55(12H,m),1.57-1.91(6H,m),2.59(1H,s),2.82(2H,s),3.32-3.46(3H,m),3.4 9-3.71(4H,m),4.01(2H,t),4.19(1H,d),5.09(2H,s),6.86(2H,d),7.07(2H,d),7.35(5H,q);m / z:(ES + ),[M+H] + = 537.5.

[0855] Intermediate 11b: 4-(dibutoxymethyl)-1-{4-[(3S)-piperidine-3-yl]phenyl}piperidine

[0856] [ka] Pd / C (10%, 0.912g, 0.86 mmol) was added to benzyl (3S-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl)piperidine-1-carboxylate (2.3g, 4.28 mmol) in SiO2:MeOH (5:1, 30 mL) under a hydrogen atmosphere at room temperature for 3 hours. The mixture was filtered through Celite® and evaporated to dryness to obtain the title compound (1.6g, 93%) as a white oil, which was used without further purification. 1 H NMR δ 0.89(6H,t),1.24-1.42(4H,m),1.43-1.57(5H,m),1.59-1.87(4H,m),2.43(4H,d),2.57(1H,s),2 .91(2H,d),3.22-3.47(7H,m),3.49-3.69(4H,m),4.19(1H,d),6.84(2H,d),7.04(2H,d);m / z:(ES + ),[M+H] + =403.1.

[0857] Intermediate 11c: 4-Chloro-7-[(3S)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0858] [ka] LHMDS (1M in THF, 10.43 mL, 10.43 mmol) is mixed with 4-(dibutoxymethyl)-1-{4-[(3S)-piperidine-3-yl]phenyl}piperidine (1.2 g, 2.98 mmol) in THF (5.0 mL), intermediate 1b (0.838 g, 3.28 mmol), and Pd-PEPPSI-IHept ClIt was added to (0.145 g, 0.15 mmol). The resulting mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, quenched with NH4Cl solution (10 mL), extracted with siRNA (2 × 20 mL), dried over Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-30% siRNA in Et2O) to obtain the title compound (1.4 g, 81%) as a brown solid. 1 H NMR δ 0.89(6H,t),1.27-1.4(6H,m),1.43-1.54(5H,m),1.72(4H,d),1.79-1.98(3H,m),2.53-2.8(4H,m),2.98(1H,d),3.3 m / z:(ES + ),[M+H] + =577.3.

[0859] Example 11: 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitride

[0860] [ka] 4-Chloro-7-[(3S)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile (1.2 g, 2.08 mmol) was heated in formic acid (16.0 ml, 417.16 mmol) at 40°C for 1 hour. The mixture was cooled, evaporated, and diluted in NMP (16.0 mL). Intermediate 5f (1.01 g, 2.08 mmol) and sodium acetate (0.205 g, 2.49 mmol) were added, and the resulting mixture was stirred at 40°C for 2 hours. The reaction mixture was then poured into a Na2CO3 solution (150 mL), the precipitate was collected by filtration, washed with water (50 mL), and dried under vacuum to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-10% DCM in EtOH) to obtain the product, which was then slurryed in MeCN (50 mL) and filtered under vacuum to obtain the title compound (1.16 g, 75%) as a white solid. 1 H NMR δ 1.21(2H,m),1.46-1.72(2H,m),1.82(3H,dd),1.87-2.05(6H,m),2.17(4H,dd ),2.63(4H,dq),2.76(2H,t),2.97(3H,d),3.30(1H,d),3.36(1H,s),3.61(2H ,d),3.77(2H,t),4.36(1H,tt),6.41(1H,d),6.84(3H,dd),6.96(1H,d),7.14 (4H,dd),7.44-7.61(2H,m),8.31(1H,s),10.34(1H,s),12.28(1H,s);m / z;ES + [M+H] + =743.3.

[0861] Example 12: 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0862] [ka] Intermediate 11c (2.3 g, 3.98 mmol) and intermediate 1i (1.7 g, 3.98 mmol) were heated in formic acid (20 mL) at 40°C for 1 hour. The reaction mixture was then cooled and evaporated to obtain a residue, which was diluted with NMP (20 mL). The resulting reaction mixture was stirred at 40°C for 16 hours and then poured into Na2CO3 solution (300 mL). The precipitate was collected by filtration, washed with water (50 mL), and dried under vacuum to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-6% DCM in EtOH) to obtain the product, which was slurryed in MeCN and filtered under vacuum to obtain the title compound (0.93 g, 30.7%) as a white solid. 1 H NMR δ 1.14-1.28(2H,m),1.46-1.61(1H,m),1.68(1H,d),1.74-1.87(3H,m),1.88-2(3H,m),2.20(2H ,d),2.28-2.44(1H,m),2.45-2.5(3H,m),2.51(1H,s),2.54-2.73(5H,m),2.83-3.03(2H,m),3 .24-3.31(4H,m),3.35(2H,d),3.61(2H,d),4.21(1H,d),4.33(1H,d),5.05(1H,dd),6.84(3H, m / z:ES + [M+H] + =759.5.

[0863] Example 13 Intermediate 13a: tert-butyl 4-[(2-amino-4-bromophenyl)ethynyl]piperidine-1-carboxylate

[0864] [ka] PdCl2(PPh3)2 (3.36 g, 4.78 mmol) was added in one batch under nitrogen at room temperature to tert-butyl 4-ethynylpiperidine-1-carboxylate (10.01 g, 47.83 mmol), 5-bromo-2-iodoaniline (14.25 g, 47.83 mmol), copper(I) iodide (1.36 g, 7.17 mmol), and triethylamine (19.97 ml, 143.49 mmol) in DMF (145 mL). The resulting dark brown solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (150 mL), and the product was extracted with MTBE (150 mL). The organic layer was washed with water (150 mL) and NaCl solution (50 mL), dried over MgSO4, and evaporated to obtain the crude product. The crude product was purified by column chromatography (elution gradient 5-20% heptane: SiO2) to obtain the title compound (24.14 g, 55%) as an orange oily substance. 1 H NMR δ 1.46(9H,s),1.68(2H,m),1.88(2H,m),2.83(1H,m),3.18-3.26(2H,m), 3.76(2H,m),4.18(2H,s),6.78(1H,m),6.84(1H,m),7.08(1H,m);m / z:ES + [M+H] + =379.1.

[0865] Intermediate 13b: tert-butyl 4-(6-bromo-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate

[0866] [ka] Potassium tert-butoxide (13.30 g, 118.48 mmol) was gradually added to tert-butyl 4-[(2-amino-4-bromophenyl)ethynyl]piperidine-1-carboxylate (21.4 g, 39.49 mmol) in NMP (200 mL), and the mixture was stirred at room temperature for 3 hours. Iodomethane (7.38 ml, 118.48 mmol) was gradually added, and the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was then quenched with NH4Cl solution (100 mL) and water (100 mL). The product was extracted with 2-MeTHF (2 × 200 mL), and the combined organic layer was washed with water (2 × 100 mL) and NaCl solution (100 mL), dried over MgSO4, and evaporated to obtain the crude product as a brown oil. The crude product was purified by flash silica chromatography (elution gradient 0-50% ELISA in heptane). The pure fraction was evaporated to obtain a solid, which was then ground with heptane (50 mL). The solid was recovered by filtration and dried in a vacuum oven at 45°C to obtain the title compound (13.74 g, 88%) as a white solid. 1 H NMR δ 1.51(9H,s),1.68(2H,qd),1.99(2H,d),2.79-2.96(3H,m),3.70(3H,s),4. 28(2H,m),6.24(1H,s),7.19(1H,m),7.39-7.44(1H,m),7.45(1H,m);m / z:ES + [M+H] + =393.3.

[0867] Intermediate 13c: tert-butyl4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-carboxylate

[0868] [ka] 10.82 g, 27.51 mmol of tert-butyl 4-(6-bromo-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate was dissolved in 1,4-dioxane (180 mL), followed by the addition of hexahydropyrimidine-2,4-dione (9.42 g, 82.53 mmol), K2CO3 (11.41 g, 82.53 mmol), and tert-butyl BrettPhos (1.33 g, 2.75 mmol). The mixture was degassed with nitrogen, and then tert-butyl BrettPhos Pd G3 (2.350 g, 2.75 mmol) was added. The mixture was stirred at 100 °C for 42 hours. The reaction mixture was cooled, and water (180 mL) and 2-MeTHF (180 mL) were added to separate the layers. The organic layer was washed with water (180 mL) and NaCl solution (50 mL), dried over MgSO4, filtered, and evaporated to obtain the crude product as a dark brown solid. The solid was slurryed in toluene (30 mL), the resulting brown suspension was filtered, washed with toluene (10 mL), and the title compound (6.59 g, 56.2%) was obtained as a light brown solid. 1 H NMR δ 1.43(11H,m),1.94(2H,dm,2.73(2H,t),2.82-3.07(3H,m),3.70(3H,s),3.79(2H,m),4 .06(2H,dd),6.24(1H,s),6.94(1H,dd),7.37(1H,d),7.43(1H,d),10.26(1H,s);m / z:ES + [M-tert-Bu+H] + =371.1.

[0869] Example 13: 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitride

[0870] [ka] tert-butyl 4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-carboxylate (1.55 g, 3.64 mmol) and intermediate 11c (2.1 g, 3.64 mmol) were heated in formic acid (20 mL, 3.64 mmol) at 40°C for 2 hours. The reaction mixture was then cooled and evaporated to obtain the residue, which was diluted with NMP (20 mL). The resulting mixture was stirred at 40°C for 16 hours. The reaction mixture was then poured into a Na2CO3 solution (150 mL), the precipitate was collected by filtration, washed with water (50 mL), and dried under vacuum to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-10% DCM in EtOH) to obtain the product, which was then slurryed in MeCN and filtered under vacuum to obtain the title compound (1.10 g, 39.9%) as a pale yellow solid. 1 H NMR δ 1.12-1.28(2H,m),1.47-1.58(1H,m),1.58-1.73(3H,m),1.73-1.88(3H,m),1.88-1.99(4H,m ),2.04(2H,t),2.18(2H,d),2.53-2.69(4H,m),2.73(3H,t),2.85-3.05(3H,m),3.30(1H,d), 3.36(1H,d),3.61(2H,d),3.68(3H,s),3.78(2H,t),6.22(1H,s),6.79-6.9(3H,m),6.93(1H, m / z;ES + [M+H] + =757.4.

[0871] Example 14 Example 14a: 1-[1-methyl-2-(piperidine-4-yl)-1H-indole-6-yl]-1,3-diadinane-2,4-diotosylate

[0872] [ka] A mixture of intermediate 13c (1.6 g, 3.75 mmol) and 4-methylbenzenesulfonic acid hydrate (0.856 g, 4.50 mmol) in MeCN (16.0 mL) was stirred at 70°C for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with MTBE (16 mL), and stirred for 15 minutes. The solid was filtered and washed with excess MTBE. The solid was dried at 40°C under vacuum to obtain the title compound (1.65 g, 88%) as a cream-colored solid. 1 H NMR δ 1.71-1.85(2H,m),2.12(2H,m),2.29(3H,m),2.74(2H,t),3.03-3.24(3H,m), 3.41(1H,m),3.71(3H,s),3.79(2H,t),6.26(1H,s),7.45-7.52(3H,m);m / z:ES + [M+H] + =327.3.

[0873] Example 14: 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride

[0874] [ka] A suspension of intermediate 9h (1.38 g, 3.08 mmol) and 1-[1-methyl-2-(piperidine-4-yl)-1H-indole-6-yl]-1,3-diadinane-2,4-dione TsOH (1.61 g, 3.23 mmol) in NMP (14.0 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (0.78 g, 3.70 mmol) was added, and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (40 mL), and the suspension was stirred at room temperature for 30 minutes. The solid was recovered by filtration and washed with water. The solid was dissolved in DCM:IPA (3:1, 150 mL), washed with NaHCO3 solution (150 mL) and NaCl solution (100 mL), dried in a phase separation cartridge, and evaporated to dryness to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient of 0-100% siRNA in heptane, followed by 0-10% MeOH in DCM) to obtain the desired product. This product was slurryed in MeCN (30 mL) at 80°C for 3 hours and then cooled to room temperature for 18 hours. The solid was filtered under vacuum to obtain the title compound (1.27 g, 54.4%) as a pale pink solid. 1 H NMR δ 1.16-1.28(2H,m),1.53-1.73(4H,m),1.76-1.98(7H,m),2.07-2.17(2H,m),2.25(2H ,d),2.56-2.65(2H,m),2.66-2.84(5H,m),2.93-3.04(3H,m),3.47-3.57(2H,m),3.6 3(2H,d),3.68(3H,s),3.78(2H,t),6.23(1H,s),6.85-6.91(3H,m),6.93(1H,dd),7. 18(2H,d),7.24(1H,d),7.36(1H,s),7.42(1H,d),10.27(1H,s),14.43(1H,s);m / z:ES + [M+H] + =758.4.

[0875] Example 15: 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride

[0876] [ka] Using the general synthesis method illustrated in Example 7, intermediate 8b was reacted with intermediate 7c, and after purification by HPLC (column A, eluate A), the title compound (formate) (31 mg, 18%) was obtained as a white solid. 1 H NMR δ 1.20-1.27(3H,m),1.68(2H,s),1.82(4H,d),1.95(3H,s),2.23(2H,s),2.31(1H,d),2 .51(4H,s),2.56-2.68(7H,m),2.74(2H,t),2.88(1H,q),3.30(2H,s),3.38(2H,d),3. 64(2H,d),3.84(3H,s),4.05-4.27(2H,m),4.96(1H,dd),6.49(1H,s),6.61(1H,s),6. 77(1H,d),6.89(3H,dd),7.13(2H,d),8.16(1H,d),10.91(1H,s),11.90(1H,s);m / z:ES + [M+H] + =769.4.

[0877] Examples 16 and 17 The enantiomers of Example 7 were separated by SFC purification using Sepiatec 100 SFC under SFC conditions (Regis(R,R)Whelk-01, 21.1 × 250 mm, 5 microns, 50% MeOH / MeCN 3:7 / 50% scCO2, flow rate 60 mL / min, 40°C), and in order of elution, Example 16 (isomer 1, 12 mg, 28.6%) and Example 17 (isomer 2, 13 mg, 31.0%) were obtained as white solids.

[0878] Example 16: 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R * )-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile [Absolute stereochemistry is unconfirmed]

[0879] [ka] 1 H NMR δ 1.26(2H,s),1.70(1H,s),1.84(4H,s),1.97(3H,d),2.24(3H,d),2.54-2.65( 4H,m),2.72-2.85(2H,m),2.88(1H,d),3.43(2H,d),3.65(2H,d),3.84(3H,s), 4.11(1H,d),4.24(1H,d),4.97(1H,dd),6.50(1H,s),6.62(1H,s),6.87(1H,d ),6.91(2H,d),7.15(3H,dd),8.32(1H,s),10.90(1H,s),12.26(1H,s);m / z:ES + [M+H] + =789.6;>99%ee.

[0880] Example 17: 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile [Absolute stereochemistry is unconfirmed]

[0881] [ka] 1H NMR δ 1.26(2H,s),1.70(1H,s),1.84(4H,s),1.98(3H,d),2.24(2H,d),2.31(1H,s) ,2.62(4H,d),2.73-2.83(2H,m),2.83-2.95(1H,m),3.43(2H,d),3.65(2H,d), 3.84(3H,s),4.11(1H,d),4.24(1H,d),4.97(1H,dd),6.50(1H,s),6.62(1H,s) ,6.89(3H,dd),7.15(3H,dd),8.32(1H,s),10.90(1H,s),12.26(1H,s);m / z:ES + [M+H] + =789.6;>99%ee.

[0882] Examples 18 and 19: The enantiomers of Example 1 were separated by SFC purification in a Sepiatec 100 SFC using SFC conditions (Regis(R,R)Whelk-01, 21.1 × 250 mm, 5 microns, 50% MeOH / MeCN 3:7 / 50% scCO2, flow rate 60 mL / min, 40°C). In order of elution, Example 18 (isomer 1, 410 mg, 20.8%) and Example 19 (isomer 2, 400 mg, 20.3%) were obtained as white solids.

[0883] Example 18: 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R * )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile [Absolute stereochemistry is unconfirmed]

[0884] [ka] 1H NMR δ 1.25(3H,s),1.70(1H,s),1.84(4H,s),1.97(4H,d),2.24(2H,d),2.35-2.43(2H ,m),2.55-2.65(3H,m),2.78(2H,t),2.84-2.97(1H,m),3.43(2H,d),3.65(2H,d) ,4.22(1H,d),4.34(1H,d),5.05(1H,dd),6.86(1H,d),6.91(2H,d),7.07(2H,d), 7.11-7.19(3H,m),7.53(1H,d),8.31(1H,s),10.94(1H,s),12.26(1H,s);m / z:ES + [M+H] + =759.7;>99%ee.

[0885] Example 19: 4-Chloro-7-[4-(4-{4-[(4-{2-[(3S * )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile [Absolute stereochemistry is unconfirmed]

[0886] [ka] 1 H NMR δ 1.16-1.32(2H,m),1.70(1H,s),1.78-1.9(4H,m),1.97(3H,d),2.24(2H,d),2.37(2 H,dd),2.55-2.59(1H,m),2.62(2H,d),2.78(2H,t),2.84-2.96(1H,m),3.43(2H,d), 3.65(2H,d),4.22(1H,d),4.34(1H,d),5.05(1H,dd),6.87(1H,d),6.91(2H,d),7.07 (2H,d),7.15(3H,dd),7.53(1H,d),8.32(1H,s),10.94(1H,s),12.26(1H,s);m / z:ES + [M+H] +=759.7;>99%ee.

[0887] Example 20: 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride

[0888] [ka] Using the general synthesis method illustrated in Example 7, intermediate 2c was reacted with intermediate 7c, and after purification by HPLC (column A, eluate A), the title compound in the form of formate (20 mg, 14%) was obtained as a white solid. 1 H NMR δ 1.24(2H,d),1.69(1H,s),1.85(4H,s),1.88-2.05(3H,m),2.23(2H,d),2.25-2.37(1H,m ),2.56-2.74(4H,m),2.78(2H,d),2.88(1H,d),3.30(8H,d),3.39(1H,s),3.65(3H,d),3 .84(3H,s),4.03-4.29(2H,m),4.91-5.03(1H,m),6.50(1H,s),6.62(1H,s),6.77-6.87( m / z:ES + [M+H] + =773.0.

[0889] Example 21 Intermediate 21a: Benzyl(3R)-3-(4-bromophenyl)piperidine-1-carboxylate

[0890] [ka] Using the general synthetic method exemplified in Example 1c, (R)-3-(4-bromophenyl)piperidine oxalate was reacted with benzylcarbonochloride to obtain the title compound (1.0 g, 64.2%) as a colorless oil. 1 H NMR δ 1.4-1.54(1H,m),1.58-1.67(1H,m),1.67-1.77(1H,m),1.87(1H,dd),2.59-2.71(1H,m),2.8 7(2H,s),3.9-4.12(2H,m),5.09(2H,d),7.24(2H,d),7.34(5H,q),7.47-7.53(2H,m);m / z:ES + [M+H] + =374.0.

[0891] Intermediate 21b: Benzyl(3R)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-carboxylate

[0892] [ka] Using the general synthetic method exemplified in Example 11a, benzyl(3R)-3-(4-bromophenyl)piperidine-1-carboxylate was reacted with 4-(dibutoxymethyl)piperidine to obtain the title compound (462 mg, 32.1%) as a yellow oil. 1 H NMR δ 0.88(6H,t),1.24-1.37(7H,m),1.41-1.54(6H,m),1.54-1.76(6H,m),1.84(1H,d),2.52-2.59(2H,m),3.35-3.45(2H,m), 3.51-3.6(2H,m),3.63(2H,d),4.01(2H,t),4.18(1H,d),5.08(2H,s),6.85(2H,d),7.07(2H,d),7.27-7.47(5H,m);m / z:ES + [M+H] + =537.2.

[0893] Intermediate 21c: 4-(dibutoxymethyl)-1-{4-[(3R)-piperidine-3-yl]phenyl}piperidine

[0894] [ka] Using the general synthesis method exemplified in Example 11b, benzyl(3R)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-carboxylate was reacted with Pd / C (10%) and hydrogen gas to obtain the title compound (300 mg, 87.0%) as a colorless oil. 1 H NMR δ 0.88(6H,t),1.23-1.4(7H,m),1.41-1.55(6H,m),1.58-1.89(5H,m),2.42(3H,q),2.54(2H,d),2.90(2H,d),3. 34-3.43(2H,m),3.52-3.57(2H,m),3.58-3.65(2H,m),4.18(1H,d),6.76-6.9(2H,m),6.99-7.1(2H,m);m / z:ES + [M+H] + =403.2.

[0895] Intermediate 21d: 4-Chloro-7-[(3R)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile

[0896] [ka] Using the general synthetic method exemplified in Example 11c, 4-(dibutoxymethyl)-1-{4-[(3R)-piperidine-3-yl]phenyl}piperidine was reacted with intermediate 1b to obtain the title compound (60 mg, 27.9%) as a brown solid. 1H NMR δ 0.89(6H,t),1.3-1.42(5H,m),1.48(5H,q),1.72(3H,d),1.8-2.06(4H,m),2.66(3H,d),3.00(1H,s),3 .41(5H,s),3.5-3.72(4H,m),4.19(1H,d),6.86(3H,t),7.15(3H,t),8.31(1H,d),12.28(1H,s);m / z:ES + [M+H] + =577.2.

[0897] Example 21: 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitride

[0898] [ka] Using the general synthesis method illustrated in Example 7, intermediate 21d was reacted with intermediate 1i, and after purification by HPLC (column A, eluate A), the title compound in the form of formate (30 mg, 28%) was obtained as a white solid. 1 H NMR δ 1.21(2,q),1.48-1.62(1H,m),1.68(1H,s),1.72-2.03(7H,m),2.21(2H,d),2. 28-2.48(2H,m),2.5-2.75(6H,m),2.84-3.07(2H,m),3.28(5H,s),3.35(2H,s) ,3.62(2H,d),4.20(1H,d),4.33(1H,d),5.05(1H,dd),6.85(3H,dd),7.07(2H, d),7.15(3H,dd),7.52(1H,d),8.31(1H,d),10.95(1H,s),12.28(1H,d);m / z:ES + [M+H] + =759.4.

[0899] Example 22 Intermediate 22a: tert-butyl 4-(4-{1-[(benzyloxy)carbonyl]piperidine-4-yl}phenyl)piperazine-1-carboxylate

[0900] [ka] Pd(t-Bu3P)2 (0.137 g, 0.27 mmol) was added under nitrogen to 1,4-dioxane (10 mL) containing tri-tert-butylphosphonium tetrafluoroborate (0.078 g, 0.27 mmol), Cs2CO3 (1.741 g, 5.34 mmol), tert-butylpiperazine-1-carboxylate (0.498 g, 2.67 mmol), and intermediate 1c (1.00 g, 2.67 mmol). The resulting mixture was stirred at 100°C for 19 hours. The reaction mixture was then cooled to room temperature, and the solvent was evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient Et2O 0-40% SiO) to obtain the title compound (1.0 g, 78%) as a yellow solid. m / z:ES + [M+H] + =480.4.

[0901] Intermediate 22b: tert-butyl 4-[4-(piperidine-4-yl)phenyl]piperazine-1-carboxylate

[0902] [ka] Pd / C (10%, 0.67 g, 0.63 mmol) and tert-butyl 4-(4-{1-[(benzyloxy)carbonyl]piperidine-4-yl}phenyl)piperazine-1-carboxylate (1.00 g, 2.08 mmol) in MeOH:SiO (1:5, 1.2 mL) were stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered through Celite® and evaporated to dryness to obtain the title compound, which was used without further purification. m / z:ES + [M+H] + =346.3.

[0903] Intermediate 22c: tert-butyl4-{4-[1-(3-cyano-4-fluoro-1H-indole-7-yl)piperidine-4-yl]phenyl}piperazine-1-carboxylate

[0904] [ka] (DiMeIHeptCl)Pd(Cinnamyl) Cl (152 mg, 0.14 mmol) was added under nitrogen to 1 mL of 1,4-dioxane containing tert-butyl 4-(4-(piperidine-4-yl)phenyl)piperazine-1-carboxylate (500 mg, 1.45 mmol), intermediate 2b (346 mg, 1.45 mmol), and Cs2CO3 (1.6 g, 5.07 mmol), and the mixture was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-50% ethyl acetate in Et2O) to obtain the title compound as a yellow solid. m / z:ES + [M+H] + =504.3.

[0905] Intermediate 22d: 3-{5-[4-(dibutoxymethyl)piperidine-1-yl]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}piperidine-2,6-dione

[0906] [ka] Pd-PEPPSI-IHept Cl(0.23 g, 0.24 mmol) was added to a degassed mixture of intermediate 1h (1.5 g, 4.64 mmol), 4-(dibutoxymethyl)piperidine (1.5 g, 6.16 mmol), and Cs2CO3 (4.54 g, 13.93 mmol) in 1,4-dioxane (45 mL) at room temperature under nitrogen. The resulting mixture was stirred at 100 °C for 3 hours under nitrogen. The reaction mixture was cooled to room temperature and diluted with DCM (75 mL) and AcOH (10%, 50 mL). The organic layer was washed with NaHCO3 solution (50 mL), dried over MgSO4, filtered, and evaporated to obtain the crude product. The crude product was ground with dimethyl (15 mL) to obtain a solid, which was recovered by filtration, washed with dimethyl (2 × 5 mL), dimethyl:Et2O (1:1, 5 mL), and Et2O (5 mL), and dried under vacuum to obtain the title compound (1.66 g, 73.6%) as a white solid. 1 H NMR δ 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,m),2.28-2.44(1H,m),2.55-2.64(1H,m),2.72-2.84(2H,m),2.9 0(1H,m),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:ES + [M+H] + =486.0.

[0907] Example 22: 7-(4-{4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitride

[0908] [ka] Using the general synthesis method exemplified in Example 7, intermediate 22c was reacted with intermediate 22d, and after purification by HPLC (column A, eluate A), the title compound in the form of formate (25.0 mg, 14.12%) was obtained as a yellow solid. 1 H NMR δ 1.19(2H,q),1.82(5H,t),1.89-2.03(3H,m),2.20(2H,d),2.29-2.44(1H,m),2.54-2.62( 2H,m),2.65-2.8(3H,m),2.83(2H,t),2.85-2.97(1H,m),3.06-3.13(4H,m),3.26-3.38(5H ,m),3.88(2H,d),4.19(1H,d),4.32(1H,d),5.05(1H,dd),6.82(1H,dd),6.87-6.97(3H,m ),7.04(2H,d),7.14(2H,d),7.50(1H,d),8.27(1H,s),10.95(1H,s),12.26(1H,s);m / z:ES + [M+H] + =743.5.

[0909] Example 23 Intermediate 23a: 7-[(3S)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile

[0910] [ka] LHMDS (1M in THF, 2.61 mL, 2.61 mmol) was dissolved under nitrogen in THF (2 mL) as intermediate 11b (300 mg, 0.75 mmol), intermediate 2b (178 mg, 0.75 mmol), and Pd-PEPPSI-IHept Cl(21.74 mg, 0.02 mmol) was added. The resulting mixture was stirred at 60°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (25 mL) and extracted with siRNA (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-60% siRNA in Et2O) to obtain the title compound (280 mg, 67.0%) as a yellow solid. 1 H NMR δ 0.87(6H,t),1.27-1.4(6H,m),1.42-1.52(5H,m),1.59-1.76(3H,m),1 .79-1.98(3H,m),2.54(2H,dd),2.59-2.7(2H,m),2.94-3.04(1H,m),3. 27(2H,d),3.35-3.41(2H,m),3.54(2H,dt),3.62(2H,d),4.16(1H,d),6 .74-6.93(4H,m),7.11-7.18(2H,m),8.26(1H,d),12.26(1H,s);m / z:ES + [M+H] + =561.0.

[0911] Example 23: 7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride

[0912] [ka] Formic acid (2 ml, 52.15 mmol) was added to 7-[(3S)-3-{4-[4-(dibutoxymethyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile (150 mg, 0.27 mmol) at room temperature, and the mixture was stirred for 1 hour. The solvent was then evaporated, and the residue was combined with intermediate 5f (84 mg, 0.27 mmol) in NMP (2 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by preparative HPLC (column A, eluate A) to obtain the title compound in the form of formate (27.0 mg, 13.89%) as a white solid. 1 H NMR δ 1.21(2H,q),1.47-1.6(1H,m),1.65(1H,s),1.76-1.88(3H,m),1.88-2.06(6H,m),2 .16(2H,t),2.23(2H,d),2.54-2.72(4H,m),2.76(2H,t),2.89-3.07(3H,m),3.40(3H ,s),3.62(2H,d),3.77(2H,t),4.3-4.46(1H,m),6.41(1H,d),6.70(1H,dd),6.84(3H m / z:ES + [M+H]+=727.0.

[0913] Example 24: 7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitride

[0914] [ka] Intermediate 23a (140 mg, 0.25 mmol) was stirred in formic acid (1 mL) at room temperature for 1 hour, and then evaporated to dryness. Intermediate 1i (107 mg, 0.25 mmol) was also stirred in formic acid (1 mL) at room temperature for 1 hour, and then evaporated to dryness. The two residues were then combined in NMP (2 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by C18 flash chromatography (elution gradient in water with 5-100% MeCN (1% NH4HCO3)) to obtain the title compound (53.0 mg, 28.6%) as a white solid. 1 H NMR δ 1.11-1.32(2H,m),1.44-1.6(1H,m),1.66(1H,s),1.74-2(6H,m),2.20(2H,d),2.3- 2.43(1H,m),2.48(3H,d),2.52-2.72(6H,m),2.84-3.04(2H,m),3.23-3.33(6H,m), 3.61(2H,d),4.16-4.38(2H,m),5.05(1H,dd),6.79(1H,dd),6.83-6.93(3H,m),7.0 5(2H,d),7.15(2H,d),7.52(1H,d),8.26(1H,s),10.96(1H,s),12.27(1H,s);m / z:ES + [M+H] + =743.0.

[0915] Example 25: 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonitride

[0916] [ka] The title compound was prepared according to the procedure described in Example 9, except that (S)-3-(4-bromophenyl)piperidine oxalate was used in step 9d. Purification by HPLC (column A, eluate A) yielded the title compound in formate form (43.0 mg, 33.4%) as a yellow solid.1 H NMR δ 0.85(1H,q),1.16-1.3(2H,m),1.52-1.72(2H,m),1.78-1.91(2H,m),1 .9-2.1(6H,m),2.24(4H,dd),2.63(2H,dd),2.67-2.8(4H,m),3.02(3H ,d),3.51(3H,q),3.64(2H,d),3.78(2H,t),4.39(1H,tt),6.42(1H,d) ,6.85-7(4H,m),7.11-7.3(4H,m),7.53(2H,dd),10.33(1H,s);m / z:ES + [M+H] + =744.5.

[0917] Example 26: 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitride

[0918] [ka] Using the general synthesis method illustrated in Example 23, intermediate 21d was reacted with intermediate 5f, and after purification by HPLC (column A, eluate A), the title compound in the form of formate (42.0 mg, 54.4%) was obtained as a white solid. 1 H NMR δ 0.84(1H,d),1.22(3H,d),1.57(1H,t),1.66(1H,s),1.81(3H,d),1.94(5H,d),2.00( 1H,d),2.07(1H,s),2.17(2H,t),2.24(2H,d),2.55-2.7(3H,m),2.76(2H,t),2.99(3H ,d),3.63(2H,d),3.78(2H,t),4.37(1H,s),6.41(1H,d),6.85(3H,dd),6.96(1H,d), 7.1-7.19(4H,m),7.47-7.56(2H,m),8.31(1H,s),10.32(1H,s),12.28(1H,s);m / z:ES +[M+H] + =743.0.

[0919] Example 27 Intermediate 27a: tert-butyl 4-[4-(benzyloxy)phenyl]piperidine-1-carboxylate

[0920] [ka] Benzyl bromide (2.89 g, 16.87 mmol) was added to tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (3.6 g, 12.98 mmol) and K2CO3 (5.38 g, 38.94 mmol) in DMF (52 mL). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with toluene (200 mL) and washed with water (100 mL) and NaCl (50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-20% toluene in Et2O) to obtain the title compound (4.50 g, 94%) as a white solid. 1 H NMR δ 1.29(11H,d),1.59(2H,d),2.40-2.55(1H,m),2.65(2H,s),3.93(2H,d),4. 94(2H,d),6.76-6.86(2H,m),6.97-7.08(2H,m),7.14-7.37(5H,m);m / z:ES + [M+H] + =353.2.

[0921] Intermediate 27b: 4-[4-(benzyloxy)phenyl]piperidine

[0922] [ka] 4.5 g, 12.25 mmol of tert-butyl 4-[4-(benzyloxy)phenyl]piperidine-1-carboxylate was stirred in 50 mL of formic acid at room temperature for 2 hours. The reaction mixture was then evaporated to dryness to obtain the crude product. The crude product was purified by ion-exchange chromatography using an SCX column. The desired product was eluted from the column using 7 M NH3 / MeOH to obtain the title compound (3.20 g, 98%) as a white solid. 1 H NMR δ 1.33-1.52(2H,m),1.56-1.68(2H,m),2.39-2.60(2H,m),2.63(2H,s),2.92-3.03(2 m / z:ES + [M+H] + =268.2.

[0923] Intermediate 27c: 7-{4-[4-(benzyloxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitride

[0924] [ka] Pd-PEPPSI-IPent (0.304 g, 0.31 mmol) was added under nitrogen to 1,4-dioxane (25 mL) containing 4-[4-(benzyloxy)phenyl]piperidine (3.20 g, 11.99 mmol), intermediate 8a (2.45 g, 10.42 mmol), and LHMDS (1 M in THF, 36.5 ml, 36.48 mmol). The resulting mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature and quenched with water (5 mL). The solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-100% DCM in Et2O, followed by 0-10% siRNA in DCM) to obtain the title compound (2.60 g, 59.2%) as a yellow solid. 1H NMR δ 1.85(2H,d),1.89-2.08(2H,m),2.60(4H,s),2.67-2.82(2H,m),3.38(2H,d),5.09(2H,s),6.77(1H,d),6.8 8(1H,d),6.93-7.04(2H,m),7.17-7.28(2H,m),7.30-7.51(5H,m),8.17(1H,d),11.88-11.95(1H,m);m / z:ES + [M+H] + =422.3.

[0925] Intermediate 27d: 7-{4-[4-(benzyloxy)phenyl]piperidine-1-yl}-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole-3-carbonitrile

[0926] [ka] Sodium hydride (0.144 g, 3.61 mmol) was added at 0°C to 7-{4-[4-(benzyloxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile (1.17 g, 2.78 mmol) in THF (18 mL), and the mixture was stirred for 1 hour. 2-(trimethylsilyl)ethoxymethyl chloride (0.591 ml, 3.33 mmol) was added, and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, and the reaction products were evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-90% DCM in Et2O) to obtain the title compound (1.3 g, 85%) as a white solid. 1 H-NMR δ-0.09(9H,s),0.76-0.87(2H,m),1.85(4H,s),2.57(4H,d),2.84(2H,s),3.16(2H,d),3.48-3.59(2H,m),5.09 (2H,s),5.97(2H,s),6.92-7.04(3H,m),7.12(1H,d),7.18-7.26(2H,m),7.28-7.51(5H,m),8.36(1H,s);m / z:ES + [M+H] +=552.4.

[0927] Intermediate 27e: 7-[4-(4-hydroxyphenyl)piperidine-1-yl]-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole-3-carbonitrile

[0928] [ka] Pd / C (10%, 1.24 g, 11.65 mmol) was added under hydrogen to 7-{4-[4-(benzyloxy)phenyl]piperidine-1-yl}-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole-3-carbonitrile (1.24 g, 2.25 mmol) in siRNA (60 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite®, and the solvent was evaporated to obtain the title compound (0.94 g, 91%) as a white solid. 1 H NMR(CDCl3)δ-0.03(9H,s),0.83-1.01(2H,m),1.83-2.01(4H,m),2.56-2.69(1H,m),2.77(3H,s),2.93(2H,td),3.29(2H,d),3 .50-3.61(2H,m),6.06(2H,s),6.79-6.90(2H,m),6.96-7.04(1H,m),7.12(1H,d),7.15-7.23(2H,m),7.73(1H,s)OH not observed;m / z:ES + [M+H] + =462.3.

[0929] Intermediate 27f: 7-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-yl)-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole-3-carbonitrile

[0930] [ka] K2CO3 (0.808 g, 5.85 mmol) was added to 7-[4-(4-hydroxyphenyl)piperidine-1-yl]-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole-3-carbonitrile (0.90 g, 1.95 mmol) and 2-(3-bromopropyl)-1,3-dioxolane (0.760 g, 3.90 mmol) in DMF (10 mL). The resulting mixture was stirred at 80°C for 8 hours. The reaction mixture was cooled to room temperature and purified by flash C18-flash chromatography (0-100% MeOH in elution gradient water (0.1% NH4HCO3)) to obtain the title compound (0.75 g, 66.8%) as a yellow solid. 1 H NMR(MeOD)δ 0.70(9H,s),1.60(2H,t),2.02(1H,s),2.46-2.60(3H,m),2.63(5H,s),3.41(3H,s),3.90-4.00(2H,m),4.11(2H,s),4.32(2 m / z:ES + [M+H] + = 576.5.

[0931] Intermediate 27g: 7-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitride

[0932] [ka] Tetrabutylammonium fluoride (1 M in THF, 9.3 mL, 9.38 mmol) was added to 7-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-yl)-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole-3-carbonitrile (360 mg, 0.63 mmol), and the resulting mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated to dryness to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-100% DCM in Et2O, followed by 0-12% siRNA in DCM) to obtain the title compound (0.19 g, 68.2%) as a white solid. 1 H NMR δ 1.73(3H,m),1.81-1.89(3H,m),1.98(2H,qd),2.61(4H,d),2.70-2.80(2H,m),3.38(2H,d),3.73-3.82(2H,m),3.87 -3.92(2H,m),3.97(2H,t),4.86(1H,t),6.77(1H,d),6.89(3H,dd),7.20(2H,d),8.17(1H,d),11.91(1H,d);m / z:ES + [M+H] + =446.35.

[0933] Example 27: 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile

[0934] [ka] 7-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile (0.159 g, 0.31 mmol) and intermediate 7c (0.162 g, 0.35 mmol) were heated in formic acid (4 mL) at 40 °C for 1 hour. The reaction mixture was cooled to room temperature and evaporated to dryness. NMP (4 mL) was added to the residue, and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with NaHCO3 solution (10 mL), extracted with DCM (30 mL), the organic layer was dried over MgSO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient 0-10% MeOH in DCM) to obtain the title compound (0.11 g, 48.2%) as a white solid. 1 H NMR δ 1.50-1.65(2H,m),1.67-1.84(2H,m),1.87-2.00(5H,m),2.18-2.46(6H,m),2.57(5H ,s),2.59-2.78(3H,m),2.80-2.90(1H,m),3.26(4H,d),3.33-3.35(2H,m),3.81(3H, s),3.97(2H,t),4.02-4.27(2H,m),4.94(1H,dd),6.47(1H,d),6.58(1H,s),6.75(1H ,d),6.82-6.93(3H,m),7.18(2H,d),8.15(1H,d),10.88(1H,s),11.89(1H,s);m / z:ES + [M+H] + =744.4.

[0935] Example 28: 7-{4-[...

Claims

1. Equation (I): 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof During the ceremony, X １ is CH or N, p is 0, 1, or 2. Here, Each R １ is a substituent on any C atom, independently of F, Cl, and C. １～３ Alkyl and C １～３ Selected from alkoxy, the C １～３ Alkyl and C １～３ The alkoxy can be independently and optionally substituted with one or more Fs. R Ｎ It is selected from H and Me, n is 0, 1, or 2. m is either 0 or 1. Q １ is CH or N, When both n and m are non-zero, Q ２ is CH or N, If both n and m are 0, Q ２ CH is, If n is 0 or 1, Q ３ CH is, n is 2, Q ２ If Q is N, ３ CH is, n is 2, Q ２ If Q is CH, ３ is CH or O, R ２ａ and R ２ｂ Q １ Or Q ２ Other substituents on the same or different C atoms, each independently of H, F, and C １～３ Selected from alkyl groups, or R ２ａ and R ２ｂ Together - (CH ２ ) ｒ - Forms a group, where r is 1, 2, or 3. Q ４ is a single bond or -NR ４ C (= O), R ４ is H or Me, Y １ , Y ２ , Y ３ , Y ４ , and Y ５ Of these, 0, 1, or 2 is N, otherwise it is C. Each R ３ Y １ , Y ２ , Y ３ , Y ４ , and Y ５ A substituent on any C atom, independently of F, Cl, CN, C １～３ Alkyl and C １～３ Selected from alkoxy, the C １～３ Alkyl and C １～３ The alkoxy can be independently and optionally substituted with one or more Fs. q is 0, 1, or 2. Linker is Y ４ and Y ５ Bonded with any available C atom, The linker is a saturated, partially, or fully unsaturated skeleton comprising C and H atoms and at least one heteroatom, wherein the skeleton has bond endpoints "a" and "b" and a length of 5 to 26 atoms between "a" and "b", and the skeleton may include one or more linear and / or branched and / or rings, which are optionally substituted on any available C atoms by one or more F atoms. W is a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is an E3 ubiquitin ligase cereblon binding unit.

2. The linker is a saturated or partially unsaturated skeleton, (a) containing C and H atoms and at least two heteroatoms, or (b) comprising C and H atoms and at least one nitrogen heteroatom in the form of a secondary or tertiary amine, or (c) At least one nitrogen-containing saturated or partially unsaturated heterocyclic group having 4 to 12 ring atoms, or A １ -CH ２ -CH ２ -A ２ Unit (here, A １ and A ２ A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising (each independently selected from N and O).

3. The aforementioned linker is, formula: "a" - Q Ａ - Q Ｂ - Q Ｃ - Having "b", During the ceremony, "a" and "b" represent the endpoints of the connection. Q Ａ is, -G-Q Ｈ - or - G - (C １～５ Alkilen) - and Q Ｂ This is a direct bond, -Q Ｂ１ - Q Ｂ２ - Q Ｂ３ - C is optionally replaced by one or more Fs (e.g., one or two). １～３ It is alkylene, and here, Q Ｂ１ and Q Ｂ３ Each is independent, directly bonded or C １～２ Represents alkylene, Q Ｂ２ Q Ｈ , -O-CH ２ CH ２ -O-, -O-, or -N(R Ｊ ) - and here, R Ｊ is H or C １～３ It is alkyl, Q Ｃ is, -Q Ｈ -G- or -(C １～５ It is alkylene-G- Each G is independently directly bonded, -CH ２ -, -O-, -C(=O)-, or -N(R Ｇ ) - and here, R Ｇ is H or C １～３ It is alkyl, Each Q Ｈ These are independently 4-12 member nitrogen-containing saturated or partially unsaturated heterocyclic groups, Here, Q Ａ Q Ｂ , and Q Ｃ The value of is selected such that the linker does not contain any N-N or N-O bond, the compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. (a) Q Ｂ However, direct bonding, -CH ２ -, or -CH ２ CH ２ - and / or (b) Q Ｃ However, -Q Ｈ -G- or -(C １～２ Alkylene)-G- and / or (c) each Q Ｈ independently represents 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, morpholine-2,3-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl, and the compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof.

5. E3 Ubiquitin Ligase Cereblon Binding Unit and Formula (Ia): 【Chemistry 2】 The AR binding unit, where R １ , p, X １ , R Ｎ , n, m, R ２ａ , R ２ｂ , Q １ , Q ２ , Q ３ , Q ４ , Y １ , Y ２ , Y ３ , Y ４ , Y ５ , R ３ , and q are as defined in claim 1, an AR binding unit, and a PROTAC compound or a pharmaceutically acceptable salt thereof.

6. W is W2, and this is, 【Transformation 3】 And, Z Ａ The following is true: 【Chemistry 4】 During the ceremony, 【Transformation 5】 This represents a single covalent bond or a double covalent bond. X Ａ２ , X Ｂ２ , X Ｃ２ , and X Ｄ２ One of them is C, and Y Ｎ Covalently bonded, X Ａ２ , X Ｂ２ , X Ｃ２ , X Ｄ２ , X Ｅ２ , and X Ｆ２ Of these, 0, 1, or 2 are N, where X Ｅ２ and X Ｆ２ Both are not N, otherwise they are C. X Ｇ２ , X Ｈ２ , and X Ｊ２ One or two of them are N, otherwise they are C. Each R ＡＡ is a substituent on any available C or N atom of Z, and in each case independently, one or more R ＡＡ２ R is optionally replaced by ＡＡ１ Selected from, here, R ＡＡ is Z Ａ If R is a substituent on an available C atom, ＡＡ R ＡＡ２ Further selections are made from these. Each R ＡＡ１ Independently, C １～４ Alkyl, C ２～３ Alkenil, C ２～３ Alkinyl, C １～３ Alkoxy C １～３ Alkyl, CarboxyC １～３ Alkyl, C ５～７ Carbocyclyl, or 4-6 membered heterocyclyl, Each R ＡＡ２ These 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 Selected from, where C １～３ Alkyl is optionally substituted with one or more F groups. v is 0, 1, or 2. Y Ｎ The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is 2,4-dioxohexahydropyrimidine-1-yl.

7. X Ａ２ and X Ｂ２ One of them is C, which is covalently bonded to Y, and X Ａ２ and X Ｂ２ The other is C, X Ｃ２ and X Ｄ２ One of these is N, otherwise it is C. X Ｇ２ and X Ｊ２ One of them is N, and X Ｇ２ and X Ｊ２ The other is C, X Ｈ２ , X Ｅ２ , and X Ｆ２ The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein all are C.

8. W is W2-1, 【Transformation 6】 During the ceremony, X Ｋ and X Ｌ These are, respectively, N-linker and CH, N-linker and CMe, or NMe and C-linker. X Ｍ and X Ｏ One of them is C-2,4-dioxohexahydropyrimidine-1-yl (Y Ｎ ) and X Ｍ and X Ｎ One of them is C-F, X Ｍ If it is not C-F, then X Ｎ It can be N, X Ｎ , X Ｍ , and X Ｏ The remainder is CH, X Ｐ The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein is CH or CMe.

9. W is W1, and this is -Z-(R Ａ ) ｈ And, Here, Z is as follows: 【Transformation 7】 During the ceremony, 【Transformation 8】 This represents a single covalent bond or a double covalent bond. X Ａ , X Ｂ , X Ｃ , X Ｄ , X Ｅ , and X Ｆ Of these, 0, 1, or 2 are N, where X Ｅ and X Ｆ Both are not N, otherwise they are C. X Ｇ , X Ｈ , and X Ｊ One of them is C(O), X Ｇ , X Ｈ , and X Ｊ One of them is N-(2,6-dioxopiperidine-3-yl)(Y), and X Ｇ , X Ｈ , and X Ｊ One of them is C(R Ｔ ) ２ ien-CH ２ CH ２ -, C(O), N(C １～３ Selected from alkyl), -O-, and -N=, where each R Ｔ is selected from H, F, Me, or C(R Ｔ ) ２ Together with the carbon, it forms a cyclopropane-1,1-diyl group, Here, X Ｇ , X Ｈ , and X Ｊ In this case, there are no two C(O) groups in adjacent positions, and the N-(2,6-dioxopiperidine-3-yl) is N(C １～３ Selected so as not to be adjacent to either an alkyl group or O, Each R Ａ These are F, Cl, and C, independently. １～３ Alkyl, C １～３ X selected from alkoxy Ａ , X Ｂ , X Ｃ , or X Ｄ A substituent on any available C atom in the C １～３ Alkyl and C １～３ The alkoxy is independently and optionally substituted with one or more Fs. h is 0, 1, or 2. The aforementioned linker, X Ａ , X Ｂ , X Ｃ , or X Ｄ A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, bonded to any C atom.

10. W is W3, which is -Z Ｂ And, Here, Z Ｂ The following is true: 【Chemistry 9】 X Ｅ３ C (=O) and CR Ｅ１ R Ｅ２ Selected from, here, R Ｅ１ and R Ｅ２ H and C are independent of each other. １～３ Selected from the group consisting of alkyl groups, or R Ｅ１ and R Ｅ２ They become C together with the carbon to which they are bonded. ３～６ Forming a cycloalkane ring, Y is N-(2,6-dioxopiperidine-3-yl), X Ａ３ , X Ｂ３ , X Ｃ３ , and X Ｄ３ All of them are C, X Ａ３ and X Ｂ３ , X Ｂ３ and X Ｃ３ , and X Ｃ３ and X Ｄ３ One pair of these forms a 5 or 6-membered fully unsaturated or partially unsaturated N-containing heterocycle, which is bonded to the "b" end of the linker via an N atom. X Ａ３ , X Ｂ３ , X Ｃ３ , and X Ｄ３ Other than the base R Ｂ It has, and here each R Ｂ H, F, Cl, C １～３ Alkyl and C １～３ A compound of formula (I) according to any one of claims 1 to 4, selected from alkoxys, or a pharmaceutically acceptable salt thereof.

11. R Ｎ However, H is and p is 0 or 1, R １ However, it is selected from Cl, F, and Me, R １ However, if Q exists, １ A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, which is bonded to the para position.

12. X １ The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein N is present.

13. Q １ However, N is Q ２ However, it is CH and Q ３ The compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, wherein the compound is CH, and n and m are 1 and 1, or 2 and 0, respectively.

14. R ２ａ and R ２ｂ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein both are H.

15. (a) Q ４ However, it is a single bond, or (b) Q ４ However, NR ４ C (= O), R ４ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein H is present.

16. Y １ , Y ２ , Y ３ , Y ４ , and Y ５ However, all are C, the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. q is 0 or 1, R ３ If (if it exists), then F is Y １ , Y ２ , Y ３ , Y ４ , and Y ５ A substituent on any C atom in the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

18. Linker, Y ５ A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, which is bonded by a compound.

19. X １ However, N is, p is 1, R Ｎ However, it is H, n is 2, m is 0, R ２ａ and R ２ｂ However, both are H, Q ４ However, it is a single bond, Y １ , Y ２ , Y ３ , and Y ４ However, they are all CH, Y ５ However, C is present, and the linker is connected, A compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein q is 0.

20. 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonil, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonil, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonil, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R ＊ )-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-chloro-7-[4-(4-{4-[(4-{2-[(3S ＊ )-2,6-dioxopiperidine-3-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R ＊ )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-chloro-7-[4-(4-{4-[(4-{2-[(3S ＊ )-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile, 7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonil, 4-Chloro-7-[(3R)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{2-[(3R ＊ )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-chloro-7-[4-(4-{4-[(4-{2-[(3S ＊ )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-chloro-7-[(3S)-3-(4-{4-[(4-{2-[(3R ＊ )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-chloro-7-[(3S)-3-(4-{4-[(4-{2-[(3S ＊ )-2,6-dioxopiperidine-3-yl]-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorophenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorophenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorophenyl}piperidine-1-yl)-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}butoxy)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazin-3-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{6-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridazin-3-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R ＊ )-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S ＊ )-3-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-yl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{5-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrazine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyrazine-2-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 7-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 7-[(3S)-3-(4-{4-[(4-{[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]methyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indazole-3-carbonil, 4-Chloro-7-{(3S)-3-[4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 7-{(3R ＊ )-1-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{(3S ＊ )-1-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{(3R ＊ )-1-[3-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{(3S ＊ )-1-[3-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-3-yl}-4-methyl-1H-indole-3-carbonitrile, 7-[(3R ＊ )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-4-methyl-1H-indole-3-carbonitrile, 7-[(3S ＊ )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-carbonyl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-(2-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}ethyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-(3-{4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}propyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R ＊ )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S ＊ )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R ＊ )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S ＊ )-1-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperazine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R ＊ )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S ＊ )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R ＊ )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S ＊ )-1-{4-[1-({1-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]phenyl}piperidine-3-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-carbonyl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-[4-(4-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]oxy}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[5-(2,4-dioxo-1,3-diadinan-1-yl)-7-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-{4-[(1-{4-[(3S)-1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-3-yl]phenyl}piperidine-4-yl)methyl]piperazine-1-yl}-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, 4-{4-[(1-{4-[1-(3-cyano-4-fluoro-1H-indole-7-yl)piperidine-4-yl]phenyl}piperidine-4-yl)methyl]piperazine-1-yl}-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, 4-{4-[(1-{4-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]phenyl}piperidine-4-yl)methyl]piperazine-1-yl}-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, 7-[4-(4-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]methyl}phenyl)piperidine-1-yl]-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{6-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}piperidine-1-yl)phenyl]piperidine-1-yl}-1H-indole-3-carbonitrile, 4-Chloro-7-[4-(4-{4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl][1,4'-bipiperidine]-1'-yl}phenyl)piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1-methyl-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{3-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-2-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S ＊ )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R ＊ )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(2S ＊ )-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}morpholine-4-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(2R ＊ )-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl }Methyl)piperidine-1-yl]phenyl}morpholin-4-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(2S ＊ )-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}morpholine-4-yl]-1H-indazole-3-carbonitrile, 4-Chloro-7-[(2R ＊ )-2-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}morpholine-4-yl]-1H-indazole-3-carbonitrile, 4-Chloro-7-[(3R ＊ )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S ＊ )-3-{6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-yl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-2-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{2-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyrimidine-5-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{2-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrimidine-5-yl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[(2R)-2-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)morpholine-4-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[(2R)-2-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)morpholine-4-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 7-(4-{4-[7-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[7-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[7-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[7-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonil, 7-[(3S)-3-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indazole-3-carbonilicate, 7-[(3S)-3-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-4-fluoro-1H-indazole-3-carbonitrile, 7-(4-{4-[7-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indole-3-carbonitrile, 4-Chloro-7-[(3R)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonil, 4-Chloro-7-[(3S)-3-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinan-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl]-1H-indazole-3-carbonil, 7-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-2-methyl-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[7-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)-2-azaspiro[3.5]nonane-2-yl]phenyl}piperidine-1-yl)-1H-indole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indazole-3-carbonitrile, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonyl, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonitrile, 4-Chloro-7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-1H-indazole-3-carbonitrile, 7-(4-{4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-fluoro-1H-indazole-3-carbonitrile, 7-{4-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]piperidine-1-yl}-4-methyl-1H-indazole-3-carbonilicate, 7-(4-{4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]phenyl}piperidine-1-yl)-4-methyl-1H-indazole-3-carbonyl, 7-{(3S ＊ )-3-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]pyrrolidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, 7-{(3R ＊ )-3-[4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}butoxy)phenyl]pyrrolidine-1-yl}-4-methyl-1H-indole-3-carbonitrile, N-[1-(4-chloro-3-cyano-1H-indazole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[5-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1~{H}-indole-7-yl)-4-piperidyl]-4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)carbamoyl]-3-fluorophenyl]piperazine-1-yl]methyl]-1-piperidyl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-(4-{[6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl]methyl}piperidine-1-yl)-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-5-fluoro-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[6-(2,4-dioxo-1,3-diadinane-1-yl)-1-methyl-1H-indole-2-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-2-cyano-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]benzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluoro-6-methylbenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-3-methylbenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-3-cyano-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]benzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}piperidine-1-yl)pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indazole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(3-cyano-4-methyl-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(3-cyano-4-methyl-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]benzamide, N-[4-(4-chloro-3-cyano-1H-indole-7-yl)cyclohexyl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-fluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinan-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2,6-difluorobenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrazine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-5-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyrimidine-2-carboxamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-4-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]-2-methylbenzamide, N-[1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-4-yl]-6-[4-({4-[4-(2,4-dioxo-1,3-diadinane-1-yl)-1H-indole-1-yl]piperidine-1-yl}methyl)piperidine-1-yl]pyridazine-3-carboxamide, N-[(3R ＊ )-1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-3-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, and N-[(3S ＊ )-1-(4-chloro-3-cyano-1H-indole-7-yl)piperidine-3-yl]-5-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}methyl)piperidine-1-yl]pyridine-2-carboxamide, A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

21. A pharmaceutical composition comprising a compound of formula (I) or a PROTAC of formula (Ia) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

22. A compound of formula (I) or a PROTAC of formula (Ia) or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 20, for use in a method of treating the body of a human or animal by therapy.

23. A compound of formula (I) or a PROTAC of formula (Ia) or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 20, for use as an anti-invasive agent in the suppression and / or treatment of solid tumor diseases.

24. Use of a compound of formula (I) or a PROTAC of formula (Ia) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 for the manufacture of a pharmaceutical product for use as an anti-invasive agent in the suppression and / or treatment of solid tumor diseases.

25. A method for generating an anti-invasive effect in a warm-blooded animal such as a human requiring an anti-invasive effect for the suppression and / or treatment of solid tumor disease, comprising administering to the animal an effective amount of a compound of formula (I) or a PROTAC of formula (Ia) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 20.

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