KR20240137054A - Compounds and their uses in the treatment of cancer - Google Patents

Abstract

Chemical formula I below:
[Chemical Formula I]
A compound of or a pharmaceutically acceptable salt thereof is a PROTAC compound useful for the treatment of prostate cancer.

Description

Compounds and their uses in the treatment of cancer

The present disclosure relates to certain Proteolytic Targeting Chimera (PROTAC) compounds and their ability to degrade at least the androgen receptor (AR) and thus to their use for the treatment of androgen receptor dependent diseases or disorders in mammals. Degradation of the androgen receptor may provide, for example, an anti-tumor effect and thus the present disclosure relates in part to the use of such compounds and pharmaceutical compositions containing them for the treatment of cancer. The present disclosure also relates to intermediate compounds that may be useful in the preparation of such PROTACs.

Traditional small molecule drugs bind reversibly (and sometimes irreversibly) to their target proteins as a means of modulating a given biological activity. In contrast, PROTACs bind to their target proteins but then cause degradation of the target protein. Having achieved this effect, the PROTAC can theoretically repeat the process with another target protein. Thus, unlike “traditional small molecule” inhibitors, the PROTAC-induced degradation mechanism can theoretically operate in a sub-stoichiometric manner, meaning that smaller exposures of the PROTAC compound could still achieve the desired level of efficacy in vivo. In practice, this could mean that the degradation capacity of a PROTAC (DC ₅₀ and D _max ) could have an enhanced effect than would be reflected solely by its binding affinity.

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

When used, PROTACs simultaneously bind to both the target protein and the E3 ubiquitin ligase, forming a ternary complex. The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex, which ubiquitinates the target protein. This has the effect of marking the target protein for degradation by the cellular proteasome machinery. The PROTAC can then dissociate from the target protein, thereby starting another cycle of this process in a catalytic manner. Meanwhile, the ubiquitinated target protein is recognized and degraded by the cellular proteasome machinery.

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

The androgen receptor (AR) belongs to the steroid hormone group of nuclear receptors and is a ligand-dependent transcription factor that regulates the expression of various genes involved in the growth and survival of prostate cells. The AR consists of four distinct domains: an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region that allows the N- and C-termini to interact, and a C-terminal ligand-binding domain (LBD). Androgens, such as testosterone and its derivative dihydrotestosterone (DHT), bind to the AR ligand-binding domain, which releases AR chaperone proteins, allowing AR to dimerize and translocate from the cytoplasm into the nucleus. Within the nuclear receptor, the dimer binds to androgen response elements (AREs) in the promoters of androgen-responsive genes, such as PSA and FKBP5. The AR signaling pathway is important for normal prostate development, and male sexual differentiation cannot occur in the absence of androgens or in the absence of a functional AR.

The relationship between androgens and prostate cancer was first discovered in 1941 in a study of semen by Huggins and Hodges, and subsequent studies have shown that androgen deprivation therapy is highly effective in the treatment of recurrent prostate cancer. However, despite a favorable response, most tumor cells initially adapt to low androgen levels, and patients relapse within a few years, developing a condition known as castration-resistant prostate cancer (CRPC). Several second-generation antiandrogens have been approved by the US FDA for the treatment of CRPC. These include enzalutamide, apalutamide, and darolutamide, all of which compete with androgens for binding to the ligand-binding domain. In addition to antagonizing the AR and preventing its activation, they also effectively block AR signaling by inhibiting nuclear translocation and DNA binding. 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, so inhibiting this enzyme reduces circulating androgen levels and thus suppresses prostate tumor growth.

The above mentioned drugs significantly prolong survival in patients with advanced prostate cancer, but they are not curative and resistance inevitably develops. However, it is clear that AR remains central to the progression of CRPC, which means that there is still a need to develop alternative AR inhibitors. Several resistance mechanisms have been identified, including AR amplification, mutations, or the generation of splice variants lacking the ligand binding domain. Mutations in the ligand binding domain, such as F877L or L702H, can convert antagonists into agonists or allow the receptor to utilize alternative steroid hormones such as glucocorticoids or progesterone. Therefore, agents that degrade AR and remove it from the cell may help to address this form of resistance. Thus, AR PROTACs that bind to the ligand binding domain of the androgen receptor and simultaneously recruit E3 ligases such as cereblon, resulting in ubiquitination and degradation of AR via the proteasome, may offer therapeutic benefit to patients with prostate cancer, particularly metastatic CRPC. AR PROTAC may also be useful in AR+ breast cancer.

Given that the above-mentioned resistance mutations may occur in the ligand binding domain and may limit the efficacy of known CRPC treatments, it would be beneficial to develop AR-degrading PROTACs that are effective not only for targeting “wild-type” AR, but also for the degradation of clinically relevant mutant forms of AR.

Whichever target protein binding unit (1) is used at one end of the PROTAC linker unit, a basic element that must always be present at the other end of the PROTAC molecule is a unit (2) that helps in inducing tagging of the target protein for degradation, for example an E3 ubiquitin ligase cereblon binder unit. Scientific efforts have already provided a number of such E3 ubiquitin ligase cereblon binder units, and additional examples are described by the present researchers hereinafter.

WO2018/071606 describes specific PROTAC compounds called AR degraders.

As with "traditional small molecule" binders and PROTACs, there is always the issue of in vivo "off-target" activity that may be important to avoid in the development of safe and effective drug therapeutics. That is, a given binding unit may be highly potent for its intended target, but if it is unintendedly potent against other unintended biological targets in the body, it may cause unacceptable toxicity, side effects, etc.

Therefore, developing potent molecules for pharmaceutical applications that are also suitably selective, i.e., avoid inhibition/binding/degradation of unintended biological targets in vivo, is an ongoing challenge.

For example, the present researchers surprisingly found that certain compounds of the present disclosure exhibit beneficial selectivity that is expected to avoid or reduce the risk of mitogenic toxicity in vivo.

As part of the development of current and future PROTAC drug therapeutics for medicinal applications (e.g., cancer), there remains a need to develop androgen receptor PROTAC compounds with combinations of beneficial/improved properties. As mentioned above, the development of PROTACs that target both wild-type AR and one or more clinically relevant mutant forms of AR is an example of such a combinatorial effect.

Furthermore, there is a need to develop androgen receptor binder units that can be incorporated into PROTACs (regardless of whether the E3 ubiquitin ligase cereblon binder unit is chosen for use at the other end of the molecule).

Other properties of interest during the pharmaceutical discovery and development of these PROTACs may relate to their selectivity profile, absorbability/bioavailability, distribution, metabolism, elimination, toxicity and side effect profiles, stability, and manufacturability.

The compounds of the present disclosure provide at least an efficacious AR binding unit suitable for inclusion in a PROTAC compound, and are directed to PROTAC compounds comprising such AR binding unit together with an E3 ubiquitin ligase cereblon binder unit at the other terminus of the PROTAC molecule. Certain AR binding units are advantageously configured to degrade not only wild-type AR but also one or more clinically relevant mutant forms of AR, e.g., L702H. Certain PROTAC compounds of the present disclosure also have a surprisingly beneficial combination of properties (e.g., relating to a combination of AR degradation and selectivity/safety profile).

The present disclosure relates to the above-mentioned AR binding unit, and PROTAC compounds (and pharmaceutically acceptable salts thereof) comprising said AR binding unit together with an E3 ubiquitin ligase cereblon binder unit, said two units being connected by a linker.

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

According to a first aspect of the present disclosure, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof:

[Chemical Formula I]:

[Here,

X ¹ is C and 0, 1 or 2 of X ² , X ³ and X ⁴ are N, otherwise they are C;

or

X ³ and X ⁴ are both C, and - X ⁵ = X ⁶ - X ⁷ = X ⁸ - (where X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ ) are substituted, where one or two of X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ are N, otherwise they are C;

p is 1 or 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -); otherwise p is 0, 1, or 2;

Each R ¹ is ^a substituent on any C atom in X ¹ , X ² , X ³ and X ⁴ (or in X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ when X ³ and X 4 are substituted such that - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), and is independently selected from F, Cl, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy may be optionally substituted independently with one or more F;

n is 0, 1, or 2;

m is 0 or 1;

Q is CH or N (if both n and m are non-zero), otherwise Q is CH;

R ^2a and R ^2b are substituents on the same or different C atoms other than Q , each independently selected from H, F and C _1-3 alkyl, or R ^2a and R ^2b together form a -(CH ₂ ) _r - group, wherein r is 1, 2 or 3;

Zero, one, or two of Y ¹ , Y ² , Y ^{3 ,} and Y ⁴ are N, otherwise they are C;

Each R ³ is a substituent on any C atom in Y ¹ , Y ² , Y ³ and Y ⁴ , and is independently selected from F, Cl, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy may be optionally substituted independently with one or more F;

q is 0, 1, or 2;

The linker is a saturated or partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has a minimum length of 6 to 26 atoms between the terminal attachment points 'a' and 'b' and 'a' and 'b'; the framework may comprise one or more straight and/or branched chains and/or rings, and is optionally substituted with one or more F on any available C atom(s);

W is the E3 ubiquitin ligase cereblon binder unit].

The present specification also describes, in part, a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

The present specification also describes, in part, a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

The present specification also describes, in part, a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

The present specification also describes, in part, a method of treating cancer in a warm-blooded animal in need thereof, comprising administering to the warm-blooded animal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

As exemplified in the experimental sections below, not only have we developed a variety of advantageous AR binding units, but we have also gained insight into where such binding units can incorporate a linker (leading to an E3 ubiquitin ligase cereblon binder unit) without the linker interfering with its AR binding ability. Thus, we understand that when incorporating such AR binding units into a PROTAC, the linker of said PROTAC need not be attached to the left or central ring of Formula I as exemplified above, but can be suitably attached at specific positions on the right ring of the compounds of Formula I as exemplified herein.

Accordingly, in a further aspect of the present disclosure, a PROTAC compound comprising an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of formula Ia below, or a pharmaceutically acceptable salt thereof, is provided:

[Chemical formula Ia]

(wherein, R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q can each take any value defined herein for each of these integers).

For the avoidance of doubt, in chemical formula Ia represents the point of attachment to the rest of the PROTAC compound via a single covalent bond.

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

As described herein, the linkage between the E3 ubiquitin ligase cereblon binder unit and the AR binding unit of formula Ia (as exemplified above) preferably has a length corresponding to the length of a linear chain of 6 to 26 atoms, wherein the atoms are linked by a single covalent bond and each is selected from carbon or a heteroatom (i.e., O, N or S).

As described herein, the linkage between the E3 ubiquitin ligase cereblon binder unit and the AR binding unit of formula Ia (as exemplified above) preferably has a length corresponding to the length of a linear chain of 7 to 14 atoms, wherein the atoms are linked by a single covalent bond and each is selected from carbon or a heteroatom (i.e., O, N or S).

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

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

Although a link length "corresponds to the length of [a particular atom in the chain]", this should not be construed as limiting the link to that atom, and it should be understood that, for example, sulfur atom(s) may also be present in a link even if the S atom is not included in the length descriptor.

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

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

In a further aspect of the present disclosure, an androgen receptor binding unit of formula Ia as described herein is provided for use in a PROTAC compound (or a pharmaceutically acceptable salt thereof) which also contains an E3 ubiquitin ligase cereblon binder unit.

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

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

Accordingly, there is provided an androgen receptor binding unit of formula Ia as described herein for use in a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein said PROTAC compound further comprises an E3 ubiquitin ligase cereblon binder unit linked to said androgen receptor binding unit.

Accordingly, provided herein is an androgen receptor binding unit of formula Ia for inclusion in a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit.

Accordingly, there is provided an androgen receptor binding unit of formula Ia as described herein for inclusion in a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein said PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit linked to said androgen receptor binding unit.

Accordingly, an androgen receptor binding unit of formula Ia as described herein is provided, comprised in a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein the PROTAC compound also comprises an E3 ubiquitin ligase cereblon binder unit.

Accordingly, there is provided an androgen receptor binding unit of formula Ia as described herein, comprised in a PROTAC compound (or a pharmaceutically acceptable salt thereof), wherein said PROTAC compound further comprises an E3 ubiquitin ligase cereblon binder unit linked to said androgen receptor binding unit.

In one embodiment, the linkage between the androgen receptor binding unit of formula Ia [as described above] and the E3 ubiquitin ligase cereblon binder unit is a linker as defined in any embodiment or claim herein, wherein the attachment point exemplified in formula Ia is linked to an 'a' attachment point on any linker as defined herein.

Many embodiments of the present invention are described throughout the specification and will be apparent to those skilled in the art.

Pharmaceutically acceptable salts of the compounds of Formula I or PROTAC compounds described herein can be, for example, acid-addition salts, if the compound contains a basic functional group, such as an amine. Acid-addition salts can be formed using inorganic acids or organic acids. Pharmaceutically acceptable salts of the compounds can be, for example, base-addition salts, if the compound contains an acid functional group, such as a carboxylic acid. Acid-addition salts can be formed using inorganic bases or organic bases. The term "pharmaceutically acceptable salt" is used to specify that the salt is suitable for use in the human or animal body. An exemplary list of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use , PH Stahl and CG Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. Pharmaceutically acceptable salts of the compound of formula I or the PROTAC compound include those salts which can be formed in the human or animal body after administration of the compound to the human or animal body.

As used herein, the term "alkyl" includes straight chain, branched chain, and cyclic alkyl groups having the specified number of carbon atoms, and combinations thereof. Thus, C _1-3 alkyl would include methyl, ethyl, n -propyl, isopropyl, and cyclopropyl; C _1-9 alkyl would include (4-isopropylcyclohexyl)methyl. The same principles apply to the term "alkoxy." Similarly, as used herein, the term "alkoxy" includes straight chain, branched chain, and/or cyclic alkoxy groups having the specified number of carbon atoms. Thus, C _1-3 alkoxy includes methoxy, ethoxy, n -propoxy, isopropoxy, and cyclopropoxy.

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

When the term "optionally" is used, it is intended that the subsequent feature may or may not occur. Thus, use of the term "optionally" includes instances where the feature is present, and also instances where the feature is not present. For example, "methyl optionally substituted with one or more F" includes -CH ₃ , -CH ₂ F, -CHF _{2 ,} and -CF ₃ .

The term "substituted" means that one or more hydrogens on the designated atom or group are replaced by the indicated substituent(s), provided that any atom(s) bearing such substituent(s) retains its permitted valences, wherein those skilled in the art understand that the standard valences of carbon, nitrogen and oxygen are 4, 3 and 2, respectively. Accordingly, it should be understood that "substituted on any possible C atom(s)" means that the substituent(s) are restricted in their positions (and/or potentially in their number) depending on whether or not any hydrogen atoms remain on the designated atom or group that can be replaced by said substituent(s).

The dashed line join included in Z, " " indicates the possibility that the bond may be a single covalent bond or a double covalent bond in each case, depending ^on the atoms (or groups of atoms) present at each of the X ^E , X ^F , X ^G , X ^H and X J positions. The skilled person understands that the standard valences of carbon, nitrogen and oxygen are as mentioned above, and thus can understand whether each dashed bond should be interpreted as a single bond or a double bond at any given Z group in the compound of formula I. The same applies to positions X ^E2 , X ^F2 , X ^G2 , X ^H2 and X ^J2 in Z ^A .

For example, the term "adjacent" or "adjacent positions" with respect to X ^G , X ^{H ,} and X ^J of Z refers to the next closest positions in the molecular chain/ring system. Thus, with respect to Z , X ^G and X ^H are adjacent to each other, and X ^H and X ^J are also adjacent to each other, but X ^G is not adjacent to X ^J .

The term "saturated" means that the atoms of the specified framework or group are linked only by single covalent bonds. Accordingly, the term "unsaturated" means that the specified framework or group contains double and/or triple covalent bonds. Examples of unsaturated molecular segments that may be present within a partially or fully unsaturated group or framework include C=C, C=N, C=O, N=N, C≡C or C≡N, where nitrogen and oxygen heteroatoms are permitted/present, and which may also include S=O, where sulfur heteroatoms are also permitted/present.

It should be understood that “heteroatom” may represent an oxygen, nitrogen or sulfur atom, unless expressly further limited in the context provided.

The term "minimum length of […] atoms between 'a' and 'b'" refers to the shortest chain of atoms within the chain between 'a' and 'b'. Thus, if the chain is composed of -CH ₂ CH ₂ CH ₂ -, the number of atoms within the chain is 3 (hydrogen atoms are not considered to be present within the chain). Alternatively, if the chain is composed of 1,3-phenylene, with the shorter path around the phenyl ring containing 3 C atoms and the longer path around the phenyl ring containing 5 C atoms, the minimum length of such a chain would be counted as 3 atoms.

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

It should be understood that the term “ring” or “heterocyclic group” herein may include single bonds, fused rings, spirocyclic rings and bridged rings.

As described herein, with respect to linkers , it should be understood that branching, if present, may be on the chain (even a chain that is one atom long) and/or on the ring. While those skilled in the art will generally interpret this way, for the avoidance of doubt, it should be understood that "branching" that inherently occurs to form a ring is not considered "branching" in the context of the linker embodiments described herein. It should be understood that the branching may occur on the same or different atoms of the linker framework. For example, it is possible to have two "=O" branches on the sulfur heteroatom to form SO ₂ groups within the linker framework. Linker #22 , described below, is an example with one branch (-Me) originating from the chain within the linker.

Additionally, it should be understood that a 'branch' (and the definition of branch provided herein) refers to a branch that splits the main atom chain between 'a' and 'b', resulting in a 'dead end' in the molecular structure.

In this specification, the point of attachment of a given group to some other group (via a single covalent bond) can be represented by a line that meets the bond substantially perpendicularly to said bond, for example, as exemplified at the far right of formula Ia herein, and at either terminus of linkers 1 to 46, as depicted below.

In this specification, when "zero, one or two of X ^A , X ^B , X ^C , X ^D , X ^E and X ^F are N (but not both X ^E and X ^F are N) or otherwise they are C", it should be understood that a particular C atom implicitly has a hydrogen atom if necessary to satisfy the standard valence (4) for a carbon atom. Those skilled in the art will appreciate that when a substituent or linker is attached to the carbon, such a H atom cannot be on C in X ^E or X ^{F ,} or on C in X ^A , X ^B , X ^C or X ^D . The same principle applies with respect to X ¹ , X ² , X ³ , X ⁴ (and X ⁵ , X ⁶ , X ⁷ and X ^{8 ,} if present), and also to Y ¹ , Y ² , Y ³ and Y ⁴ . The same applies to X ^A2 , X ^B2 , X ^C2 , X ^D2 , X ^E2 , X ^F2 , X ^G2 , X ^{H2 ,} and X ^J2 .

References herein 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 should not be considered a secondary or tertiary amine.

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

When referring to a cyclic group having a specified number of ring atoms (e.g., a heterocyclic group), this includes the atoms making up the rings (including the atoms included in the bridges of a bridged ring and all atoms of a fused ring or spiro ring) but does not include any hydrogen atoms or other substituent atoms attached to the ring atoms. Thus, for example, a cyclic group which is 1,4-piperazine-1,4-diyl has 6 ring atoms (4C and 2N).

As used herein, an alkylene group (e.g., C _1-5 alkylene) is a saturated group consisting of only carbon and hydrogen atoms having two points of attachment to adjacent atoms/groups. It can include straight chain(s), branched chain(s) and/or ring(s). Thus, C ₁ alkylene represents -CH ₂ -, C ₂ alkylene can represent -CH ₂ CH ₂ - or -CH(Me)-, and C _1-5 alkylene includes, for example, -CH ₂ (cyclobut-1,3-diyl)-. "Straight-chain C _u1-u2 alkylene" corresponds to -(CH ₂ ) _u -, where u is an integer from u1 to u2.

As used herein, a hydrocarbyl group means any group consisting of only C and H atoms. For example, C _1-7 hydrocarbyl includes methyl, phenyl, and p -tolyl.

The term "therapy" is intended to have its ordinary meaning of treating a disease so as to alleviate, in whole or in part, one, some or all of its symptoms, or to correct or redress the underlying pathology. The term "therapy" also includes "prevention" or "prophylaxis" unless there is a specific indication to the contrary. The terms "therapeutic" and "therapeutically" are to be construed in a corresponding manner.

The term "prevention" is intended to have its ordinary meaning and includes primary prevention, which is aimed at preventing the onset of a disease, and secondary prevention, whereby a patient is temporarily or permanently protected against exacerbation or worsening of the disease or the onset of new symptoms associated with the disease, when the disease has already developed.

The term "treatment" is used interchangeably with "therapy." Similarly, the term "treating" may be considered as "applying a therapy," where "therapy" is defined herein.

Some of the values of the variable are as follows. Any one, two or more of these values may be used in any combination with any other definition, claim, aspect or embodiment herein (where the context permits) to provide additional embodiments/claims of the present disclosure.

In one embodiment, X ¹ is C and zero or one of X ² , X ³ and X ⁴ is N and otherwise they are C; or both X ³ and X ⁴ are C and - X ⁵ = X ⁶ - X ⁷ = X ⁸ - are substituted, wherein X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ , wherein one of X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ is N and otherwise they are C.

In one embodiment, X ¹ is C, and zero, one, or two of X ² , X ^{3 ,} and X ⁴ are N, otherwise they are C.

In one embodiment, X ¹ is C, zero or one of X ² , X ³ and X ⁴ is N, otherwise they are C.

In one embodiment, X ¹ is C, and one or two of X ² , X ³ and X ⁴ are N, otherwise they are C.

In one embodiment, X ¹ is C and one of X ² , X ³ and X ⁴ is N, otherwise they are C.

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

In one embodiment, X ¹ and X ² are C, X ³ and X ⁴ are both C, and - X ⁵ = X ⁶ - X ⁷ = X ⁸ -, wherein X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ , wherein one of X ⁵ , X ⁶ , X ⁷ and X ⁸ is N, otherwise they are C.

In one embodiment, X ³ and X ⁴ are both C, and - X ⁵ = X ⁶ - X ⁷ = X ⁸ - are substituted, wherein X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ ; X ⁶ and X ⁷ are both C, and X ⁸ is N.

In one embodiment, each R ¹ is a substituent on X ¹ , and when p is 2, a substituent on any other C atom in X ² , X 3 and X ⁴ (or each R ¹ is a substituent on X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ or X ⁸ when X ³ and X ⁴ are substituted with -X ⁵ =X ⁶ -X ⁷ =X 8 ^- ) , and each occurrence is independently selected from F, Cl, Me _, cyclopropyl, CHF ₂ , CF ³ and OMe.

In one embodiment, each R ¹ is a substituent on X ¹ , and when p is 2, a substituent on any other C atom in X ² , X ³ and X ⁴ (unless X ³ and X ⁴ are substituted by - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), and the value of R ¹ is otherwise as defined herein.

In one embodiment, each R ¹ is selected from Cl, F, C _1-3 alkyl (optionally substituted with one or more F), and C _1-3 alkoxy.

In one embodiment, p is 1 or 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), otherwise p is 1 or 2.

In one embodiment, p is 1 or 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), otherwise p is 0 or 1.

In one embodiment, p is 1 or 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), otherwise p is 0.

In one embodiment, p is 1 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), otherwise p is 0, 1 or 2.

In one embodiment, p is 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), otherwise p is 0, 1 or 2.

In one embodiment, p is 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), otherwise p is 0.

In one embodiment, p is 0 and both X ³ and X ⁴ are C, and - X ⁵ = X ⁶ - X ⁷ = X ⁸ - are substituted, where X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ .

In one embodiment, p is 1 or 2 and X ³ and X ⁴ are not substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -.

In one embodiment, p is 1 or 2; X ³ and X ⁴ are not substituted, - X ⁵ = X ⁶ - X ⁷ = X ⁸ -, and X ¹ is C attached to R ¹ , wherein - R ¹ is CF ₃ .

In one embodiment, p is 1; X ³ and X ⁴ are not substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -, and X ¹ is C attached to R ¹ .

In one embodiment, p is 1; X ³ and X ⁴ are not substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -, and X ¹ is C attached to R ¹ , wherein R ¹ is CF ₃ .

In one embodiment, p is 1 and R ¹ is selected from Cl, C _1-3 alkyl (optionally substituted with one or more F), and C _1-3 alkoxy.

In one embodiment, p is 1 and R ¹ is selected from Cl, Me, cyclopropyl, CHF ₂ , CF ₃ and OMe.

In one embodiment, p is 1, X ¹ is C attached to R ¹ , wherein R ¹ is selected from Cl, Me, cyclopropyl, CHF ₂ , CF ₃ and OMe.

In one embodiment, p is 1, X ¹ is C attached to R ¹ , X ³ and X ⁴ are not substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -, and R ¹ is selected from Cl, Me, cyclopropyl, CHF ₂ , CF ₃ and OMe.

In one embodiment, p is 1 or 2; X ³ and X ⁴ are not substituted such that - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ is C attached to R ¹ , wherein R ¹ is selected from Cl, C _1-3 alkyl (optionally substituted with one or more F) and C _1-3 alkoxy, and when present (i.e. when p is 2) other R ¹ is F.

In one embodiment, p is 1 or 2; X ³ and X ⁴ are not substituted such that - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ is C attached to R ¹ , wherein said R ¹ is selected from Cl, Me, cyclopropyl, CHF ₂ , CF ₃ and OMe, and when present (i.e. when p is 2) other R ¹ is F.

In one embodiment, p is 1 or 2; X ³ and X ⁴ are not substituted such that - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ is C attached to R ¹ , wherein R ¹ is selected from Cl, Me, cyclopropyl, CHF ₂ , CF ₃ and OMe, and when present (i.e. when p is 2) the additional R ¹ substituent is F attached to X ² and X ² is C.

In one embodiment, p is 1 and R ¹ is C _1-3 alkyl optionally substituted with one or more F.

In one embodiment, p is 1 and R ¹ is methyl, cyclopropyl, CF ₃ or CHF ₂ .

In one embodiment, p is 1 and R ¹ is CF ₃ or CHF ₂ .

In one embodiment, p is 1 and R ¹ is CHF ₂ .

In one embodiment, p is 1 and R ¹ is CF ₃ .

In one embodiment, p is 1 and R ¹ is methyl.

In one embodiment, p is 1 and R ¹ is cyclopropyl.

In one embodiment, p is 1 and R ¹ is methoxy.

The above eight embodiments can be in the context where, for example, X ³ and X ⁴ are not substituted as - X ⁵ = X ⁶ - X ⁷ = X ⁸ -, X ¹ is C, and the above-mentioned R ¹ is a substituent on C in X ¹ .

In one embodiment, p is 2; X ¹ and X ² are both C; X ³ and X ⁴ are not substituted such that - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; and the value of R ¹ is such that X ¹ is replaced by CF ₃ and X ² is replaced by F.

In one embodiment, p is 1; X ³ and X ⁴ are not substituted with - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ , X ² , X ³ and X ⁴ are all C and R ¹ is a substituent on X ¹ as defined herein.

In one embodiment, p is 1; X ³ and X ⁴ are not substituted by - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ , X ² , X ³ and X ⁴ are all C, and R ¹ is CF ₃ as a substituent on X ¹ .

In one embodiment, p is 2, one R ¹ is CF ₃ and the other R ¹ is F or ethyl.

In one embodiment, p is 2, one R ¹ is CF ₃ and the other R ¹ is F.

In one embodiment, p is 2, one R ¹ is CF ₃ and the other R ¹ is ethyl.

In one embodiment, p is 2, X ¹ is C attached to the first R ¹ and X ² is C attached to the second R ¹ .

In one embodiment, p is 2, X ¹ is C attached to CF ₃ and X ² is C attached to F or ethyl.

In one embodiment, p is 2, X ¹ is C attached to CF ₃ and X ² is C attached to F.

In one embodiment, p is 2, X ¹ is C attached to CF ₃ and X ² is C attached to ethyl.

The above seven embodiments can be in a context where, for example, X ³ and X ⁴ are not substituted as - X ⁵ = X ⁶ - X ⁷ = X ⁸ -.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

In one embodiment, m is 0.

In one embodiment, m is 1.

In one embodiment, n is 0 and m is 1.

In one embodiment, n is 1 and m is 1.

In one embodiment, n is 0 and m is 0.

In one embodiment, n is 0, 1, or 2; and m is 1.

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

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

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

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

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

In one embodiment, n is 1, m is 0, R ^2a is H and R ^2b is C _1-3 alkyl attached to a C atom other than Q , wherein said C atom has the ( R )-stereochemical configuration.

In one embodiment, n is 1, m is 0, R ^2a is H and R ^2b is C _1-3 alkyl attached to a C atom other than Q , wherein said C atom has the ( S )-stereochemical configuration.

In one embodiment, n is 1, m is 1, R ^2a is H and R ^2b is C _1-3 alkyl attached to a C atom other than Q , wherein said C atom has the ( R )-stereochemical configuration.

In one embodiment, n is 1, m is 1, R ^2a is H and R ^2b is C _1-3 alkyl attached to a C atom other than Q , wherein said C atom has the ( S )-stereochemical configuration.

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

In one embodiment, Q is CH having the ( R )-stereochemical configuration at said C atom.

In one embodiment, Q is CH having the ( S )-stereochemical configuration at said C atom.

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

In one embodiment, n is 2; m is 1; R ^2a and R ^2b are both H; and Q is CH having the ( R )-stereochemical configuration at said C atom.

In one embodiment, n is 2; m is 1; R ^2a and R ^2b are both H; and Q is CH having the ( S )-stereochemical configuration at said C atom.

In one embodiment, R ^2a and R ^2b are substituents on the same or different C atoms other than Q , each independently selected from H and C _1-3 alkyl.

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

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

In one embodiment, R ^2a and R ^2b are substituents on the same or different C atom adjacent to Q , each independently selected from H and C _1-3 alkyl (e.g., Me).

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

In one embodiment, R ^2a and R ^2b are same or different substituents on C atom other than Q , each independently selected from H, F and C _1-3 alkyl.

In one embodiment, R ^2a and R ^2b are substituents on the same or different C atoms other than Q , each independently selected from H and C _1-3 alkyl, or R ^2a and R ^2b together form a (CH ₂ ) _r - group, wherein r is 1, 2 or 3.

In one embodiment, r is 1.

In one embodiment, r is 2.

In one embodiment, r is 3.

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

In one embodiment, R ^2a and R ^2b are substituents on the same C atom other than Q , wherein R ^2a and R ^2b are both Me.

In one embodiment, R ^2a and R ^2b are substituents on the same C atom adjacent to Q , wherein R ^2a and R ^2b are both Me.

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

In one embodiment, zero or one of Y ¹ , Y ² , Y ³ and Y ⁴ is N, otherwise they are C.

In one embodiment, one or two of Y ¹ , Y ² , Y ³ and Y ⁴ are N, otherwise they are C.

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

In one embodiment, one of Y ¹ , Y ² , Y ³ and Y ⁴ is N, otherwise they are C.

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

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

In one embodiment, two of Y ¹ , Y ² , Y ³ and Y ⁴ are N, otherwise they are C.

In one embodiment, Y ¹ and Y ³ are N; Y ² and Y ⁴ are C.

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

In one embodiment, q is 0 or 1.

In one embodiment, q is 0.

In one embodiment, q is 1.

In one embodiment, q is 2.

In one embodiment, q is 0, 1 or 2 and R ³ (if present) is a substituent on any C atom in Y ¹ , Y ² , Y ³ and Y ⁴ selected from F, CN and C _1-3 alkyl.

In one embodiment, q is 0, 1 or 2 and R ³ (if present) is a substituent on any C atom in Y ¹ , Y ² , Y ³ and Y ⁴ selected from F and C _1-3 alkyl.

In one embodiment, q is 0 or 1 and R ³ (if present) is a substituent on any C atom in Y ¹ , Y ² , Y ³ and Y ⁴ selected from F or C _1-3 alkyl.

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

In one embodiment, R ³ (if present) is C _1-3 alkyl.

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

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

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

In one embodiment, q is 1 and R ³ is attached to C in Y ¹ .

In one embodiment, q is 1 and R ³ is attached to C in Y ¹ , and R ³ is selected from F, CN and Me.

In one embodiment, q is 2 and both R ³ groups are F.

In one embodiment, q is 2 and R ³ groups are attached to C in Y ¹ and Y ³ .

In one embodiment, q is 2 and each R ³ group is F, which is attached to C in Y ¹ and Y ³ .

In one embodiment, the linker is a saturated or partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has a minimum length of 6 to 26 atoms between the terminal attachment points 'a' and 'b' and 'a' and 'b'; and wherein the framework may comprise one or more straight and/or branched chains and/or rings, and is optionally substituted with one or more F on any available C atom(s).

In one embodiment, the framework of the linker is a saturated or partially unsaturated framework.

In one embodiment, the framework of the linker is a saturated framework.

In one embodiment, the framework of the linker comprises C and H atoms and at least two heteroatoms.

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

In one embodiment, the framework of the linker comprises C and H atoms and at least one nitrogen heteroatom.

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

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

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

In one embodiment, the framework of the linker comprises at least two heteroatoms comprising C and H atoms and at least one nitrogen heteroatom in the form of a secondary or tertiary amine.

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

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

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

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

In one embodiment, the total number of C and heteroatoms within the linker framework is from 6 to 26.

In one embodiment, the total number of C and heteroatoms within the linker framework is 7 to 24.

In one embodiment, the total number of C and heteroatoms within the linker framework is 8 to 22.

In one embodiment, the total number of C and heteroatoms within the linker framework is 9 to 20.

In one embodiment, when W is -Z - R ^A , the linker is attached at any available C atom in X ^B or X ^C of Z.

In one embodiment, the framework of the linker may comprise one or more straight chains and/or rings, optionally substituted with one or more F on any available C atom(s).

In one embodiment, the framework of the linker comprises one or more straight chains and/or rings, optionally substituted with one or more F on any available C atom(s).

In one embodiment, the framework of the linker may comprise (or consist of) one or more straight and/or branched chains and/or rings (wherein the total number of branches is from 0 to 5), optionally substituted with one or more F on any available C atom(s).

In one embodiment, the framework of the linker may comprise (or consist of) one or more straight and/or branched chains and/or rings (wherein the total number of branches is from 0 to 3), optionally substituted with one or more F on any available C atom(s).

In one embodiment, the framework of the linker may comprise (or consist of) one or more straight and/or branched chains and/or rings, optionally substituted with one or more F on any available C atom(s), wherein the total number of branches is 0 or 1.

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

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

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

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

In one embodiment, any/each branch within the framework of the linker has 1 to 5 C and/or hetero atoms.

In one embodiment, any/each branch within the framework of the linker has 1 or 2 C and/or heteroatoms.

In one embodiment, any/each branch within the framework of the linker has one C and/or hetero atom.

In one embodiment, any/each branch within the framework of the linker has one C atom.

In one embodiment, the total number of C and/or heteroatoms within the branch(es) (if present) of the framework of the linker is from 1 to 5.

In one embodiment, the total number of C and/or heteroatoms within the branch(es) of the framework of the linker (if present) is 1 to 3.

In one embodiment, the total number of C and/or heteroatoms within the branch(es) (if present) of the framework of the linker is 1.

In one embodiment, any framework of the linker is unbranched or has a single branch that is Me.

In one embodiment, the framework of the linker is optionally substituted with one or two F's on any available C atom(s) (e.g., with two F's, e.g., where the two F's are substituted on the same carbon atom).

In one embodiment, the framework of the linker is not replaced by any F.

In one embodiment, the linker is a saturated or partially unsaturated framework comprising C and H atoms and at least one heteroatom, said framework comprising terminal attachment points 'a' and 'b'; and

having a minimum length of 7 to 14 atoms between 'a' and 'b';

The total number of C and heteroatoms within the linker framework is 9 to 20;

The above framework comprises one or more straight and/or branched chains and/or rings optionally substituted with one or two F (e.g., two F) on any available C atom(s);

The total number of branches is 0 or 1, and if present, the branch is Me.

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

In one embodiment, the framework of the linker comprises at least one nitrogen-containing saturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A ¹ -CH ₂ -CH ₂ - A ² units, wherein A ¹ and A ² are each independently selected from N and O.

In one embodiment, the framework of the linker comprises A ¹ -CH ₂ -CH ₂ - A ² units, wherein A ¹ and A ² are each independently selected from N and O.

In one embodiment, the framework of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A ¹ -CH ₂ -CH ₂ - A ² units, wherein one of A ¹ and A ² is N and the other of A ¹ and A ² is selected from N or O.

In one embodiment, the framework of the linker comprises at least one nitrogen-containing saturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A ¹ -CH ₂ -CH ₂ - A ² units, wherein one of A ¹ and A ² is N and the other of A ¹ and A ² is selected from N or O.

In one embodiment, the framework of the linker comprises A ¹ -CH ₂ -CH ₂ - A ² units, wherein one of A ¹ and A ² is N and the other of A ¹ and A ² is selected from N or O.

In one embodiment, the framework of the linker comprises at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g., having 4 to 12 ring atoms) or A ¹ -CH ₂ -CH ₂ - A ² units, wherein one of A ¹ and A ² is N in the form of a secondary or tertiary amine and the other of A ¹ and A ² is selected from N or O.

In one embodiment, the framework of the linker comprises A ¹ -CH ₂ -CH ₂ - A ² units, wherein one of A ¹ and A ² is N in the form of a secondary or tertiary amine and the other of A ¹ and A ² is selected from N or O.

In one embodiment, the framework of the linker comprises at least one saturated or partially unsaturated heterocyclic group.

In one embodiment, the framework of the linker comprises at least one saturated heterocyclic group.

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

In one embodiment, the framework of the linker comprises at least one nitrogen-containing saturated heterocyclic group.

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

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

In one embodiment, the linker framework includes:

(1) A ¹ -CH ₂ -CH ₂ - A ² unit, wherein A ¹ and A ² are each independently selected from N and O; and/or

(2) At least one nitrogen-containing saturated or partially unsaturated heterocyclic group selected from piperazine, azetidine, piperidine, 1,4-diazepane, 12-oxa-3,9-diazaspiro[5.6]dodecane, pyrrolidine, 3,9-diazaspiro-[5.5]undecane, 2,5-diazabicyclo[2.2.1]heptane, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4 -c ]pyrrole, 1,2,3,6-tetrahydropyridine, and 9-azaspiro[5.5]undecane.

In one embodiment, the linker framework includes:

(1) A ¹ -CH ₂ -CH ₂ - A ² unit, wherein one of A ¹ and A ² is N in the form of a secondary or tertiary amine, and the other of A ¹ and A ² is selected from N or O; and/or

(2) At least one nitrogen-containing saturated or partially unsaturated heterocyclic group selected from piperazine, azetidine, piperidine, 1,4-diazepane, 12-oxa-3,9-diazaspiro[5.6]dodecane, pyrrolidine, 3,9-diazaspiro-[5.5]undecane, 2,5-diazabicyclo[2.2.1]heptane, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4 -c ]pyrrole, 1,2,3,6-tetrahydropyridine, and 9-azaspiro[5.5]undecane.

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

In one embodiment, the framework of the linker comprises O-CH ₂ -CH ₂ -N units.

In one embodiment, the framework of the linker comprises O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -N units.

In one embodiment, the framework of the linker comprises a piperazine group.

In one embodiment, the framework of the linker comprises an azetidine group.

In one embodiment, the framework of the linker comprises a piperidine group.

In one embodiment, the framework of the linker comprises a 1,4-diazepane group.

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

In one embodiment, the framework of the linker comprises a pyrrolidine group.

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

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

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

In one embodiment, the framework of the linker comprises a 1,2,3,6-tetrahydropyridine group.

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

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

In one embodiment, the framework of the linker comprises at least two nitrogen-containing saturated heterocyclic groups.

In one embodiment, the framework of the linker comprises a C, N or O atom at the 'a' attachment point.

In one embodiment, the framework of the linker comprises an N or O atom at the 'a' attachment point.

In one embodiment, the framework of the linker comprises an N or O atom at the 'b' attachment point.

In one embodiment, the framework of the linker comprises a C atom at the 'a' attachment point.

In one embodiment, the framework of the linker comprises an N atom at the 'a' attachment point.

In one embodiment, the framework of the linker comprises a C or N atom at the 'b' attachment point.

In one embodiment, the framework of the linker comprises an N atom at the 'b' attachment point.

In one embodiment, the framework of the linker comprises a C atom at the 'b' attachment point.

In one embodiment, the framework of the linker comprises an O atom at the 'a' attachment point.

In one embodiment, the framework of the linker comprises an O atom at the 'b' attachment point.

In one embodiment, the framework of the linker comprises N or O atoms at both the 'a' and 'b' attachment points.

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

In one embodiment, the linker framework includes:

(1) A ¹ -CH ₂ -CH ₂ - A ² unit, wherein one of A ¹ and A ² is N in the form of a secondary or tertiary amine, and the other of A ¹ and A ² is selected from N or O; and/or

(2) at least one 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-2 H -pyridine-1,4-diyl, and 9-azaspiro[5.5]undecane-3,9-diyl. A single nitrogen-containing saturated or partially saturated heterocyclic group.

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

In one embodiment, the framework of the linker comprises a piperazine-1,4-diyl group.

In one embodiment, the framework of the linker comprises an azetidine-1,3-diyl group.

In one embodiment, the framework of the linker comprises a piperidine-1,4-diyl group.

In one embodiment, the framework of the linker comprises a 1,4-diazepane-1,4-diyl group.

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

In one embodiment, the framework of the linker comprises a pyrrolidine-1,3-diyl group.

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

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

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

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

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

In one embodiment, the linker has the following chemical formula:

'a' - Q ^A - Q ^B - Q ^C - 'b'

[Here,

'a' and 'b' indicate terminal attachment points;

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g., 1 or 2 F, for example 2 F));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O-, -O- or -N( R ^J )- (wherein R ^J is H or C _1-3 alkyl);

Q ^C is -Q ^H -G- or -(C _1-5 alkylene)- G -;

Each G is independently a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein each R ^G is independently H or C _1-3 alkyl);

Each Q ^H is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A , Q ^B and Q ^C are chosen such that the linker does not contain NN or NO bonds.

In one embodiment, the linker has the following chemical formula:

'a' - Q ^A - Q ^B - Q ^C - 'b'

[Here,

' a ' and ' b ' indicate terminal attachment points;

Q ^A is -GQ ^H - or -G -(C _1-5 alkylene)-;

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O- or -N( R ^J )- (wherein R ^J is C _1-3 alkyl);

Q ^C is -Q ^H -G- or -(C _1-5 alkylene)- G -;

Each G is independently a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein each R ^G is independently H or C _1-3 alkyl);

Each Q ^H is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A , Q ^B and Q ^C are chosen such that the linker does not contain NN or NO bonds.

In one embodiment, the linker has the following chemical formula:

'a' - Q ^A - Q ^B - Q ^C - 'b'

[Here,

' a ' and ' b ' indicate terminal attachment points;

Q ^A is -G ^A -Q ^HA - or - G ^A -(C _1-5 alkylene)-; G ^A is a direct bond, -CH ₂ -, -O-, -NH- or -N(Me)-;

Q ^HA is a 4- to 11-membered nitrogen-containing saturated heterocyclic group;

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is piperazine-1,4-diyl, -O-CH ₂ CH ₂ -O- or -N( R ^J )- (wherein R ^J is C _1-3 alkyl);

Q ^C is -Q ^HC -G ^C - or -(C _1-2 alkylene)- G ^C -; G ^C is a direct bond, -O- or -NH-;

Q ^HC is a 6- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A , Q ^B and Q ^C are chosen such that the linker does not contain NN or NO bonds.

In one embodiment, Q ^A is - G ^A - Q ^HA - or - G ^A -(C _1-5 alkylene)-, wherein,

G ^A is selected from a direct bond, -CH ₂ -, -O- or -N( R ^G )-;

Each R ^G is independently H or C _1-3 alkyl;

Q ^HA is a 4- to 11-membered nitrogen-containing saturated heterocyclic group.

In one embodiment, Q ^A is -G ^A -Q ^HA - or -G ^A - (C _1-5 alkylene)-, wherein,

G ^A is selected from a direct bond, -CH ₂ -, -O- or -N( R ^G )-;

Each R ^G is independently H or C _1-3 alkyl;

Q ^HA is selected from azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl and 9-azaspiro[5.5]undecan-3,9-diyl.

In one embodiment, Q ^A is -G ^A -Q ^HA - or -G ^A - (C _1-5 alkylene) - , wherein,

G ^A is selected from a direct bond, -CH ₂ -, -O- or -NH- or -N(Me)-;

Q ^HA is selected from azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl and 9-azaspiro[5.5]undecan-3,9-diyl;

In the above - G ^A -(C _1-5 alkylene)-, C _1-5 alkylene is selected from -(CH ₂ ) _f - (wherein, f is an integer from 1 to 5), cyclobut-1,3-diyl and -CH ₂ (cyclobut-1,3-diyl)-.

In one embodiment, Q ^A is selected from azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl, -O(piperidine-1,4-diyl)-, -CH ₂ (piperidine-1,4-diyl)-, piperazine-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, -O(9-azaspiro[5.5]undecane-3,9-diyl)-, -O(cyclobut-1,3-diyl)-, -OCH ₂ (cyclobut-1,3-diyl)-, -(CH ₂ ) _f -, -O-(CH ₂ ) _f -, -NH-(CH ₂ ) _f -, and -N(Me)-(CH ₂ ) _f -, wherein f is 1 It is an integer from 0 to 5.

In one embodiment, Q ^A is azetidine-1,3-diyl.

In one embodiment, Q ^A is pyrrolidine-1,3-diyl.

In one embodiment, Q ^A is piperidine-1,4-diyl.

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

In one embodiment, Q ^A is -CH ₂ (piperidine-1,4-diyl)-.

In one embodiment, Q ^A is piperazine-1,4-diyl.

In one embodiment, Q ^A is 3,9-diazaspiro[5.5]undecan-3,9-diyl.

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

In one embodiment, Q ^A is -G- (C _1-5 alkylene)-.

In one embodiment, Q ^A is selected from -O(cyclobut-1,3-diyl)-, -OCH ₂ (cyclobut-1,3-diyl)-, -(CH ₂ ) _f -, -O(CH ₂ ) _f -, -NH-(CH ₂ ) _f -, and -N(Me)-(CH ₂ ) _f -, wherein f is an integer from 1 to 5.

In one embodiment, Q ^A is -O(cyclobut-1,3-diyl)-.

In one embodiment, Q ^A is -OCH ₂ (cyclobut-1,3-diyl)-.

In one embodiment, Q ^A is -(CH ₂ ) _f -, where f is an integer from 1 to 4 (e.g., f is 4).

In one embodiment, Q ^A is -O-(CH ₂ ) _f -, wherein f is an integer from 1 to 5 (e.g., f is 1 or 2).

In one embodiment, Q ^A is -NH-(CH ₂ ) _f -, where f is an integer from 1 to 5.

In one embodiment, Q ^A is -N(Me)-(CH ₂ ) _f -, where f is an integer from 1 to 4.

In one embodiment, Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or straight chain C _1-3 alkylene (optionally substituted with one or more F (e.g., 1 or 2 F, for example, 2 F)).

In one embodiment, Q ^B is a direct bond.

In one embodiment, Q ^B is - Q ^B1 - Q ^B2 - Q ^B3 -.

In one embodiment, Q ^B is C _1-3 alkylene optionally substituted with one or more F.

In one embodiment, Q ^B is C _1-3 alkylene optionally substituted with 1 or 2 F (e.g., 2 F).

In one embodiment, Q ^B is a straight chain C _1-3 alkylene optionally substituted with one or two F (e.g., two F).

In one embodiment, Q ^B is C _1-3 alkylene.

In one embodiment, Q ^B is a straight chain C _1-3 alkylene.

In one embodiment, Q ^B is -CF ₂ -CH ₂ -CH ₂ - or -(CH ₂ ) _w -, wherein w is 1 to 3.

In one embodiment, Q ^B1 and Q ^B3 each independently represent a direct bond, -CH ₂ - or -CH ₂ CH ₂ -.

In one embodiment, Q ^B1 is a direct bond or -CH ₂ -.

In one embodiment, Q ^B1 is a direct bond.

In one embodiment, Q ^B1 is -CH ₂ -.

In one embodiment, Q ^B3 is a direct bond, -CH ₂ - or -CH ₂ CH ₂ -.

In one embodiment, Q ^B3 is a direct bond.

In one embodiment, Q ^B3 is -CH ₂ -.

In one embodiment, Q ^B3 is -CH ₂ CH ₂ -.

In one embodiment, Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O- or -N( R ^J )-, wherein R ^J is C _1-3 alkyl.

In one embodiment, Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O- or -N(Me)-.

In one embodiment, Q ^B2 is piperazine-1,4-diyl, azetidine-1,3-diyl, -O-CH ₂ CH ₂ -O- or -N(Me)-.

In one embodiment, Q ^B2 is piperazine-1,4-diyl, -O-CH ₂ CH ₂ -O- or -N(Me)-.

In one embodiment, Q ^B2 is Q ^H.

In one embodiment, Q ^B2 is piperazine-1,4-diyl.

In one embodiment, Q ^B2 is azetidine-1,3-diyl.

In one embodiment, Q ^B2 is -O-CH ₂ CH ₂ -O-.

In one embodiment, Q ^B2 is -N( R ^J )-, wherein R ^J is C _1-3 alkyl.

In one embodiment, Q ^B2 is -N(Me)-.

In one embodiment, Q ^C is -Q ^H -G- or -(C _1-4 alkylene)- G -.

In one embodiment, Q ^C is -Q ^H -G- or -(C _1-3 alkylene)- G -.

In one embodiment, Q ^C is -Q ^H -G- or -(C _1-2 alkylene)- G -.

In one embodiment, Q ^C is -Q ^HC -G ^C - or -(C _1-5 alkylene) -G ^C -, wherein,

G ^C is selected from a direct bond, -O- or -NH-;

Q ^HC is a 6- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.

In one embodiment, Q ^C is -Q ^HC -G ^C - or -(C _1-2 alkylene)- G ^C -, wherein,

G ^C is selected from a direct bond, -O- or -NH-;

Q ^HC is a 6- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.

In one embodiment, Q ^C is -Q ^HC -G ^C - or - (C _1-2 alkylene) -G ^C - , wherein,

G ^C is selected from a direct bond, -O- or -NH-;

Q ^HC is selected from piperazine-1,4-diyl, piperidine-1,4-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,4-diazepane-1,4-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 12-oxa-3,9-diazaspiro[5.6]-dodecane-3,9-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c ]pyrrole-2,5-diyl, and 3,6-dihydro-2 H -pyridine-1,4-diyl.

In one embodiment, Q ^C is selected from 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-2 H -pyridine-1,4-diyl, and -CH ₂ CH ₂ - NH- and -(CH ₂ ) _g - O-, wherein, g is an integer from 1 to 4.

In one embodiment, Q ^C is piperazine-1,4-diyl.

In one embodiment, Q ^C is piperidine-1,4-diyl.

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

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

In one embodiment, Q ^C is 1,4-diazepane-1,4-diyl.

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

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

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

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

In one embodiment, Q ^C is -(C _1-5 alkylene)- G -[e.g., -(CH ₂ ) _g - O- (wherein g is an integer from 1 to 5)].

In one embodiment, Q ^C is -(C _1-4 alkylene)- G -[e.g., -(CH ₂ ) _g - O- (wherein g is an integer from 1 to 4)].

In one embodiment, Q ^C is -(C _1-3 alkylene)- G -[e.g., -(CH ₂ ) _g - O- (wherein g is 1, 2 or 3)].

In one embodiment, Q ^C is -(C _1-2 alkylene)- G -[e.g., -(CH ₂ ) _g - O- (wherein g is 1 or 2)].

In one embodiment, Q ^C is -(CH ₂ ) _g -G ^C -, wherein g is an integer from 1 to 5 and G ^C is -O- or -NH-.

In one embodiment, Q ^C is -(CH ₂ ) _g -G ^C -, where g is 1 or 2 and G ^C is -O- or -NH-.

In one embodiment, Q ^C is -CH ₂ CH ₂ NH-.

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

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

In one embodiment, Q ^H is piperazine-1,4-diyl.

In one embodiment, Q ^H is azetidine-1,3-diyl.

In one embodiment, Q ^H is piperidine-1,4-diyl.

In one embodiment, Q ^H is 1,4-diazepane-1,4-diyl.

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

In one embodiment, Q ^H is pyrrolidine-1,3-diyl.

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

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

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

In one embodiment, Q ^H is 3,6-dihydro-2 H -pyridin-1,4-diyl.

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

In one embodiment, R ^J is C _1-3 alkyl.

In one embodiment, R ^J is Me.

In one embodiment, R ^G is C _1-3 alkyl.

In one embodiment, R ^G is H or Me.

In one embodiment, R ^G is Me.

In one embodiment, R ^G is H.

In one embodiment, the linker (e.g., 'a' - Q ^A - Q ^B - Q ^C - 'b') is selected from any of linkers 1 to 46 or 1 to 48 exemplified below:

.

In one embodiment, W is an E3 ubiquitin ligase cereblon binder unit that is attached to the 'b' terminus of the linker via an available C atom within the E3 ubiquitin ligase cereblon binder unit.

In one embodiment, W is W1 , which is - Z -( R ^A ) _h ,

Here, Z is And,

Here,

represents a single covalent bond or a double covalent bond;

Zero, one, or two of X ^A , X ^B , X ^C , X ^D , X ^E , and X ^F are N (provided that not both X ^E and X ^F are N), otherwise they are C;

One of X ^G , X ^H and X ^J is C(O);

One of X ^G , X ^{H ,} and X ^J is N-(2,6-dioxopiperidin-3-yl)( Y );

One of X ^G , X ^H and X ^J is selected from C( R ^T ) ₂ , -CH ₂ CH ₂ -, C(O), N(C _1-3 alkyl), -O- and -N= (wherein each R ^T is selected from H, F, Me or forms a cycloprop-1,1-diyl group together with the carbon of C( R ^T ) ₂ ;

X ^G , X ^H and X ^J are selected such that no two C(O) groups exist at adjacent positions and N-(2,6-dioxopiperidin-3-yl) is not at a position adjacent to N(C _1-3 alkyl) or O;

Each R ^A is independently a substituent on any available C atom in X ^A , X B , X ^C or X ^D selected from F, ^Cl , C _1-3 alkyl, C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy are independently optionally substituted with one or more F;

h is 0, 1 or 2;

The linker is attached to any C atom in X ^A , X ^B , X ^C , or X ^D .

In one embodiment, zero or one of X ^A , X ^B , X ^C , X ^D , X ^E and X ^F is N, otherwise they are C.

In one embodiment, one or two of X ^A , X ^B , X ^C , X ^D , X ^E and X ^F are N, otherwise they are C.

In one embodiment, X ^A , X ^B , X ^C , X ^D , X ^E and X ^F are all C.

In one embodiment, one of X ^A , X ^B , X ^C , X ^D , X ^E and X ^F is N, otherwise they are C.

In one embodiment, X ^A , X ^B , X ^C , X ^D , X ^E and X ^F are N (provided that not both X ^E and X ^F are N), otherwise they are C.

In one embodiment, X ^B , X ^D , and X ^F are all C, and zero, one, or two of X ^A , X ^C , and X ^E are N, otherwise they are C.

In one embodiment, X ^B , X ^D and X ^F are all C, and zero, one or two of X ^A , X ^C and X ^E are N, otherwise they are C; wherein when X ^A is C, the linker is attached to X ^B or X ^A .

In one embodiment, X ^B , X ^D and X ^F are all C, and zero, one or two of X ^A , X ^C and X ^E are N, otherwise they are C; wherein the linker is attached to X ^B .

In one embodiment, X ^G - X ^H - X ^J are:

(i) X ^G -N Y -C(O) (wherein, X ^G is -CH ₂ -, -CH ₂ CH ₂ -, =N-, or C(O));

(ii) X ^G -C(O)-N Y (wherein X ^G is -O- or N(C _1-3 alkyl) [e.g., N(Me)]; or

(iii) C(O)-N Y -CH ₂ .

In one embodiment, the linker is attached to a C atom in X ^A or X ^B , and X ^G - X ^H - X ^J are:

(i) X ^G -N Y -C(O) (wherein, X ^G is -CH ₂ -, -CH ₂ CH ₂ -, =N-, or C(O));

(ii) X ^G -C(O)-N Y (wherein X ^G is -O- or N(C _1-3 alkyl) [e.g., N(Me)]; or

(iii) C(O)-N Y -CH ₂ .

In one embodiment, the linker is attached to the C atom in X ^{B ,} and X ^G - X ^H - X ^J are:

(i) X ^G -N Y -C(O) (wherein, X ^G is -CH ₂ -, -CH ₂ CH ₂ -, =N-, or C(O));

(ii) X ^G -C(O)-N Y (wherein X ^G is -O- or N(C _1-3 alkyl) [e.g., N(Me)]; or

(iii) C(O)-N Y -CH ₂ .

In one embodiment, X ^G - X ^H - X ^J is CH ₂ -N Y -C(O).

In one embodiment, X ^G - X ^H - X ^J is CH ₂ CH ₂ -N Y -C(O).

In one embodiment, X ^G - X ^H - X ^J is =NN Y -C(O).

In one embodiment, X ^G - X ^H - X ^J is C(O)-N Y -C(O).

In one embodiment, X ^G - X ^H - X ^J is OC(O)-N Y.

In one embodiment, X ^G - X ^H - X ^J is N(C _1-3 alkyl)-C(O)-N Y [e.g., N(Me)-C(O)-N Y ].

In one embodiment, X ^G - X ^H - X ^J is C(O)-N Y -CH ₂ .

In one embodiment, each R ^A is any available substituent on C in X ^A , X ^B , X ^C or X ^D selected from F, Cl and C _1-3 alkoxy (optionally substituted with one or more F).

In one embodiment, each R ^A is any available substituent on C in X ^A , X ^B , X ^C or X ^D selected from F, Cl, OMe and -OCHF ₂ .

In one embodiment, h is 0.

In one embodiment, h is 1.

In one embodiment, h is 2.

In one embodiment, the linker is attached to X ^C (wherein X ^C is C); and X ^A is C attached to R ^A (wherein R ^A is OMe, wherein the methyl is optionally substituted with one or more F (e.g., -OCHF ₂ )).

In one embodiment, the linker is attached to X ^C (wherein X ^C is C); and X ^A is C attached to R ^A (wherein R ^A is OMe or -OCHF ₂ ).

In one embodiment, - Z -( R ^A ) _h together represent any one of groups 1, 4, 16, 17 and 19 (see specific - Z -( R ^A ) _h groups 1 to 21 whose structures are illustrated below).

In one embodiment, h is 1 and R ^A is C _1-3 alkoxy [e.g., OMe].

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

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

In one embodiment, h is 1 and R ^A is F.

In one embodiment, h is 1 and R ^A is Cl.

In one embodiment, h is 1 and R ^A is -OCHF ₂ .

In one embodiment, the linker is attached to a C atom in X ^A or X ^B , and h is 0.

In one embodiment, the linker is attached to C in X ^A or X ^B , h is 1 and R ^A is a substituent on X ^C , wherein X ^C is C and R ^A is F.

In one embodiment, the linker is attached to C in X ^A or X ^B , h is 1 and R ^A is a substituent on X ^D , wherein X ^D is C and R ^A is OMe or -OCHF ₂ .

In one embodiment, the linker is attached to C in X ^B , h is 0, 1 or 2; the first R ^A (if present, i.e., when h is 1 or 2) is a substituent on an available C in X ^D and the second R ^A (if present, i.e., when h is 2) is on an available C in X ^A .

In one embodiment, the linker is attached to C in X ^B , h is 0, 1 or 2; the first R ^A (if present, i.e., when h is 1 or 2) is a substituent on an available C in X ^D selected from Cl, OMe and -OCHF ₂ , and the second R ^A (if present, i.e., when h is 2) is on an available C in X ^A and is selected from Cl and OMe.

In one embodiment, - Z -( R ^A ) _h together represent any of groups 1 to 21 as exemplified below:

.

In one embodiment, W is W2 , which is And,

Z ^A is And,

Here,

represents a single covalent bond or a double covalent bond;

One of X ^A2 , X ^B2 , X ^{C2 ,} and X ^D2 is C and is covalently bonded to Y ;

Zero, one, or two of X ^A2 , X ^B2 , X ^C2 , X ^D2 , X ^E2 , and X ^F2 are N (provided that not both X ^E2 and X ^F2 are N), otherwise they are C;

One or two of X ^G2 , X ^H2 and X ^J2 N; otherwise, they are C;

Each R ^AA is a substituent on any available C or N atom of Z , independently selected from R ^AA1 optionally substituted with one or more R ^AA2 in each case; when R ^AA is a substituent on an available C atom of Z ^A , R ^AA is additionally selected from R ^AA2 ;

Each R ^AA1 is independently C _1-4 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxyC _1-3 alkyl, carboxyC _1-3 alkyl, C _5-7 carbocyclyl or 4- to 6-membered heterocyclyl;

Each R ^AA2 is independently selected from 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 (wherein said C _1-3 alkyl is optionally substituted with one or more F);

v is 0, 1, or 2;

Y is N-(2,6-dioxopiperidin-3-yl).

In one embodiment, Z ^A is And,

Here,

represents a single covalent bond or a double covalent bond;

One of X ^A2 and X ^B2 is C and covalently bonded to Y, and the other of X ^A2 and X ^B2 is C;

Zero or one of X ^C2 and X ^D2 N, otherwise they are C;

One of X ^G2 and X ^J2 N and the other of X ^G2 and X ^J2 is C;

X ^H2 , X ^E2 and X ^F2 are All are C.

In one embodiment - Z ^A - Y together represent any one or more of groups A1 to A6 exemplified below, wherein in each case said Z ^A group is optionally substituted on available C and/or N atom(s) with -[ R ^AA ] _V as further defined herein.

.

In one embodiment, each R ^AA is independently selected from R ^AA1, optionally substituted with one or more R ^AA2 , in each case as a substituent on any available C or N atom of Z ^A ; wherein when R ^AA is a substituent on an available C atom of Z , R ^AA is further selected from R ^AA2 ; each R ^AA1 is independently C _1-4 alkyl or 4-6 membered heterocyclyl; and each R ^AA2 is independently selected from F, Cl, CN and C _1-3 alkyl.

In one embodiment, each R ^AA is independently selected from R ^AA1, optionally substituted with one or more R ^AA2 in each case as a substituent on any available C or N atom of Z ^A ; wherein when R ^AA is a substituent on an available C atom of Z ^A , R ^AA is further selected from R ^AA2 ; each R ^AA1 is independently methyl, isopropyl, cyclopropyl, pyridinyl or pyrazolyl; and each R ^AA2 is independently F, Cl, CN or methyl.

In one embodiment, each R ^AA is a substituent on an available C atom of Z ^A independently selected from methyl, isopropyl, cyclopropyl, pyridin-2-yl, 1-methylpyrazol-4-yl, -CH ₂ CN, F, Cl, CN; and/or a methyl substituent on an available N atom of Z ^A .

In one embodiment, v is 0.

In one embodiment, v is 1.

In one embodiment, v is 2.

In one embodiment, v is 1 or 2.

In one embodiment, v is either 0 or 1.

In one embodiment, v is 1; X ^A1 is a C atom; and R ^AA is a substituent on X ^A1 .

In one embodiment, v is 1; X ^A1 is a C atom; and R ^AA is a C _1-4 alkyl substituent on X ^A1 .

In one embodiment, v is 1; X ^B1 is a C atom; and R ^AA is a substituent on X ^B1 .

In one embodiment, v is 1; X ^B1 is a C atom; and R ^AA is a C _1-4 alkyl (e.g., methyl) substituent on X ^B1 .

In one embodiment, v is 1; X ^C1 is a C atom; and R ^AA is a substituent on X ^C1 .

In one embodiment, v is 1; X ^C1 is a C atom; and R ^AA is a C _1-4 alkyl (e.g., methyl) substituent on X ^C1 .

In one embodiment, v is 1; X ^D1 is a C atom; and R ^AA is a substituent on X ^D1 .

In one embodiment, v is 1; X ^D1 is a C atom; and R ^AA is a C _1-4 alkyl (e.g., methyl) or F substituent on X ^D1 .

In one embodiment, v is 1; X ^G1 is a C atom; and R ^AA is a substituent on X ^G1 .

In one embodiment, v is 1; X ^G1 is a C atom; R ^AA is a substituent on X ^G1 ; wherein R ^AA is selected from R ^AA1 optionally substituted with one or more R ^AA2 ; or R ^AA is selected from R ^AA2 ; R ^AA1 is C _1-4 alkyl or 4-6 membered heterocyclyl; R ^AA2 is selected from F, Cl, CN and C _1-3 alkyl.

In one embodiment, v is 1; X ^G1 is a C atom; and R ^AA is a substituent on X ^G1 ; wherein R ^AA is selected from methyl, isopropyl, cyclopropyl, pyridin-2-yl, 1-methylpyrazol-4-yl, -CH ₂ CN, F, Cl and CN.

In one embodiment, v is 1 or 2; X ^G1 is a C atom; one/ the R ^AA is a substituent on X ^G1 ; wherein R ^AA is selected from R ^AA1 optionally substituted with one or more R ^AA2 ; or R ^AA is selected from R ^AA2 ; R ^AA1 is C _1-4 alkyl or 4-6 membered heterocyclyl; R ^AA2 is selected from F, Cl, CN and C _1-3 alkyl; when v is 2, additional R ^AA is fluoro substituted on an available C atom of Z ^A .

In one embodiment, v is 1; X ^G1 is an N atom; and R ^AA is a substituent on X ^G1 .

In one embodiment, v is 1; X ^G1 is a N atom; and R ^AA is a C _1-4 alkyl (e.g., methyl) substituent on X ^G1 .

In one embodiment, v is 1; X ^H1 is a C atom; and R ^AA is a substituent on X ^H1 .

In one embodiment, v is 1; X ^H1 is a C atom; and R ^AA is a substituent on X ^H1 that is CN or C _1-4 alkyl (e.g., methyl).

In one embodiment, v is 1 or 2; and X ^H1 and X ^G1 are both C atoms, one or both of which are substituted with R ^AA , wherein each R ^AA is independently selected from CN or C _1-4 alkyl (e.g., methyl).

In one embodiment:

Together, represents one or more of the following elements A1 to A29:

.

In some of these embodiments, W is W2-1

And,

Here,

X ^K and X ^L are N-linker and CH or NMe and C-linker, respectively;

One of X ^M and X ^O is N-(2,6-dioxopiperidin-3-yl)( Y );

Zero or one of X ^M and X ^N is CF;

X ^N can be N if X M ^is not CF;

The remainder of X ^N , X ^M and X ^O are CH.

In one embodiment, W represents any of groups 22 to 26 as exemplified below:

.

In a further embodiment of the present disclosure, formula Ia is selected from any one or more of the following groups (1) to (28) or (1) to (39):

(1) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl,

(2) 4-[1-(4-cyano-3-cyclopropyl-phenyl)-4-piperidyl]phenyl,

(3) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl,

(4) 2-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyrimidin-5-yl,

(5) 6-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyridin-3-yl,

(6) 4-[1-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-4-piperidyl]phenyl,

(7) 4-[1-(3-chloro-4-cyano-phenyl)-4-piperidyl]phenyl,

(8) 4-[1-(4-cyano-3-methoxy-phenyl)-4-piperidyl]phenyl,

(9) 4-[1-(5-cyano-6-methyl-2-pyridyl)-4-piperidyl]phenyl,

(10) 4-[1-(5-cyano-8-quinolyl)-4-piperidyl]phenyl,

(11) 4-[( 4S )-1-[4-cyano-3-(trifluoromethyl)phenyl]-3,3-dimethyl-4-piperidyl]phenyl

(12) 4-[(4 R )-1-[4-cyano-3-(trifluoromethyl)phenyl]-3,3-dimethyl-4-piperidyl]phenyl

(13) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-3,3-dimethyl-4-piperidyl]phenyl,

(14) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-2-fluorophenyl,

(15) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-fluorophenyl,

(16) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-methylphenyl,

(17) 4-[( 2S )-4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl,

(18) 4-[(2 R )-4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl,

(19) 4-[4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl,

(20) 5-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyridin-2-yl,

(21) 4-[4-[4-cyano-3-(trifluoromethyl)phenyl]piperazin-1-yl]phenyl,

(22) 4-[(3 R )-1-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl,

(23) 4-[( 3S )-1-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl,

(24) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl,

(25) 4-[1-[4-cyano-3-(difluoromethyl)phenyl]-4-piperidyl]phenyl,

(26) 4-[(4 R )-1-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl,

(27) 4-[(4 R )-1-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl,

(28) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl,

(29) 4-[1-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-3,5-difluoro-phenyl,

(30) 4-[( 2S )-4-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-1-yl]phenyl,

(31) 4-[(3R)-4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methyl-piperazin-1-yl]phenyl,

(32) 4-[(3S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methyl-piperazin-1-yl]phenyl,

(33) (3S,4R)-1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-4-piperidyl,

(34) (3R,4S)-1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-4-piperidyl,

(35) 4-[1-[4-cyano-2-ethyl-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl,

(36) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3,5-difluoro-phenyl,

(37) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-fluoro-phenyl,

(38) 4-[1-(4-cyano-3-cyclopropyl-phenyl)-4-piperidyl]-3-fluoro-phenyl and

(39) 4-[1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-methyl-phenyl.

In a further aspect of the present disclosure, a PROTAC compound comprising an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof, is provided:

[Chemical formula Ib]

[Here,

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein each R ^G is independently H or C _1-3 alkyl);

Q ^H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q can each take any value defined herein for each of these variables/parameters.

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

For the avoidance of doubt, in chemical formula Ib represents the point of attachment to the rest of the PROTAC compound via a single covalent bond.

In a further aspect of the present disclosure, a PROTAC compound or a pharmaceutically acceptable salt thereof comprising an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of formula Ia of formula Ib, as defined herein, is provided.

In a further embodiment of the present disclosure, formula Ib may be:

(wherein L ^X can be any group (1) to (28) or (1) to (39) enumerated above with respect to formula Ia; and Q ^A can take any value(s) disclosed herein for Q ^A ).

In a further aspect of the present disclosure, a PROTAC compound comprising an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of formula Ia of formula Ic, or a pharmaceutically acceptable salt thereof, is provided:

[Chemical formula Ic]

[Here,

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O-, -O- or -N( R ^J )- (wherein R ^J is H or C _1-3 alkyl);

Each Q ^H is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A and Q ^B are chosen such that the chemical formula Ic does not contain NN or NO bonds;

Otherwise, R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q can take any value defined herein for each of these variables/parameters respectively.

In one embodiment, Q ^H is a 4- to 12-membered nitrogen-containing saturated heterocyclic group. For the avoidance of doubt, in formula Ic represents the point of attachment to the rest of the PROTAC compound via a single covalent bond.

In a further aspect of the present disclosure, a PROTAC compound or a pharmaceutically acceptable salt thereof comprising an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of formula Ia of formula Ic, as defined herein, is provided.

In a further embodiment of the present disclosure, formula Ib may be:

(wherein L ^X can be any group (1) to (28) listed above with respect to formula Ia; and Q ^A and Q ^B can take any value(s) disclosed herein for Q ^A and Q ^B ).

In a further embodiment, a compound(s) or a pharmaceutically acceptable salt thereof is provided, wherein the compound(s) is selected from one or more of the " Examples " listed below. Accordingly, 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, , 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 153, 164, 165, 166 and One or more specific embodiments (e.g., one specific embodiment , or two or three specific embodiments ) selected from the group consisting of 167.

It should be understood that the compounds of the examples listed below are by their title compound name and are in no way limited by the method of manufacture, nor by whether the given compound is isolated in the form of a salt rather than as a neutral molecule.

In some embodiments, a compound of Formula VI, or a pharmaceutically acceptable salt thereof, is provided:

[Chemical Formula VI]

(Here,

R ^Z1 is H or F;

R ^Z2 is H or F;

R ^Z3 is H or F;

L ^Z is a linker selected from 1, 3, 45 and 47:

W ^Z is selected from 1, 2, 3, 10, 16, 22, 23, 24 and 26:

Y is N-(2,6-dioxopiperidin-3-yl)).

In some embodiments, a compound of formula VI-1, or a pharmaceutically acceptable salt thereof, is provided:

[Chemical Formula VI-1]

(Here,

R ^Z1 is H or F;

L ^Z is A linker selected from 1 and 3:

W ^Z is selected from 1, 2 and 10:

Y is N-(2,6-dioxopiperidin-3-yl)).

In some embodiments, a compound of formula VI-2, or a pharmaceutically acceptable salt thereof, is provided:

[Chemical Formula VI-2]

(Here,

R ^Z1 is H or F;

R ^Z2 is H or F;

R ^Z3 is H or F;

L ^Z is a linker selected from 3, 45 and 47:

W ^Z is selected from 1, 3, 16, 22, 23, 24 and 26:

Y is N-(2,6-dioxopiperidin-3-yl)).

Additional embodiments provide any of the embodiments, claims or aspects defined herein, except that 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, , 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, Any one or more specific embodiments (e.g., one embodiment, or two or three specific embodiments) selected from the group consisting of 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 and 136 are individually disclaimed .

Additional embodiments provide any of the embodiments, claims or aspects defined herein, except that 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, , 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 9, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, Any one or more specific embodiments (e.g., one specific embodiment , or two or three specific embodiments) selected from the group consisting of 164, 165, 166 and 167 are individually disclaimed.

It will be appreciated that the PROTAC compounds containing the compounds of formula I and the linking units of formula Ia may have one or more chiral centers, and that such compounds may be prepared, isolated and/or supplied in the presence or absence of one or more of the other possible enantiomers and/or diastereomers of said compounds, or which enantiomers may be provided in any relative proportions. The preparation of enantiomerically enriched/enantiomerically pure and/or diastereomerically enriched/diastereomerically pure compounds may be accomplished by standard techniques of organic chemistry well known in the art, for example, by synthesis from enantiomerically enriched or enantiomerically pure starting materials and/or by use of a suitable enantiomerically enriched or enantiomerically pure catalyst during the synthesis and/or by resolution of a racemic or partially enriched mixture of stereoisomers, for example, by chiral chromatography.

For use in a pharmaceutical context, it may be desirable to provide such compounds (or pharmaceutically acceptable salts thereof) without the presence of large amounts of other stereoisomeric forms.

Thus, in one embodiment, a composition is provided comprising a compound of Formula I [or a PROTAC compound comprising units of Formula Ia] or a pharmaceutically acceptable salt thereof, optionally together with one or more other stereoisomeric forms of the compound of Formula I [or a PROTAC compound comprising units of Formula Ia] or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I [or a PROTAC compound comprising units of Formula Ia] or a pharmaceutically acceptable salt thereof is present in the composition in a diastereomeric excess (% de) of greater than or equal to 90%.

In a further embodiment, the %de in the above-mentioned composition is greater than or equal to 95%.

In a further embodiment, the %de in the above-mentioned composition is greater than or equal to 98%.

In a further embodiment, the %de in the above-mentioned composition is greater than or equal to 99%.

In a further embodiment, a composition is provided comprising a compound of formula I [or a PROTAC compound containing units of formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, optionally together with one or more other stereoisomeric forms of the compound of formula I [or a PROTAC compound containing units of formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of formula I [or a PROTAC compound containing units of formula Ia as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of greater than or equal to 90%.

In a further embodiment, the %ee in the above-mentioned composition is greater than or equal to 95%.

In a further embodiment, the %ee in the above-mentioned composition is greater than or equal to 98%.

In a further embodiment, the %ee in the above-mentioned composition is greater than or equal to 99%.

In a further embodiment, a composition is provided comprising a compound of formula I [or a PROTAC compound containing units of formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, optionally together with one or more other stereoisomeric forms of the compound of formula I [or a PROTAC compound containing units of formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of formula I [or a PROTAC compound containing units of formula Ia as defined herein] or pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of greater than or equal to 90% and a diastereomeric excess (%de) of greater than or equal to 90%.

In further embodiments of the compositions mentioned above, %ee and %de can take any combination of values as listed below:

· %ee is less than 5%, and %de is more than 80%.

· %ee is less than 5%, and %de is more than 90%.

· %ee is less than 5%, and %de is more than 95%.

· %ee is less than 5%, and %de is more than 98%.

· %ee is more than 95%, and %de is more than 95%.

· %ee is more than 98%, and %de is more than 98%.

· %ee is more than 99%, and %de is more than 99%.

In a further embodiment, a compound of formula I [or formula Ia as defined herein], associated with a pharmaceutically acceptable excipient. A pharmaceutical composition comprising a PROTAC compound containing a unit] or a pharmaceutically acceptable salt thereof is provided.

In one embodiment, a pharmaceutical composition is provided, comprising a compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomeric forms of the compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of greater than or equal to 90%.

In a further embodiment, the %ee in the above-mentioned composition is greater than or equal to 95%.

In a further embodiment, the %ee in the above-mentioned composition is greater than or equal to 98%.

In a further embodiment, the %ee in the above-mentioned composition is greater than or equal to 99%.

In one embodiment, a pharmaceutical composition is provided, comprising a compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomeric forms of the compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in a diastereomeric excess (% de) of greater than or equal to 90%.

In a further embodiment, the %de in the above-mentioned composition is greater than or equal to 95%.

In a further embodiment, the %de in the above-mentioned composition is greater than or equal to 98%.

In a further embodiment, the %de in the above-mentioned composition is greater than or equal to 99%.

In one embodiment, a pharmaceutical composition is provided, comprising a compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomeric forms of the compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I [or a PROTAC compound containing units of Formula Ia as defined herein] or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomeric excess (%ee) of greater than or equal to 90% and a diastereomeric excess (%de) of greater than or equal to 90%.

In further embodiments of the pharmaceutical composition mentioned above, %ee and %de can take any combination of values as listed below:

· %ee is more than 95%, and %de is more than 95%.

· %ee is more than 98%, and %de is more than 98%.

· %ee is more than 99%, and %de is more than 99%.

The compounds of formula I [or PROTAC compounds containing units of formula Ia as defined herein] and pharmaceutically acceptable salts thereof can be manufactured, used, or supplied in amorphous form, crystalline form, or semi-crystalline form, and it is possible that any given compound of formula I [or PROTAC compounds containing units of formula Ia as defined herein] or pharmaceutically acceptable salts thereof can be formed in more than one crystalline/polymorphic form, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate or hydrates of different stoichiometries) and/or solvated forms. It is to be understood that the present disclosure includes any and all such solid forms of the compound of formula I [or PROTAC compounds containing units of formula Ia as defined herein] and pharmaceutically acceptable salts thereof.

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

Intermediate compound

As demonstrated in the experimental sections below, compounds of formula I or PROTACs of formula Ia can be prepared, for example, by the following methods.

A compound of formula I [or a salt thereof] or a PROTAC compound of formula Ia [or a salt thereof] can be prepared from a compound of formula II or a salt thereof:

[Chemical Formula II]

[Here,

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

Q ^D is C _1-2 alkylene which is directly bonded or optionally substituted with one or more F;

R ^L1 and R ^L2 together form "=O", and R ^L3 is H;

Here, if Q ^D is a direct bond and Q ^A is - G - Q ^H - , the value of Q ^H is chosen so that Q ^D is connected to the C atom of Q ^H ;

R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , Q , R ^2a , R ^2b , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q can each take any value disclosed herein for each of the above variables/bases.

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

Therefore, such compounds of formula II as described above are aldehydes which can react, either directly or after one or more further 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. This reaction of the aldehyde with the amine can be carried out under reductive amination conditions, for example using NaBH(OAc) ₃ or other reductive amination protocols known to the skilled person.

These aldehydes can ultimately be prepared from the corresponding acetals as defined above, for example compounds of formula II or salts thereof, except that: R ^L1 and R ^L2 are each independently C _1-6 alkoxy (for example C _1-3 alkoxy) or R ^L1 and R ^L2 together form -O-(CH ₂ ) _k -O-, wherein k is 2 or 3. These acetals can be converted into the corresponding aldehydes under acidic conditions, for example using formic acid, under conditions well known to the skilled person.

Alternatively, as exemplified in the experimental section below, the above-mentioned aldehydes can be prepared by oxidation of the corresponding primary alcohol, i.e. a compound of formula II as defined above, except that R ^L1 is OH and R ^L2 is H, or a salt thereof. This oxidation can be carried out using mild oxidation conditions, for example Dess-Martin periodinane or some other mild oxidation protocol known to the skilled person.

As exemplified in the Experimental Section below, a compound of formula I [or a salt thereof] or a PROTAC compound of formula Ia [or a salt thereof] can be prepared from a compound of formula II or a salt thereof as described above, except that R ^L1 is a leaving group and R ^L2 is H. Accordingly, such a compound of formula II is an electrophile which can react with a molecule containing an amine group (e.g., a secondary amine group) via an alkylation reaction to form a compound of formula I or a PROTAC compound of formula Ia, either directly or after one or more additional reaction steps. Suitable leaving groups for alkylation reactions are well known to those skilled in the art and include Cl, Br, I, trifluoromethanesulfonate, mesylate and tosylate. Alkylation reaction conditions are well known to those skilled in the art and typically comprise a non-nucleophilic base (e.g., DIPEA) and a polar aprotic solvent (e.g., MeCN). As demonstrated in the experimental section below, when the leaving group is not I, a metal iodide salt can be used in the reaction mixture to facilitate the overall alkylation process by forming the corresponding iodide in situ (i.e., when R ^L1 is I). As exemplified in the experimental section below, compounds of formula II wherein R ^L1 is a bromo leaving group can be prepared from the corresponding primary alcohols (i.e., as already described above when R ^L1 is OH and both R ^L2 and R ^L3 are H).

Finally, the primary alcohol compound of the above-mentioned formula II can be prepared by reduction of the corresponding ester compound, i.e. the compound of the formula II as defined above or a salt thereof, except that: R ^L1 and R ^L2 together form "=O" and R ^L3 is C _1-6 alkoxy (e.g. C _1-3 alkoxy). This reduction can be carried out using strong reducing conditions, for example using DIBAL or other stronger reducing conditions well known to the skilled person.

Alternatively, as demonstrated in the experimental section below, it may be convenient to form the primary alcohol compound of the above-mentioned formula II by deprotection of the alcohol in a protected form. For example, the alcohol is deprotected from a compound protected by a silicon-based protecting group using a fluoride source, such as TBAF, or other deprotection methods well known to those skilled in the art to achieve deprotection.

Thus, as described above, various compounds of formula II and salts thereof can 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 aspects of the present disclosure.

Therefore, in a further embodiment, there is provided a compound of formula II or a salt thereof as exemplified above, wherein:

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

Q ^D is C _1-2 alkylene which is directly bonded or optionally substituted with one or more F (e.g., 1 or 2 F);

(i) R ^L1 and R ^L2 together form “=O” and R ^L3 is H or C _1-6 alkoxy (e.g., OMe); or

(ii) R ^L1 and R ^L2 are each independently C _1-6 alkoxy (e.g., OMe), and R ^L3 is H;

(iii) R ^L1 and R ^L2 together form -O-(CH ₂ ) _k -O- (wherein k is 2 or 3), and R ^L3 is H; or

(iv) R ^L1 is OH, O PG ¹ (wherein PG ¹ is a protecting group), or LG ¹ (wherein LG ¹ is a leaving group), and R ^L2 and R ^L3 are both H;

Here, if Q ^D is a direct bond and Q ^A is - G - Q ^H - , the value of Q ^H is chosen so that Q ^D is connected to the C atom of Q ^H ;

R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , Q , R ^2a , R ^2b , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q may each take any value disclosed herein for each of the above variables/bases.

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

The skilled person knows suitable protecting groups for alcohol groups and therefore suitable values for PG ¹ . For example, PG ¹ is an alcohol protecting group.

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

In one embodiment, PG ¹ is Si( R ^Si ) ₃ , wherein each R ^Si is independently a C _1-6 hydrocarbyl group.

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

In one embodiment, LG ¹ is selected from Cl, Br, I, trifluoromethanesulfonate and C _1-7 hydrocarbylsulfonate (e.g., mesylate or p -toluenesulfonate).

In one embodiment, LG ¹ is Br or I.

In one embodiment, LG ¹ is Br.

In one embodiment, LG ¹ is Cl.

In one embodiment, LG ¹ is I.

In one embodiment, LG ¹ is trifluoromethanesulfonate.

In one embodiment, LG ¹ is a C _1-7 hydrocarbylsulfonate.

In one embodiment, LG ¹ is a mesylate.

In one embodiment, LG ¹ is p -toluenesulfonate.

In one embodiment, Q ^D is a direct bond, -CH ₂ -, -CH ₂ CH ₂ -, or -CF ₂ CH ₂ -.

In one embodiment, Q ^D is a direct bond.

In one embodiment, Q ^D is CH ₂ .

In one embodiment, Q ^D is C _1-2 alkylene optionally substituted with 1 or 2 F.

In one embodiment, Q ^D is C _1-2 alkylene.

In one embodiment, Q ^D is -CH ₂ CH ₂ -.

In one embodiment, Q ^D is -CF ₂ CH ₂ -.

In a further embodiment of the present disclosure, formula II can be formula IIa:

[Chemical Formula IIa]:

(wherein, L ^X can be any group (1) to (28) or (1) to (39) listed above with respect to formula Ia; and Q ^A , Q ^D , R ^L1 , R ^L2 and R ^L3 can each take any value(s) disclosed herein for each of the above groups).

As demonstrated in the experimental sections below, certain compounds of formula I and certain PROTACs of formula Ia and certain intermediate compounds of formula II can be prepared using compounds of formula III or salts thereof:

[Chemical Formula III]

Here, G ^X is OH, and the oxygen atom of said OH is alkylated by a suitable molecule to form 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 as described above). This alkylation reaction can be carried out under conditions well known to the skilled person, for example using primary alkyl bromides (or using some other leaving group instead of Br), using a non-nucleophilic base such as a metal carbonate (e.g. K ₂ CO ₃ ), in a polar aprotic solvent such as MeCN, optionally in the presence of a metal iodide salt such as KI.

Alternatively, as exemplified in the Experimental Section below, compounds of formula III wherein G ^X is -NH( R ^G ) [wherein R ^G is H or C _1-3 alkyl (e.g., Me)] can be used as intermediates for the preparation of compounds of formula I or PROTACs of formula Ia via reductive amination chemistry using an appropriate aldehyde-containing compound.

Alternatively, as exemplified in the experimental section below, compounds of formula III wherein G ^X is bromo can be coupled, either directly or after one or more additional reaction steps (e.g. via formula II as described above), with secondary amine compounds to provide specific compounds of formula I or PROTACs of formula Ia. Similarly, compounds of formula III wherein G ^X is chloro or trifluoromethanesulfonate can also be used in coupling reactions with relevant secondary amines to provide specific compounds of formula I or PROTACs of formula Ia. Such couplings can be carried out by heating with CuI in the presence of a base and an anhydrous solvent such as 1,4-dioxane under an inert atmosphere, under palladium-based coupling conditions (e.g. using 'Ruphos Pd G3' and 'Ruphos'), or in the presence of a base such as K ₃ PO ₄ in a polar solvent such as DMSO. Alternatively, as also exemplified in the Experimental Section herein, a compound of formula III wherein G ^X is bromo may be coupled, either directly or after one or more further reaction steps (e.g. via formula II as described above), with a suitable alcohol to form a specific compound of formula I or a PROTAC of formula Ia. Such coupling can be carried out using a palladium-based reagent such as 'Rockphos Pd G3' in the presence of a base such as Cs ₂ CO ₃ in a solvent such as toluene.

Accordingly, the compounds of formula III and their salts can be useful as intermediates in the synthesis of certain compounds of formula I or PROTAC compounds of formula Ia or compounds of formula II, and such intermediate compounds thus provide further aspects of the present disclosure.

Therefore, in a further embodiment, there is provided a compound of formula III or a salt thereof as exemplified above, wherein:

G ^X is OH, Cl, Br, trifluoromethanesulfonate, or -NH( R ^G ) (wherein R ^G is H or C _1-3 alkyl);

R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , Q , R ^2a , R ^2b , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q may each take any value disclosed herein for each of the above variables/bases.

G ^X is OH, Cl, Br, trifluoromethanesulfonate, or -NH( R ^G ), where R ^G is C _1-3 alkyl (e.g., Me).

In one embodiment, G ^X is OH, Br, trifluoromethanesulfonate or -NH( R ^G ), wherein R ^G is C _1-3 alkyl (e.g., Me).

In one embodiment, G ^X is OH, Br or -NH( R ^G ), wherein R ^G is C _1-3 alkyl (e.g., Me).

In one embodiment, G ^X is OH or Br.

In one embodiment, G ^X is OH.

In one embodiment, G ^X is Br.

In one embodiment, G ^X is Cl.

In one embodiment, G ^X is trifluoromethanesulfonate.

In one embodiment, G ^X is -NH( R ^G ), wherein R ^G is H or C _1-3 alkyl.

In one embodiment, G ^X is -NH( R ^G ), wherein R ^G is C _1-3 alkyl.

In one embodiment, G ^X is -NH(Me).

In a further embodiment of the present disclosure, formula III can be L ^X - G ^X , wherein L ^X can be any group (1) to (28) or (1) to (39) enumerated above with respect to formula Ia; and G ^X can take any value(s) disclosed herein for G ^X .

As demonstrated in the experimental sections below, certain compounds of formula I and PROTACs of formula Ia can be prepared using intermediate compounds of formula IV or salts thereof (as further defined below):

[Chemical Formula IV]

.

For example, a compound of formula IV wherein J is H, or a salt thereof (i.e., a secondary amine compound), can be coupled to additional chemical fragments using chemistries well known to those skilled in the art and exemplified in the Experimental Section below, to provide a compound of formula I or a PROTAC of formula Ia, either directly or after one or more additional reaction steps.

Finally, compounds of formula IV wherein J is H can be conveniently prepared via deprotection of the N -protected form of the aforementioned amine compounds. Thus, compounds of formula IV wherein J is H can be conveniently prepared using compounds of formula IV wherein J is PG ² , wherein PG ² is a nitrogen protecting group (e.g., a C _1-6 alkoxycarbonyl group such as tert -butoxycarbonyl). Thus, compounds of formula IV wherein J is PG ² are useful intermediates for the preparation of compounds of formula I and PROTACs of formula Ia and provide further aspects of the present disclosure.

Therefore, in a further aspect of the present specification, there is provided a compound of formula IV as described above, or a salt thereof, wherein:

J is H or PG ² (wherein PG ² is a nitrogen protecting group (e.g., tert -butoxycarbonyl group));

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O-, -O- or -N( R ^J )- (wherein R ^J is H or C _1-3 alkyl);

Each Q ^H (including the " Q ^H ring " attached to J ) is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A , Q ^B and Q ^H rings are chosen such that formula IV does not contain NN or NO bonds;

R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q can each take any value defined herein for each of these variables/parameters.

In one embodiment, each Q ^H (including the " Q ^H ring " attached to J ) is independently a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

In one embodiment, the Q ^H ring is piperidine-1,4-diyl or piperazine-1,4-diyl.

In one embodiment, J is H.

In one embodiment, J is PG ² .

In one embodiment, PG ² is C _1-6 alkoxycarbonyl.

In one embodiment, PG ² is tert -butoxycarbonyl.

In one embodiment, when PG ² is C _1-6 alkoxycarbonyl (e.g. tert -butoxycarbonyl), the 'and salts thereof' element of the claim is excluded.

In a further embodiment, the compound of formula IV can take any combination of the alternative values recited in connection with Q ^A , Q ^B and Q ^H in any other context, embodiment, aspect or claim found herein.

In a further embodiment of the present disclosure, formula IV can be formula IVa:

[Chemical Formula IVa]:

(wherein L ^X can be any group (1) to (28) or (1) to (39) listed above with respect to formula Ia; and Q ^A , Q ^B , Q ^H and J can each take any value(s) disclosed herein for each of the above groups).

As further demonstrated in the experimental sections below, certain compounds of formula I and PROTACs of formula Ia can be prepared using intermediate compounds of formula V or salts thereof:

[Chemical formula V]

[Here,

X ^X is N substituted with J (where J is H);

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^H ring is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

G and Q ^H The values of the rings are chosen such that the chemical formula V does not contain NN or NO bonds;

R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q can each take any value defined herein for each of these variables/parameters.

These compounds of formula V can be converted to compounds of formula I or PROTACs of formula Ia, either directly or after one or more additional steps, via reductive amination or alkylation or other coupling chemistries known to those skilled in the art to give compounds of formula I or PROTACs of formula Ia.

Finally, as exemplified in the experimental section below, such compounds of formula V or salts thereof can be conveniently prepared by deprotection of the corresponding N -protected compounds. Such N -protected forms may be BOC-protected forms (i.e., tert -butoxycarbonyl) or another N -protecting group known to those skilled in the art may be used. Accordingly, such N -protected compounds are also useful intermediates for the preparation of compounds of formula I and PROTACs of formula Ia and provide further aspects of the present disclosure.

Accordingly, one aspect of the present disclosure provides a compound of formula V as described above, except that X ^X is N substituted with J , wherein J is PG ³ and PG ³ is a protecting group, or a salt thereof. In one embodiment, PG ³ is C _1-6 alkoxycarbonyl. In one embodiment, PG ³ is tert -butoxycarbonyl. In one embodiment, when PG ³ is C _1-6 alkoxycarbonyl (e.g., tert -butoxycarbonyl), the elements "and salts thereof" of the claim are excluded.

Other compounds of formula I and PROTACs of formula Ia (and their salts) can be prepared from intermediate compounds of formula V as described above, or salts thereof, except that X ^X is C=O. These intermediates can be converted, directly or through one or more additional synthetic steps, to compounds of formula I or PROTACs of formula Ia by reductive amination chemistry using appropriate amine-containing compounds using reductive amination conditions well known to those skilled in the art.

Finally, as demonstrated in the experimental sections below, such compounds of formula V wherein X ^X is C=O can be conveniently prepared from the corresponding compounds wherein the ketone is protected/masked as a ketal. Accordingly, such ketal compounds and their salts are useful intermediates for the preparation of compounds of formula I or PROTACs of formula Ia and provide further aspects of the present disclosure.

Therefore, such ketal compounds can be represented by a compound of formula V as described above, or a salt thereof, except that X ^X is C substituted with R ^U1 and R ^U2 ; R ^U1 and R ^U2 are each C _1-6 alkoxy; or R ^U1 and R ^U2 together represent -O-(CH ₂ ) _u -O-, wherein u is 2 or 3.

Therefore, in a further aspect of the present specification, a compound of formula V or a salt thereof as described above is provided, wherein:

X ^X is selected from:

(i) N substituted with J (wherein J is H) or PG ³ (wherein PG ³ is a protecting group); and

(ii) C substituted with oxo or substituted with R ^U1 and R ^U2 (wherein R ^U1 and R ^U2 are each C _1-6 alkoxy; or R ^U1 and R ^U2 together represent -O-(CH ₂ ) _u -O- (wherein u is 2 or 3);

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^H ring is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of the G and Q ^H rings are chosen such that formula V does not contain NN or NO bonds;

R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q can each take any value defined herein for each of these variables/parameters.

In one embodiment, J is H.

In one embodiment, J is PG ³ .

In one embodiment, PG ³ is C _1-6 alkoxycarbonyl.

In one embodiment, PG ³ is tert -butoxycarbonyl.

In one embodiment, X ^X is C=O.

In one embodiment, X ^X is C substituted with R ^U1 and R ^U2 ; wherein R ^U1 and R ^U2 are each C _1-6 alkoxy.

In one embodiment, X ^X is C substituted with R ^U1 and R ^U2 ; wherein R ^U1 and R ^U2 together represent -O-(CH ₂ ) _u -O-, and u is 2 or 3 (e.g., u = 2).

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

In one embodiment, the Q ^H ring is a 4- to 12-membered nitrogen-containing saturated heterocyclic group.

The value of the Q ^H ring can take any value mentioned herein for Q ^H .

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

In a further embodiment of the present disclosure, formula V can be formula Va:

[Chemical formula Va]:

(wherein L ^X can be any group (1) to (28) or (1) to (39) listed above with respect to formula Ia; and G , Q ^H ring and X ^X can each take any value(s) disclosed herein for each of the above groups).

In addition to the methods described above, compounds of formulae I, II, III, IV and V and PROTAC compounds comprising formula Ia can be prepared according to the general procedures and chemical transformations illustrated in the Experimental Section below and using standard procedures and knowledge known to skilled chemists.

In a further embodiment of the present disclosure, a compound(s) or a salt thereof is provided, wherein the compound(s) is selected from one or more of the " Intermediates " listed below in the Experimental Section.

It should be understood that the compounds of the intermediates listed below are with respect to the title chemical names listed in the Experimental Section and are in no way limited by the method of manufacture nor by whether a given intermediate compound was isolated in the form of a salt rather than as a neutral molecule.

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

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

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

According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula I as defined herein [or a PROTAC compound comprising an AR binding unit of formula Ia and (for example linked thereto) an E3 ubiquitin ligase cereblon binder unit], or a pharmaceutically acceptable salt thereof, for use in the treatment of an AR sensitive tumor type.

According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula I as defined herein [or a PROTAC compound comprising an AR binding unit of formula Ia and (for example linked thereto) an E3 ubiquitin ligase cereblon binder unit] or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumor type carrying one or more mutant forms of the androgen receptor.

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

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

In any embodiment, aspect or claim herein where “cancer” is mentioned without further specificity, additional embodiments, aspects or claims can be provided wherein the cancer is (or comprises) AR+ breast cancer.

The compositions 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 for parenteral administration (e.g. as sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular administration). The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorants and/or preservatives.

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

The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host to be treated and the particular route of administration.

The size of the dosage for therapeutic or prophylactic purposes of the compounds of the present disclosure will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient, and the route of administration, in accordance with the well-known principles of medicine.

As described above, the compounds of the present disclosure may be valuable as anti-tumor agents, particularly as selective inhibitors of the proliferation, survival, migration, dissemination and invasiveness of mammalian cancer cells, resulting in inhibition of tumor growth and survival and inhibition of metastatic tumor growth. In particular, the compounds of the present disclosure may be valuable as anti-proliferative and anti-invasive agents in the blockade and/or treatment of solid tumor diseases.

Accordingly, the compounds of the present disclosure may be useful for the prevention or treatment of tumors that are sensitive to androgen receptor degradation and that are involved in signaling cascades that lead to proliferation and survival of tumor cells and the ability of metastatic tumor cells to migrate and to become invasive. In addition, the compounds of the present disclosure may be useful for the prevention or treatment of tumors that are treatable by androgen receptor degradation, i.e., the compounds may be used to produce an androgen receptor degradation effect in a warm-blooded animal in need of such treatment.

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

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

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

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

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

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

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

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

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

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

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

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

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

According to a further aspect of the present disclosure, there is provided the use of a compound of formula I as defined herein [or a PROTAC compound comprising an AR binding unit of formula Ia and (for example linked thereto) an E3 ubiquitin ligase cereblon binder unit] or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing or treating solid tumor(s), for example in a warm-blooded animal such as a human.

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

According to a further aspect of the present disclosure, there is provided a compound of formula I as defined herein [or a PROTAC compound comprising an AR binding unit of formula Ia and (for example linked thereto) an E3 ubiquitin ligase cereblon binder unit], or a pharmaceutically acceptable salt thereof, for use in preventing or treating a tumor type sensitive to degradation of androgen receptor.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula I as defined herein [or a PROTAC compound comprising an AR binding unit of formula Ia and (for example linked thereto) an E3 ubiquitin ligase cereblon binder unit] or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing or treating a tumor type sensitive to degradation of androgen receptor.

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

As described above, tumor types sensitive to androgen receptor degradation include prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC).

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

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

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

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

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

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

According to a further aspect of the present disclosure, there is provided a compound of formula I as defined herein [or a PROTAC compound comprising an AR binding unit of formula Ia and (for example linked thereto) an E3 ubiquitin ligase cereblon binder unit], or a pharmaceutically acceptable salt thereof, for use in treating a tumor type harboring an androgen receptor mutation.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula I as defined herein [or a PROTAC compound comprising an AR binding unit of formula Ia and (for example linked thereto) an E3 ubiquitin ligase cereblon binder unit] or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing or treating a tumor type harboring an androgen receptor mutation.

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

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

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

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

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

In one embodiment, when cancer is mentioned herein, the cancer is prostate cancer.

In one embodiment, when cancer is mentioned herein, the cancer is CRPC.

In one embodiment, when cancer is referred to herein, the cancer is metastatic CRPC.

General experimental conditions and abbreviations

The following abbreviations were used: AcOH = acetic acid; AIBN = 2,2'-azobis(2-methylpropionitrile); aq. = aqueous; 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; CDI = 1,1'-carbonyldiimidazole; Dave-phos-Pd G3 = methanesulfonato 2-dicyclohexylphosphino-2-( N , N -dimethylamino)biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II); DCM = dichloromethane; DIAD = diisopropyl azodicarboxylate; DIPEA = N , N -diisopropylethylamine; Cbz = carboxybenzyl; Dess-Martin periodinane = 3-oxo-1l5-benzo[ d ][1,2]iodaoxole-1,1,1(3 H )-triyl triacetate; DMF = N , N -dimethylformamide; DMSO = dimethyl sulfoxide; _Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; FSC = flash silica chromatography; h = hour; HPLC = high-performance liquid chromatography; IPA = isopropyl alcohol; MeCN = acetonitrile; MeOH = methanol; mins. = minutes; m/z = mass-to-charge ratio observed for the major mass spectrometric peak; MTBE = methyl- tert -butyl ether; NBS = N -bromosuccinimide; NMP = N -methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; Pd ₂ dba ₃ = tris(dibenzylideneacetone)dipalladium; Pd-PEPPSI-IHept ^Cl = dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-yldiene(3-chloropyridyl)palladium(II); Pd-PEPPSI-IPent = dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II), Pd(dppf) ₂ Cl ₂ -DCM = 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex; 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 (approximately 17–25 °C); RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G3 = methanesulfonato(2-dicyclohexylphosphino-2',6'-di-iso-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)-palladium(II); TFA = trifluoroacetic acid; THF = tetrahydrofuran; sat. = saturated; SFC = supercritical fluid chromatography; S Phos = 2-dicyclohexylphosphino-2,6-di-methyloxy-1,1-biphenyl; XPhos = 2-dicyclo-hexylphosphino-2',4',6'-triisopropylbiphenyl.

Unless otherwise stated, NMR was performed in deuterated DMSO at 400 MHz and 20–30 °C. The following standard abbreviations were used for NMR data: s = singlet, d = doublet, m = multiplet, br = broad, dd = doublet of doublets, q = quartet, dt = doublet of triplets, etc.

Preparative reverse phase HPLC (RP HPLC) using a mixture of decreasing polarity eluents (e.g., water and MeCN) can typically involve a gradient from a 95:5 solvent mixture to a 5:95 mixture at 40-50 mL/min over 10-20 minutes. The following column and eluent conditions are used herein:

Column A : Waters XSelect CSH C18 ODB column, 5 μm silica, 30 mm diameter, 100 mm length

Column B : Waters XSelect CSH C18 ODB column, 5 μm silica, 19 mm diameter, 150 mm length

Dissolving agent A : A mixture of decreasing polarity of water (containing 0.1% formic acid) and MeCN.

Dissolving agent B : A mixture of decreasing polarity of water (containing 0.3% aqueous formic acid) and MeCN.

Dissolving agent C : A mixture of decreasing polarity of water (containing 0.1% TFA) and MeCN.

Dissolving agent D: A mixture of decreasing polarity of water (containing 0.1% _NH3 ) and MeCN

After HPLC (which often involves the presence of formic acid or trifluoroacetic acid in the eluent), fractions containing the desired product are in some cases treated with a suitable base as part of a further work-up step to ensure delivery of the title compound as a neutral molecule and not as a salt. Thus, where " basic work-up A" is mentioned, fractions containing the desired compound are concentrated to remove MeCN. The resulting mainly aqueous fractions are basified with a NaHCO ₃ solution (e.g. 50 mL) and extracted with DCM (e.g. 3 x 100 mL). The combined organic solutions are washed with brine (e.g. 100 mL), dried (e.g. using Na ₂ SO ₄ or MgSO ₄ ) and concentrated to give the title compound.

Concentration: When a solution or mixture is described as being concentrated, this is usually done in a rotary evaporator under reduced pressure using a hot or hot water bath.

Salts : When a particular compound is obtained as an acid addition salt, for example, a mono-hydrochloride salt or a bis-hydrochloride salt, the stoichiometry of the salt is assumed based on the number and nature of the basic groups in the compound and may not be determined experimentally, for example, by elemental analysis data.

Chemical Naming : Typically, examples and intermediate compounds were named using the "Structure to Name" section of Biovia Draw 2016 or ChemDraw Ultra (CambridgeSoft), ACD Name.

Intermediate 1a: Benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate

4-Formyl- N -Cbz-piperidine (5.00 g, 20.22 mmol) was dissolved in MeOH (11 mL) at 0 °C under N ₂ . A solution of TiCl ₄ (0.11 mL, 1.01 mmol) in DCM (1.1 mL) was then added, followed by NEt ₃ (0.338 mL, 2.43 mmol) after 15 min and the resulting solution was stirred at room temperature for 0.5 h. The mixture was then diluted with DCM (50 mL) and water (20 mL) and stirred at room temperature for 0.5 h. The layers were then separated and the organic fraction was dried on a hydrophobic frit and then concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (5.16 g, 87%) as a colorless oil; ^1H NMR: (CDCl ₃ ) 1.14-1.33 (2H, m), 1.63-1.82 (3H, m), 2.63-2.84 (2H, m), 3.35 (6H, s), 4.02 (1H, d), 4.13-4.3 (2H, m), 5.12 (2H, s), .44 (5H, m).

Intermediate 1b: 4-(dimethoxymethyl)piperidine

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

Intermediate 1c: Methyl 4-bromo-2-methoxy-6-methylbenzoate

A 25% methanolic solution of NaOMe (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) at _room temperature under N 2 . The resulting mixture was stirred at room temperature for 18 h (the reaction was complete within 1 h). The mixture was then cooled to 0 °C and quenched with EtOAc (20 mL) and 1 N HCl (10 mL). The phases were separated, and the aqueous portion was extracted with EtOAc (2 x 30 mL). The combined organic solutions were dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-25% EtOAc in heptane) gave the title compound (0.410 g, 74%) as a colorless oil which solidified on standing; ¹ H NMR: (CDCl ₃ ) 2.25 (3H, s), 3.81 (3H, s), 3.90 (3H, s), 6.91 (1H, d), 6.98 (1H, dd).

Intermediate 1d: 3-(5-Bromo-7-methoxy-1-oxo-1,3-dihydro-2 H -Isoindole-2-yl)piperidine-2,6-dione

NBS (1.574 g, 8.84 mmol) was added to a stirred solution of methyl 4-bromo-2-methoxy-6-methylbenzoate (1.432 g, 5.53 mmol) and AIBN (0.182 g, 1.11 mmol) in tert -butyl acetate (20 mL), and the mixture was stirred at 100 °C for 3 h. The mixture was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water (50 mL). The organic layer was passed through a phase separation cartridge and concentrated. Purification by FSC (gradient: 0-15% EtOAc in heptane) gave 4-bromo-2-(bromomethyl)-6-methoxybenzoate (1.495 g, 80%) as a yellow gum with 70% purity. At room temperature under air, DIPEA (1.654 mL, 9.29 mmol) was added in one portion to a stirred solution of methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate (1.495 g, 3.10 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.510 g, 3.10 mmol) in MeCN (20 mL). The resulting solution was stirred at 80 °C for 16 h. The mixture was then cooled to 0 °C and the solid was collected by filtration. The solid was washed with MeCN (50 mL) and Et ₂ O (50 mL) and dried in vacuo to afford the title compound (0.761 g, 39% (over two steps)) as a purple solid; ^1H NMR: 1.97 (1H, dtd), 2.34 (1H, qd), 2.54-2.63 (1H, m), 2.90 (1H, ddd), 3.90 (3H, s), 4.25 (1H, d), 4.38 (1H, d), 5.02 (1H, dd), 7.26 (1H, d) ), 7.39 (1H, d), 10.94 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 355.0.

Intermediate 1e: tert -Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -Isoindole-5-yl]piperazine-1-carboxylate

Pd-PEPPSI-IHept ^Cl (0.380 g, 0.39 mmol) was added to tert -butyl piperazine-1-carboxylate (2.183 g, 11.72 mmol), Cs ₂ CO ₃ (3.82 g, 11.72 mmol) and 3-( ₅ -bromo-7-methoxy-1-oxo-1,3-dihydro-2 H -isoindol-2-yl)-piperidine-2,6-dione (1.38 g, 3.91 mmol) in degassed 1,4-dioxane (39 mL) at room temperature under N 2 . The resulting suspension was stirred at 100 °C for 6 h. The mixture was then diluted with DCM (100 mL) and washed sequentially with 5% AcOH in water (100 mL), water (100 mL), saturated NaHCO ₃ (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO ₄ ) and concentrated. EtOAc (40 mL) and washed with Et ₂ O (50 mL) to give a solid which was collected by filtration and dried in vacuo to give the title compound (1.154 g, 64%) as a dark gray powder; ^1H NMR: 1.43 (9H, s), 1.79-1.97 (1H, m), 2.28 (1H, dd), 2.53-2.62 (1H, m), 2.76-2.94 (1H, m), 3.32 (4H, s), 3.41-3.54 (4H, m), 3.85 (3H, s), 4.12 (1H, d), 4.24 (1H, d), 4.95 (1H, dd), 6.51 (1H, d), 6.62 (1H, s), 10.87 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 459.2.

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

At room temperature under air, 4 M HCl in 1,4-dioxane (2 mL, 8.00 mmol) was added in one portion to tert -butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazine-1-carboxylate (107 mg, 0.19 mmol). The resulting mixture was stirred at room temperature for 1 day and then diluted with Et ₂ O (20 mL). The resulting mixture was filtered, and the solid was washed with Et ₂ O (20 mL) to give the title compound as the hydrochloride salt (0.080 g, 100%) as a white solid; ^1H NMR: 1.93 (1H, dd), 2.25-2.4 (1H, m), 2.57 (1H, d), 2.89 (1H, s), 3.19 (4H, s), 3.59 (4H, s), 3.86 (3H, s), 4.14 (1H, d), 4.26 (1H, d), 4.97 (1H, dd), 6.49-6.6 (1H, m), 6.68 (1H, s), 9.55 (2H, s), 10.89 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 359.2.

Intermediate 1g: 4-(4-(4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (6.93 mL, 39.66 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (5.00 g, 26.44 mmol) and 4-(piperidin-4-yl)phenol (4.69 g, 26.44 mmol) were stirred in DMSO (10 mL) at 50 °C for 18 h. The mixture was then cooled to room temperature, diluted with water (150 mL), and stirred for 18 h. The resulting solid was collected by filtration, washed with Et ₂ O (50 mL) and dried in vacuo to afford the title compound (5.65 g, 62%) as a yellow solid; ^1H NMR: (CDCl ₃ ) 1.75 (2H, qd), 1.88-2 (2H, m), 2.73 (1H, tt), 3.06 (2H, td), 3.98-4.1 (2H, m), 4.78 (1H, s), 6.76-6.83 (2H, m), 6.99 (1H, dd) , 7.06-7.12 (2H, m), 7.16 (1H, d), 7.62 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 347.0.

Intermediate 1h: 4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

2-(3-Chloropropyl)-1,3-dioxolane (2.57 mL, 19.49 mmol) was added simultaneously to 4-(4-(4-hydroxy-phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.75 g, 10.83 mmol), K ₂ CO ₃ (3.74 g, 27.07 mmol) and KI (4.49 g, 27.07 mmol) in MeCN (100 mL) under air at room temperature. The resulting suspension was stirred at 90 °C for 2 days. The mixture was then cooled to room temperature, filtered and washed with DCM (100 mL). The filtrate was concentrated under reduced pressure. The crude residue was diluted with EtOAc (300 mL), washed with water (100 mL), then saturated brine (100 mL), dried (MgSO ₄ ), and concentrated. Purification by FSC (gradient: 0–5% MeOH in DCM) gave the title compound (3.10 g, 62%) as a yellow solid; ^1H NMR: (CDCl ₃ ) 1.56-1.67 (2H, m), 1.71 (2H, ddd), 1.74-1.82 (2H, m), 1.85 (2H, d), 2.77 (1H, ddd), 3-3.1 (2H, m), 3.75-3.82 (2H, m), 2 (2H, m), 3.95 (2H, q), 4.17 (2H, d), 4.85 (1H, t), 6.79-6.9 (2H, m), 7.15 (2H, d), 7.23-7.38 (2H, m), 7.81 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 461.3.

Example 1: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (178 mg, 0.39 mmol) and tert -butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazine-1-carboxylate (177 mg, 0.39 mmol) were stirred in formic acid (0.5 mL) and 1,4-dioxane (0.5 mL) at 40 °C for 18 h. The mixture was then concentrated and the residue was redissolved in IPA (2 mL) and DCM (2 mL) (at room temperature under air). After 10 min, NaBH(OAc) ₃ (164 mg, 0.77 mmol) was added in one portion. The resulting dark suspension was stirred at room temperature for 1 h and then concentrated. The residue was purified by preparative HPLC (column A, eluent A) to give the title compound (70 mg, 23%) as a formate salt as a dry film; ^1H NMR: (CDCl ₃ ) 1.54-1.68 (4H, m), 1.74 (2H, q), 1.84 (2H, d), 1.92 (1H, dd), 2.28 (1H, dd), 2.39 (2H, t), 2.54-2.62 (2H, m), 2.76 (1H, td), 2 .89 (1H, ddd), 3.04 (2H, t), 3.2-3.38 (6H, m), 3.47 (1H, s), 3.84 (3H, s), 3.97 (2H, t), 4.07-4.29 (4H, m), 4.96 (1H, dd), 6.48 (1H, 6.60) (1H, s), 6.81-6.94 (2H, m), 7.16 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d), 8.16 (2H, s), 10.88 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 759.4.

Intermediate 2a: 3-(5-Bromo-1-oxo-1,3-dihydro-2 H -Isoindole-2-yl)piperidine-2,6-dione

DIPEA (25 mL, 143.52 mmol) _{was added} to methyl 4-bromo-2-(bromomethyl)benzoate (14.65 g, 47.57 mmol) and 3-aminopiperidine-2,6-dione hydrochloride salt (11.74 g, 71.35 mmol) in MeCN (200 mL) under N 2 . The resulting suspension was stirred at 80 °C for 4 h. The mixture was cooled to room temperature and filtered. The resulting solid was washed with MeCN (60 mL), MeCN:Et ₂ O (50 mL [2:3]), and Et ₂ O (2 x 50 mL) to afford the title compound (13.10 g, 85%) as a blue solid; ^1H NMR: 1.95-2.08 (1H, m), 2.34-2.46 (1H, m), 2.57-2.65 (1H, m), 2.91 (1H, ddd), 4.35 (1H, d), 4.48 (1H, d), 5.11 (1H, dd), 7.67 (1H, d), 2 (1H, dd), 7.83-7.96 (1H, m), 10.98 (1H, s). m/z : ES ⁺ [M+H] ⁺ = 323.0.

Intermediate 2b: tert -Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -Isoindole-5-yl]piperazine-1-carboxylate

Under N _{2 ,} Cs ₂ CO ₃ (57.40 g, 176 mmol) and Pd-PEPPSI-IPent (2.33 g, 2.94 mmol) were added simultaneously to a degassed solution of tert -butyl piperazine-1-carboxylate (14.22 g, 76.36 mmol) and 3-(5-bromo-1-oxo-1,3-dihydro-2 H -isoindol-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 h. The mixture was then cooled to room temperature, diluted with DCM (1 L) and washed sequentially with 5% AcOH in water (500 mL) and brine (500 mL). The organic solution was then dried (MgSO ₄ ), concentrated and triturated with EtOAc (250 mL) to give a solid which was collected by filtration, washed with Et ₂ O (100 mL) and dried in vacuo to give the title compound (22.10 g, 88%) as a gray solid; ^1H NMR: 1.43 (9H, s), 1.96 (1H, d), 2.31-2.41 (1H, m), 2.59 (1H, d), 2.87 (1H, s), 3.29 (4H, d), 3.47 (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.

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

A solution of 4 M HCl in dioxane (8.75 mL, 35.0 mmol) was added to tert -butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazine-1-carboxylate (1.50 g, 3.50 mmol) in 1,4-dioxane (2 mL) at room temperature, and the mixture was stirred for 1 h. EtOAc (5 mL) was then added, and the mixture was stirred for 10 min. The resulting precipitate was collected by filtration, washed with EtOAc (2 x 5 mL), and dried in vacuo to afford the title compound (1.08 g, 85%) as a dark gray solid in the form of its hydrochloride salt; ^1H NMR: 1.97 (1H, dd), 2.36-2.44 (1H, m), 2.60 (1H, d), 2.84-2.99 (1H, m), 3.23 (4H, s), 3.5-3.57 (4H, m), 4.27 (1H, s), 4.34 (1H, s), 5. 06 (1H, dd), 7.11-7.18 (2H, m), 7.59 (1H, d), 9.17 (2H, s), 10.93 (1H, s); m/z : ES ⁺ [M+H] ⁺ 329.0.

Intermediate 2d: 4-(4-(4-(4-oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

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

Example 2: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

4-(4-(4-(4-Oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (4.17 g, 8.71 mmol), 3-[1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (3.18 g, 8.71 mmol) and NaOAc (2.144 g, 26.13 mmol) were dissolved in DCM (150 mL) at room temperature. The resulting suspension was stirred at room temperature for 1 h, after which NaBH(OAc) ₃ (3.69 g, 17.42 mmol) was added, and the mixture was stirred for 0.5 h. The mixture was then diluted with DCM (200 mL) and washed with saturated NaHCO ₃ (2 x 200 mL), then saturated brine (200 mL). The organic solution was then dried (MgSO ₄ ) and concentrated. The residue was purified by preparative HPLC (column A, eluent B, basic workup A) to give the title compound (820 mg, 13%); ^1H NMR: 1.52-1.69 (4H, m), 1.74 (2H, p), 1.84 (2H, d), 1.91-2.03 (1H, m), 2.34-2.42 (3H, m), 2.52-2.54 (4H, m), 2.59 (1H, d), 2.76 (1H, td), 2.83-2.96 (1H, m), 2.96-3.1 (2H, m), 3.27-3.29 (4H, m), 3.97 (2H, t), 4.1-4.28 (3H, m), 4.33 (1H, d), 5.05 (1H, dd), 6.78-6.9 (2H, m), 7.05 (2H, d), 7.15 (2H, d), 7.23-7.36 (2H, m), 7.52 (1H, d), 7.81 (1H, d), 10.92 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 729.5.

Intermediate 3a: 2-Cyclopropyl-4-fluorobenzonitrile

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

Intermediate 3b: 4-(4-(4-bromophenyl)piperidin-1-yl)-2-cyclopropylbenzonitrile

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

Intermediate 3c: 2-Cyclopropyl-4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)benzonitrile

Ruphos Pd G3 (88 mg, 0.10 mmol) and Ruphos (46 mg, 0.10 mmol) were added to a mixture of Cs ₂ CO ₃ (1.025 _g , 3.15 mmol), 4-(dimethoxymethyl)piperidine (334 mg, 2.10 mmol) and 4-(4-(4-bromophenyl)-piperidin-1-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1,4-dioxane (6 mL) under N 2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After cooling, the solvent was removed under reduced pressure. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (0.228 g, 47%) as a yellow solid; ^1H NMR: 0.79-0.90 (2H, m), 0.97-1.10 (2H, m), 1.20-1.41 (2H, m), 1.50-1.74 (5H, m), 1.80 (2H, d), 1.97-2.15 (1H, m), 2.52-2.71 (3H, m), 2. 81-2.95 (2H, m), 3.27 (6H, s), 3.58-3.68 (2H, m), 3.99-4.11 (3H, m), 6.46 (1H, d), 6.81-6.90 (3H, m), 7.06 (2H, d), 7.47 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 460.3.

Example 3: 2-Cyclopropyl-4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)benzonitrile

2-Cyclopropyl-4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)benzonitrile (150 mg, 0.33 mmol) and 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (130 mg, 0.33 mmol) were stirred in formic acid (0.5 mL) and 1,4-dioxane (0.5 mL) at 40 °C for 7 days. The resulting mixture was then concentrated, and the residue was dissolved in IPA (2 mL) and DCM (2 mL) (at room temperature under air). After that, NaBH(OAc) ₃ (138 mg, 0.65 mmol) was added all at once after 10 min, and the resulting dark suspension was stirred at room temperature for 1 h. The mixture was then concentrated, dissolved in DMF (3 mL), and filtered. The mixture was purified by preparative HPLC (column A, eluent A) to give the title compound (59 mg, 24%) as a formate salt as a white solid; ^1H NMR: 0.8-0.88 (2H, m), 0.98-1.07 (2H, m), 1.23 (2H, q), 1.51-1.64 (2H, m), 1.67 (1H, d), 1.79-1.83 (4H, m), 1.88-1.96 (1H, m), 2.09 (1H, s), 2.23 (2H, d), 2.28-2.37 (1H, m), 2.52-2.53 (4H, m), 2.54-2.72 (4H, m), 2.82-2.95 (3H, m), 3.30-3.32 (4H, d), 3.62 (2H, d), 3.84 (3H, s) ), 4.02 (2H, d), 4.11 (1H, d), 4.24 (1H, d), 4.96 (1H, dd), 6.44-6.52 (2H, m), 6.61 (1H, s), 6.86 (3H, td), 7.07 (2H, d), 7.47 (1H, d), 8.15 (2H, s) , 10.88 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 756.7.

Intermediate 4a: 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Cs ₂ CO ₃ (73.6 g, 225.95 mmol) was added portionwise to 4-fluoro-2-(trifluoromethyl)benzonitrile (20.51 g, 108.46 mmol) and 4-(4-bromophenyl)piperidine hydrochloride salt (25.0 g, 90.38 mmol) in DMSO (260 mL) at room temperature. The resulting cream-colored suspension was stirred at room temperature for 18 h and then slowly diluted with water (600 mL). The resulting cream-colored suspension was stirred at room temperature for 0.5 h and then filtered and washed with water (2 x 25 mL) and Et ₂ O (50 mL). The solid was dried in vacuo to afford the title compound (35.0 g, 95%) as a cream-colored solid; ^1H NMR: 1.65 (2H, qd), 1.87 (2H, d), 2.85 (1H, tt), 3.06 (2H, td), 4.19 (2H, d), 7.22-7.26 (2H, m), 7.28 (1H, dd), 7.33 (1H, d), 7.43-7.59 (2 H, m), 7.74-7.88 (1H, m).

Intermediate 4b: 4-(4-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

Anhydrous 1,4-dioxane (160 mL) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile (10.00 g, 24.43 mmol), 4-(1,3-dioxolan-2-yl)piperidine (4.17 g, 26.51 mmol), RuPhos Pd G3 (1.533 g, 1.83 mmol), RuPhos (0.855 g, 1.83 mmol), and sodium 2-methylpropan-2-oleate (7.04 g, 73.30 mmol). The mixture was degassed by bubbling N ₂ through the mixture for 5 min and then stirred at 100 °C for 2 h. The mixture was then cooled to room temperature and water (320 mL) was added. A precipitate formed and was collected by filtration to give an orange solid. The solid was slurried in MTBE (50 mL), heated at 45 °C for 0.5 h, then cooled to room temperature and filtered. The solid was washed with MTBE (2 x 5 mL) and dried to give the title compound (12.0 g, 100%) as a pale orange solid; ^1H NMR: 1.39 (2H, qd), 1.54-1.68 (3H, m), 1.72 (2H, d), 1.84 (2H, d), 2.58 (2H, td), 2.65-2.79 (1H, m), 2.99-3.12 (2H, m), 3.66 (2H, d), 6-3.83 (2H, m), 3.83-3.91 (2H, m), 4.17 (2H, d), 4.61 (1H, d), 6.86 (2H, d), 7.08 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 486.3.

Intermediate 4c: 4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (10.00 g, 20.60 mmol) was dissolved in toluene (100 mL), formic acid (100 mL) and water (50 mL), and then warmed to 80 °C for 1 h. The mixture was then cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The layers were separated. The organic solution was washed with water (50 mL), saturated NaHCO ₃ (50 mL) and brine (50 mL), and then dried (MgSO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0-100% EtOAc in heptane) to afford the title compound (4.60 g, 51%) as a white solid; ¹ H NMR: 1.53-1.68 (4H, m), 1.84 (2H, d), 1.92 (2H, dd), 2.45 (1H, dd), 2.73 (1H, d), 2.74-2.85 (2H, m), 2.97-3.11 (2H, m), 3.54 (2H, dt), 4.17 (2H, d), 6.88 (2H, d), 7.09 (2H, d), 7.22-7.4 (2H, m), 7.81 (1H, d), 9.59-9.72 (1H, m); m/z : ES ⁺ [M+H] ⁺ 442.3.

Example 4: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (4.60 g, 10.42 mmol) and 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt at room temperature under air (4.11 g, 10.42 mmol) and NaOAc (1.71 g, 20.84 mmol) were stirred in IPA (2 mL) and DCM (250 mL). After 1 h NaBH(OAc) ₃ (4.42 g, 20.84 mmol) was added portionwise. The resulting dark suspension was stirred at room temperature for 1 h. The mixture was then diluted with DCM (2 x 250 mL), washed (saturated NaHCO ₃ (250 mL), water (250 mL), then saturated brine (250 mL)), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane, then 0-5% IPA in EtOAc) gave a solid which was slurried in MeCN (100 mL) (at room temperature) and collected by filtration to give the title compound (2.05 g, 31%) as a white solid; ^1H NMR: 1.18-1.31 (2H, m), 1.55-1.74 (3H, m), 1.80-1.86 (4H, m), 1.88-1.97 (1H, m), 2.23 (2H, d), 2.27-2.34 (1H, m), 2.52-2.53 (4H, m), 2. 54-2.67 (3H, m), 2.73 (1H, t), 2.82-2.97 (1H, m), 3.04 (2H, t), 3.32-3.35 (4H, s), 3.62 (2H, d), 3.84 (3H, s), 4.08-4.28 (4H, m), 4.96 (1H, dd), 6.49 (1H, s), 6.61 (1H, s), 6.87 (2H, d), 7.08 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d), 10.88 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 784.6.

Intermediate 5a: Ethyl 2-(3-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-cyclobutyl)acetate

RockPhos Pd G3 (0.103 g, 0.12 mmol) was added in _one portion to a degassed mixture of ethyl 2-(3-hydroxy-cyclobutyl)acetate (0.387 g, 2.44 mmol), 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), and Cs ₂ CO ₃ (2.79 g, 8.55 mmol) in toluene (20 mL) under N 2 at room temperature. The resulting mixture was stirred at 90 °C for 18 h. The mixture was then cooled to room temperature and diluted with EtOAc (50 mL) and water (15 mL). The organic layer was separated, washed with saturated brine (20 mL), dried (MgSO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0–60% EtOAc in heptane) to give the title compound (0.34 g, 29%) as a white solid; ¹ H NMR: (CDCl ₃ ) 1.25 (3H, td), 1.75 (2H, qd), 1.81-1.91 (1H, m), 1.97 (2H, d), 2.25 (1H, ddd), 2.29-2.45 (1H, m), 2.50 (2H, dd), 2.71 (3H, dddd), 3.05 (2H, td), 4.01 (2H, d), 4.07-4.18 (2H, m), 4.51 (1H, p), 6.7-6.81 (2H, m), 6.98 (1H, dd), 7.05-7.12 (2H, m), 7.15 (1H, d), 7.61 (1H, d); m/z : ES ⁺ [M+H] ⁺ 487.3.

Intermediates 5b and 5c: 4-(4-(4-((1r,3s)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile and 4-(4-(4-((1s,3r)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

_{Diisobutylaluminum} hydride (1 M in toluene, 1.048 mL, 1.05 mmol) was added dropwise to a stirred solution of ethyl 2-(3-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)cyclobutyl)acetate (340 mg, 0.70 mmol) in THF (10 mL) at 0 °C under N 2 . The resulting mixture was stirred at 0 °C for 10 min. The reaction was then quenched by the addition of Rochelle salt (15 mL). EtOAc (25 mL) was added and the mixture was stirred at room temperature for 18 h. The phases were then separated and the aqueous portion was extracted with EtOAc (3 × 50 mL). The combined organic solution was washed with brine (50 mL), dried (MgSO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0-100% EtOAc in heptane) to give approximately 2:1 mixture of cis/trans isomers (0.280 g, 90%). The sample was purified on a Sepiatec SFC system (column: YMC Chiral Art Cellulose-SJ, 20 x 250 mm, 5 μm, eluent: 70% CO ₂ , 30% MeOH+0.1% NH ₃ ) to give the following title compounds: Intermediate 5b ( cis , 0.142 g, 53%) and Intermediate 5c ( trans , 0.054 g, 20%); Intermediate 5b ( cis ) : ^1H NMR: 1.52-1.69 (6H, m), 1.85 (2H, d), 1.98 (1H, ddd), 2.53-2.61 (2H, m), 2.7-2.83 (1H, m), 2.97-3.1 (2H, m), 3.36 (2H, td), 4. 17 (2H, d), 4.31 (1H, t), 4.49 (1H, p), 6.65-6.83 (2H, m), 7.06-7.19 (2H, m), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d); Intermediate 5c ( trans ) : ^1H NMR: 1.55-1.72 (4H, m), 1.85 (2H, d), 2.14-2.16 (4H, m), 2.34-2.4 (1H, m), 2.7-2.82 (1H, m), 2.96-3.13 (2H, m), 3.34-3.44 (2H) , m), 4.17 (2H, d), 4.33 (1H, t), 4.76 (1H, p), 6.64-6.78 (2H, m), 7.14 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d).

Intermediate 5d: 4-(4-(4-((1s,3s)-3-(2-bromoethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

A solution of PPh ₃ (142 mg, 0.54 mmol) in THF (2 mL) was added dropwise to a stirred mixture of 4-(4-(4-((1r,3s)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (120 mg, 0.27 mmol) and CBr ₄ (179 mg, 0.54 mmol) in THF (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h and then filtered. The solid was then washed with EtOAc (20 mL), and the filtrate was concentrated under reduced pressure. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (0.140 g, 100%) as a colorless oil; ^1H NMR: (500 MHz, CDCl ₃ ) 1.21-1.26 (1H, m), 1.63-1.78 (4H, m), 1.90 (2H, d), 1.95 (1H, d), 2.01-2.15 (1H, m), 2.49-2.73 (3H, m), 2.98 (2H, td), 3.28 (2H, t), 3.9-3.98 (2H, m), 4.44 (1H, p), 6.68-6.75 (2H, m), 6.92 (1H, dd), 6.98-7.07 (2H, m), 7.09 (1H, d), 7.55 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 507.1.

Example 5: 4-[4-(4-{[(1r,3s)-3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethyl)cyclobutyl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

4-(4-(4-((1s,3s)-3-(2-bromoethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (65.0 mg, 0.13 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (50.6 mg, 0.13 mmol), KI (63.8 mg, 0.38 mmol), and DIPEA (112 μL, 0.64 mmol) were dissolved in MeCN (2.5 mL) and stirred at 70 °C for 18 h. The mixture was then diluted with DCM (20 mL), washed (5% AcOH in water (20 mL), water (20 mL), then saturated NaHCO ₃ (20 mL)), dried (Na ₂ SO ₄ ) and concentrated. The mixture was purified by preparative HPLC (column A, eluent A, basic workup A) to give the title compound (8 mg, 8%) as a white solid; ^1H NMR: 1.66-1.75 (3H, m), 1.75-1.84 (3H, m), 1.92-1.99 (3H, m), 2.15 (1H, dtd), 2.28 (1H, td), 2.32-2.4 (2H, m), 2.54-2.61 (4H, m), 2.61- 2.69 (2H, m), 2.69-2.78 (1H, m), 2.78-2.85 (1H, m), 2.85-2.91 (1H, m), 3.05 (2H, td), 3.27-3.36 (4H, m), 3.94 (3H, s), 4.02 (2H, d), 4.19 (1) H, d), 4.35 (1H, d), 4.49 (1H, p), 5.12 (1H, dd), 6.36 (1H, d), 6.45 (1H, s), 6.7-6.82 (2H, m), 6.98 (1H, dd), 7.10 (2H, dd), 7.15 (1H, d), 7.61 (1 H, d), 7.96 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 785.4.

Intermediate 6a : 3,4-Difluoro-2-(trifluoromethyl)benzonitrile

1-Bromo-3,4-difluoro-2-(trifluoromethyl)benzene (5.00 g, 19.16 mmol) and cyanocopper (1.89 g, 21.07 mmol) were stirred in NMP (48 mL) at 150 °C for 3 h. The mixture was then cooled to room temperature, diluted with Et ₂ O (100 mL), washed with saturated brine (3 × 100 mL), then diluted NH ₃ solution (50 mL), dried (MgSO ₄ ), and concentrated to give the title compound (4.27 g) which was used in the next step without further purification; ¹ H NMR: (500 MHz, CDCl ₃ ) 7.46 (1H, q), 7.59 (1H, dddd).

Intermediate 6b : 4-(4-(4-bromophenyl)piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

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

Intermediate 6c: 3-Fluoro-4-(4-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

Under N _{2 ,} CuI (44.6 mg, 0.23 mmol) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-3-fluoro-2-(trifluoro-methyl)benzonitrile (500 mg, 1.17 mmol), piperidin-4-ylmethanol (202 mg, 1.76 mmol), 2-((2,6-dimethyl-phenyl)amino)-2-oxoacetic acid (45.2 mg, 0.23 mmol) and K ₃ PO ₄ (497 mg, 2.34 mmol) in DMSO (5 mL). The mixture was stirred at 110 °C for 18 h. The mixture was then cooled to room temperature, poured into water (50 mL), and then extracted with EtOAc (3 x 50 mL). The combined organic solution was washed with NaHCO ₃ (50 mL) and brine (50 mL), dried (MgSO ₄ ), and concentrated. Purification by FSC (gradient: 0–100% EtOAc in heptane) gave the title compound (0.10 g, 19%) as a white solid; ¹ H NMR: (CDCl ₃ ) 1.28 (1H, d), 1.41 (2H, qd), 1.53 (1H, s), 1.57-1.71 (1H, m), 1.82-1.91 (3H, m), 1.91-1.99 (2H, m), 2.53-2.79 (3H, m), 2.98 (2H, td) ), 3.55 (2H, d), 3.63-3.81 (4H, m), 6.88-6.95 (2H, m), 7.05-7.16 (3H, m), 7.48 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 462.2.

Intermediate 6d: 3-Fluoro-4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

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

Example 6: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

3-Fluoro-4-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.100 g, 0.22 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (0.086 g, 0.22 mmol) and NaOAc (0.054 g, 0.65 mmol) were dissolved in DCM (3 mL) at room temperature and stirred for 10 min. NaBH(OAc) ₃ (0.092 g, 0.44 mmol) was added and the mixture was stirred for 1 h. The mixture was diluted with DCM (20 mL), washed (saturated NaHCO ₃ (20 mL), water (20 mL), then saturated brine (20 mL)), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC (column A, eluent A) to give the title compound (42 mg, 24%) as a formate salt as a white solid; ^1H NMR: 1.23 (2H, q), 1.62-1.78 (3H, m), 1.82-1.84 (4H, m), 1.89-1.97 (1H, m), 2.23 (2H, d), 2.26-2.38 (2H, m), 2.52-2.54 (4H, m), 2.56-2. 67 (3H, m), 2.83-2.96 (1H, m), 3.04 (2H, t), 3.31 (4H, s), 3.68 (4H, dd), 3.84 (3H, s), 4.12 (1H, d), 4.24 (1H, d), 4.96 (1H, dd), 6.49 (1H, s), 6.61 (1H, s), 6.88 (2H, d), 7.11 (2H, d), 7.46 (1H, t), 7.80 (1H, d), 10.88 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 802.7.

Intermediate 7a: 3-Fluoro-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

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

Intermediate 7b: 3-Fluoro-4-(4-(4-(4-oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

3-Oxo-1l5-benzo[ d ][1,2]iodaoxole-1,1,1(3 H )-triyl triacetate (192 mg, 0.45 mmol) was added to 3-fluoro-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.41 mmol) in DCM (2 mL) at 0 °C and warmed to room temperature for 1 h. The mixture was then diluted with DCM (15 mL) and poured into a mixture of saturated NaHCO ₃ (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 min and then the phases were separated. The organic solution was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.120 g, 67%) as a yellow film which was used in the next step without further purification; m / z : ES ⁺ [M + H] ⁺ = 435.1.

Example 7: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-3-fluoro-2-(trifluoromethyl)benzonitrile

3-Fluoro-4-(4-(4-(4-oxobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.120 g, 0.28 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (0.109 g, 0.28 mmol) and NaOAc (0.068 g, 0.83 mmol) were dissolved in DCM (3 mL) and stirred at room temperature for 10 min. Then NaBH(OAc) ₃ (0.117 g, 0.55 mmol) was added, and the mixture was stirred for 1 h. The mixture was then diluted with DCM (20 mL), washed (saturated NaHCO ₃ (20 mL), water (20 mL), then saturated brine (20 mL)), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC (column A, eluent A) to give the title compound (0.084 g, 39%) as a white solid; ^1H NMR: 1.61 (2H, p), 1.75-1.76 (4H, m), 1.86 (2H, d), 1.89-1.98 (1H, m), 2.28 (1H, dd), 2.39 (2H, t), 2.52-2.53 (4H, m), 2.54-2.62 (1H, m), 2.67-2.78 (1H, m), 2.89 (1H, ddd), 2.99-3.08 (2H, m), 3.27-3.32 (4H, m), 3.72 (2H, d), 3.84 (3H, s), 3.98 (2H, t), 4.05-4.18 (1H, m), 4.24 ( 1H, d), 4.96 (1H, dd), 6.48 (1H, d), 6.60 (1H, s), 6.8-6.92 (2H, m), 7.18 (2H, d), 7.46 (1H, t), 7.80 (1H, d), 10.88 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 777.3.

Intermediate 8a: tert -Butyl 4-(5-hydroxypyrimidin-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate

Na ₂ CO ₃ (1.211 g, 11.43 mmol) was added to a solution of 2-bromopyrimidin-5-ol (1.00 g, 5.71 mmol) and tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (2.65 g, 8.57 mmol) in toluene (8.0 mL), EtOH (2.0 mL), and water (4.0 mL). The mixture was degassed with N ₂ for 15 min. Pd(dppf) ₂ Cl ₂ -DCM complex (0.467 g, 0.571 mmol) was then added, and the resulting mixture was heated to 100 °C for 3 h and then cooled to room temperature. The mixture was then diluted with water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organic solutions were washed with brine (80 mL), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0-40% EtOAc in heptane) to afford the title compound (1.10 g, 65%) as a light brown sticky liquid; ¹ H NMR: 1.43 (9H, s), 2.56 (2H, d), 3.51 (2H, t), 4.04 (2H, s), 6.91 (1H, s), 8.34 (2H, s), 10.42 (1H, br s); m/z : ES ⁺ [M-56] ⁺ = 222.2.

Intermediate 8b: tert -Butyl 4-(5-hydroxypyrimidin-2-yl)piperidine-1-carboxylate

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

Intermediate 8c: 2-(piperidin-4-yl)pyrimidin-5-ol

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

Intermediate 8d: 4-(4-(5-hydroxypyrimidin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

At room temperature under air, DIPEA (0.831 mL, 4.76 mmol) was added to a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (300 mg, 1.586 mmol) and 2-(piperidin-4-yl)pyrimidin-5-ol hydrochloride salt (513 mg, 2.380 mmol) in DMSO (5 mL). The mixture was heated at 50 °C for 6 h, then cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (2 x 150 mL). The combined organic solutions were washed with cold water (2 x 80 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-6% MeOH in DCM) gave the title compound (380 mg, 64%) as a pale yellow sticky liquid; ^1H NMR: (CDCl ₃ ) 1.92-2.05 (2H, m), 2.14 (2H, d), 3.11-3.21 (3H, m), 4.03 (2H, d), 7.00 (1H, dd), 7.17 (1H, d), 7.62 (1H, d), 8.37 (2H, s); m/z : ES ⁺ [M+H] ⁺ = 349.2.

Intermediate 8e: 4-[4-[5-(4-bromobutoxy)pyrimidin-2-yl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile

Cs ₂ CO ₃ (711 mg, 2.182 mmol) and 1,4-dibromobutane (0.391 mL, 3.27 mmol) were added to a solution of 4-(4-(5-hydroxypyrimidin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (380 mg, 1.091 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 2 h, then diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic solutions were washed with brine (50 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-40% EtOAc in heptane) afforded the title compound (390 mg, 71%) as an off-white solid; ^1H NMR: (CDCl ₃ ) 1.96-2.21 (8H, m), 3.12-3.22 (3H, m), 3.51 (2H, t), 4.02 (2H, d), 4.11 (2H, t), 7.01 (1H, dd), 7.17 (1H, d), 7.62 (1H, d), 9 (2H, s); m/z : ES ⁺ [M+H] ⁺ = 483.1.

Example 8: 4-[4-[5-[4-[4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazin-1-yl]-butoxy]pyrimidin-2-yl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile

A mixture of DIPEA (0.216 mL, 1.241 mmol), 3-[ ₇ -methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (137 mg, 0.348 mmol), 4-(4-(5-(4-bromobutoxy)pyrimidin-2-yl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (120 mg, 0.248 mmol), and KI (124 mg, 0.745 mmol) in DMSO (4 mL) was stirred at room temperature under N 2 . The mixture was then heated to 80 °C for 16 h, cooled to room temperature, and diluted with DCM (30 mL). The phases were separated and the organic solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ (20 mL), then saturated brine (20 mL)), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by preparative HPLC (column B, eluent C). The fractions containing the desired compound were combined, cryo-concentrated to the minimum of solvent and basified with saturated NaHCO ₃ solution. The phases were separated and the aqueous phase was extracted with DCM (4 x 30 mL). The combined organic solution was washed with water (20 mL), dried in a phase separator and lyophilized to give the title compound (55 mg, 29%) as an off-white solid; ^1H NMR: 1.57-1.67 (2H, m), 1.69-1.83 (4H, m), 1.92-2.04 (3H, m), 2.34-2.42 (3H, m), 2.59 (1H, d), 2.85-2.97 (1H, m), 3.06-3.20 (3H, m), 3. 26 (4H, s), 4.08-4.25 (5H, m), 4.30-4.38 (1H, m), 5.05 (1H, dd), 7.07 (2H, s), 7.27 (1H, dd), 7.32 (1H, s), 7.52 (1H, d), 7.82 (1H, d), 8.4 9 (2H, s), 10.95 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 761.2.

Intermediate 9a: tert -Butyl 5-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2' H )-carboxylate

Na ₂ CO ₃ (1.218 g, 11.49 mmol) and tert -Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-pyridine-1(2 H )-carboxylate (2.67 g, 8.62 mmol) were added to a solution of 6-bromopyridin-3-ol (1.0 g, 5.75 mmol) in EtOH (4.0 mL), toluene (8.0 mL), and water (2.0 mL) at room temperature. The mixture was degassed with N ₂ for 15 min, after which Pd(dppf)Cl ₂ ·DCM (0.079 g, 0.575 mmol) was added, and the mixture was heated to 100 °C for 3 h. The mixture was then cooled to room temperature, diluted with water (120 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 150 mL) and the combined organic solutions were washed with brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-35% EtOAc in heptane) gave the title compound (1.52 g, 95%) as a pale yellow sticky liquid; ¹ H NMR: (CDCl ₃ ) 1.51 (9H, s), 2.61 (2H, d), 3.64 (2H, t), 4.11 (2H, d), 6.40 (1H, s), 7.18 (1H, dd), 7.30 (1H, d), 8.21 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 277.2.

Intermediate 9b: tert -Butyl 4-(5-hydroxypyridin-2-yl)piperidine-1-carboxylate

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

Intermediate 9c: 6-(piperidin-4-yl)pyridin-3-ol. TFA salt

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

Intermediate 9d: 4-(4-(5-hydroxypyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (0.831 mL, 4.76 mmol) and 6-(piperidin-4-yl)pyridin-3-ol (424 mg, 2.380 mmol) were added to a stirred solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (300 mg, 1.586 mmol) in DMSO (5.0 mL) at room temperature. The mixture was then heated to 50 °C for 5 h, then cooled to room temperature and diluted with water (80 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 120 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. Trituration with hexanes (100 mL) gave the title compound (530 mg, 96%) as an off-white solid; ^1H NMR: 1.69 (2H, qd), 1.88 (2H, d), 2.86-2.99 (1H, m), 3.09 (2H, t), 4.16 (2H, d), 7.08-7.12 (2H, m), 7.27 (1H, dd), 7.32 (1H, s), 7.81 (1H , d), 8.04 (1H, d), 9.66 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 348.1.

Intermediate 9e: 4-(4-(5-(4-bromobutoxy)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

K ₂ CO ₃ (80 mg, 0.576 mmol) and 1,4-dibromobutane (186 mg, 0.864 mmol) were added to a stirred solution of 4-(4-(5-hydroxypyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.288 mmol) in acetone (3.0 mL) at room temperature. The mixture was heated to 60 °C for 4 h, then cooled to room temperature and concentrated. The mixture was then partitioned between water (80 mL) and EtOAc (100 mL). The aqueous portion was extracted with EtOAc (2 x 100 mL) and the combined organic solutions were washed with brine (50 mL), dried (Na ₂ SO ₄ ), and concentrated to give the crude compound (170 mg). The above procedure was repeated using Cs ₂ CO ₃ (188 mg, 0.576 mmol) instead of K ₂ CO ₃ and the mixture was stirred at room temperature for 2 h. After the same workup as described previously, the crude products from both reactions were combined. Purification by FSC (gradient: 0-20% EtOAc in heptane) gave the title compound (160 mg, 58%) as an off-white solid; ^1H NMR: (CDCl ₃ ) 1.84-2.03 (4H, m), 2.05-2.14 (4H, m), 2.93-3.02 (1H, m), 3.13 (2H, td), 3.51 (2H, t), 4.02-4.10 (4H, m), 7.01 (1H, dd), (1H, d), 7.17 (2H, dd), 7.63 (1H, d), 8.25 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 482.1.

Example 9: 4-(4-(5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (0.221 mL, 1.266 mmol), 4-(4-(5-(4-bromobutoxy)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (147 mg, 0.304 mmol) and _KI (126 mg, 0.760 mmol) were added to a solution of 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (100 mg, 0.253 mmol) in DMSO (3.0 mL) at room temperature under N 2 . The mixture was then heated to 80 °C for 16 h, then cooled to room temperature and diluted with DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ (20 mL), then saturated brine (20 mL)), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by preparative HPLC (column C, eluent C). The fractions containing the desired compound were combined, cryo-concentrated to the minimum of solvent and basified with saturated NaHCO ₃ solution. The phases were separated and the aqueous portion was extracted with DCM (4 x 30 mL). The combined organic solutions were washed with water (20 mL), dried in a phase separator and lyophilized to give the title compound (28 mg, 14%) as an off-white solid; ^1H NMR: 1.62-1.95 (10H, m), 2.34-2.40 (1H, m), 2.59 (2H, s), 2.75-3.03 (5H, m), 3.10 (4H, t), 3.84 (3H, s), 4.03-4.29 (7H, m), 4.97 (1H, dd), 6.52 (1H, s), 6.64 (1H, s), 7.21-7.38 (4H, m), 7.82 (1H, d), 8.21 (1H, s), 10.91 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 760.3.

Intermediate 10a: tert -Butyl 3-(2-(( tert -Butyldiphenylsilyl)oxy)ethyl)azetidine-1-carboxylate

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

Intermediate 10b: 3-(2-(( tert -Butyldiphenylsilyl)oxy)ethyl)azetidine

TFA (1.92 mL, 25.0 mmol) was carefully added to a solution of tert -butyl 3-(2-(( tert -butyldiphenylsilyl)oxy)-ethyl)azetidine-1-carboxylate (1.10 g, 2.502 mmol) in DCM (8 mL) at 0 °C. The mixture was then stirred at 0 °C for 2 h, then further diluted with DCM (5 mL) and washed with saturated NaHCO ₃ (20 mL). The organic solution was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (810 mg, 91%) as a thick liquid which was used in the next step without further purification; m / z : ES ⁺ [M+H] ⁺ = 340.4.

Intermediate 10c: 4-(4-(4-(3-(2-(( tert -Butyldiphenylsilyl)oxy)ethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

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

Intermediate 10d: 4-(4-(4-(3-(2-hydroxyethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

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

Intermediate 10e: 4-(4-(4-(3-(2-bromoethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

PPh ₃ (286 mg, 1.090 mmol) was added to a solution of 4-(4-(4-(3-(2-hydroxyethyl)azetidin-1-yl)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (360 mg, 0.838 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 5 min. CBr ₄ (361 mg, 1.090 mmol) was then added, and the mixture was stirred at room temperature for 2 h. After concentration, the solvent was reduced to half the amount (2 mL), and the product was then triturated with pentane to give the title compound, which was used in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ = 492.0.

Example 10: 4-(4-(4-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

A mixture of DIPEA (0.25 mL, 1.422 mmol), 4-(4-(4-(3-(2-bromoethyl)azetidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile (140 mg, 0.284 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (112 mg, 0.284 mmol) and KI (142 mg, 0.853 mmol) was stirred in DMSO (5 mL) at room temperature. The mixture was then heated to 80 °C for 12 h, then concentrated and slowly poured into ice water. The resulting solid was collected by filtration, washed with water (10 mL) and dried under vacuum. The residue was purified by preparative HPLC (column B, eluent C, basic workup A) to give the title compound (34 mg, 15%) as an off-white solid; ^1H NMR: 1.50-1.66 (2H, m), 1.66-1.77 (1H, m), 1.77-1.87 (2H, m), 1.87-1.99 (1H, m), 2.09-2.18 (1H, m), 2.24-2.43 (4H, m), 2.54-2.61 (4H, m) ), 2.65-2.75 (2H, m), 2.79-2.93 (1H, m), 2.93-3.10 (4H, m), 3.17-3.26 (2H, m), 3.84 (3H, s), 4.04-4.30 (4H, m), 4.94 (1H, dd), 3H, m), 6.57-6.68 (1H, m), 6.96-7.11 (2H, m), 7.23-7.37 (2H, m), 7.81 (1H, d), 11.0 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 770.2.

Intermediate 11a: 5-(4-(4-hydroxyphenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

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

Intermediate 11b: 5-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

K ₂ CO ₃ (119 mg, 0.864 mmol) was added to a solution of 5-(4-(4-hydroxyphenyl)piperidin-1-yl)-3-(trifluoro-methyl)picolinonitrile (150 mg, 0.432 mmol) and 1,4-dibromobutane (140 mg, 0.648 mmol) in DMF (3.0 mL) at room temperature. The mixture was heated to 70 °C for 6 h, then cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (2 x 80 mL). The combined organic solutions were washed with saturated brine (30 mL), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0-30% EtOAc in heptane) to afford the title compound (145 mg, 65%) as an off-white semi-solid; ¹ H NMR: 1.23-1.32 (4H, m), 1.60-1.73 (2H, m), 1.91-2.04 (2H, m), 2.75-2.90 (1H, m), 3.11 (2H, t), 3.54-3.67 (2H, m), 3.97 (2H, t), 4.30 (2H, d), 6.86 (2H, d), 7.17 (2H, d), 7.64 (1H, d), 8.66 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 482.1.

Example 11: 5-(4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

DIPEA (0.332 mL, 1.899 mmol) was added to a solution of 3-[ ₇ -methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (150 mg, 0.380 mmol), 5-(4-(4-(4-bromobutoxy)-phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile (220 mg, 0.456 mmol) and KI (189 mg, 1.140 mmol) in DMSO (4 mL) at room temperature under N 2 . The mixture was stirred at 80 °C for 16 h, then cooled to room temperature and diluted with DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ (20 mL), then saturated brine (20 mL)), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC (column B, eluent C, basic workup A) and dissolved in pentane (10 mL) to give the title compound (52 mg, 18%) as an off-white solid; ^1H NMR: 1.58-1.78 (6H, m), 1.81-2.01 (3H, m), 2.27-2.38 (3H, m), 2.60-2.78 (2H, m), 2.80-2.98 (2H, m), 3.11 (3H, t), 3.83 (3H, s), 3.97 (2 H, s), 4.06-4.34 (4H, m), 4.97 (1H, d), 6.48 (1H, s), 6.61 (1H, s), 6.86 (2H, d), 7.17 (2H, d), 7.65 (1H, s), 8.65 (1H, s), 10.91 (1H, s) ; m/z : ES ⁺ [M+H] ⁺ = 760.4.

Intermediate 12a: 4-(4-(4-((3,3-difluoro-5-hydroxypentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

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

Intermediate 12b: 5-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3-difluoropentyl methanesulfonate

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

Example 12: 4-(4-(4-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)-3,3-difluoropentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

KI (200 mg, 1.21 mmol), 5-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3-difluoro-pentyl methanesulfonate (220 mg, 0.40 mmol), 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (166 mg, 0.42 mmol) and DIPEA (0.247 mL, 1.41 mmol) were dissolved in MeCN (3 mL) and stirred at 80 °C for 18 h. The mixture was then cooled to room temperature and concentrated. The resulting residue was dissolved in DCM (20 mL), washed with water (20 mL), separated through a phase separator, and concentrated. The residue was purified by preparative HPLC (column A, eluent A, basic workup A) to give the title compound (10.2 mg, 3%) as a yellow dry film; ¹ H NMR: (CDCl ₃ ) 1.75 (2H, qd), 1.97 (2H, d), 2.13-2.34 (4H, m), 2.34-2.48 (2H, m), 2.64-2.93 (9H, m), 3.06 (2H, td), 3.29-3.39 (4H, m), 3.94 (3H, s), 4.02 (2H, d), 4.13-4.26 (3H, m), 4.36 (1H, d), 5.13 (1H, dd), 6.36 (1H, d), 6.46 (1H, s), 6.79-6.9 (2H, m), 6.99 (1H, dd), 7.09-7. 19 (3H, m), 7.61 (1H, d), 7.89 (1H, s); m/z : ES ^- [MH] ^- 807.5.

Intermediate 13a: 4-(4-(4-(3-hydroxypropoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Prepared from 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile according to the procedure described in Example 12, except that propane-1,3-diol was used.

Intermediate 13b: 4-(4-(4-(3-bromopropoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

A solution of PPh ₃ (419 mg, 1.60 mmol) in THF (10 mL) was added dropwise to a stirred mixture of 4-(4-(4-(3-hydroxypropoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (323 mg, 0.80 mmol) and CBr ₄ (530 mg, 1.60 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h, then filtered and washed with EtOAc (20 mL). The combined filtrates were concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) afforded the title compound (346 mg, 93%) as a pale yellow solid; ^1H NMR: (CDCl ₃ ) 1.76 (2H, qd), 1.98 (2H, dd), 2.31 (2H, p), 2.74 (1H, tt), 3.06 (2H, td), 3.60 (2H, t), 4.02 (2H, dd), 4.09 (2H, t), (2H, m), 6.99 (1H, dd), 7.09-7.19 (3H, m), 7.58-7.64 (1H, m).

Example 13: 4-(4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

A _mixture of 3-[7-methoxy-1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (100 mg, 0.253 mmol), DIPEA (164 mg, 1.266 mmol), 4-(4-(4-(3-bromopropoxy)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (142 mg, 0.304 mmol) and KI (126 mg, 0.760 mmol) in DMSO (4 mL) was stirred at room temperature under N 2 . The mixture was then heated at 80 °C for 12 h, then cooled to room temperature and diluted with DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ (20 mL), then saturated brine (20 mL)), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC (column B, eluent C, basic workup A), this time lyophilized and washed with hexanes, to give the title compound (26 mg, 13%) as a brown solid; ^1H NMR: 1.55-1.72 (2H, m), 1.80-1.97 (5H, m), 2.22-2.31 (1H, m), 2.58 (2H, br s), 2.75-2.82 (1H, m), 2.85-2.96 (1H, m), 3.05 (2H, br t), 3. 44-3.59 (4H, m), 3.83 (3H, s), 4.00 (2H, br t), 4.07-4.29 (5H, m), 4.96 (1H, br dd), 6.49 (1H, s), 6.61 (1H, s), 6.87 (2H, br d), 7.16 (2H, br d), 7.27 (1H, br d), 7.33 (1H, br s), 7.81 (1H, br d), 10.90 (1H, br s); m/z : ES ⁺ [M+H] ⁺ 745.4.

Intermediate 14a: 2-Cyclopropyl-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)benzonitrile

RockPhos Pd G3 (88 mg, 0.10 mmol) was _added to a mixture of butane-1,4-diol (142 mg, 1.57 mmol), Cs ₂ CO ₃ (1.03 g, 3.15 mmol) and 4-(4-(4-bromophenyl)piperidin-1-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1,4-dioxane (5 mL) under N 2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (0.10 g, 25%) as a white solid; ^1H NMR: (300 MHz) 0.77-0.88 (2H, m), 0.93-1.08 (2H, m), 1.43-1.91 (8H, m), 1.98-2.13 (1H, m), 2.60-2.74 (1H, m), 2.79-2.93 (2H, m), 3.36-3. 48 (2H, m), 3.86-3.96 (2H, m), 3.99 (1H, s), 4.03 (1H, s), 4.36-4.46 (1H, m), 6.44 (1H, d), 6.77-6.88 (3H, m), 7.07-7.17 (2H, m), 7.45 (1H, d); m/z ES ⁺ [M+H] ⁺ = 391.3.

Intermediate 14b 4-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)-2-cyclopropylbenzonitrile

CBr ₄ (153 mg, 0.46 mmol) was added to a mixture of PPh ₃ (121 mg, 0.46 mmol) and 2-cyclopropyl-4-(4-(4-(4-hydroxybutoxy)phenyl)piperidin-1-yl)benzonitrile (90 mg, 0.23 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 2 h and then concentrated. Purification by FSC (gradient: 0-23% EtOAc in petroleum ether) gave the title compound (81 mg, 78%) as a white solid; ^1H NMR: 0.79-0.90 (2H, m), 1.00-1.10 (2H, m), 1.60 (2H, m), 1.78-1.86 (4H, m), 1.91-2.03 (2H, m), 2.08 (1H, m), 2.65-2.75 (1H, m), 2.85-2. 95 (2H, m), 3.61 (2H, t), 3.94-4.07 (4H, m), 6.47 (1H, d), 6.83-6.89 (3H, m), 7.12-7.19 (2H, m), 7.48 (1H, d); m/z ES ⁺ [M+H] ⁺ = 453.2.

Example 14: 2-Cyclopropyl-4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)benzonitrile

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

Intermediate 15a: Benzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate

To a solution of 2-(piperidin-4-yl)ethan-1-ol (5.00 g, 38.7 mmol) in DCM (100 mL) was added Na ₂ CO ₃ (18.46 g, 174.1 mmol) in water (100 mL) at 0 °C, followed by dropwise addition of benzyl carbonochloridate (6.08 mL, 42.6 mmol). The mixture was stirred at room temperature for 6 h, then diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic solutions were washed with saturated brine (100 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-70% EtOAc in heptane) afforded the title compound (8.34 g, 82%) as a pale yellow oil; ¹ H NMR: (CDCl ₃ ) 1.15 (2H, qd), 1.43 (1H, t), 1.52 (2H, q), 1.62 (1H, dddd), 1.69 (2H, t), 2.78 (2H, t), 3.69 (2H, q), 4.14 (2H, dd), 5.12 (2H, s), 7.2 8-7.45 (5H, m); m/z : ES ⁺ [M+H] ⁺ 264.3.

Intermediate 15b: Benzyl 4-(2-oxoethyl)piperidine-1-carboxylate

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

Intermediate 15c: Benzyl 4-(2,2-dimethoxyethyl)piperidine-1-carboxylate

To a solution of benzyl 4-(2-oxoethyl)piperidine-1-carboxylate (5.20 g, 19.9 mmol) in MeOH (60 mL) were added trimethoxymethane (10.9 mL, 99.5 mmol) and 4-methylbenzenesulfonic acid (0.17 g, 0.99 mmol) at 15 °C. The mixture was stirred at this temperature for 1 h. The reaction was then quenched by the addition of water (50 mL) and diluted with DCM (100 mL). The phases were separated and the organic solution was washed with saturated brine (3 x 20 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give the title compound (5.90 g, 96%) as a colorless oil; ¹ H NMR: (CDCl ₃ ) 1.04-1.25 (2H, m), 1.5-1.57 (2H, m), 1.57-1.63 (1H, m), 1.68 (2H, t), 2.78 (2H, t), 3.31 (6H, s), 4.15 (2H, d), 4.46 (1H, t), 5.12 ( 2H, s), 7.27-7.37 (5H, m).

Intermediate 15d: 4-(2,2-dimethoxyethyl)piperidine

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

Intermediate 15e: 4-(4-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

RuPhos Pd G3 (0.205 g, 0.24 mmol) was _added to a mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), 4-(2,2-dimethoxyethyl)piperidine (0.64 g, 3.67 mmol), Cs ₂ CO ₃ (2.388 g, 7.33 mmol), and RuPhos (0.114 g, 0.24 mmol) in 1,4-dioxane (20 mL) at room temperature under N 2 . The resulting solution was stirred at 100 °C for 10 h and then concentrated. The residue was purified by flash C18-flash chromatography (gradient: 0-100% MeCN in water) to give the title compound (1.20 g, 98%) as a yellow solid; ^1H NMR: 1.21-1.31 (2H, m), 1.39-1.51 (3H, m), 1.52-1.67 (2H, m), 1.70-1.77 (2H, m), 1.79-1.87 (2H, m), 2.51-2.61 (2H, m), 2.71 (1H, t), 2. 98-3.08 (2H, m), 3.22 (6H, s), 3.58 (2H, d), 4.16 (2H, d), 4.43-4.50 (1H, m), 6.84 (2H, d), 7.07 (2H, d), 7.26 (1H, d), 7.32 (1H, s), 7.80 (1) H, d); m/z ES ⁺ [M+H] ⁺ = 502.2.

Intermediate 15f: 4-(4-(4-(4-(2-oxoethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

A solution of 4-(4-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (200 mg, 0.40 mmol) in formic acid (2 mL) was stirred at room temperature for 5 h. The mixture was then concentrated to give the title compound (0.17 g, 94%) which was used in the next step without further purification; ^1H NMR: 1.23-1.33 (2H, m), 1.54-1.67 (2H, m), 1.67-1.76 (2H, m), 1.79-1.87 (2H, m), 1.95 (1H, s), 2.36-2.43 (2H, m), 2.57-2.69 (2H, m), 2 .69-2.76 (1H, m), 3.03 (2H, t), 3.58 (2H, d), 4.16 (2H, d), 6.85 (2H, d), 7.07 (2H, d), 7.22-7.29 (1H, m), 7.31 (1H, s), 7.80 (1H, d), H, d); m/z ES ⁺ [M+H] ⁺ = 456.1.

Example 15: 4-(4-(4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

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

Intermediate 16a: tert -Butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate

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

Intermediate 16b: tert -Butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate

tert -Butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (2.20 g, 7.93 mmol), K ₂ CO ₃ (1.32 g, 9.52 mmol) and 1,4-dibromobutane (2.37 mL, 19.83 mmol) were dissolved in anhydrous MeCN ₍ 80 mL) under N 2 . The mixture was stirred at 80 °C for 3 h and then cooled to room temperature. The mixture was then filtered and washed with DCM (200 mL). The filtrate was then concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (1.08 g, 33%) as a white oil which solidified on standing; ^1H NMR: (CDCl ₃ ) 1.48 (9H, s), 1.51-1.69 (2H, m), 1.75-1.86 (2H, m), 1.89-1.98 (2H, m), 2-2.13 (2H, m), 2.58 (1H, tt), 2.78 (2H, t), 3.48 (2H , t), 3.97 (2H, t), 4.16-4.32 (2H, m), 6.75-6.89 (2H, m), 7.10 (2H, dt). (1H, m); m/z : ES ⁺ [M -t Bu] ⁺ 356.0.

Intermediate 16c: tert -Butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate

DIPEA (2.3 mL, 13.10 mmol) was added to 3-[1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]-piperidine-2,6-dione hydrochloride salt (1.05 g, 2.88 mmol) in DMSO (20 mL) at room temperature. The mixture was sonicated until a turbid solution was obtained and then stirred at room temperature for 0.5 h. KI (1.30 g, 7.86 mmol) was then added, followed by a solution of tert -butyl 4-(4-(4-bromobutoxy)phenyl)piperidine-1-carboxylate (1.08 g, 2.62 mmol) in DMSO (7 mL), and the mixture was stirred at 70 °C for 18 h. After cooling, the mixture was diluted with EtOAc (200 mL), washed with water (3 x 100 mL), then brine (2 x 100 mL), dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (1.08 g, 63%) as a pale yellow gum; ¹ H NMR: 1.48 (9H, s), 1.53-1.89 (9H, m), 2.14-2.25 (1H, m), 2.32 (1H, qd), 2.41-2.52 (2H, m), 2.53-2.65 (5H, m), 2.71-2.95 (4H, m), 3.26-3.39 (3H, m), 3.98 (2H, t), 4.15-4.31 (3H, m), 4.41 (1H, d), 5.18 (1H, dd), 6.79-6.89 (3H, m), 6.99 (1H, dd), 7.08-7.16 (2H, m), 7.73 (1H, d), 8.01-8.25 (1H, m); m/z : ES ⁺ [M+H] ⁺ 660.3.

Intermediate 16d: 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

At room temperature under air, 4 M HCl in dioxane (2 mL, 8.00 mmol) was added in one portion to tert -butyl 4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidine-1-carboxylate (1.07 g, 1.62 mmol) in DCM (5 mL), and the mixture was stirred for 2 h. The mixture was then concentrated, slurried in _Et2O (30 mL), and filtered to give the title compound as the hydrochloride salt as a beige solid, which was used in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ 560.3.

Example 16: 2-Chloro-4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}benzonitrile

A mixture of 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (100 mg, 0.17 mmol), 2-chloro-4-fluorobenzonitrile (27.4 mg, 0.18 mmol) and K ₂ CO ₃ (58.0 mg, 0.42 mmol) was suspended in DMSO (1 mL) and stirred at 90 °C for 1.5 h. The mixture was purified by preparative HPLC (column A, eluent A) to give the title compound (65 mg, 56%) as a white solid; ^1H NMR: 1.55-1.65 (4H, m), 1.68-1.77 (2H, m), 1.81 (2H, d), 1.89-2.02 (1H, m), 2.34-2.43 (3H, m), 2.52-2.64 (1H, m), 2.7-2.94 (2H, m), 2.9 9 (2H, t), 3.21-3.4 (8H, m), 3.97 (2H, t), 4.09 (2H, d), 4.21 (1H, d), 4.33 (1H, d), 5.04 (1H, dd), 6.85 (2H, d), 7.00 (1H, dd), 7.05 (2H, d), 7.11-7.18 (3H, m), 7.51 (1H, d), 7.62 (1H, d), 10.91 (1H, s); m/z : ES ⁺ [M+H] ⁺ 695.5.

Example 17: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-methoxybenzonitrile

A mixture of 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (100 mg, 0.17 mmol), 4-fluoro-2-methoxybenzonitrile (26.6 mg, 0.18 mmol) and K ₂ CO ₃ (58.0 mg, 0.42 mmol) was suspended in DMSO (1 mL) and stirred at 90 °C for 2.5 h. After cooling to room temperature, the mixture was purified by preparative HPLC (column A, eluent A) to give the title compound (40 mg, 35%) as a white solid; ^1H NMR: 1.54-1.68 (4H, m), 1.74 (2H, q), 1.83 (2H, d), 1.92-2.02 (1H, m), 2.29-2.44 (4H, m), 2.56-2.8 (3H, m), 2.82-3.02 (3H, m), 9 (6H, m), 3.88 (3H, s), 3.98 (2H, t), 4.08 (2H, d), 4.21 (1H, d), 4.33 (1H, d), 5.05 (1H, dd), 6.53-6.67 (2H, m), 6.87 (2H, d), 7.06 (2H, d), 7.16 (2H, d), 7.41 (1H, d), 7.52 (1H, d), 10.92 (1H, s); m/z : ES ⁺ [M+H] ⁺ 691.5.

Example 18: 6-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-methylpyridine-3-carbonitrile

A mixture of 3-(1-oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (68 mg, 0.11 mmol), 6-fluoro-2-methylnicotinonitrile (16.3 mg, 0.12 mmol) and K ₂ CO ₃ (39.4 mg, 0.29 mmol) was suspended in DMSO (1.5 mL) and then stirred in a microwave at 120 °C for 1 h. The mixture was purified by preparative HPLC (column A, eluent A) to give the title compound (0.018 g, 23%) as a beige solid; ¹ H NMR: (CDCl ₃ ) 1.62-1.77 (4H, m), 1.79-1.88 (2H, m), 1.93 (2H, d), 2.20 (1H, ddq), 2.32 (1H, qd), 2.42-2.51 (2H, m), 2.56 (3H, s), 2.59-2.64 (4H, m), 2.71-2.9 (3H, m), 2.91-3.02 (2H, m), 3.24-3.41 (4H, m), 3.98 (2H, t), 4.25 (1H, d), 4.41 (1H, d), 4.60 (2H, d), 5.19 (1H, dd), 6.47 (1H, d) ), 6.81-6.9 (3H, m), 6.99 (1H, dd), 7.07-7.16 (2H, m), 7.54 (1H, d), 7.73 (1H, d), 7.91 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 676.6.

Intermediate 19a: 8-Fluoroquinoline-5-carbonitrile

KOAc (0.104 g, 1.062 mmol) and potassium(II) hexacyanoferrate trihydrate (1.869 g, 4.42 mmol) were added to 5-bromo-8-fluoroquinoline (2.00 g, 8.85 mmol) in 1,4-dioxane (30 mL) and water (30 mL). The mixture was degassed under N ₂ at room temperature for 5 min, then XPhos (0.422 g, 0.885 mmol) and Xphos Pd G3 (0.374 g, 0.442 mmol) were added. The mixture was then stirred at 100 °C for 3 h and then cooled to room temperature. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic solution was washed with saturated brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0–30% EtOAc in hexanes) gave the title compound (0.4 g, 26%) as a yellowish-white solid; ¹ H NMR: 7.82 (1H, dd), 7.91 (1H, dd), 8.35 (1H, dd), 8.56 (1H, dt), 9.15 (1H, dd); m/z : ES ⁺ [M+H] ⁺ = 173.0.

Intermediate 19b: 8-(4-(4-hydroxyphenyl)piperidin-1-yl)quinoline-5-carbonitrile

4-(Piperidin-4-yl)phenol hydrobromide (0.900 g, 3.49 mmol) and DIPEA (1.217 mL, 6.97 mmol) were added to 8-fluoroquinoline-5-carbonitrile (0.400 g, 2.323 mmol) in DMSO (10 mL) at room temperature. The mixture was stirred at 50 °C for 6 h, then cooled to room temperature and concentrated. The mixture was slowly poured into ice water. The solid was collected by filtration, washed with water (20 mL) and dried in vacuo to give the title compound (0.700 g, 89%) as a yellow solid; ^1H NMR: 1.81-1.98 (4H, m), 2.63-2.79 (1H, m), 2.95-3.16 (2H, m), 4.37 (2H, d), 6.63-6.78 (2H, m), 7.11 (2H, d), 7.21 (1H, d), 7.74 (1H, dd), 8.04 (1H, d), 8.40 (1H, dd), 8.97 (1H, dd), 9.14 (1H, s); m/z : ES- [MH] ^- = 328.0.

Intermediate 19c: 8-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)quinoline-5-carbonitrile

1,4-Dibromobutane (0.262 g, 1.214 mmol) and K ₂ CO ₃ (0.252 g, 1.821 mmol) were added to 8-(4-(4-hydroxy-phenyl)piperidin-1-yl)quinoline-5-carbonitrile (0.200 g, 0.607 mmol) in MeCN (5 mL) at room temperature. The mixture was then stirred at 60 °C for 6 h. Water (40 mL) was then added, and the mixture was extracted with EtOAc (2 x 70 mL). The combined organic solutions were washed with saturated brine (50 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (0.200 g, 68%) as a yellow solid; ^1H NMR: 1.76-2.02 (8H, m), 2.70-2.82 (1H, m), 3.00-3.12 (2H, m), 3.62 (2H, t), 3.99 (2H, t), 4.37 (2H, d), 6.89 (2H, d), 7.23 (3H, dd), (1H, dd), 8.05 (1H, d), 8.40 (1H, dd), 8.98 (1H, dd).

Example 19: 8-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}quinoline-5-carbonitrile

KI (0.205 g, 1.233 mmol) and DIPEA (0.359 mL, 2.056 mmol) were added to a mixture of 3-[1-oxo-5-(piperazin-1-yl)-1,3-dihydro-2 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride salt (0.150 g, 0.411 mmol) and 8-(4-(4-(4-bromobutoxy)phenyl)piperidin-1-yl)quinoline-5-carbonitrile (0.115 g, 0.247 mmol) in DMSO (5 mL) at room temperature. The mixture was then stirred at 80 °C for 16 h, then cooled to room temperature and concentrated. The residue was slowly poured into ice water. The solid was collected by filtration, washed with water (10 mL) and dried under vacuum. The residue was purified by preparative HPLC (column C, eluent C, basic workup A) to give the title compound (0.090 g, 30%) as an off-white solid; ^1H NMR: 1.57-1.67 (2H, m), 1.70-1.80 (2H, m), 1.84-2.00 (5H, m), 2.27-2.43 (3H, m), 2.51-2.64 (5H, m)2.69-2.82 (1H, m), 2.84-2.97 (1H, m), 3.00-3.11 (2H, m), 3.24-3.31 (4H, m), 3.99 (2H, t), 4.17-4.25 (1H, m), 4.27-4.42 (3H, m), 5.05 (1H, dd), 6.89 (2H, d), 7.01-7.10 (2H, m), 7 .22 (3H, dd), 7.52 (1H, d), 7.71-7.77 (1H, m), 8.05 (1H, d), 8.40 (1H, dd), 8.97 (1H, dd), 10.94 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 712.4.

Intermediate 20a: 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione

Potassium acetate (5.04 g, 51.37 mmol) was added simultaneously to 3-aminopiperidine-2,6-dione hydrochloride salt (3 g, 18.23 mmol) and 4,5-difluorophthalic acid (3.35 g, 16.57 mmol) in AcOH (30 mL) at room temperature. The resulting solution was stirred at 90 °C for 18 h. The mixture was then cooled to room temperature and a solid formed. Water (30 mL) was added. The solid was collected by filtration, washed with water (2 x5 mL) and dried in vacuo at 45 °C overnight to give the title compound (3.43 g, 70%) as a dark gray/purple solid; ^1H NMR: 2.01-2.12 (1H, m), 2.53-2.7 (2H, m), 2.83-2.95 (1H, m), 5.17 (1H, dd), 8.15 (2H, t), 11.13 (1H, s); m/z : ES-[MH] ^-293 .

Intermediate 20b: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

DMSO (0.5 mL), followed by DIPEA (118 μL, 0.68 mmol), was added to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (100 mg, 0.34 mmol) and tert -butyl piperazine-1-carboxylate (69.6 mg, 0.37 mmol). The mixture was then heated at 100 °C for 2 h. Saturated NH ₄ Cl solution (0.5 mL) and water (1.5 mL) were then added. The brown precipitate was collected by filtration, washed with water and dried in a vacuum oven to afford the title compound (86 mg, 55%) as a dark brown/black solid; ^1H NMR: 1.44 (9H, s), 2.04 (1H, dq), 2.55-2.62 (1H, m), 2.89 (1H, ddd), 3.09 (1H, d), 3.16-3.26 (4H, m), 3.45-3.55 (4H, m), 5.11 (1H, dd), 7 .49 (1H, d), 7.75 (1H, d), 11.09 (1H, s); m/z : ES-[MH] ^-459 .

Intermediates 20c and 20d: 3-(5-fluoro-1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione and 3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

Zinc powder (72.4 mg, 1.11 mmol) was added in one portion to tert -butyl-4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (170 mg, 0.37 mmol) in AcOH (3.4 mL) at room temperature. The resulting suspension was stirred at 60 °C for 48 h. Additional Zn powder (72.4 mg, 1.11 mmol) was added, and the mixture was stirred at 60 °C for 24 h. The mixture was then diluted with MeOH (25 mL), filtered, and the filtrate was concentrated. The resulting gum was dissolved in TFA (5 mL) at room temperature, and triethylsilane (587 μL, 3.68 mmol) was added in one portion. The resulting orange solution was stirred at room temperature for 1 h. The mixture was then concentrated. After diluting with _Et2O and collecting the solid by filtration, the title compound (in the form of trifluoroacetate salt) (170 mg, 57%) as a mixture of isomers was obtained as a beige solid, which was used in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ = 347.

Example 20: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2d was reacted with intermediates 20c and 20d using the general synthetic method exemplified by Example 1 to give the title compound after purification by HPLC (column A, eluent A). ^1H NMR: (500 MHz, CDCl ₃ ) 1.85 (2H, q), 1.88-1.94 (1H, m), 1.94-2.01 (3H, m), 2.22 (1H, dtd), 2.35 (1H, qd), 2.77 (0H, s), 2.82-2.88 (1H, m), 2 .88-2.98 (3H, m), 3.06 (2H, td), 3.13 (4H, s), 3.32-3.44 (4H, m), 3.98 (2H, t), 4.02 (2H, dq), 4.22-4.47 (2H, m), 5.18 (1H, dd), 2H, m), 6.96-7.03 (2H, m), 7.1-7.15 (2H, m), 7.16 (1H, d), 7.52 (1H, d), 7.62 (1H, dd), 8-8.04 (1H, m), 8.21 (2H, s); m/z ES ⁺ [M+H]+ = 747.4.

Example 21: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2d was reacted with intermediates 20c and 20d using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A); ^1H NMR: (500 MHz, CDCl ₃ ) 0.87-0.94 (1H, m), 1.76 (2H, qd), 1.8-1.94 (1H, m), 1.94-2.01 (2H, m), 2.22 (1H, dtd), 2.34 (1H, qd), 2.74 (1H, tt), 2 .84-2.89 (2H, m), 2.93 (1H, ddd), 3.01-3.1 (5H, m), 3.32 (3H, q), 3.48-3.55 (1H, m), 3.98 (2H, t), 4.02 (2H, dt), 4.28 (1H, d), 4.42 (1H, d), 5.19 (1H, dd), 6.65 (0H, s), 6.82-6.88 (2H, m), 6.99 (1H, dd), 7.09-7.18 (4H, m), 7.48 (1H, d), 7.55 (0H, dd), 7.61 (1H, d), 7.98 (1H, s), 8.16 (2H, s); m/z ES ⁺ [M+H]+ = 747.4.

Example 22: 4-{4-[5-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)pyrimidin-2-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 8e was reacted with intermediate 2c using the general synthetic method exemplified by Example 8 to give the title compound after purification by HPLC (column: Zorbax Eclipse Plus C18 50 x 2.1 mm, 1.8 μm, eluent C, basic workup A); ^1H NMR: 1.52-1.68 (2H, m), 1.66-1.84 (4H, m), 1.9-2.08 (3H, m), 2.26-2.49 (6H, m), 2.59 (2H, d), 2.8-2.98 (1H, m), 3.05-3.2 (3H, m), 3.23- 3.3 (4H, m), 4.05-4.26 (5H, m), 4.33 (1H, d), 5.05 (1H, dd), 6.99-7.12 (2H, m), 7.27 (1H, d), 7.32 (1H, s), 7.52 (1H, d), 7.82 (1H, d), 2H, s), 10.95 (1H, s); m/z ES ⁺ [M+H]+ = 731.2.

Example 23: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 1h was reacted with intermediate 20b using the general synthetic method exemplified by Example 1 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: (CDCl ₃ ) 1.65-1.87 (6H, m), 1.92-2 (2H, m), 2.07-2.2 (1H, m), 2.41-2.53 (2H, m), 2.56-2.67 (4H, m), 2.67-2.96 (4H, m), 3.06 (2H, td), 3.22-3.35 (4H, m), 3.92-4.1 (4H, m), 4.93 (1H, dd), 6.78-6.92 (2H, m), 6.99 (1H, dd), 7.07-7.21 (3H, m), 7.37 (1H, d), 7.47 (1H, d), 7.61 (1 H, d), 7.97 (1H, s); m/z ES ⁺ [M+H]+ = 761.5.

Intermediate 24a: tert -Butyl 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2 H )-carboxylate

At -78 °C under N ₂ , lithium bis(trimethylsilyl)amide (60.7 mL, 60.71 mmol) was slowly added to tert -butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (9.2 g, 40.47 mmol) in THF (80 mL) over 20 min. The resulting mixture was stirred at -78 °C for 0.5 h. N -(5-chloropyridin-2-yl)-1,1,1-trifluoro- N -((trifluoromethyl)-sulfonyl)methanesulfonamide (23.84 g, 60.71 mmol) was then added and the resulting mixture was stirred at room temperature for 16 h. The reaction was then quenched with saturated NH ₄ Cl solution. The mixture was diluted with EtOAc, washed with water and then with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0-5% EtOAc in petroleum ether) to give the title compound (11.00 g, 76%) as a yellow liquid; ¹ H NMR (300 MHz) 5.82 (s, 1H), 4.01 (d, 2H), 3.35 (s, 2H), 1.40 (s, 9H), 1.05 (s, 6H).

Intermediate 24b: tert -Butyl 4-(4-(benzyloxy)phenyl)-3,3-dimethyl-3,6-dihydropyridine-1(2 H )-carboxylate

At room temperature under N _{2 ,} Pd(dppf) ₂ Cl ₂ -DCM (0.818 g, 1.00 mmol) was added to tert -butyl 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)-oxy)-3,6-dihydropyridine-1(2 H )-carboxylate (3.600 g, 10.02 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetra-methyl-1,3,2-dioxaborolane (4.66 g, 15.03 mmol) and K ₂ CO ₃ (4.15 g, 30.05 mmol) in 1,4-dioxane (40 mL) and water (10 mL). The resulting mixture was stirred at 100 °C for 3 h. The mixture was then diluted with EtOAc, washed with water and then with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by C18-flash chromatography (gradient: 5-90% MeCN in water (0.1% NH ₄ HCO ₃ )) to give the title compound (1.980 g, 50%) as a pale yellow solid; ^1H NMR: 7.47-7.43 (m, 2H), 7.42-7.37 (m, 2H), 7.36-7.30 (m, 1H), 7.12-7.05 (m, 2H), 6.99-6.93 (m, 2H), 5.40 (s, 1H), 5.08 (s, 2H), 3.94 (d, 2H), 3.26 (s, 2H), 1.43 (s, 9H), 0.97 (s, 6H); m/z ES ⁺ [M-tBu+MeCN] ⁺ = 379.

Intermediate 24c: tert-Butyl 4-(4-hydroxyphenyl)-3,3-dimethyl-piperidine-1-carboxylate

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

Intermediate 24d: 4-(3,3-dimethylpiperidin-4-yl)phenol

4 M HCl in dioxane (7.00 mL, 28.00 mmol) was added to tert -butyl 4-(4-hydroxyphenyl)-3,3-dimethyl-piperidine-1-carboxylate (820 mg, 2.68 mmol) in DCM (7 mL) at room temperature, and the mixture was stirred for 16 h. The mixture was then concentrated to give the title compound as a hydrochloride salt (0.750 g, 116%), which was used in the next step without further purification; ^1H NMR (300 MHz) 6.93 (d, 2H), 6.71 (d, 2H), 3.29 (d, 1H), 3.04 (d, 1H), 2.92 (d, 1H), 2.78 (d, 1H), 2.60 (m, 1H), 2.25-2.06 (m, 1H), 1 .61 (d, 1H), 0.87 (s, 3H), 0.76 (s, 3H); m/z ES ⁺ [M+H] ⁺ = 206.

Intermediates 24e and 24f: rel -( S )-4-(4-(4-hydroxyphenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (isomer 1) and rel -( R )-4-(4-(4-hydroxyphenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (isomer 2)

4-Fluoro-2-(trifluoromethyl)benzonitrile (2017 mg, 10.67 mmol) was added to 4-(3,3-dimethylpiperidin-4-yl)phenol (730 mg, 3.56 mmol) and DIPEA (1863 μL, 10.67 mmol) in DMSO (10 mL) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The mixture was then diluted with EtOAc, washed with water, then with saturated brine, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FSC (Gradient: 0–30% EtOAc in petroleum ether) to give the product, which was further purified by preparative chiral-HPLC (Column: CHIRALPAK AD-3, 3.0 mm*100 mm, 3 μm; Mobile phase A, Mobile phase B: MeOH (0.1% diethylamine); Flow rate: 2 mL/min; Gradient: 10% B; 220 nm) to give the title compounds as light yellow solids: Intermediate 24e (0.320 g, 24%); Intermediate 24f (0.289 g, 22%). Intermediate 24e (first eluted): ¹ H NMR: 0.69 (3H, s), 0.78 (3H, s), 1.53 (1H, d), 2.12 (1H, qd), 2.55 (1H, d), 2.82 (1H, d), 2.91-3.03 (1H, m), 3.90 (1H, dd), 4.19 (1H, d), 6.65-6.70 (2H, m), 6.92-6.98 (2H, m), 7.24-7.31 (2H, m), 7.77 (1H, d), 9.21 (1H, s); m/z E .85-3.93 ⁽ 1H, m), 4.14-4.25 (1H, m), ^{6.56-6.78 (} 2H, m), 6.81-7.06 (2H, m), 7.16-7.35 (2H, m), 7.77 (1H, d), 9.21 (1H, s); m/z ES ⁺ [M+H] ⁺ = 375.

Intermediate 24g: rel -( S )-4-(4-(4-(4-bromobutoxy)phenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile

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

Example 24: rel-(S) -4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]-3,3-dimethylpiperidin-1-yl}-2-(trifluoromethyl)benzonitrile (Absolute stereochemistry not yet confirmed)

Intermediate 2c was reacted with intermediate 24 g using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ^1H NMR: (CDCl ₃ ) 0.84 (3H, s), 0.86 (3H, s), 1.65-1.79 (1H, m), 1.77-1.95 (4H, m), 2.14-2.42 (3H, m), 2.54 (1H, dd), 2.7-3.05 (10H, m), 3.4 6 (4H, q), 3.63 (1H, dd), 3.93-4.14 (3H, m), 4.26 (1H, d), 4.42 (1H, d), 5.19 (1H, dd), 6.8-6.86 (2H, m), 6.89 (1H, d), 6.98 (2H, ddd), 7.02-7. 08 (2H, m), 7.12 (1H, d), 7.58 (1H, d), 7.75 (1H, d), 8.07 (1H, s), 8.23 (1H, s); m/z ES ⁺ [M+H]+ = 757.4.

Intermediate 25a: rel -( R )-4-(4-(4-(4-bromobutoxy)phenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

rel- ( R )-4-(4-(4-hydroxyphenyl)-3,3-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 24f, isomer 2, 250 mg, 0.67 mmol), K ₂ CO ₃ (346 mg, 0.80 mmol) and _1,4 -dibromobutane (0.199 mL, 1.67 mmol) were dissolved in anhydrous MeCN (4 mL) under N 2 . The mixture was stirred at 70 °C for 2 h and then cooled to room temperature. The mixture was filtered and washed with DCM (20 mL). The filtrate was concentrated to give the title compound as a colorless oil, which was used in the next step without further purification.

Example 25: rel-(R) -4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]-3,3-dimethylpiperidin-1-yl}-2-(trifluoromethyl)benzonitrile (Absolute stereochemistry not yet confirmed)

Intermediate 2c was reacted with intermediate 25a using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A); ^1H NMR: (CDCl ₃ ) 0.84 (3H, s), 0.86 (3H, s), 1.66-1.78 (1H, m), 1.81-2 (4H, m), 2.13-2.26 (2H, m), 2.33 (1H, qd), 2.54 (1H, dd), 2.76-2.91 ( 5H, m), 2.92-3.05 (5H, m), 3.49-3.59 (4H, m), 3.63 (1H, dd), 3.95-4.1 (3H, m), 4.27 (1H, d), 4.42 (1H, d), 5.19 (1H, dd), 6.8-6.86 (2H, m), 6 .90 (1H, d), 6.98 (2H, td), 7.02-7.09 (2H, m), 7.12 (1H, d), 7.59 (1H, d), 7.75 (1H, d), 7.97 (1H, s); m/z ES ⁺ [M+H]+ = 757.4.

Intermediate 26a: tert -Butyl 4-(2-oxo-2,3-dihydrobenzo[ d ]oxazol-6-yl)piperazine-1-carboxylate

6-Bromobenzo[ d ]oxazol-2(3 H )-one (0.321 g, 1.5 mmol) and Dave-phos-Pd G3 (0.114 g, 0.15 mmol) were added to an oven-dried microwave vial with a stir bar. The vial was sealed with a rubber septum and then degassed with N ₂ . THF (3 mL), lithium bis(trimethylsilyl)amide (3.30 mL, 3.30 mmol), and tert -butyl piperazine-1-carboxylate (0.335 g, 1.80 mmol) were then added. The reaction was again degassed with N ₂ . The resulting solution was stirred at 70 °C for 16 h. AcOH was then added, and the mixture was concentrated. The residue was purified by FSC (gradient: 0-80% EtOAc in hexanes) to afford the title compound (0.250 g, 52%) as a gray solid; ¹ H NMR (500 MHz) 1.41 (11H, s), 2.35 (1H, br s), 2.51-2.53 (1H, m), 2.94-3.04 (5H, m), 3.26-3.32 (3H, m), 3.44 (5H, br s), 6.73 (1H, dd), 6.93 (1H, d), 6.98 (1H, d), 11.30 (1H, br s); m/z (ES-) [MH] ^- = 318.2.

Intermediate 26b: tert -Butyl-4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[ d ]oxazol-6-yl)piperazine-1-carboxylate

tert -Butyl 4-(2-oxo-2,3-dihydrobenzo[ d ]oxazol-6-yl)piperazine-1-carboxylate (0.048 g, 0.15 mmol), 3-bromopiperidine-2,6-dione (1.1 eq) and Cs ₂ CO ₃ (0.147 g, 0.45 mmol) were added to an oven-dried microwave vial with a stir bar. The vial was then purged with N ₂ . DMF (1 mL) was then added. The resulting slurry was stirred at 90 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) afforded the title compound (0.027 g, 41.8%) as a white solid; ^1H NMR (500 MHz, CDCl ₃ ) 1.49-1.54 (9H, m), 2.28-2.41 (1H, m), 2.64-2.78 (1H, m), 2.79-2.90 (1H, m), 2.95-3.02 (1H, m), 3.05-3.23 (4H, m), 3.5 5-3.81 (4H, m), 4.95-5.15 (1H, m), 6.66-6.78 (1H, m), 6.79-6.92 (1H, m), 6.94-7.07 (1H, m), 7.95-8.13 (1H, m); m/z ES ⁺ [M+H] ⁺ = 431.

Intermediate 26c: 3-(2-oxo-6-(piperazin-1-yl)benzo[d]oxazole-3(2 H )-1)piperidine-2,6-dione

4 M HCl in dioxane (2.3 mL, 9.3 mmol) was added to a solution of tert -butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[ d ]oxazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.46 mmol) in 1,4-dioxane (2.3 mL) at room temperature, and the mixture was stirred at 40 °C for 3 h. The mixture was then concentrated to give the title compound as the hydrochloride salt (0.170 g, 100%) as an off-white solid, which was used without further purification; ^1H NMR (500MHz) 2.09-2.20 (1H, m), 2.60-2.74 (2H, m), 2.84-2.97 (1H, m), 3.22 (4H, br s), 3.33 (4H, br d), 5.33 (1H, br dd), 6.85 (1H, br d), 7. 10-7.28 (2H, m), 9.13 (2H, br s), 11.18 (1H, s); m/z ES ⁺ [M+H] ⁺ = 331.

Example 26: 4-{4-[4-(4-{4-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2d was reacted with intermediate 26c using the general synthetic method exemplified by Example 2 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ^1H NMR: 1.56-1.69 (4H, m), 1.74 (2H, p), 1.85 (2H, d), 2.13 (1H, dt), 2.38 (2H, t), 2.53 (4H, d), 2.59-2.71 (2H, m), 2.71-2.83 (1H, m), 2.83 -2.94 (1H, m), 2.99-3.06 (2H, m), 3.09 (4H, d), 3.31 (1H, s), 3.97 (2H, t), 4.17 (2H, d), 5.29 (1H, dd), 6.77 (1H, dd), 6.82-6.89 (2H, m), 7.03-7.12 (2H, m), 7.16 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d), 8.18 (1H, s), 11.15 (1H, s); m/z ES ⁺ [M+H]+ = 731.6.

Intermediate 27a: tert-Butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

NaBH(OAc) ₃ (6.80 g, 32.08 mmol) was added simultaneously to a solution of 1-Boc-piperazine (4.00 g, 21.48 mmol), 4-formyl- N -Cbz-piperidine (6.40 g, 25.88 mmol) and AcOH (1.50 mL, 26.23 mmol) in DCM (50 mL) at room temperature under air, and the mixture was stirred at room temperature for 2 h. The mixture was then diluted with saturated NaHCO ₃ solution (60 mL) and the phases were separated. The aqueous layer was extracted with DCM (3 × 40 mL). The combined organic solutions were dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-70% EtOAc in 5 heptanes) gave the title compound (8.83 g, 98%) as a colorless oil; ^1H NMR: 0.91-1.05 (2H, m), 1.40 (9H, s), 1.6-1.77 (3H, m), 2.12 (2H, d), 2.22-2.32 (4H, m), 2.79 (2H, s), 3.26-3.33 (4H, m), 3.99 (2H, d), 5.07 (2H, s), 7.28-7.44 (5H, m); m/z : ES ⁺ [M+H] ⁺ 418.3.

Intermediate 27b: tert -Butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate

A mixture of tert -butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (9.50 g, 22.75 mmol) and 10% Pd(OH) ₂ on activated carbon (3.20 g, 2.28 mmol) in EtOH (40 mL) was stirred at 1 atm and room temperature under H ₂ atmosphere for 18 h. The mixture was then filtered through Celite, washing with EtOH. The filtrate was concentrated. The residue was dissolved in EtOH (40 mL) and 10% Pd(OH) ₂ on activated carbon (3.20 g, 2.28 mmol) was added. The suspension was stirred at 1 atm and room temperature under H ₂ for 3 days. The mixture was then filtered through Celite, washing with EtOH (100 mL). The filtrate was concentrated to dryness to afford the crude product (5.61 g, 87%) as a gray solid. A portion (2.32 g) of the crude product was purified by ion exchange chromatography (SCX column, eluted with 1 M NH ₃ /MeOH) to afford the title compound (1.84 g, 79%) as a gray oil; ¹ H NMR: 0.83-0.99 (2H, m), 1.37 (9H, s), 1.45-1.54 (1H, m), 1.58 (2H, d), 2.07 (2H, d), 2.14-2.28 (4H, m), 2.40 (2H, td), 2.87 (2H, d), 3.2-3.35 (4H, m); m/z : ES ⁺ [M+H]+ 284.2.

Intermediate 27c: tert -Butyl 4-((1-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)-piperidin-4-yl)methyl)piperazine-1-carboxylate

A mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (350 mg, 0.86 mmol), tert -butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (242 mg, 0.86 mmol), RuPhos G3 (53.6 mg, 0.06 mmol), RuPhos (29.9 mg, 0.06 mmol), sodium tert -butoxide (247 mg, 2.57 mmol) and anhydrous 1,4-dioxane (50 mL) was degassed, the flask was filled with N ₂ and the mixture was stirred at 100 °C for 1 h. The mixture was then cooled and concentrated to dryness. Water (10 mL) was added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.360 g, 69%) as a pale yellow solid; ^1H NMR: 1.20 (2H, tt), 1.40 (9H, s), 1.53-1.67 (3H, m), 1.77 (2H, d), 1.84 (2H, d), 2.16 (2H, d), 2.26-2.31 (4H, m), 2.54-2.64 (2H, m), 8-2.77 (1H, m), 2.94-3.11 (2H, m), 3.31 (4H, d), 3.60 (2H, d), 4.17 (2H, d), 6.85 (2H, d), 7.07 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d); m/z ES ⁺ [M+H] ⁺ = 611.9.

Intermediate 27d: Benzyl 4-(dibutoxymethyl)piperidine-1-carboxylate

4-Methylbenzenesulfonic acid hydrate (0.100 g, 0.53 mmol) was added to 4-formyl- N -Cbz-piperidine (20.0 g, 80.88 mmol) in n -butanol (40 mL) at room temperature under air. The resulting solution was stirred at 50 °C for 1 h. (The reaction was not complete). MgSO ₄ (10.6 g, 88.07 mmol) was added and the suspension was stirred at 50 °C for an additional 1 h. As the reaction was not complete, the temperature was increased to 70 °C and the mixture was stirred for an additional 1 h. The mixture was then filtered, washing with EtOAc (200 mL), whereupon the filtrate was collected in a vessel containing 2 M aqueous K ₂ CO ₃ (40 mL). The phases were separated. The organic solution was washed (2 M aqueous K ₂ CO ₃ (2 x 40 mL), then saturated brine (2 x 20 mL)), dried (MgSO ₄ ), concentrated and purified by FSC (gradient: 0–30% EtOAc in heptane) to give the title compound (20.5 g, 67%) as a colorless liquid; ^1H NMR: 0.88 (6H, t), 1.11 (2H, qd), 1.27-1.4 (4H, m), 1.47 (4H, dq), 1.65 (2H, d), 1.73 (1H, dtt), 2.75 (2H, s), 3.37 (2H, dt), 3.54 (2H, ), 3.95-4.06 (2H, m), 4.16 (1H, d), 5.07 (2H, s), 7.25-7.44 (5H, m).

Intermediate 27e: 4-(dibutoxymethyl)piperidine

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

Intermediate 27f: 3-(5-(4-(dibutoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Pd-PEPPSI-IHeptCl (0.23 g, 0.24 mmol) was added to a degassed mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.5 _g , 4.64 mmol), 4-(dibutoxymethyl)piperidine (1.5 g, 6.16 mmol) and Cs ₂ CO ₃ (4.54 g, 13.93 mmol) in 1,4-dioxane (45 mL) under N _{2 at room temperature. The resulting mixture was degassed under vacuum, backfilled with N 2} , and stirred at 100 °C for 3 h. After cooling, the mixture was diluted with DCM (75 mL) and 10% aqueous AcOH (50 mL) and the phases were separated. The aqueous portion was extracted with DCM (75 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), dried (MgSO ₄ ) and concentrated. The residue was partitioned between DCM (50 mL) and water (20 mL), and the aqueous portion was extracted with DCM (50 mL). The combined organic solutions were then dried (MgSO ₄ ) and concentrated. Elution with EtOAc (15 mL) gave a solid which was collected by filtration and washed sequentially with EtOAc (2 x 5 mL), EtOAc:Et ₂ O (1:1; 5 mL), and Et ₂ O (5 mL), and then dried in vacuo to give the title compound (1.659 g, 74%) as a white solid; ^1H NMR: 0.89 (6H, t), 1.23-1.42 (6H, m), 1.43-1.56 (4H, m), 1.67-1.85 (3H, m), 1.96 (1H, ddd), 2.28-2.44 (1H, m), 2.55-2.64 (1H, m), 2.72-2 .84 (2H, m), 2.90 (1H, ddd), 3.40 (2H, dt), 3.56 (2H, dt), 3.89 (2H, d), 4.09-4.25 (2H, m), 4.32 (1H, d), 5.04 (1H, dd), 7.04 (2H, d), 7.50 (1H, d), 10.91 (1H, s); m/z ES ⁺ [M+H] ⁺ = 486.0.

Example 27: 4-{4-[4-(4-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]methyl}piperidin-1-yl)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 27c was reacted with intermediate 27f using the general synthetic method exemplified by Example 1 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ^1H NMR: 1.09-1.27 (4H, m), 1.53-1.69 (3H, m), 1.77 (5H, d), 1.84 (2H, d), 1.92-2.01 (1H, m), 2.15 (4H, d), 2.28-2.42 (9H, m), 2.56-2.64 (3H , m), 2.74 (1H, d), 2.82 (2H, t), 2.86-2.95 (1H, m), 3.04 (2H, t), 3.60 (2H, d), 3.86 (2H, d), 4.11-4.26 (3H, m), 4.32 (1H, d), 5.04 (1H, dd), 6.85 (2H, d), 7.05 (4H, q), 7.27 (1H, dd), 7.32 (1H, d), 7.50 (1H, d), 7.81 (1H, d), 8.17 (1H, s), 10.91 (1H, s); m/z ES ⁺ [M+H]+ = 851.6.

Intermediate 28a: 5-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3-difluoropentyl 4-methylbenzenesulfonate

4-Methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) was added in one portion to 4-(4-(4-((3,3-difluoro-5-hydroxypentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (190 mg, 0.41 mmol) and Et ₃ N (113 μL, 0.81 mmol) in DCM (2 mL) at room temperature, and the solution was stirred for 2 h. The reaction was incomplete, and additional 4-methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) and Et ₃ N (113 μl, 0.81 mmol) were added in one portion and the solution was stirred at room temperature for an additional 18 h. The reaction was not completed, and additional 4-methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) and Et ₃ N (113 μL, 0.81 mmol) were added simultaneously and the solution was stirred at room temperature for an additional 3 h. The mixture was then diluted with DCM (25 mL), washed (saturated NH ₄ Cl (10 mL), saturated NaHCO ₃ (10 mL), water (20 mL), then saturated brine (10 mL)), dried on a phase separation cartridge, and concentrated. The residue was purified by FSC (gradient: 0-60% EtOAc in heptane) to give the title compound (0.147 g, 58%) as a yellow gum; m/z : ES ⁺ [M+H] ⁺ 623.3

Example 28: 4-(4-{4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}-3,3-difluoropentyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 28a using the general synthetic method exemplified by Example 12 to give the title compound after purification by HPLC (column A, eluent A). ^1H NMR: (CDCl ₃ ) 1.69-1.83 (2H, m), 1.97 (2H, d), 2.15-2.52 (6H, m), 2.65-2.96 (9H, m), 3.05 (2H, td), 3.32-3.46 (4H, m), 4.02 (2H, d), 4.16 ( 2H, t), 4.26 (1H, d), 4.42 (1H, d), 5.19 (1H, dd), 6.83-6.91 (3H, m), 6.99 (2H, dd), 7.09-7.18 (3H, m), 7.61 (1H, d), 7.74 (1H, d), 7.90 (1H, s); m/z ES ⁺ [M+H]+ = 779.4.

Intermediate 29a: D- tert -Butyl (4-bromo-2-nitrophenyl)- L -Glutamate

4-Bromo-1-fluoro-2-nitrobenzene (11.69 mL, 93.91 mmol) was added to a stirred milky suspension of di- tert -butyl L -glutamate hydrochloride salt (50.00 g, 169.03 mmol) and Et ₃ N (52.4 mL, 375.62 mmol) in THF (500 mL) at room temperature. The mixture was then stirred at 70 °C for 72 h. Water (500 mL) was then added, and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic solutions were then washed with brine (500 mL), passed through a phase separation cartridge, and concentrated. Purification by FSC (gradient: 0-20% EtOAc in heptane) afforded the title compound (49.50 g, 115%) as a yellow gum; ^1H NMR (CDCl ₃ ) 1.44 (9H, s), 1.48 (9H, s), 2.16 (2H, q), 2.38 (2H, t), 4.22 (1H, q), 6.77 (1H, d), 7.50 (1H, dd), 8.34 (2H, d) .

Intermediate 29b: D- tert -Butyl (2-amino-4-bromophenyl)-L-glutamate

Iron powder (26.20 g, 469.15 mmol) was added simultaneously to di- tert -butyl (4-bromo-2-nitrophenyl)- L -glutamate (43.10 g, 93.83 mmol) and NH ₄ Cl (25.09 g, 469.15 mmol) in IPA (400 mL) and water (80 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After cooling, the mixture was filtered through celite and washed with EtOAc (500 mL). The dark red filtrate was washed with water (250 mL), saturated brine (250 mL), dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (36.1 g, 90%) as an orange gum; ^1H NMR (CDCl ₃ ) 1.44 (9H, s), 1.44 (9H, s), 1.89-2.17 (2H, m), 2.27-2.53 (2H, m), 3.53 (2H, s), 3.68-3.97 (2H, m), 6.48 (1H, d), (2H, m); m/z : ES ⁺ [M+H] ⁺ 429.

Intermediate 29c: Di-tert-butyl (S)-2-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioate

CDI (14.30 g, 88.19 mmol) was added in one portion to di- tert -butyl (2-amino-4-bromophenyl)- L -glutamate (36.1 g, 83.99 mmol) in THF (500 mL) at room temperature. The resulting dark red solution was stirred at 60 °C for 2 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (500 mL). The solution was washed with water (500 mL) and brine (200 mL), dried (MgSO ₄ ), and concentrated to give the title compound (41.0 g, 107%) as a beige solid; ^1H NMR (CDCl ₃ ) 1.40 (18H, d), 2.13-2.43 (3H, m), 2.46-2.64 (1H, m), 5.07 (1H, dd), 6.86 (1H, d), 7.17 (1H, dd), 7.23 (1H, d), 9.98 (1H, s)

Intermediate 29d: D- tert -Butyl ( S )-2-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1 H -Benzo[ d ]imidazol-1-yl)pentanedioate

Di- tert -butyl ( S )-2-(5-bromo-2-oxo-2,3-dihydro-1 H -benzo[ d ]imidazol-1-yl)pentanedioate (38.0 g, 83.45 mmol) was dissolved in DMF.DMA (333 mL), and the solution was stirred at 100 °C for 16 h, and then concentrated. Purification by FSC (gradient: 0-25% EtOAc in heptane) gave the title compound (35.0 g, 89%) as a pale yellow gum which solidified on standing; ^1H NMR (CDCl ₃ ) 1.39 (9H, s), 1.40 (9H, s), 2.09-2.41 (3H, m), 2.43-2.63 (1H, m), 3.39 (3H, s), 5.06 (1H, dd), 6.85 (1H, d), 7.11 (1H, d), 7 .17 (1H, dd).

Intermediate 29e: (S)-2-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanedioic acid

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

Intermediate 29f: 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1 H -Benzo[ d ]imidazol-1-yl)piperidine-2,6-dione

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

Intermediate 29g: tert -Butyl-4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -Benzo[ d ]imidazol-5-yl)piperazine-1-carboxylate

(DiMeIHept ^Cl )Pd(cinnamyl)Cl (commercially available from Total Synthesis Ltd., Toronto, Canada, 0.031 g, 0.03 mmol) was added to 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1 _H -benzo[ d ]imidazol-1- yl )piperidine-2,6-dione (0.100 g, 0.30 mmol), Cs ₂ CO ₃ (0.289 g, 0.89 mmol), and tert -butyl piperazine-1-carboxylate (0.138 g, 0.74 mmol) in 1,4-dioxane (4.5 mL) at room temperature under N 2 . The resulting suspension was stirred at 100 °C for 6 h. The mixture was then diluted with DCM (25 mL), washed (5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ solution (20 mL), then saturated brine (20 mL)), dried (MgSO ₄ ) and concentrated. Etration with EtOAc gave a solid which was collected by filtration, washed with Et ₂ O and dried in vacuo to give the title compound (0.107 g, 82%) as a cream solid; ^1H NMR: 1.43 (9H, s), 1.91-1.99 (1H, m), 2.54-2.65 (2H, m), 2.74-2.88 (1H, m), 3-3.07 (4H, m), 3.31 (3H, s), 3.45-3.51 (4H, m), 6 (1H, m), 6.65 (1H, dd), 6.87 (1H, d), 6.92 (1H, d); m/z : ES ⁺ [M+H] ⁺ 444.2.

Example 29: 4-{4-[4-(4-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 1h was reacted with intermediate 29g using the general synthetic method exemplified by Example 1 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A); ^1H NMR: 1.56-1.68 (4H, m), 1.69-1.79 (2H, m), 1.85 (2H, d), 1.94-2.04 (1H, m), 2.39 (2H, t), 2.52-2.54 (4H, m), 2.58-2.65 (1H, m), 2.67-2. 71 (1H, m), 2.72-2.82 (1H, m), 2.85-2.96 (1H, m), 3.00-3.12 (6H, m), 3.31 (5H, br), 3.97 (2H, t), 4.17 (2H, d), 5.29 (1H, dd), 6.62 (1H, dd), 6.81-6.91 (3H, m), 6.94 (1H, d), 7.16 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d), 8.17 (1H, s), 11.04 (1H, s); m/z ES ⁺ [M+H]+ = 743.9.

Intermediate 30a: Trans -4-(4-(4-((1r,3r)-3-(2-bromoethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

A solution of PPh ₃ (63.7 mg, 0.24 mmol) in THF (1 mL) was added dropwise to a stirred mixture of trans -4-(4-(4-((1s,3r)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 5c) (54.0 mg, 0.12 mmol) and CBr ₄ (81.0 mg, 0.24 mmol) in THF (1.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 week. The mixture was then filtered, washed with EtOAc (20 mL), and the filtrate was concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) afforded the title compound (0.034 g, 55%) as a colorless oil; ^1H NMR (CDCl ₃ ) 1.75 (2H, qd), 1.97 (2H, d), 2.07 (2H, q), 2.14-2.23 (2H, m), 2.36 (2H, dddd), 2.54 (1H, ddq), 2.72 (1H, tt), 3.05 (2H, td), 3.3 6 (2H, t), 4.02 (2H, d), 4.72 (1H, t), 6.62-6.8 (2H, m), 6.98 (1H, dd), 7.04-7.14 (2H, m), 7.15 (1H, d), 7.61 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 507.2.

Example 30: Trans -4-[4-(4-{[(1s,3r)-3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}ethyl)cyclobutyl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 30a using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ^1H NMR: 1.56-1.69 (2H, m), 1.76 (2H, s), 1.85 (2H, d), 1.91-2.03 (1H, m), 2.16-2.20 (4H, m), 2.29 (1H, d), 2.36-2.44 (2H, m), 2.51-2.53 (4 H, m), 2.60 (2H, d), 2.78 (1H, d), 2.86-2.96 (1H, m), 3.04 (2H, t), 4.20 (3H, dd), 4.34 (1H, d), 4.79 (1H, q), 5.05 (1H, dd), 6.75 (2H, d), 9 (2H, d), 7.15 (2H, d), 7.22-7.37 (2H, m), 7.54 (1H, d), 7.81 (1H, d), 10.92 (1H, s); 4H (below solvent peak); m/z ES ⁺ [M+H]+ = 755.4.

Intermediate 31a: tert -Butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate

Di- tert -Butyl carbonate (8.86 mL, 38.15 mmol) was added 4-(piperidin-4-yl)butan-1-ol (4.00 g, 25.44 mmol) in THF (50 mL) and saturated Na ₂ CO ₃ solution (50 mL) at room temperature, and the mixture was stirred for 16 h. The mixture was then diluted with EtOAc (300 mL), washed with saturated brine (200 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-50% petroleum ether in EtOAc) gave the title compound (5.30 g, 81%) as a white liquid; ^1H NMR: 0.86-1.00 (2H, m), 1.13-1.22 (2H, m), 1.25-1.33 (2H, m), 1.35-1.40 (12H, m), 1.57-1.65 (2H, m), 2.65 (2H, s), 3.34-3.42 (2H, m), 3.91 (2H, d), 4.31 (1H, t); m/z : ES ⁺ [M-tBu] ⁺ = 202.

Intermediate 31b: tert -Butyl 4-(4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-butyl)piperidine-1-carboxylate

RockPhos Pd G3 (0.488 g, 0.58 mmol) was added to tert -butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (1.50 g, 5.83 mmol), 4-(4-(4-bromophenyl)piperidin-1-yl) _-2- (trifluoromethyl)benzonitrile (3.58 g, 8.74 mmol), and Cs ₂ CO ₃ (5.70 g, 17.48 mmol) in 1,4-dioxane (30 mL) over 10 min at room temperature under N 2 . The resulting mixture was stirred at 100 °C for 16 h. The mixture was then diluted with EtOAc (200 mL), washed with saturated brine (100 mL), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0–15% EtOAc in petroleum ether) to give the title compound (1.50 g, 44%) as a yellow liquid; ^1H NMR: 0.88-0.99 (2H, m), 1.22-1.28 (2H, m), 1.33-1.45 (14H, m), 1.55-1.69 (6H, m), 1.79-1.88 (2H, m), 2.72-2.80 (1H, m), 2.98-3.08 (2H, m), 3.87-3.96 (4H, m), 4.16 (2H, d), 6.81-6.86 (2H, m), 7.11-7.17 (2H, m), 7.23-7.28 (1H, m), 7.32 (1H, d), 7.78-7.82 (1H, m); m/z : ES ⁺ [M-tBu] ⁺ = 530.

Intermediate 31c: 4-(4-(4-(4-(piperidin-4-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

tert -Butyl 4-(4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)butyl)piperidine-1-carboxylate (500 mg, 0.85 mmol) was added to DCM (2 mL) and HCl in dioxane (7 mL) at room temperature, and the mixture was stirred for 16 h. It was then concentrated under reduced pressure to give the title compound, which was used in the next step without further purification; ¹ H NMR (300 MHz) 1.19-1.31 (4H, m), 1.32-1.54 (4H, m), 1.54-1.70 (3H, m), 1.73-1.84 (4H, m), 2.68-2.88 (3H, m), 3.02 (2H, t), 3.19 (2H, d), 3 .90 (2H, t), 4.16 (2H, d), 6.82 (2H, d), 7.13 (2H, d), 7.21-7.29 (1H, m), 7.30 (1H, d), 7.79 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 486.

Example 31: 4-{4-[4-(4-{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperidin-4-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

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

Example 32: 4-[4-(4-{[(1r,3s)-3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}ethyl)cyclobutyl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 5d using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A); ^1H NMR: 1.55-1.7 (6H, m), 1.85 (2H, d), 1.9-2.02 (2H, m), 2.25-2.31 (2H, m), 2.39 (2H, dd), 2.56-2.64 (3H, m), 2.75 (1H, d), 2.82-2.95 (1H, m), 3.04 (2H, t), 3.29 (8H, br), 4.11-4.27 (3H, m), 4.33 (1H, d), 4.51 (1H, p), 5.04 (1H, dd), 6.77 (2H, d), 7.06 (2H, d), 7.14 (2H, d), 1H, dd), 7.32 (1H, d), 7.52 (1H, d), 7.81 (1H, d), 8.14 (1H, s), 10.92 (1H, s); m/z ES ⁺ [M+H]+ = 755.7.

Intermediate 33a: tert -Butyl-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-oxa-3,10-diazaspiro[5.6]dodecane-10-carboxylate

Pd-PEPPSI-IHept.Cl (0.083 g, 0.09 mmol) was added to tert -butyl 7-oxa-3,10-diazaspiro[5.6]dodecane-10-carboxylate (0.603 g, 2.23 mmol), Cs ₂ CO ₃ (1.66 g, 5.11 mmol) and _3- (5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.550 g, 1.70 mmol) in 1,4-dioxane (12 mL) at room temperature under N 2 . The resulting suspension was stirred at 100 °C for 20 h. The mixture was then diluted with DCM (25 mL), washed (5% AcOH in water (10 mL), water (10 mL), then saturated brine (10 mL)), dried (MgSO ₄ ), concentrated. Purification by FSC (gradient: 0-5% MeOH in DCM) gave the title compound (0.490 g, 56%) as a yellow solid. ^1H NMR: 1.41 (9H, s), 1.49-1.6 (2H, m), 1.7-1.85 (4H, m), 1.91-2.02 (1H, m), 2.33-2.44 (1H, m), 2.55-2.64 (1H, m), 2.84-2.96 (1H, m), 3.0 9-3.17 (2H, m), 3.38-3.47 (4H, m), 3.49-3.61 (2H, m), 3.62-3.69 (2H, m), 4.20 (1H, d), 4.32 (1H, d), 5.04 (1H, dd), 7-7.11 (2H, m), 7.50 (1H, d), 10.91 (1H, s); m/z ES ⁺ [M+H]+ = 513.3.

Example 33: 4-{4-[4-(4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-7-oxa-3,10-diazaspiro[5.6]dodecane-10-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 1h was reacted with intermediate 33a using the general synthetic method exemplified by Example 1 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ^1H NMR: 1.43-1.53 (2H, m), 1.53-1.67 (4H, m), 1.67-1.81 (6H, m), 1.85 (2H, d), 1.91-2 (1H, m), 2.35-2.4 (1H, m), 2.41-2.47 (2H, m), 2.54-2 .63 (4H, m), 2.77 (1H, t), 2.85-2.95 (1H, m), 3.05 (2H, t), 3.16 (2H, t), 3.30 (2H, s), 3.54 (2H, d), 3.62 (2H, d), 3.95 (2H, t), 4.18 (3H, dd) , 4.32 (1H, d), 5.04 (1H, dd), 6.85 (2H, d), 7.04 (2H, d), 7.15 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.50 (1H, d), 7.81 (1H, d), 8.16 (1H, 10.9) 1 (1H, s); m/z ES ⁺ [M+H]+ = 813.4.

Intermediate 34a: tert -Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

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

Intermediate 34b: Methyl 2-(bromomethyl)-4-(( tert -Butyldimethylsilyl)oxy)benzoate

AIBN (0.094 g, 0.57 mmol) was added to methyl 4-(( tert -butyldimethylsilyl)oxy)-2-methylbenzoate (8 g, 28.53 mmol) and NBS (6.60 g, 37.08 mmol) in EtOAc (71 mL) _at 80 °C under N 2 . The resulting mixture was stirred at 80 °C for 3 h. The mixture was then poured into water (100 mL). The mixture was then extracted with EtOAc (3 x 50 mL). The combined organic solutions were washed with brine (50 mL), dried (MgSO ₄ ), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (6.90 g, 67%) as a colorless liquid; ^1H NMR (CDCl ₃ ) 0.22 (6H, s), 0.99 (9H, s), 2.15-2.24 (1H, m), 2.33 (1H, qd), 2.75-2.95 (2H, m), 4.22-4.46 (2H, m), 5.18 (1H, dd), 6.88 (1H, s), 6.89-6.96 (1H, m), 7.74 (1H, d), 8.02-8.19 (1H, m).

Intermediate 34c: 3-(5-(( tert -Butyldimethylsilyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

DIPEA (9.89 mL, 56.77 mmol) was added to a stirred solution of methyl 2-(bromomethyl)-4-(( tert -butyl-dimethylsilyl)oxy)benzoate (6.80 g, 18.92 mmol) and 3-aminopiperidine-2,6- _dione hydrochloride salt (3.11 g, 18.92 mmol) in MeCN (60 mL) at room temperature under N 2 , and the mixture was stirred for 25 h. The mixture was then diluted with water (50 mL). The mixture was then extracted with EtOAc (25 mL x 3), and the combined organic solutions were dried (MgSO ₄ ) and concentrated to give the title compound (2.00 g, 28%); ^1H NMR (CDCl ₃ ) 0.22-0.25 (6H, m), 0.98-0.99 (9H, m), 3.87-3.92 (3H, m), 4.93 (2H, s), 6.76-6.82 (1H, m), 6.93 (1H, d), 7.91 (1H, d).

Intermediate 34d: 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione

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

Intermediate 34e: tert -Butyl-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate

At room temperature under N _{2 ,} K ₂ CO ₃ (0.320 g, 2.31 mmol) was added in one portion to a stirred solution of tert -butyl 4-((methylsulfonyl)-oxy)piperidine-1-carboxylate (0.644 g, 2.31 mmol) and 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.500 g, 1.92 mmol) in DMF (10 mL). The resulting solution was stirred at 100 °C for 18 h. The mixture was then diluted with water (50 mL). The mixture was then extracted with EtOAc (3 × 30 mL) and the combined organic solutions were washed with brine (75 mL), dried (MgSO ₄ ), and concentrated. The residue (500 mg) was dissolved in 4.5 mL of 7:2 DMSO:MeOH (111 mg/mL) and then purified by preparative HPLC (column A, eluent A) to give the title compound (0.461 g, 54%) as a white solid; ^1H NMR: 1.42 (9H, s), 1.56 (2H, d), 1.91-2.02 (3H, m), 2.40 (1H, td), 2.55-2.65 (1H, m), 2.8-2.98 (1H, m), 3.20 (2H, t), 3.68 (2H, dt), 4.2 7 (1H, d), 4.39 (1H, d), 4.70 (1H, dt), 5.07 (1H, dd), 7.09 (1H, dd), 7.22 (1H, d), 7.63 (1H, d), 10.94 (1H, s); m/z (ES-) [MH] ^- = 442.2.

Example 34: 4-(4-{4-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]oxy}piperidin-1-yl)butoxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 1h was reacted with intermediate 34e using the general synthetic method exemplified by Example 1 to give the title compound after purification by HPLC (column A, eluent A). ^1H NMR: 1.54-1.75 (8H, m), 1.85 (2H, d), 1.92-2.05 (3H, m), 2.21-2.32 (2H, m), 2.35-2.41 (3H, m), 2.56-2.65 (1H, m), 2.7-2.82 (3H, m), 2.8 4-2.95 (1H, m), 3.05 (3H, t), 3.96 (2H, t), 4.17 (2H, d), 4.26 (1H, d), 4.38 (1H, d), 4.51 (1H, dt), 5.07 (1H, dd), 6.81-6.91 (2H, m), 7.06 (1H) , dd), 7.13-7.22 (3H, m), 7.27 (1H, dd), 7.32 (1H, d), 7.61 (1H, d), 7.81 (1H, d), 8.15 (1H, s), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 744.4.

Intermediate 35a: Benzyl 4-(3-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

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

Intermediate 35b: tert -Butyl 4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate

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

Intermediate 35c: 2-Fluoro-4-(piperidin-4-yl)phenol

tert -Butyl 4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (500 mg, 1.69 mmol) was added 4 M HCl in 1,4-dioxane (8 mL, 32.00 mmol) at room temperature, and the mixture was stirred for 2 h. It was then concentrated under reduced pressure to give the title compound as the hydrochloride salt (0.430 g, 130%) as a white solid; ^1H NMR (300 MHz) 1.66-1.96 (4H, m), 2.72 (1H, tt), 2.91 (2H, q), 3.29 (2H, d), 6.82 (1H, dd), 6.89 (1H, d), 6.94 (1H, dd), 8.85 (0H, s), 9.72 ( 1H, s); m/z ES ⁺ [M+H] ⁺ = 196.0.

Intermediate 35d: 4-(4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

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

Intermediate 35e: 4-(4-(4-(4-bromobutoxy)-3-fluorophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

At room temperature under air, K ₂ CO ₃ (228 mg, 1.65 mmol) was added 4-(4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile (200 mg, 0.55 mmol) and 1,4-dibromobutane (593 mg, 2.74 mmol) in DMF (2 mL), and the mixture was stirred for 2 h. The mixture was then poured into water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. Flash C18-flash chromatography (gradient: 0-100% MeCN in water) gave the title compound (0.210 g, 77%) as a white solid; ^1H NMR (300 MHz) 1.62 (2H, qd), 1.78-1.92 (4H, m), 1.92-2.04 (2H, m), 2.79 (1H, t), 3.03 (2H, dd), 3.61 (2H, t), 4.05 (2H, t), 4.18 (2H, d), 7. 01 (1H, dd), 7.07 (1H, d), 7.13 (1H, dd), 7.27 (1H, dd), 7.33 (1H, d), 7.82 (1H, d); m/z ES ⁺ [M+H] ⁺ = 499.

Example 35: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-3-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 35e using the general synthetic method exemplified by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH; 10:1); ^1H NMR: (300 MHz) 1.23-1.28 (2H, m), 1.54-1.89 (8H, m), 1.89-2.02 (1H, m), 2.30-2.48 (4H, m), 2.53-2.65 (2H, m), 2.70-2.83 (1H, m), 2.81-2. 97 (1H, m), 3.03 (2H, t), 3.10-3.29 (4H, m), 4.06 (2H, t), 4.13-4.27 (3H, m), 4.34 (1H, d), 5.06 (1H, dd), 6.97-7.18 (5H, m), 7.23-7.35 (2H, m) ), 7.54 (1H, d), 7.82 (1H, d), 10.95 (1H, s); m/z ES ⁺ [M+H]+ = 747.4.

Intermediate 36a: Methyl 3-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)methyl)-cyclobutane-1-carboxylate

RockPhos Pd G3 (291 mg, 0.35 mmol) was _added to methyl 3-(hydroxymethyl)cyclobutane-1-carboxylate (500 mg, 3.47 mmol), Cs ₂ CO ₃ (3.39 g, 10.40 mmol) and 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (1.42 g, 3.47 mmol) in 1,4-dioxane (5 mL) under N 2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (1.20 g, 73%) as a pale yellow solid; ^1H NMR (300 MHz) 1.51-1.68 (2H, m), 1.82 (2H, d), 1.95-2.10 (2H, m), 2.20-2.37 (2H, m), 2.56-2.82 (2H, m), 2.94-3.10 (2H, m), 3.37-3.52 (1H, m), 3.59 (3H, d), 3.85 (1H, d), 3.96 (1H, d), 4.15 (2H, d), 6.83 (2H, t), 7.13 (2H, dd), 7.25 (1H, dd), 7.30 (1H, d), 7.79 (1H, d); m/z ES ⁺ , [M+H]+ = 473.4.

Intermediates 36b and 36c: 4-(4-(4-(((1r,3r)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile and 4-(4-(4-(((1s,3s)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Methyl 3-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)methyl)cyclobutane-1-carboxylate (1.10 g, 2.33 mmol) was added NaBH ₄ (0.264 g, 6.98 mmol) in MeOH (10 mL) at room temperature, and the mixture was stirred for 16 h. After concentration under reduced pressure, the mixture was poured into water (100 mL). The mixture was extracted with EtOAc (250 mL x 3), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) afforded the title compounds (700 mg) as a mixture of cis/trans isomers. Further purification by preparative Prep-SFC (Column: CHIRAL ART Amylose-SA S, 3*25 cm, 5 μm; Mobile phase A:CO ₂ , Mobile phase B:MeOH (0.5% 2 M NH ₃ -MeOH)--HPLC; Flow rate: 6.1 mL/min; Gradient: 40% B; 220 nm; 36b RT1:9.47; 36c RT2:10.97; Injection volume: 1.5 mL; Number of runs: 33) afforded 36b (0.123 g, 12%) and 36c (0.154 g, 15%) as light yellow solids.

Intermediate 36b: ¹ H NMR (CDCl ₃ , 300 MHz) 1.76 (2H, qd), 1.90-2.06 (6H, m), 2.54 (1H, dt), 2.67-2.81 (2H, m), 3.06 (2H, td) ), 3.69 (2H, d), 3.97 (2H, d), 4.03 (2H, d), 6.84-6.92 (2H, m), 6.99 (1H, dd), 7.08-7.20 (3H, m), 7.62 ( 1H, d); m/z ES ⁺ , [M+H]+ = 445.2.

Intermediate 36c: ¹ H NMR (CDCl ₃ , 300 MHz) 1.59-1.86 (4H, m), 1.93-2.08 (2H, m), 2.14-2.29 (2H, m), 2.37-2.56 (1H, m), 2.60 -2.80 (2H, m), 2.98-3.13 (2H, m), 3.60 (2H, d), 3.87 (2H, d), 4.02 (2H, d), 6.80-6.91 (2H, m), 6.94-7.04 (1H, m), 7.07-7.21 (3H, m), 7.61 (1H, d); m/z ES ⁺ , [M+H]+ = 445.2

Intermediate 36d: 4-(4-(4-(((1r,3r)-3-(bromomethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

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

Example 36: 4-[4-(4-{[(1r,3r)-3-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}methyl)cyclobutyl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 36d using the general synthetic method exemplified by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 20:1); ¹ H NMR: (300 MHz) 1.53-1.71 (2H, m), 1.79-2.09 (7H, m), 2.24-2.48 (5H, m), 2.53-2.98 (5H, m), 3.05 (2H, t), 3.29 (6H, d), 3.51 (1H, s), (2H, d), 4.12-4.24 (2H, m), 4.27-4.38 (1H, m), 5.05 (1H, dd), 6.87 (2H, d), 7.05 (2H, d), 7.16 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.50 (1H, t), 7.82 (1H, d), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 755.4.

Intermediate 37a: 4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), 4-(dimethoxy-methyl)piperidine (0.467 g, 2.93 mmol), RuPhos G3 (0.153 g, 0.18 mmol), RuPhos (0.086 g, 0.18 mmol) sodium tert -butoxide (0.704 g, 7.33 mmol) and anhydrous 1,4-dioxane (24.4 mL) were added to the flask. The mixture was degassed and the flask was filled with N ₂ . The mixture was then stirred at 100 °C overnight and then concentrated (after cooling to room temperature). Water (10 mL) was added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.393 g, 33%) as a pale yellow solid; ^1H NMR (CDCl ₃ ) 1.45 (2H, qd), 1.67-1.8 (3H, m), 1.8-1.89 (2H, m), 1.97 (2H, d), 2.55-2.77 (3H, m), 3.05 (2H, td), 3.37 (6H, s), 3.67 (2H, d), 4.01 (2H, d), 4.08 (1H, d), 6.88-6.92 (2H, m), 6.98 (1H, dd), 7.06-7.12 (2H, m), 7.15 (1H, d), 7.61 (1H, d); m/z : ES ⁺ [M+H] ⁺ 488.8.

Example 37: 4-[4-(4-{4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]oxy}-piperidin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 34e was reacted with intermediate 37a using the general synthetic method exemplified by Example 1 to give the title compound after purification by HPLC (column A, eluent A); ^1H NMR: (CDCl ₃ ) 1.42-1.59 (2H, m), 1.75 (2H, qd), 1.97 (5H, dd), 2.09-2.19 (2H, m), 2.22 (1H, ddq), 2.28-2.4 (1H, m), 2.4-2.5 (2H, m), 2.71 ( 3H, td), 2.77-2.86 (1H, m), 2.92 (3H, dd), 2.99-3.16 (4H, m), 3.41 (2H, d), 3.65 (2H, d), 4.01 (2H, d), 4.30 (1H, d), 4.45 (1H, d), 4.72 (1H, s), 5.20 (1H, dd), 6.89 (2H, dd), 6.96 (2H, dd), 6.98-7.04 (2H, m), 7.10 (2H, d), 7.15 (1H, d), 7.57-7.63 (1H, m), 7.82 (1H, d), 8.30 (2H, s); m/z ES ⁺ [M+H]+ = 769.0.

Intermediate 38a: tert -Butyl 4-(2-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

At room temperature under N _{2 ,} PdCl ₂ (dppf) (118 mg, 0.16 mmol) was added tert -Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (500 mg, 1.62 mmol), 4-bromo-2-fluorophenol (340 mg, 1.78 mmol) and K ₂ CO ₃ (670 mg, 4.85 mmol) in 1,4-dioxane (8 mL) and water (2 mL ). The resulting solution was stirred at 80 °C for 4 h. The mixture was then filtered through Celite, and the filtrate was concentrated. The residue was purified by FCC (gradient: 0–10% EtOAc in petroleum ether) to afford the title compound (0.40 g, 84%) as a colorless oil; ¹ H NMR (300 MHz) 1.40 (9H, s), 2.35 (2H, s), 3.43-3.52 (2H, m), 3.93 (2H, d), 5.83 (1H, s), 6.46-6.61 (2H, m), 7.06-7.18 (1H, m), 9.86 (1H, s); m/z : ES ⁺ [M-tBu] ⁺ 238.

Intermediate 38b: tert -Butyl 4-(2-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate

At room temperature under H ₂ , 10% Pd on C (1.451 g, 1.36 mmol) was added tert -Butyl 4-(2-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate (2.00 g, 6.82 mmol) in MeOH (10 mL). The resulting mixture was stirred at 80 °C for 16 h. The mixture was then filtered through celite, and the filtrate was concentrated. Flash C18-flash chromatography (gradient: 0-70% MeCN in water (0.1% formic acid)) gave the title compound (1.20 g, 60%) as a white solid; ^1H NMR: 1.42 (9H, s), 1.40-1.55 (2H, m), 1.63-1.72 (2H, m), 2.71-2.92 (3H, m), 3.99-4.13 (2H, m), 6.51 (1H, dd), 6.56 (1H, dd), 7.08 (1H, t ), 9.65 (1H, s); m/z : ES ⁺ [M-tBu]+ 240.

Intermediate 38c: 3-Fluoro-4-(piperidin-4-yl)phenol

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

Intermediate 38d: 4-[4-(2-fluoro-4-hydroxyphenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

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

Intermediate 38e: 4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)-2-fluorophenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

2-(3-Bromopropyl)-1,3-dioxolane (0.613 mL, 4.53 mmol) was added _{simultaneously} to 4-(4-(2-fluoro-4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.50 g, 4.12 mmol) and K ₂ CO ₃ (1.707 g, 12.35 mmol) in MeCN (10 mL) under N 2 at room temperature. The resulting suspension was stirred at 80 °C for 5 h. After cooling, the mixture was filtered, and water (150 mL) was added to the filtrate. The white precipitate was then collected by filtration to give the title compound (1.85 g, 94%) as a yellow solid; ^1H NMR: 1.62-1.84 (8H, m), 3.03-3.12 (3H, m), 3.75-3.8 (2H, m), 3.86-3.9 (2H, m), 3.98 (2H, t), 4.18 (2H, d), 4.85 (1H, t), 6.7-6.8 (2H, m), 7.20 (1H, t), 7.27 (1H, dd), 7.32 (1H, s), 7.81 (1H, d); m/z : ES ⁺ [M+H]+ 479.4.

Example 38: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2b was reacted with intermediate 38e using the general synthetic method exemplified by Example 1 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: (300 MHz) 1.21-1.32 (1H, m), 1.56-1.86 (8H, m), 1.91-2.03 (1H, m), 2.26-2.49 (4H, m), 2.52-2.65 (3H, m), 2.84-2.98 (1H, m), 3.07 (3H) , t), 3.20-3.33 (4H, m), 4.00 (2H, t), 4.12-4.28 (3H, m), 4.34 (1H, d), 5.05 (1H, dd), 6.70-6.84 (2H, m), 7.07 (2H, d), 7.20 (1H, t), 7.27 (1H) ,d), 7.33 (1H, d), 7.53 (1H, d), 7.82 (1H, d), 10.95 (1H, s); m/z ES ⁺ [M+H]+ = 747.5.

Intermediate 39a: 4-(4-(4-(((1r,3r)-3-(bromomethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

CBr ₄ (74.6 mg, 0.22 mmol) was added to PPh ₃ (59.0 mg, 0.22 mmol) and 4-(4-(4-(((1s,3s)-3-(hydroxyl-methyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.11 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 2 h and then concentrated. Preparative TLC (eluent EtOAc: petroleum ether = 1:5) was purified to give the title material (0.050 g, 88%) as a colorless gum; ^1H NMR: 1.51-1.70 (4H, m), 1.85 (2H, d), 2.13-2.24 (2H, m), 2.53-2.64 (2H, m), 2.71-2.83 (1H, m), 3.05 (2H, dd), 3.56 (2H, d), 3.88 (2H, d), 4.18 (2H, d), 6.85 (2H, d), 7.15 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.82 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 507.

Example 39: 4-[4-(4-{[(1s,3s)-3-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}methyl)cyclobutyl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 39a using the general synthetic method exemplified by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 20:1); ^1H NMR: (300 MHz) 1.43-1.75 (4H, m), 1.85 (2H, d), 1.91-2.10 (1H, m), 2.12-2.27 (2H, m), 2.31-2.44 (3H, m), 2.50 (4H, q), 2.52-2.67 (3H, m), 2.77-2.98 (2H, m), 2.99-3.11 (2H, m), 3.22-3.31 (4H, m), 3.86 (2H, d), 4.12-4.25 (3H, m), 4.33 (1H, d), 5.05 (1H, dd), 6.84 (2H, d), 7.05 (2H) ,d), 7.15 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.52 (1H, d), 7.82 (1H, d), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 755.4.

Intermediate 40a: tert -Butyl 4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-piperidine-1-carboxylate

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

Intermediate 40b: 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Pd-PEPPSI-IPent (0.355 g, 0.45 mmol) was added to 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.45 _g , 4.49 mmol), 4-(dimethoxymethyl)piperidine (1.00 g, 6.28 mmol) and Cs ₂ CO ₃ (4.38 g, 13.46 mmol) in 1,4-dioxane (45 mL) under N 2 at room temperature. The resulting suspension was degassed under vacuum, backfilled with N ₂ , and stirred at 90 °C for 4.5 h. The mixture was then allowed to stand at room temperature for 16 h. The mixture was then diluted with DCM (75 mL) and 10% aqueous AcOH (150 mL), and the layers were separated. The aqueous layer was extracted with DCM (75 mL x 2). The combined organic solutions were washed with saturated brine (60 mL), dried (MgSO ₄ ), and concentrated. Purification by FSC (gradient: 0–8% EtOH in EtOAc) gave the title compound (0.800 g, 44%) as an off-white solid; ^1H NMR: 1.24-1.39 (2H, m), 1.71 (2H, d), 1.76-1.9 (1H, m), 1.9-2.04 (1H, m), 2.26-2.43 (1H, m), 2.58 (1H, td), 2.73-3.02 (3H, m), 3.27 (1H, s), 3.28 (6H, s), 3.89 (2H, d), 4.20 (1H, d), 4.32 (1H, d), 5.04 (1H, dd), 7.04 (2H, d), 7.50 (1H, d), 10.92 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 402.

Example 40: 4-[4-(4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]oxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 40a was reacted with intermediate 40b using the general synthetic method exemplified by Example 1, and the title compound was purified by preparative SFC (Column: DAICEL DCpak P4VP, 20 mm*250 mm, 5 μm; Mobile phase A:CO ₂ , Mobile phase B:MeOH--HPLC; Flow rate: 50 mL/min; Gradient: 45% B; 254 nm; RT1:5.67; Injection volume: 1 mL; Number of runs: 5 times) to give the title compound; ^1H NMR: (300 MHz) 1.09-1.21 (2H, m), 1.52-1.68 (4H, m), 1.70-2.02 (8H, m), 2.10-2.44 (5H, m), 2.54-3.14 (9H, m), 3.87 (2H, d), 4.12-4.25 (3H) , m), 4.26-4.39 (2H, m), 5.05 (1H, dd), 6.82-6.93 (2H, m), 7.04 (2H, d), 7.12-7.18 (2H, m), 7.25-7.35 (2H, m), 7.50 (1H, d), 7.82 (1H, d), 10 .94 (1H, s); m/z ES ⁺ [M+H]+ = 769.4.

Intermediate 41a: Benzyl 4-(4-bromo-2-methylphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

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

Intermediate 41b: Benzyl 4-(4-(4-(( tert -Butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

Rockphos Pd G3 (0.217 g, 0.26 mmol) was _added to benzyl 4-(4-bromo-2-methylphenyl)-3,6-dihydro-pyridine-1(2 H )-carboxylate (1.00 g, 2.59 mmol), 4-(( tert -butyldimethylsilyl)oxy)butan-1-ol (0.794 g, 3.88 mmol) and Cs ₂ CO ₃ (2.53 g, 7.77 mmol) in 1,4-dioxane (1 mL) under N 2 at room temperature. The resulting solution was stirred at 100 °C for 12 h and then concentrated. Flash C18-flash chromatography (gradient: 0-100% MeCN in water) gave the title compound (0.700 g, 53%) as a yellow solid; ¹ H NMR (300 MHz) 0.02 (6H, s), 0.84 (9H, d), 1.49-1.64 (2H, m), 1.66-1.78 (2H, m), 2.17 (3H, s), 2.22-2.36 (2H, m), 3.31 (2H, s), 3.62 (2H, t), 3.92 (2H, t), 4.01 (2H, q), 5.11 (2H, s), 5.50 (1H, s), 6.67 (1H, dd), 6.72 (1H, d), 6.95 (1H, d), 7.35-7.39 (5H, m); m/z ES ⁺ [M+H]+ = 510.

Intermediate 41c: 4-(4-(4-(( tert -Butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)piperidine

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

Intermediate 41d: 4-(4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

At room temperature under air, Cs ₂ CO ₃ (518 mg, 1.59 mmol) was added 4-(4-(4-(( tert -butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)-piperidine (200 mg, 0.53 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (150 mg, 0.79 mmol) in DMSO (5 mL). The resulting solution was stirred at 60 °C for 2 h and then concentrated. Flash C18-flash chromatography (gradient: 0-100% MeCN in water) gave the title compound (0.125 g, 43%) as a white solid; ¹ H NMR (CD ₃ OD, 300 MHz) 0.82 (6H, s), 1.65 (9H, s), 2.30-2.45 (4H, m), 2.44-2.60 (4H, m), 3.09 (3H, s), 3.74 (1H, t), 3.87 (2H, t), 4.42 (2 H, t), 4.71 (2H, t), 4.98 (2H, d), 7.47 (1H, dd), 7.51 (1H, d), 7.84 (1H, d), 8.06 (1H, dd), 8.12 (1H, d), 8.61 (1H, d); m/z ES ⁺ [M+H]+ = 547.

Intermediate 41e: 4-(4-(4-(4-hydroxybutoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

4-(4-(4-(4-(( tert -Butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (90 mg, 0.16 mmol) was added tetra- n -butylammonium fluoride (86 mg, 0.33 mmol) in THF (2 mL) at room temperature, and the mixture was stirred for 16 h and then concentrated. The residue was diluted with DCM (250 mL). The solution was washed with water (30 mL), then saturated brine (50 mL), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (0.085 g, 119%); ^1H NMR: 1.51-1.58 (2H, m), 1.61 (2H, dd), 1.71 (2H, dd), 1.77 (2H, d), 2.31 (3H, s), 2.95 (1H, ddd), 3.08 (2H, t), 3.40-3.50 (2H, m), 3.91 (2 H, t), 4.19 (2H, d), 4.43 (1H, t), 6.69 (1H, dd), 6.73 (1H, d), 7.05 (1H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.82 (1H, d); m/z ES ⁺ [M+H] ⁺ = 433.2.

Intermediate 41f: 4-(4-(4-(4-bromobutoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

4-(4-(4-(4-Hydroxybutoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (80.0 mg, 0.18 mmol) was added to PPh ₃ (97.0 mg, 0.37 mmol) and CBr ₄ (123 mg, 0.37 mmol) in DCM (2 mL) at room temperature, and the mixture was stirred for 3 h and then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (0.075 g, 82%) as a colorless gum; ^1H NMR (300 MHz) 1.59 (2H, qd), 1.68-1.85 (4H, m), 1.93 (2H, dtd), 2.29 (3H, s), 2.88-2.99 (1H, m), 3.06 (2H, t), 3.58 (2H, t), 3.93 (2H, t), 4.17 (2H, d), 6.68 (1H, dd), 6.72 (1H, d), 7.04 (1H, d), 7.25 (1H, dd), 7.31 (1H, d), 7.80 (1H, d); m/z ES ⁺ [M+H]+ = 495.2.

Example 41: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-2-methylphenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 41f using the general synthetic method exemplified by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 10:1); ^1H NMR: 1.54-1.67 (4H, m), 1.69-1.78 (4H, m), 1.92-2.01 (1H, m), 2.31 (3H, s), 2.31-2.44 (3H, m), 2.54-2.62 (1H, m), 2.84-2.98 (2H, m), 3 .07 (2H, t), 3.23-3.31 (8H, m), 3.95 (2H, t), 4.14-4.25 (3H, m), 4.33 (1H, d), 5.04 (1H, dd), 6.70 (1H, dd), 6.74 (1H, d), 7.02-7.08 (3H, m), 7.26 (1H, dd), 7.32 (1H, d), 7.52 (1H, d), 7.81 (1H, d), 10.93 (1H, s); m/z ES ⁺ [M+H]+ = 743.6.

Example 42: 2-Cyclopropyl-4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)benzonitrile

Intermediate 2b was reacted with intermediate 3c using the general synthetic method exemplified by Example 1, and the title compound was obtained after purification by preparative SFC (column: Triart Diol-NP, 20*250 mm, 5 μm; mobile phase A:CO ₂ , mobile phase B:IPA (0.2% Et ₂ NH); flow rate: 50 mL/min; gradient: 40% B); ^1H NMR: 0.79-0.88 (2H, m), 0.97-1.08 (2H, m), 1.15-1.28 (3H, m), 1.49-1.74 (3H, m), 1.80 (4H, d), 1.96 (1H, d), 2.01-2.12 (1H, m), 2.21 (2H) , d), 2.28-2.43 (1H, m), 2.52-2.67 (5H, m), 2.82-2.97 (3H, m), 3.23-3.32 (6H, m), 3.61 (2H, d), 4.02 (2H, d), 4.20 (1H, d), 4.33 (1H, d), 5.00-5.09 (1H, m), 6.45 (1H, d), 6.81-6.89 (3H, m), 7.02-7.10 (4H, m), 7.44-7.56 (2H, m), 10.95 (1H, s); m/z ES ⁺ [M+H]+ = 726.5.

Example 43: 2-Cyclopropyl-4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}benzonitrile

Intermediate 2c was reacted with intermediate 14b using the general synthetic method exemplified by Example 5 to give the title compound after purification by flash C18-flash chromatography (Gradient: 0-37% MeCN in water) and further purification by preparative Prep-SFC (Column: GreenSep Basic; Mobile phase A:CO ₂ , Mobile phase B:MeOH (8 mmol/L NH ₃ .MeOH)--HPLC; Flow rate: 50 mL/min; Gradient: 50% B); ¹ H NMR: (300 MHz) 0.79-0.88 (2H, m), 1.00-1.09 (2H, m), 1.60 (2H, qd), 1.71-1.88 (6H, m), 1.92-2.14 (2H, m), 2.32-2.48 (2H, m), 2.56-2.78 (2 H, m), 2.83-2.97 (4H, m), 3.09-3.24 (5H, m), 3.49-3.73 (2H, m), 3.92-4.10 (5H, m), 4.19-4.40 (2H, m), 5.07 (1H, dd), 6.46 (1H, d), 0 (3H, m), 7.11-7.19 (4H, m), 7.48 (1H, d), 7.59 (1H, d), 10.96 (1H, s); m/z ES ⁺ [M+H]+ = 701.4.

Intermediate 44a: 2-Hydrazinyl-4-iodopyridine

At room temperature under air, hydrazine monohydrate (1.23 g, 24.66 mmol) was added to 2-fluoro-4-iodopyridine (5.50 g, 24.66 mmol) in EtOH (50 mL), and the mixture was stirred for 2 days. Then water was added, and the solid was collected by filtration to afford the title compound (4.30 g, 74%) as a pale yellow solid; ¹ H NMR (300 MHz) 4.15 (2H, s), 6.85 (1H, dd), 7.11 (1H, d), 7.58 (1H, s), 7.65 (1H, d); m/z ES ⁺ [M+H]+ = 236.

Intermediate 44b: 7-Iodo-[1,2,4]triazolo[4,3-a]pyridine-3(2 H )-on

At room temperature under air, CDI (4.45 g, 27.44 mmol) was added 2-hydrazinyl-4-iodopyridine (4.30 g, 18.30 mmol) in MeCN (40 mL). The resulting solution was stirred at 60 °C for 17 h. The mixture was then filtered (using suction) and the solid washed with MeCN to afford the title compound (4.40 g, 92%) as a pale yellow solid; ¹ H NMR (300 MHz) 6.74 (1H, dd), 7.58 (1H, dd), 7.75 (1H, t), 12.47 (1H, s); m/z ES ⁺ [M+H]+ = 262.

Intermediate 44c: tert -Butyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate

RuPhos Pd G3 (0.481 g, 0.57 mmol) was added to 7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2 H )-one (1.5 g, 5.75 mmol), tert -butyl piperazine-1-carboxylate ( _2.14 g, 11.49 mmol) and sodium 2-methylpropan-2-oleate (1.66 g, 17.24 mmol) in t BuOH (10 mL) at room temperature under N 2 . The resulting solution was stirred at 100 °C for 3 h and then concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (1.50 g, 82%) as a yellow solid; ^1H NMR (300 MHz) 1.40 (9H, s), 3.20 (4H, dd), 3.41 (4H, t), 6.11 (1H, d), 6.58 (1H, dd), 7.63 (1H, d); m/z ES ⁺ [M+H]+ = 320.

Intermediate 44d: tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate

NaH (0.095 g, 3.95 mmol) (60%) was added to tert -butyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3- a ]pyridin-7-yl)piperazine-1-carboxylate ( _1.05 g, 3.29 mmol) in DMF (10 mL) at room temperature under N 2 . The resulting solution was stirred at 60 °C for 0.5 h. 3-Bromopiperidine-2,6-dione (0.631 g, 3.29 mmol) was then added and the solution was stirred at 60 °C for 10 h and then concentrated. Flash C-18 chromatography (gradient: 10-80% MeCN in water) gave the title compound (0.600 g, 42%) as a green solid; ^1H NMR (300 MHz) 1.40 (9H, s), 2.04-2.17 (1H, m), 2.48-2.62 (1H, m), 2.59-2.68 (1H, m), 2.87 (1H, ddd), 3.20-3.26 (4H, m), 3.37-3.45 (4H, m), 5.22 (1H, dd), 6.13 (1H, d), 6.66 (1H, dd), 7.72 (1H, d), 11.03 (1H, s); m/z ES ⁺ [M+H]+ = 431.

Intermediate 44e: 3-(3-oxo-7-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine-2(3 H )-1)piperidine-2,6-dione

tert -Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate (151 mg, 0.35 mmol) was added HCl in 1,4-dioxane (3 mL, 12.00 mmol) at room temperature, and the mixture was stirred for 2 h. It was then concentrated under reduced pressure to give the title compound (0.120 g, 104%) as a white solid; ^1H NMR (300 MHz) 2.06-2.16 (1H, m), 2.38-2.45 (1H, m), 2.61 (1H, dt), 2.88 (1H, ddd), 3.18 (4H, s), 3.50 (4H, s), 5.24 (1H, dd), 6.28 (1H, d), 6.67 (1H, dd), 7.78 (1H, d), 9.10 (1H, s), 11.04 (1H, s); m/z ES ⁺ [M+H]+ = 331.1.

Example 44: 4-{4-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3- a ]pyridin-7-yl]piperazin-1-yl}propoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 13a was reacted with intermediate 44e using the general synthetic method exemplified by Example 12 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 10:1); ^1H NMR: 1.21-1.30 (5H, m), 1.61 (2H, qd), 1.79-1.99 (4H, m), 2.08-2.17 (1H, m), 2.62 (1H, dt), 2.77 (1H, ddt), 2.88 (1H, ddd), 3.04 (2H, td), 3.10-3.19 (1H, m), 3.19-3.28 (4H, m), 3.56-3.67 (1H, m), 3.99 (2H, t), 4.17 (2H, d), 5.23 (1H, dd), 6.11 (1H, d), 6.69 (1H, dd), 6.86 (2H, d) , 7.15 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.71 (1H, d), 7.81 (1H, d), 11.03 (1H, s); m/z ES ⁺ [M+H]+ = 717.4.

Example 45: 4-(4-{4-[4-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 15f using the general synthetic method exemplified by Example 2 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 10:1); ^1H NMR: (300 MHz) 1.17-1.35 (2H, m), 1.45 (3H, s), 1.62 (2H, t), 1.80 (4H, dd), 1.90-2.02 (1H, m), 2.29-2.45 (4H, m), 2.53-2.79 (6H, m), 2.9 1 (1H, ddd), 3.04 (2H, t), 3.24-3.31 (5H, m), 3.61 (2H, d), 4.12-4.25 (3H, m), 4.34 (1H, d), 5.05 (1H, dd), 6.86 (2H, d), 7.03-7.13 (4H, m), 7. 27 (1H, dd), 7.33 (1H, d), 7.53 (1H, d), 7.81 (1H, d), 10.95 (1H, s); m/z ES ⁺ [M+H]+ = 768.5.

Example 46: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 6d using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: 1.19-1.27 (4H, m), 1.72 (3H, dd), 1.83 (4H, t), 1.93-2.01 (1H, m), 2.23 (2H, d), 2.39 (2H, td), 2.51-2.54 (4H, m), 2.58 (1H, dd), 2. 64 (2H, d), 2.81-2.97 (1H, m), 3.04 (2H, t), 3.28-3.31 (4H, m), 3.63 (2H, d), 3.72 (2H, d), 4.22 (1H, d), 4.34 (1H, d), 5.05 (1H, dd), 6.88 (2H) ,d), 7.03-7.14 (4H, m), 7.46 (1H, t), 7.53 (1H, d), 7.80 (1H, d), 10.92 (1H, s); m/z ES ⁺ [M+H]+ = 772.4.

Example 47: 4-[4-(4-{4-[(4-{2-[-2,6-dioxopiperidin-3-yl]-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3- a ]-pyridin-7-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 4c was reacted with intermediate 44e using the general synthetic method exemplified by Example 2 to give the title compound after purification by flash C18-flash chromatography (gradient: 0-40% MeCN in water (0.1% formic acid)) as a white solid, which was further purified by preparative TLC (eluent: DCM:MeOH, 10:1); ^1H NMR: 1.10-1.29 (4H, m), 1.52-1.69 (3H, m), 1.81 (4H, t), 2.09-2.18 (1H, m), 2.21 (2H, d), 2.41-2.49 (4H, m), 2.61 (3H, t), 2.89 (1H, ddd), 2.98-3.10 (2H, m), 3.23-3.28 (4H, m), 3.61 (2H, d), 4.17 (2H, d), 5.23 (1H, dd), 6.11 (1H, d), 6.69 (1H, dd), 6.82-6.90 (2H, m), 7.07 (2H, d) , 7.26 (1H, dd), 7.32 (1H, d), 7.71 (1H, d), 7.81 (1H, d), 11.02 (1H, s); m/z ES ⁺ [M+H]+ = 756.4.

Intermediate 48a: tert -Butyl ( S )-3-methyl-4-(4-((( RS )-tetrahydro-2 H -pyran-2-yl)oxy)phenyl)piperazine-1-carboxylate

2-(4-Bromophenoxy)tetrahydro-2 H -pyran (1.00 g, 3.89 mmol), tert -Butyl ( S )-3-methylpiperazine-1-carboxylate (1.17 g, 5.83 mmol), RuPhos (0.091 g, 0.19 mmol), RuPhos Pd G3 (0.163 g, 0.19 mmol) and potassium tert -butoxide (0.873 g, 7.78 mmol) were stirred in 1,4-dioxane (20 mL), and the mixture was degassed by N ₂ bubbling. The mixture was then heated to 90 °C for 2 h. After cooling, the mixture was partitioned between EtOAc and water. The organic solution was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0-50% EtOAc in heptane) to give the title compound (1.10 g, 75%) as a colorless oil; ^1H NMR (CDCl ₃ ) 0.91 (3H, d), 1.30 (1H, dd), 1.48 (9H, s), 1.62-1.72 (2H, m), 1.84 (2H, dt), 2.00 (1H, ddt), 2.86-3.11 (2H, m), 3.43 (3H, s), 3.59 (2H, dtd), 3.70 (1H, s), 3.94 (1H, ddd), 5.32 (1H, q), 6.84-6.95 (2H, m), 6.95-7.06 (2H, m); m/z ES ⁺ [M+H]+ = 377.3.

Intermediate 48b: ( S )-4-(2-methylpiperazin-1-yl)phenol

4 M HCl in 1,4-dioxane (5.70 mL, 22.82 mmol) was added dropwise to a solution of tert -butyl ( S )-3-methyl-4-(4-((( RS )-tetrahydro-2 H -pyran-2-yl)oxy)phenyl)piperazine-1-carboxylate (1.10 g, 2.92 mmol) in DCM (20 mL), and the mixture was stirred at room temperature overnight. Et ₂ O (100 mL) was added, and the precipitate was collected by filtration under vacuum to afford the title compound as the hydrochloride salt (0.696 g, 104%) as a yellow solid; m / z ES ⁺ [M+H]+ = 193.1.

Intermediate 48c: ( S )-4-(4-(4-hydroxyphenyl)-3-methylpiperazin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (1.27 mL, 7.30 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (0.552 g, 2.92 mmol) and ( S )-4-(2-methylpiperazin-1-yl)phenol hydrochloride salt (0.668 g, 2.92 mmol) were dissolved in DMSO (5 mL), and the mixture was stirred at room temperature overnight. The mixture was then partitioned between water (25 mL) and EtOAc (25 mL). The organic solution was washed with brine, dried (MgSO ₄ ), and concentrated. Purification by FSC (gradient: 0-60% EtOAc in heptane) gave the title compound (0.551 g, 52%) as a yellow gum; ^1H NMR (CDCl ₃ ) 1.00 (3H, d), 3.11 (1H, ddd), 3.14-3.2 (1H, m), 3.23 (1H, dd), 3.46 (1H, ddq), 3.5-3.59 (2H, m), 3.64 (1H, dd), 4.64 (1H, s), 6 .75-6.84 (2H, m), 6.9-6.96 (2H, m), 6.98 (1H, dd), 7.14 (1H, d), 7.63 (1H, d); m/z ES ⁺ [M+H]+ = 362.1.

Intermediate 48d: ( S )-4-(4-(4-(4-bromobutoxy)phenyl)-3-methylpiperazin-1-yl)-2-(trifluoromethyl)-benzonitrile

( S )-4-(4-(4-hydroxyphenyl)-3-methylpiperazin-1-yl)-2-(trifluoromethyl)benzonitrile (0.244 g, 0.68 mmol), K ₂ CO ₃ (0.112 g, 0.81 mmol) and _1,4 -dibromobutane (0.161 mL, 1.35 mmol) were dissolved in anhydrous DMF (7 mL) under N 2 . The mixture was stirred at 50 °C for 16 h. After cooling, the mixture was diluted with EtOAc (50 mL), washed with saturated NaHCO ₃ (50 mL), then saturated brine (50 mL), dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-40% EtOAc in heptane) gave the title compound (0.215 g, 64%) as a yellow oil; ^1H NMR (CDCl ₃ ) 1.00 (3H, d), 1.93 (2H, dq), 2-2.15 (2H, m), 3-3.33 (3H, m), 3.4-3.58 (5H, m), 3.64 (1H, dd), 3.97 (2H, t), 6.82-6.9 (2H, m), 6 .93-7.02 (3H, m), 7.14 (1H, d), 7.63 (1H, d); m/z ES ⁺ [M+H]+ = 498.2.

Example 48: 4-{(3 S )-4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]-3-methylpiperazin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 48d using the general synthetic method exemplified by Example 5 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: 0.91 (3H, d), 1.62 (2H, q), 1.74 (2H, p), 1.89-2.01 (1H, m), 2.39 (3H, t), 2.51-2.54 (4H, m), 2.55-2.64 (1H, m), 2.90 (1H, ddd), 3.04 -3.18 (2H, m), 3.26-3.29 (4H, m), 3.42-3.58 (2H, m), 3.61-3.69 (2H, m), 3.69-3.76 (1H, m), 3.94 (2H, q), 4.21 (1H, d), 4.33 (1H, d), 5.05 (1H) , dd), 6.86 (2H, d), 6.94 (2H, d), 7.06 (2H, d), 7.28 (1H, dd), 7.34 (1H, d), 7.52 (1H, d), 7.84 (1H, d), 10.92 (1H, s); m/z ES ⁺ [M+H]+ = 744.4.

Intermediate 49a : 5-(4-(4-bromophenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

Cs ₂ CO ₃ (4.07 g, 12.49 mmol) was added to 5-bromo-3-(trifluoromethyl)picolinonitrile (1.57 g, 6.25 mmol) and 4-(4-bromophenyl)piperidine (1.00 g, 4.16 mmol) in DMSO (10 mL) at room temperature. The resulting solution was stirred at 60 °C for 10 h. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (0.80 g, 47%) as a yellow solid; ^1H NMR (300 MHz) 1.65 (2H, qd), 1.84 (2H, d), 2.85 (1H, tt), 3.10 (2H, t), 4.30 (2H, d), 7.23 (2H, d), 7.47 (2H, d), 7.63 (1H, d), 8.64 (1H, d); m/z ES ⁺ [M+H]+ = 410.

Intermediate 49b : 5-(4-(4-((5-hydroxypentyl)oxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

RockPhos Pd G3 (112 mg, 0.13 mmol) was added to pentane-1,5-diol (209 mg, 2.01 mmol), Cs ₂ CO ₃ (1310 mg, 4.02 mmol) and 5-(4-(4-bromophenyl)piperidin-1 _- yl)-3-(trifluoromethyl)picolinonitrile (550 mg, 1.34 mmol) in 1,4-dioxane (7 mL) under N 2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-100% EtOAc in petroleum ether) gave the title compound (0.120 g, 21%) as a white solid; ^1H NMR: 1.39-1.53 (4H, m), 1.60-1.75 (4H, m), 1.85 (2H, dd), 2.80 (1H, tt), 3.11 (2H, t), 3.41 (2H, q), 3.92 (2H, t), 4.30 (2H, d), 4.37 (1H, t), 6.85 (2H, d), 7.16 (2H, d), 7.64 (1H, d), 8.66 (1H, d); m/z ES ⁺ [M+H]+ = 434.3.

Intermediate 49c: 5-(4-(4-((5-bromopentyl)oxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

CBr ₄ (153 mg, 0.46 mmol) was added to PPh ₃ (121 mg, 0.46 mmol) and 5-(4-(4-((5-hydroxypentyl)oxy)-phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile (100 mg, 0.23 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 2 h and then concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (0.110 g, 96%) as a yellow oil; m/z ES ⁺ [M+H]+ = 496.1.

Example 49: 5-(4-{4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}pentyl)oxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)pyridine-2-carbonitrile

Intermediate 2c was reacted with intermediate 49c using the general synthetic method exemplified by Example 5 to give the title compound after purification by FSC (gradient: 0-10% MeOH in DCM); ^1H NMR: 1.38-1.47 (2H, m), 1.47-1.58 (2H, m), 1.64 (2H, d), 1.67-1.77 (2H, m), 1.84 (2H, d), 1.90-2.00 (1H, m), 2.35-2.43 (2H, m), 2.58 (2H) , d), 2.73-2.85 (1H, m), 2.90 (1H, ddd), 3.10 (2H, t), 3.24-3.29 (3H, m), 3.29-3.30 (5H, m), 3.93 (2H, t), 4.19-4.39 (4H, m), 5.04 (1H, dd), 6 .85 (2H, d), 7.05 (2H, d), 7.16 (2H, d), 7.52 (1H, d), 7.63 (1H, d), 8.65 (1H, d), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 744.3.

Intermediate 50a: 4-[4-[4-(4-bromobutoxy)phenyl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile

4-(4-(4-Hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.95 g, 5.63 mmol), K ₂ CO ₃ (0.934 g, 6.76 mmol) and 1,4-dibromobutane (2.02 mL, 16.89 mmol) were suspended in MeCN (55 mL). The suspension was heated to 70 °C. After 6 h, since starting material remained, additional portions of K ₂ CO ₃ (500 mg) and 1,4-dibromobutane (1 mL) were added, and the mixture was stirred at 70 °C overnight. Since a small amount of starting material remained, additional portions of K ₂ CO ₃ (500 mg) and 1,4-dibromobutane (1 mL) were added, and the mixture was stirred at 70 °C for 4 h. The mixture was then cooled to room temperature and filtered (washed with MeCN). The filtrate was concentrated under reduced pressure. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (2.44 g, 90%) as a yellow oil which solidified upon standing; ^1H NMR (CDCl ₃ ) 1.80 (2H, qd), 1.88-2.02 (4H, m), 2.02-2.12 (2H, m), 2.74 (1H, tt), 3.07 (2H, td), 3.48 (2H, t), 3.94-4.07 (4H, m), (2H, m), 7.04 (1H, dd), 7.1-7.16 (2H, m), 7.19 (1H, d), 7.6-7.66 (1H, m); m/z ES ⁺ [M+H]+ = 481.2.

Intermediate 50b : tert -Butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate

NEt ₃ (2.77 mL, 19.87 mmol) was added to 2,4-dichloropyrimidine (1.48 g, 9.93 mmol) and tert -butyl piperazine-1-carboxylate (2.035 g, 10.93 mmol) in DMF (20 mL) at room temperature, and the mixture was stirred for 2 h. The mixture was then diluted with EtOAc, washed (water, then saturated brine), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-25% EtOAc in petroleum ether, then 0-10% MeOH in DCM) gave the title compound (2.10 g, 71%) as a white solid; ^1H NMR (300 MHz) 1.42 (9H, s), 3.39-3.44 (4H, m), 3.58-3.67 (4H, m), 6.83 (1H, d), 8.09 (1H, d); m/z ES ⁺ [M+H]+ = 299.

Intermediate 50c : tert -Butyl 4-(2-hydrazinylpyrimidin-4-yl)piperazine-1-carboxylate

Hydrazine (1.641 mL, 33.47 mmol) was added to tert -Butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (2.00 g, 6.69 mmol) in EtOH (15 mL) and water (3 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 h and then concentrated. Elution with water gave a solid which was collected by filtration and dried in vacuo to give the title compound (2.00 g, 101%) as a white solid; m/z ES ⁺ [M+H]+ = 295.

Intermediate 50d : tert -Butyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3- a ]pyrimidine-7-yl)piperazine-1-carboxylate

CDI (1.32 g, 8.15 mmol) was added to tert -Butyl 4-(2-hydrazinylpyrimidin-4-yl)piperazine-1-carboxylate (2.00 g, 6.79 mmol) in THF (20 mL) at room temperature, and the mixture was stirred for 1.5 h and then concentrated. Dissolving with MeCN and Et ₂ O gave a solid which was collected by filtration and dried in vacuo to give the title compound (1.93 g, 89%) as a pale yellow solid; ¹ H NMR: 1.43 (9H, s), 3.39-3.48 (4H, m), 3.66-3.80 (4H, m), 6.59 (1H, d), 7.98 (1H, d), 11.59 (1H, s); m/z ES ⁺ [M+H]+ = 321.

Intermediate 50e : tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3- a ]pyrimidine-7-yl)piperazine-1-carboxylate

NaH (0.233 g, 5.84 mmol) was added to tert -Butyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3- a ]pyrimidin-7-yl)piperazine-1-carboxylate (1.70 g, 5.31 mmol) in DMF (1 mL) at 0 °C. The mixture was stirred at 0 °C for 20 min and warmed to room temperature for an additional 20 min. 3-Bromopiperidine-2,6-dione (1.223 g, 6.37 mmol) was then added and the mixture was stirred at 60 °C for 2 h. After cooling, the mixture was diluted with DCM. The solution was washed (5% AcOH, water then saturated brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by flash C18-flash chromatography (gradient: 0-30% MeCN in water (0.1% formic acid)) to afford the title compound (0.586 g, 26%) as a white solid; ¹ H NMR: 1.42 (9H, s), 2.04-2.16 (1H, m), 2.35-2.48 (1H, m), 2.57-2.73 (1H, m), 2.87 (1H, ddd), 3.38-3.44 (4H, m), 3.65-3.80 (4H, m), 5.19 (1H, dd), 6.65 (1H, d), 8.06 (1H, d), 11.01 (1H, s); m/z ES ⁺ [M+H]+ = 432.

Intermediate 50f : 3-(3-oxo-7-piperazin-1-yl-[1,2,4]triazolo[4,3- a ]pyrimidin-2-yl)piperidine-2,6-dione

1,4-Dioxane HCl (1 mL, 4.00 mmol) was added to tert -butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3- a ]pyridin-7-yl)piperazine-1-carboxylate (200 mg, 0.46 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 1 h and then concentrated. _Et2O was added to give a solid, which was collected by filtration and dried in vacuo to give the title compound (0.180 g, 96%) as a pale yellow solid; ^1H NMR: 2.06-2.17 (1H, m), 2.37-2.48 (1H, m), 2.57-2.70 (1H, m), 2.83-2.95 (1H, m), 3.14-3.22 (4H, m), 3.91-4.04 (4H, m), 5.21 (1H, dd), 6 .70 (1H, d), 8.15 (1H, d), 9.22 (1H, br), 11.03 (1H, s).

Example 50: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3- a ]pyrimidin-7-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 50f using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by flash C18-flash chromatography (gradient: 0-40% MeCN in water (0.1% formic acid)); ^1H NMR: (300 MHz) 1.53-1.66 (4H, m), 1.65-1.79 (2H, m), 1.85 (2H, d), 2.04-2.17 (1H, m), 2.33-2.48 (7H, m), 2.54-2.66 (1H, m), 2.75-2.95 (2H) , m), 3.05 (2H, t), 3.61-3.83 (4H, m), 3.96 (2H, t), 4.18 (2H, d), 5.19 (1H, dd), 6.67 (1H, d), 6.86 (2H, t), 7.16 (2H, t), 7.24-7.36 (2H, m), 7.82 (1H, d), 8.03 (1H, d), 11.03 (1H, s); m/z ES ⁺ [M+H]+ = 732.3.

Intermediate 51a: 4-(4-(4-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzo-nitrile

At room temperature under air, K ₂ CO ₃ (1.197 g, 8.66 mmol) was added 4-(4-(4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzo-nitrile (1.00 g, 2.89 mmol) and 2-(4-bromobutyl)-1,3-dioxolane (0.604 g, 2.89 mmol) in DMF (2 mL). The resulting solution was stirred at 80 °C for 10 h. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (1.10 g, 80%) as a yellow solid; m/z ES ⁺ [M+H]+ = 475.

Intermediate 51b: 4-(4-(4-((5-oxopentyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.11 mmol) was added to formic acid (10 mL) at room temperature, and the mixture was stirred for 4 h and then concentrated. Purification by FSC (gradient: 0-100% MeCN in 3 water) gave the title compound (0.500 g, 55%) as a purple oil; m/z ES ⁺ [M+H]+ = 431.

Example 51: 4-(4-{4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3- a ]pyridin-7-yl]piperazin-1-yl}pentyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 44e was reacted with intermediate 51b using the general synthetic method exemplified by Example 2, and the title compound was purified by preparative SFC (Column: Triart Diol-NP, 20*250 mm, 5 μm; Mobile phase A:CO ₂ , Mobile phase B:IPA(8 mmol/L NH ₃ .MeOH)-HPLC; Flow rate: 50 mL/min; Gradient: 27% B; 254 nm; RT1:4.03; Injection volume: 1.5 mL; Number of runs: 10 times) to give the title compound; ¹ H NMR: (300 MHz) 1.40-1.90 (12H, m), 2.10-2.25 (1H, m), 2.30-2.40 (3H, m), 2.55-2.65 (2H, m), 2.70-2.95 (3H, m), 3.01-3.12 (2H, m), 3.20-3 .30 (4H, m), 3.90-4.00 (2H, m), 4.22 (2H, d), 5.24 (1H, d), 6.10-6.14 (1H, m), 6.69 (1H, d), 6.80-6.90 (2H, m), 7.10-7.21 (2H, m), 7.27- 3 (2H, m), 7.72 (1H, d), 7.82 (1H, d), 11.04 (1H, s); m/z ES ⁺ [M+H]+ = 745.4.

Example 52: 5-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-3-(trifluoromethyl)pyridine-2-carbonitrile

Intermediate 2c was reacted with intermediate 11b using the general synthetic method exemplified by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 10:1); ^1H NMR: (300 MHz) 1.54-1.89 (8H, m), 1.90-2.02 (1H, m), 2.36-2.40 (4H, m), 2.52-2.65 (2H, m), 2.75-2.98 (2H, m), 3.11 (2H, t), 3.23-3.35 (6H) , m), 3.97 (2H, t), 4.15-4.38 (4H, m), 5.05 (1H, dd), 6.86 (2H, d), 7.01-7.10 (2H, m), 7.17 (2H, d), 7.52 (1H, d), 7.64 (1H, d), 8.65 (1H, d), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 730.3.

Intermediate 53a: 4-[4-[4-[3-(2-hydroxyethyl)pyrrolidin-1-yl]phenyl]-1-piperidyl]-2-(trifluoromethyl)-benzonitrile

Under N _{2 ,} CuI (46.5 mg, 0.24 mmol) was added to 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (500 mg, 1.22 mmol), 2-(pyrrolidin-3-yl)ethan-1-ol (211 mg, 1.83 mmol), 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (47.2 mg, 0.24 mmol) and K ₃ PO ₄ (519 mg, 2.44 mmol) in DMSO (7 mL). The resulting mixture was stirred at 115 °C for 18 h. The mixture was then cooled to room temperature, poured into water (50 mL), and then extracted with EtOAc (3 x 50 mL). The combined organic solution was washed with brine (50 mL), dried (MgSO ₄ ), and concentrated. Purification by FSC (gradient: 0–50% EtOAc in heptane) gave the title compound (0.347 g, 64%) as a white solid; ^1H NMR (CDCl ₃ ) 1.26 (1H, d), 1.63-1.82 (5H, m), 1.96 (2H, d), 2.18 (1H, dtd), 2.33-2.49 (1H, m), 2.69 (1H, ddt), 2.90-2.99 (1H, m), 3.04 (2H, td), 3.27 (1H, td), 3.35 (1H, td), 3.46 (1H, dd), 3.7-3.79 (2H, m), 4.01 (2H, d), 6.46-6.56 (2H, m), 6.98 (1H, dd), 7.02-7.12 (2H, m), 7.15 ( 1H, d), 7.60 (1H, d); m/z : ES ⁺ [M+H] ⁺ 444.3.

Intermediate 53b: 4-[4-[4-[3-(2-oxoethyl)pyrrolidin-1-yl]phenyl]-1-piperidyl]-2-(trifluoromethyl)-benzonitrile

Dess-Martin periodinane (184 mg, 0.43 mmol) was added to 4-[4-[4-[3-(2-hydroxyethyl)pyrrolidin-1-yl]phenyl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile (175 mg, 0.39 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (15 mL) and poured into a mixture of saturated NaHCO ₃ (15 mL) and sodium thiosulfate solution (15 mL). The resulting suspension was stirred vigorously for 10 min after which the layers were separated. The organic solution was dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a red gum which was used without further purification; m / z : ES ⁺ [M+H] ⁺ 442.2.

Example 53: 4-(4-{4-[3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethyl)pyrrolidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 53b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: (CDCl ₃ ) 1.75 (6H, ddd), 1.96 (2H, d), 2.19 (2H, ddq), 2.32 (2H, qd), 2.42-2.53 (2H, m), 2.59-2.66 (4H, m), 2.66-2.73 (1H, m), 2.82 (1H , td), 2.88 (1H, dd), 2.93 (1H, t), 2.99-3.1 (2H, m), 3.23-3.32 (1H, m), 3.35 (4H, q), 3.41-3.51 (1H, m), 4.01 (2H, d), 4.25 (1H, d), 4.41 (1H) , d), 5.19 (1H, dd), 6.52 (2H, d), 6.88 (1H, s), 6.99 (2H, ddd), 7.08 (2H, d), 7.15 (1H, d), 7.60 (1H, d), 7.74 (1H, d), 7.93 (1H, s); m/z ES ⁺ [M+H]+ = 754.4.

Example 54: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-3-fluoro-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 7b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: 1.56-1.66 (2H, m), 1.76 (4H, dd), 1.86 (2H, d), 1.92-2.01 (1H, m), 2.37 (3H, d), 2.53 (4H, d), 2.59 (1H, d), 2.72 (1H, d), (1H, m), 3.04 (2H, t), 3.28 (4H, s), 3.72 (2H, d), 3.98 (2H, t), 4.21 (1H, d), 4.33 (1H, d), 5.05 (1H, dd), 6.88 (2H, d), 7.06 (2H, d), 7.18 (2 H, d), 7.46 (1H, t), 7.52 (1H, d), 7.80 (1H, d), 10.92 (1H, s); m/z ES ⁺ [M+H]+ = 747.4.

Intermediate 55a: tert -Butyl ( R )-3-methyl-4-(4-((( RS )-tetrahydro-2 H -pyran-2-yl)oxy)phenyl)piperazine-1-carboxylate

2-(4-Bromophenoxy)tetrahydro-2 H -pyran (1.0 g, 3.89 mmol), tert -Butyl ( R )-3-methylpiperazine-1-carboxylate (1.168 g, 5.83 mmol), RuPhos (0.091 g, 0.19 mmol), RuPhos Pd G3 (0.163 g, 0.19 mmol) and potassium tert -butoxide (0.873 g, 7.78 mmol) were stirred in 1,4-dioxane (20 mL), and the mixture was degassed by N ₂ bubbling. The mixture was then heated to 80 °C for 2 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic solution was dried and concentrated. The residue was purified by FSC (gradient: 0-50% EtOAc in heptane) to afford the title compound (0.859 g, 59%) as a colorless oil; ¹ H NMR (CDCl ₃ ) 0.91 (3H, d), 1.48 (9H, s), 1.66 (3H, dddd), 1.85 (2H, dq), 1.92-2.11 (1H, m), 2.99 (2H, d), 3.44 (3H, s), 3.60 (2H, ddt), 3.63-3.85 (1H, m), 3.94 (1H, ddd), 5.32 (1H, dt), 6.90 (2H, d), 6.96-7.03 (2H, m); m/z ES ⁺ [M+H]+ = 377.3.

Intermediate 55b: ( R )-4-(2-methylpiperazin-1-yl)phenol

4 M HCl in dioxane (5.7 mL, 22.82 mmol) was added dropwise to a solution of tert -butyl ( R )-3-methyl-4-(4-((( R S )-tetrahydro-2 H -pyran-2-yl)oxy)phenyl)piperazine-1-carboxylate (859 mg, 2.28 mmol) in DCM (20 mL), and the mixture was stirred at room temperature overnight. Et ₂ O (100 mL) was added, and the resulting precipitate was collected by filtration under vacuum to afford the title compound as the hydrochloride salt (0.600 g, 115%) as a yellow solid; m / z ES ⁺ [M+H]+ = 193.1.

Intermediate 55c: ( R )-4-(4-(4-hydroxyphenyl)-3-methylpiperazin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (0.993 mL, 5.70 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (0.431 g, 2.28 mmol) and ( R )-4-(2-methylpiperazin-1-yl)phenol hydrochloride salt (0.521 g, 2.28 mmol) were dissolved in DMSO (5 mL), and the mixture was stirred at room temperature overnight. The mixture was then partitioned between water (25 mL) and EtOAc (25 mL). The organic solution was washed with brine, dried (MgSO ₄ ), and concentrated. Purification by FSC (gradient: 0-60% EtOAc in heptane) gave the title compound (0.610 g, 74%) as a yellow gum; ^1H NMR (CDCl ₃ ) 1.00 (3H, d), 3.11 (1H, ddd), 3.16-3.25 (2H, m), 3.41-3.6 (3H, m), 3.64 (1H, dd), 4.72 (1H, s), 6.73-6.85 (2H, m), 6.89-7.01 ( 3H, m), 7.14 (1H, d), 7.57-7.71 (1H, m); m/z ES ⁺ [M+H]+ = 362.

Intermediate 55d: ( R )-4-(4-(4-(4-bromobutoxy)phenyl)-3-methylpiperazin-1-yl)-2-(trifluoromethyl)-benzonitrile

N ₂ ( R )-4-(4-(4-Hydroxyphenyl)-3-methylpiperazin-1-yl)-2-(trifluoromethyl)benzonitrile (0.184 g, 0.51 mmol), K ₂ CO ₃ (0.084 g, 0.61 mmol) and 1,4-dibromobutane (0.122 mL, 1.02 mmol) were dissolved in anhydrous DMF (7 mL). The mixture was stirred at 50 °C for 16 h. The mixture was then diluted with EtOAc (50 mL), washed with saturated NaHCO ₃ (50 mL), then brine (50 mL), dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-40% EtOAc in heptane) gave the title compound (0.159 g, 63%) as a yellow oil; ^1H NMR (CDCl ₃ ) 1.00 (3H, d), 1.86-2 (2H, m), 2.02-2.15 (2H, m), 3.07-3.29 (3H, m), 3.49 (3H, t), 3.53 (2H, t), 3.64 (1H, dd), 3.97 (2H, t), 6. 82-6.91 (2H, m), 6.93-7.02 (3H, m), 7.14 (1H, d), 7.57-7.72 (1H, m); m/z ES ⁺ [M+H]+ = 496.2

Example 55: 4-{(3 R )-4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]-3-methylpiperazin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 55d using the general synthetic method exemplified by Example 5 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: 0.91 (3H, d), 1.54-1.68 (2H, m), 1.73 (2H, q), 1.97 (1H, dd), 2.35-2.43 (3H, m), 2.53 (4H, d), 2.59 (1H, d), 2.83-2.96 (1H, m), 3.04 -3.17 (2H, m), 3.30 (4H, s), 3.42-3.56 (2H, m), 3.6-3.69 (2H, m), 3.69-3.8 (1H, m), 3.95 (2H, t), 4.21 (1H, d), 4.33 (1H, d), 5.04 (1H, dd), 6.86 (2H, d), 6.94 (2H, d), 7.06 (2H, d), 7.23-7.38 (2H, m), 7.52 (1H, d), 7.84 (1H, d), 10.92 (1H, s); m/z ES ⁺ [M+H]+ = 744.4.

Intermediate 56a: tert-Butyl 6-chloro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

tert -Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2 H -pyridine-1-carboxylate (50.0 g, 161 mmol), 5-bromo-2-chloro-pyridine (62.2 g, 323 mmol), K ₂ CO ₃ (112 g, 808 mmol), and Pd(dppf)Cl ₂ (5.92 g, 8.09 mmol) were added to 1,4-dioxane (350 mL) and H ₂ O (35.0 mL). The mixture was degassed and purged with N ₂ three times. The mixture was then stirred at 95 °C for 1 h. H ₂ O (500 mL) and EtOAc (200 mL) were then added. The mixture was filtered, and the filtrate was extracted with EtOAc (200 mL x 2). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: petroleum ether/EtOAc = 10/1∼2/1) to afford the title compound (34.2 g, 65%) as a pale yellow solid; ¹ H NMR (CDCl ₃ ) 1.49 (9H, s), 2.50 (1H, s), 3.65 (2H, t), 4.10 (2H, s), 6.09 (1H, s), 7.26 (1H, d), 7.62 (1H, dd), 8.40 (1H, s).

Intermediate 56b: tert -Butyl 4-(6-chloro-3-pyridyl)piperidine-1-carboxylate

MeOH (400.0 mL) was added to tert-butyl 6-chloro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (27.8 g, 94.3 mmol) and PtO ₂ (4.29 g, 18.9 mmol) were added. The resulting suspension was degassed and purged three times with H ₂ . The mixture was then stirred at 15 °C for 4.5 h under H ₂ (30 psi). The mixture was then filtered and the filtrate was concentrated. Purification by FSC (Gradient: petroleum ether/EtOAc = 10/1∼2/1) gave the title compound (13.09 g, 42%) as a pale yellow oil; ^1H NMR (CDCl ₃ ) 1.49 (9H, s), 1.65-1.54 (2H, m), 1.82 (2H, d), 2.73-2.65 (2H, m), 2.82 (2H, t), 4.27 (2H, s), 7.28 (1H, d), 7.49 (1H, dd), 8. 26 (1H, s);

Intermediate 56c: 2-chloro-5-(4-piperidyl)pyridine

4 N HCl in MeOH (130 mL) was added to tert -butyl 4-(6-chloro-3-pyridyl)piperidine-1-carboxylate (12.9 g, 43.4 mmol), and the mixture was stirred at room temperature for 20 min. The mixture was then concentrated to give the title compound as a hydrochloride salt (11.6 g, 43.0 mmol, 99%) as a pale yellow solid; ¹ H NMR (CD ₃ OD) 1.96 (2H, m), 2.04- 8.47 (1H, s), 2.14-2.11 (2H, m), 3.21-3.07 (3H, m), 3.54 (2H, d), 7.66 (1H, d), 8.03 (1H, dd).

Intermediate 56d: 4-[4-(6-chloro-3-pyridyl)-1-piperidyl]-2-(trifluoromethyl)benzonitrile

2-Chloro-5-(4-piperidyl)pyridine (10.0 g, 37.0 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (14.0 g, 74.0 mmol), DIPEA (23.9 g, 185 mmol, 32.2 mL) were dissolved in DMSO (120.0 mL) and stirred at 50 °C for 5.5 h. The solution was then cooled to 0 °C, and hydrochloric acid (1 M, 50.0 mL) was added to the solution (pH = 2). Then, saturated NaHCO ₃ (200.0 mL) solution was added to the mixture until pH = 8. The solid was collected by filtration and dried under vacuum. The solid was purified by recrystallization (petroleum ether/EtOAc = 10/1) to give the title compound (5.50 g, 37% yield) as a pale yellow solid; ¹ H NMR (CDCl ₃ ) 1.84-1.77 (2H, m), 2.03-2.00 (2H, m), 2.87-2.81 (1H, m), 3.08 (2H, t), 4.05 (2H, d), 7.02-7.00 (1H, m), 7.17 (1H, s), 7.30 (1H, d), 7.51 (1H, dd), 7.63 (1H, d), 8.28 (1H, s); m/z ES ⁺ [M+H]+ = 366.1.

Intermediate 56e: 4-[4-[6-(4-hydroxybutoxy)-3-pyridyl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile

Butane-1,4-diol (0.606 mL, 6.83 mmol) was dissolved in THF (10 mL) and cooled to 0 °C (ice bath). NaH (60%, 0.137 g, 3.42 mmol) was added and the reaction was allowed to warm to room temperature. 4-(4-(6-chloropyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.500 g, 1.37 mmol) was added in one portion and the mixture was heated to 85 °C for 16 h. The mixture was then diluted with DMF (5.00 mL), additional NaH (0.137 g, 3.42 mmol) was added and the mixture was heated to 120 °C for 16 h. After cooling, the mixture was diluted with EtOAc (50 mL). The solution was washed with water (50 mL), saturated NaHCO ₃ (50 mL), and then saturated brine (50 mL). The solution was dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.413 g, 72%) as a colorless oil; ^1H NMR (CDCl ₃ ) 1.68 (1H, t), 1.71-1.73 (1H, m), 1.73-1.82 (3H, m), 1.82-1.9 (2H, m), 1.98 (2H, d), 2.75 (1H, tt), 3.06 (2H, td), 3.73 (2H, q), 4.03 (2H, d), 4.32 (2H, t), 6.70 (1H, d), 6.99 (1H, dd), 7.16 (1H, d), 7.43 (1H, dd), 7.62 (1H, d), 8.01 (1H, d); m/z ES ⁺ [M+H]+ = 420.0.

Intermediate 56f: 4-[4-[6-(4-oxobutoxy)-3-pyridyl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile

Dess-Martin periodinane (228 mg, 0.54 mmol) was added to 4-(4-(6-(4-hydroxybutoxy)pyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (205 mg, 0.49 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 1 h. The mixture was then diluted with DCM (15 mL) and poured into a mixture of saturated NaHCO ₃ (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 min, and the layers were separated. The organic portion was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.204 g, 100%) as a yellow dry film, which was used without further purification; m / z ES ⁺ [M+H] + = 418.2.

Intermediate 56g: Ethyl 6-chloro-2-methylnicotinate

POCl ₃ (61.7 mL, 662.28 mmol) was added to ethyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (24 g, 132.46 mmol) at room temperature. The resulting solution was stirred at 100 °C for 1 h and then concentrated. Purification by FSC (gradient: 0–20% EtOAc in petroleum ether) afforded the title compound (23.00 g, 87%) as a white solid; ¹ H NMR (300 MHz) 1.32 (3H, t), 2.67 (3H, s), 4.31 (2H, q), 7.46 (1H, dd), 8.17 (1H, d); m/z ES ⁺ [M+H] ⁺ = 200.2.

Intermediate 56h: Ethyl 2-(bromomethyl)-6-chloronicotinate

AIBN (5.18 g, 31.56 mmol) was added to ethyl 6-chloro-2-methylnicotinate (21.0 g, 105.19 mmol) and NBS (28.1 g, 157.79 mmol) in CCl ₄ (300 mL). The resulting mixture was stirred at 80 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) afforded the title compound (28.0 g, 96%) as a yellow oil; 1H NMR (300 MHz) 1.34-1.38 (3H, m), 4.34-4.40 (2H, m), 4.93 (2H, s), 7.64 (1H, d), 8.29 (1H, d); m/z ES ⁺ [M+H] ⁺ = 278.

Intermediate 56i: 3-(2-chloro-5-oxo-5,7-dihydro-6 H -Pyrrolo[3,4- b ]pyridin-6-yl)piperidine-2,6-dione

DIPEA (47.0 mL, 269.27 mmol) was added to ethyl 2-(bromomethyl)-6-chloronicotinate (25.00 g, 89.76 mmol) and 3-aminopiperidine-2,6-dione (9.20 g, 71.81 mmol) in DMF (250 mL). The resulting mixture was stirred at 40 °C for 2 h and then at 100 °C for 16 h and then concentrated under reduced pressure. Purification by FSC (gradient: 0-100% EtOAc in petroleum ether) gave the material which was further purified by crystallization from EtOAc to give the title compound (10.00 g, 40%) as a purple solid; ^1H NMR: 1.96-2.08 (1H, m), 2.35-2.47 (1H, m), 2.56-2.66 (1H, m), 2.85-2.99 (1H, m), 4.39 (1H, d), 4.55 (1H, d), 5.17 (1H, dd), 7.67 (1H, d), 8.19 (1H, d), 11.02 (1H, s); m/z ES ⁺ [M+H] ⁺ = 280.1.

Intermediate 56j: tert -Butyl-4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -Pyrrolo[3,4- b ]pyridin-2-yl)piperazine-1-carboxylate

DIPEA (1.40 mL, 7.79 mmol) was added 3-(2-chloro-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyridin-6-yl)-piperidine-2,6-dione (1.09 g, 3.90 mmol) and tert -butyl piperazine-1-carboxylate (0.726 g, 3.90 mmol) in DMSO (8 mL). The resulting mixture was stirred in a microwave reactor at 120 °C for 3.5 h. The mixture was then poured into ice water. The precipitate was collected by filtration and dried in vacuo for 2 days to give the title compound (0.950 g, 57%) as a beige solid; ^1H NMR: 1.43 (9H, s), 1.97 (1H, dq), 2.34-2.44 (1H, m), 2.54-2.65 (1H, m), 2.83-2.98 (1H, m), 3.38-3.50 (4H, m), 3.57-3.74 (4H, m), 4.12 ( 1H, d), 4.29 (1H, d), 5.07 (1H, dd), 6.91 (1H, d), 7.80 (1H, d), 10.92 (1H, s); m/z : ES ⁺ [M+H] ⁺ 430.2.

Intermediate 56k: 3-(5-oxo-2-(piperazin-1-yl)-5,7-dihydro-6 H -Pyrrolo[3,4- b ]pyridin-6-yl)piperidine-2,6-dione

4 M HCl in dioxane (8.7 mL, 34.93 mmol) was added in one portion to tert -butyl-4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ]pyridin-2-yl)piperazine-1-carboxylate (150 mg, 0.35 mmol) at room temperature, and the mixture was stirred for 4 h. The mixture was then concentrated to give the title compound as a bis-hydrochloride salt as a yellow solid, which was used in the next step without further purification; ^1H NMR: 1.92-2.04 (1H, m), 2.39 (1H, dt), 2.62 (1H, s), 2.85-2.99 (1H, m), 3.20 (4H, br), 3.85-3.99 (4H, m), 4.15 (1H, d), 4.31 (1H, d), 5. 09 (1H, dd), 7.01 (1H, d), 7.88 (1H, d), 9.13 (2H, s), 10.94 (1H, s); m/z : ES ⁺ [M+H] ⁺ 330.0.

Example 56: 4-{4-[6-(4-{4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -Pyrrolo[3,4- b ]pyridin-2-yl]piperazin-1-yl}butoxy)pyridin-3-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 56f was reacted with intermediate 56k using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: 1.54-1.62 (2H, m), 1.70 (2H, s), 1.71-1.78 (2H, m), 1.86 (2H, d), 1.93-2.01 (1H, m), 2.34-2.4 (3H, m), 2.42-2.47 (4H, m), 2.61 (1H) , s), 2.86 (1H, s), 2.86-2.97 (1H, m), 3.05 (2H, t), 3.62 (4H, d), 4.11 (1H, d), 4.18 (2H, d), 4.22-4.35 (3H, m), 5.07 (1H, dd), 6.74 (1H, d) , 6.90 (1H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.61 (1H, dd), 7.77 (1H, d), 7.81 (1H, d), 8.04 (1H, d), 10.92 (1H, s); m/z ES ⁺ [M+H]+ = 731.4.

Example 57: 4-{4-[5-(4-{4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -Pyrrolo[3,4- b ]pyridin-2-yl]piperazin-1-yl}butoxy)pyridin-2-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 9e was reacted with intermediate 56k using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by flash C-18 chromatography (eluent A: 0-11% MeCN in water (0.1% formic acid)); ^1H NMR: (300 MHz) 1.56-1.67 (2H, m), 1.67-1.84 (4H, m), 1.84-2.02 (3H, m), 2.32-2.50 (7H, m), 2.52-2.65 (1H, m), 2.82-3.00 (2H, m), 3.10 (2H) , t), 3.62-3.65 (4H, m), 4.05 (2H, t), 4.10-4.22 (3H, m), 4.28 (1H, d), 5.07 (1H, dd), 6.90 (1H, d), 7.20-7.37 (4H, m), 7.79 (2H, dd), H, d), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 731.4.

Example 58: 4-{4-[5-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)pyridin-2-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 9e using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by flash C-18 chromatography (gradient: 0-21% MeCN in water (0.1% formic acid)); ^1H NMR: (300 MHz) 1.56-1.83 (6H, m), 1.83-2.03 (3H, m), 2.33-2.45 (4H, m), 2.52-2.65 (1H, m), 2.83-3.00 (2H, m), 3.09 (2H, t), 3.21-3.34 (7H) , m), 4.06 (2H, t), 4.09-4.40 (4H, m), 5.05 (1H, dd), 7.06 (2H, d), 7.20-7.35 (4H, m), 7.50-7.56 (1H, m), 7.82 (1H, d), 8.20 (1H, d), 10.94 (1) H, s); m/z ES ⁺ [M+H]+ = 730.4.

Intermediate 59a: tert -Butyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

tert -Butyl piperazine-1-carboxylate (7.35 g, 39.48 mmol) was added to methyl 2-bromo-4-fluorobenzoate (9.2 g, 39.48 mmol) and DIPEA (6.90 mL, 39.48 mmol) in DMSO (180 mL) at room temperature. The resulting mixture was stirred at 120 °C for 3 h. The mixture was then poured into saturated brine (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 10-40% EtOAc in petroleum ether) gave the title compound (8.10 g, 51%) as a yellow solid; m / z ES ⁺ [M + H] + = 399.

Intermediate 59b: tert -Butyl ( E )-4-(3-(2-ethoxyvinyl)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

RuPhos Pd G3 (1.678 g, 2.00 mmol) was _added to tert -butyl 4-( ₃ -bromo-4-(methoxycarbonyl)phenyl)-piperazine-1-carboxylate (8.00 g, 20.04 mmol), ( E )-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.94 g, 40.07 mmol) and Cs ₂ CO ₃ (6.53 g, 20.04 mmol) in 1,4-dioxane (50 mL0 and H 2 O (50 mL) at room temperature under N 2 . The resulting mixture was stirred at 80 °C for 2 h. The mixture was poured into saturated brine (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic The solution was dried (Na ₂ SO ₄ ), concentrated and purified by FSC (gradient: 10–40% EtOAc in petroleum ether) to give the title compound (7.68 g, 98%) as a yellow oil; ¹ H NMR: 1.27 (3H, t), 1.42 (9H, s), 3.28-3.30 (4H, m), 3.44-3.46 (4H, m), 3.74 (3H, s), 3.91 (2H, q), 6.75 (2H, t), 6.93 (1H, s), 7.16 (1H, d), 7.72 (1H, d); m/z ES ⁺ [M+H]+ = 391.

Intermediate 59c: tert -Butyl 4-(4-(methoxycarbonyl)-3-(2-oxoethyl)phenyl)piperazine-1-carboxylate

tert -Butyl ( E )-4-(3-(2-ethoxyvinyl)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (1.00 g, 2.56 mmol) was added hydrochloric acid (1.5 mL, 1.50 mmol) in THF (10 mL) at room temperature. The resulting mixture was stirred at 40 °C for 16 h. The mixture was then poured into saturated NaHCO ₃ solution (50 mL), and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 20-50% EtOAc in petroleum ether) afforded the title compound (0.47 g, 51%) as a pale yellow oil; ^1H NMR: 1.42 (9H, d), 3.30-3.47 (8H, m), 3.72 (3H, d), 3.98 (2H, s), 5.75 (1H, d), 6.84-6.94 (2H, m), 7.85 (1H, d), 9.64 (1H, s); m/z ES ⁺ [M+H] ⁺ = 363.

Intermediate 59d: tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazine-1-carboxylate

tert -Butyl 4-(4-(methoxycarbonyl)-3-(2-oxoethyl)phenyl)piperazine-1-carboxylate (2.50 g, 6.90 mmol) was added to 3-amino-piperidine-2,6-dione hydrochloride salt (1.135 g, 6.90 mmol) in a mixture of IPA (15 mL) and DCM (15 mL) at room temperature, and the mixture was stirred for 1 h. Then NaBH(OAc) ₃ (2.92 g, 13.80 mmol) was added, and the mixture was stirred at 40 °C for 16 h, and then concentrated. Purification by FSC (gradient: 10-50% EtOAc in petroleum ether) gave the title compound (0.50 g, 16%) as a white solid; ^1H NMR: 1.42 (9H, s), 1.83-1.94 (1H, m), 2.37 (1H, ddd), 2.54 (1H, d), 2.86 (3H, dtd), 3.26-3.28 (4H, m), 3.34-3.52 (6H, m), 5.16 (1H, s), 6.78 (1H, s), 6.89 (1H, d), 7.70 (1H, d), 10.85 (1H, s); m/z ES ⁺ [M+H] ⁺ = 443.

Intermediate 59e: 3-(1-oxo-6-(piperazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione

tert -Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazine-1-carboxylate (100 mg, 0.23 mmol) was added HCl in 1,4-dioxane (3 mL, 12.00 mmol) at room temperature, and the mixture was stirred for 1 h. The crude mixture was eluted with _Et2O to give a solid which was collected by filtration and dried in vacuo to give the title compound (0.088 g, 114%) as a white solid; ^1H NMR (300 MHz) 1.82-1.95 (1H, m), 2.30-2.44 (1H, m), 2.57 (1H, d), 2.71-3.02 (3H, m), 3.19-3.20 (4H, m), 3.36-3.61 (6H, m), 5.07-5.29 (1H, m), 6.86 (1H, d), 6.95 (1H, dd), 7.74 (1H, d), 9.21 (1H, br, s), 10.87 (1H, s) m/z ES ⁺ [M+H] ⁺ = 343.

Example 59: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 59e using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by C-18 flash chromatography (eluent: 5-50% MeCN in water (0.1% formic acid)); ^1H NMR: 1.53-1.68 (4H, m), 1.68-1.80 (2H, m), 1.79-1.97 (3H, m), 2.31-2.45 (2H, m), 2.53-2.69 (3H, m), 2.69-2.96 (5H, m), 3.04 (2H, t), 3. 32-3.51 (8H, m), 3.97 (2H, t), 4.17 (2H, d), 5.16 (1H, s), 6.78 (1H, s), 6.87 (3H, t), 7.15 (2H, d), 7.26 (1H, d), 7.32 (1H, s), 7.69 (1H, d) , 7.81 (1H, d), 10.84 (1H, s); m/z ES ⁺ [M+H]+ = 743.3.

Example 60: 4-{4-[4-(4-{4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -Pyrrolo[3,4- b ]pyridin-2-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 56k using the general synthetic method exemplified by Example 5 to give the title compound after purification by C-18 flash chromatography (eluent: 0-40% MeCN in water (0.1% formic acid)); ^1H NMR: 1.54-1.67 (4H, m), 1.68-1.78 (2H, m), 1.84 (2H, d), 1.92-2.00 (1H, m), 2.31-2.42 (3H, m), 2.42-2.49 (4H, m), 2.54-2.69 (1H, m), 2. 71-2.82 (1H, m), 2.83-2.97 (1H, m), 2.98-3.09 (2H, m), 3.57-3.71 (4H, m), 3.90-4.02 (2H, m), 4.05-4.32 (4H, m), 5.02-5.11 (1H, m), 6.82-6. 93 (3H, m), 7.15 (2H, d), 7.26 (1H, d), 7.32 (1H, s), 7.73-7.84 (2H, m), 10.93 (1H, s); m/z ES ⁺ [M+H]+ = 730.5.

Intermediate 61a: Methyl 4-(bromomethyl)-6-chloronicotinate

NBS (4.79 g, 26.94 mmol) was added to AIBN (0.885 g, 5.39 mmol) and methyl 6-chloro-4-methylnicotinate (5.00 g, 26.94 mmol) in CCl ₄ (5 mL) at room temperature. The resulting mixture was stirred at 80 °C for 4 h and then concentrated. Flash C18-flash chromatography (gradient: 0-70% MeCN in water (0.1% formic acid)) gave the title compound (2.5 g, 35%) as a white solid; m/z ES ⁺ [M+H] ⁺ = 266.

Intermediate 61b: 3-(6-chloro-3-oxo-1,3-dihydro-2 H -Pyrrolo[3,4- c ]pyridin-2-yl)piperidine-2,6-dione

At room temperature under air, DIPEA (4.95 mL, 28.4 mmol) was added to methyl 4-(bromomethyl)-6-chloronicotinate (2.50 g, 9.45 mmol) and 3-aminopiperidine-2,6-dione (1.82 g, 14.18 mmol) in DMF (10 mL). The resulting solution was stirred at 80 °C for 15 h and then the mixture was poured into water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in petroleum ether) gave the title compound as a colorless solid which was used in the next step without further purification.

Intermediate 61c: tert -Butyl 4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-1-{ H }-pyrrolo[3,4- c ]pyridin-6-yl]piperazine-1-carboxylate

Pd-PEPPSI- i Pent (93 mg, 0.12 mmol) was _added to 3-(6-chloro-3-oxo-1,3-dihydro-2 H -pyrrolo[3,4- c ]pyridin-2-yl)piperidine-2,6-dione (330 mg, 1.18 mmol), tert -butyl piperazine-1-carboxylate (330 mg, 1.77 mmol) and Cs ₂ CO ₃ (1153 mg, 3.54 mmol) in 1,4-dioxane (3 mL) at room temperature under N 2 . The resulting solution was stirred at 100 °C for 3 h. Purification by FSC (gradient: 0-100% MeCN in water) gave the title compound (0.118 g, 23%) as a white solid; [M+H] ⁺ = 430.

Intermediate 61d: 3-(3-oxo-6-(piperazin-1-yl)-1,3-dihydro-2 H -Pyrrolo[3,4- c ]pyridin-2-yl)piperidine-2,6-dione

tert -Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4- c ]pyridin-6-yl)piperazine-1-carboxylate (118 mg, 0.27 mmol) was added to 4 M HCl in 1,4-dioxane (2 mL) at room temperature under air, and the mixture was stirred for 2 h. It was then concentrated to give the title compound (0.110 g, 122%) which was used in the next step without further purification; ^1H NMR (300 MHz) 1.90-2.01 (1H, m), 2.30-2.42 (1H, m), 2.55-2.65 (1H, m), 2.85-2.95 (1H, m), 3.17-3.19 (4H, m), 4.88-4.90 (4H, m), 4.38 (1H, d), 4.40 (1H, d), 5.08 (1H, d), 7.10 (1H, s), 8.50 (1H, s), 9.20-9.33 (2H, m), 11.00 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 330.

Example 61: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1 H -Pyrrolo[3,4- c ]pyridin-6-yl]-piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 4c was reacted with intermediate 61d using the general synthetic method exemplified by Example 2, and the title compound was purified by preparative chiral-HPLC (Column: Viridis BEH 2-Ethylpyridine Prep OBD, 30*150 mm, 5 μm; Mobile phase A: CO ₂ , Mobile phase B: MeOH (8 mmol/L NH ₃ .MeOH); Flow rate: 50 mL/min; Gradient: 28% B; 254 nm; RT1:6.18; Injection volume: 1 mL; Number of runs: 10 times) to give the title compound; ¹ H NMR: (300 MHz) 1.11-1.41 (4H, m), 1.55-1.70 (2H, m), 1.70-2.00 (7H, m), 2.25-2.40 (3H, m), 2.60-2.80 (6H, m), 2.85-3.00 (2H, m), 3.02-3. 15 (2H, m), 3.72 (4H, d),4.13-4.31 (3H, m), 4.39 (1H, d), 5.06 (1H, dd), 6.88 (2H, d), 7.02-7.12 (3H, m), 7.22-7.38 (2H, m), 7.82 (1H, d), 8. 49 (1H, s), 10.97 (1H, s); m/z ES ⁺ [M+H]+ = 755.4.

Example 62: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3- a ]pyridin-7-yl]-piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 44e was reacted with intermediate 50a using the general synthetic method exemplified by Example 12, and the title compound was purified by HPLC (Column: DAICEL DCpak P4VP, 20 mm*250 mm, 5 μm; Mobile phase A:CO ₂ , Mobile phase B:MeOH; Flow rate: 50 mL/min; Gradient: 40% B; 254 nm; RT1:5.75; Injection volume: 3 mL; Number of runs: 5 times) to give the title compound; ^1H NMR: (300 MHz) 1.53-1.77 (6H, m), 1.84 (2H, d), 2.07-2.18 (1H, m), 2.37 (2H, t), 2.42-2.50 (5H, m), 2.57-2.68 (1H, m), 2.69-2.97 (2H, m), 3.04 (2H, t), 3.20-3.27 (4H, m), 3.96 (2H, t), 4.18 (2H, d), 5.24 (1H, dd), 6.10 (1H, d), 6.69 (1H, dd), 6.86 (2H, d), 7.15 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.72 (1H, d), 7.82 (1H, d), 11.06 (1H, s); m/z ES ⁺ [M+H]+ = 731.4.

Intermediate 63a: 4-(4-(4-hydroxyphenyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (1.47 mL, 8.42 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (1.06 g, 5.61 mmol) and 4-(piperazin-1-yl)phenol (1.00 g, 5.61 mmol) were dissolved in DMSO (5 mL). The mixture was stirred at room temperature overnight. Water (20 mL) was then added to give a suspension. The suspension was stirred at room temperature for 20 min. The solid was collected by filtration and washed with water (50 mL) and hexanes (50 mL) to give the title compound (1.58 g, 81%) as a cream solid; ^1H NMR (CDCl ₃ ) 3.21 (4H, dd), 3.54 (4H, dd), 5.10 (1H, d), 6.77-6.84 (2H, m), 6.87-6.91 (2H, m), 7.01 (1H, dd), 7.18 (1H, d), 7.65 (1H, d); m/z: ES ⁺ [M+H]+ 348.4.

Intermediate 63b: 4-[4-[4-(4-bromobutoxy)phenyl]piperazin-1-yl]-2-(trifluoromethyl)benzonitrile

4-(4-(4-Hydroxyphenyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile (0.520 g, 1.50 mmol), K ₂ CO ₃ (0.248 g, 1.80 mmol) and 1,4-dibromobutane (0.358 mL, 2.99 mmol) were dissolved in anhydrous DMF (20 mL) under N ₂ , and the mixture was stirred for 18 h. The mixture was then warmed to 50 °C for 16 h. The mixture was then diluted with EtOAc (50 mL), washed with saturated NaHCO ₃ (50 mL) and brine (50 mL), and then dried (MgSO ₄ ). Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (0.214 g, 30%) as a yellow oil; ^1H NMR (CDCl ₃ ) 1.86-1.99 (2H, m), 2.02-2.14 (2H, m), 3.21-3.23 (4H, m), 3.48 (2H, t), 3.52-3.58 (4H, m), 3.97 (2H, t), 6.88 (2H, s), 6.89-6 .95 (2H, m), 7.01 (1H, dd), 7.18 (1H, d), 7.65 (1H, d); m/z: ES ⁺ [M+H] ⁺ 483.9.

Intermediate 63c: 2-(2,6-dioxopiperidine - 3-(3-fluoroisoindoline)-5-fluoroisoindoline-1,3-dione

To a solution of 5-fluoroisobenzofuran-1,3-dione (7.50 g, 45.2 mmol) in AcOH (100 mL) was added sodium acetate (7.41 g, 90.3 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (7.43 g, 45.2 mmol). The resulting mixture was stirred at 120 °C for 18 h and then concentrated. The residue was poured into water (200 mL) and stirred for 10 min. The solid was collected by filtration, washed with water (2 x 50 mL) and dried in vacuo to give the title compound (11.8 g, 94%) as a white solid; ^1H NMR: 2.03-2.12 (1H, m), 2.52-2.66 (2H, m), 2.90 (1H, ddd), 5.17 (1H, dd), 7.73 (1H, ddd), 7.85 (1H, dd), 8.01 (1H, dd), 11.12 (1H, s); m/z : ES-[MH] ^-275.1 .

Intermediate 63d: tert- Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

tert -Butyl piperazine-1-carboxylate (2.97 g, 15.9 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (4.00 g, 14.5 mmol), DIPEA (7.80 mL, 43.4 mmol) and NMP (60 mL) were heated in a microwave reactor at 140 °C for 2 h. The mixture was then cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organic solutions were washed with brine (2 x 50 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (3.95 g, 62%) as a yellow solid; ^1H NMR: 1.43 (9H, s), 2.03 (1H, ddd), 2.53-2.65 (2H, m), 2.77-2.97 (1H, m), 3.48 (8H, s), 5.08 (1H, dd), 7.25 (1H, dd), 7.35 (1H, d), 7.70 ( 1H, d), 11.06 (1H, s).

Intermediate 63e: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione

4 M HCl in dioxane (22.3 mL, 89.3 mmol) was added to tert -butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-isoindolin-5-yl)piperazine-1-carboxylate (3.95 g, 8.93 mmol) in DCM (100 mL) at room temperature, and the mixture was stirred for 18 h. It was then concentrated under reduced pressure to give the title compound as the hydrochloride salt (3.40 g, 100%) as a pale yellow solid; ^1H NMR: 2.04 (1H, ddd), 2.55-2.65 (2H, m), 2.90 (1H, ddd), 3.22 (4H, s), 3.67-3.73 (4H, m), 5.09 (1H, dd), 7.33 (1H, dd), 7.46 (1H, d), 7.75 ( 1H, d), 9.22 (2H, s), 11.07 (1H, s); m/z : ES ⁺ [M+H] ⁺ 343.2.

Example 63: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperazin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 63b was reacted with intermediate 63e using the general synthetic method exemplified by Example 5 to give the title compound after purification by HPLC (column A, eluent A); ^1H NMR: (CDCl ₃ ) 1.71 (2H, p), 1.78-1.9 (2H, m), 2.09-2.18 (1H, m), 2.43-2.49 (2H, m), 2.57-2.64 (4H, m), 2.66-2.94 (3H, m), 3.22 (4H, dd), 3 .39-3.46 (4H, m), 3.51-3.59 (4H, m), 3.97 (2H, t), 4.93 (1H, dd), 6.85-6.9 (2H, m), 6.9-6.95 (2H, m), 7.03 (2H, ddd), 7.18 (1H, d), 7.28 (1H, d) ), 7.67 (2H, dd), 7.96 (1H, s); m/z (ES-) [MH]- = 742.1.

Example 64: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperazin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 63b was reacted with intermediate 2c using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A); ^1H NMR: (CDCl ₃ ) 1.81-1.87 (2H, m), 1.88 (1H, s), 2.21 (1H, ddq), 2.33 (1H, qd), 2.82 (1H, d), 2.85 (1H, s), 2.88-2.9 (2H, m), 2.93 (1H, s), 3.01-3.04 (4H, m), 3.22 (4H, d), 3.47-3.52 (4H, m), 3.52-3.57 (4H, m), 3.96 (2H, t), 4.27 (1H, d), 4.42 (1H, d), 5.20 (1H, d), 6.82-6.88 ( 2H, m), 6.89 (1H, s), 6.91-6.95 (2H, m), 7.00 (2H, ddd), 7.18 (1H, d), 7.65 (1H, d), 7.76 (1H, d), 8.03 (1H, s), 8.16 (2H, s); m/z ES ⁺ [M+H]+ = 730.1.

Intermediate 65a: 3-(4-bromophenyl)pyrrolidine

1-Bromopyrrolidine-2,5-dione (10.00 g, 56.18 mmol) was added 3-phenylpyrrolidine (10.00 g, 67.93 mmol) and H ₂ SO ₄ (53.00 g, 540.42 mmol) in water (53 mL) at room temperature. The resulting mixture was stirred at 70 °C for 2 h. The reaction was then quenched with saturated Na ₂ CO ₃ solution. The resulting mixture was extracted with EtOAc and the combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a brown liquid which was used in the next step without further purification; m / z ES ⁺ [M+H] ⁺ = 226.

Intermediates 65b and 65c: 4-[(3 r )-3-(4-bromophenyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile and 4-[(3 s )-3-(4-bromophenyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (absolute configuration not yet established)

Cs ₂ CO ₃ (28.80 g, 88.45 mmol) was added to 4-fluoro-2-(trifluoromethyl)benzonitrile (12.55 g, 66.34 mmol) and 3-(4-bromophenyl)pyrrolidine (10.00 g, 44.22 mmol) in DMF (100 mL) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The mixture was then concentrated and diluted with EtOAc. The resulting solution was washed with water, dried (Na ₂ SO ₄ ), and concentrated. The material was purified by FSC (Gradient: 0–10% EtOAc in petroleum ether) to give the product, which was further purified by SFC (Column: CHIRALPAK AD-H SFC, 5*25 cm, 5 μm; Mobile phase A:CO ₂ , Mobile phase B:MeOH (2 mM NH ₃ -MeOH); Flow rate:150 mL/min; Gradient: 40% B; 220 nm; 65b RT1:6.85 min; 65c RT2:7.97 min) to give the title compounds: Intermediate 65b (1.90 g, 11%)FMF as a light yellow solid; Intermediate 65c (2.200 g, 13%) as a light yellow solid.

Intermediate 65b : ^1H NMR: (300 MHz) 2.01-2.17 (1H, m), 2.35-2.46 (1H, m), 3.40-3.67 (4H, m), 3.82-3.94 (1H, m), 6.87 (1H) , dd), 6.95 (1H, d), 7.33 (2H, d), 7.54 (2H, d), 7.80 (1H, d); 99% ee.

Intermediate 65c : ¹ H NMR (300 MHz) 2.01-2.14 (1H, m), 2.35-2.44 (2H, m), 3.43-3.65 (3H, m), 3.84-3.93 (1H, m), 6.88 (1H, dd), 6.95 (1H, d), 7.33 (2H, d), 7.54 (2H, d), 7.80 (1H, d); m/z ES ⁺ [M+H] ⁺ = 395; >99% ee.

Intermediate 65d: ( R )-4-(3-(4-(3-hydroxypropoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

RockPhos Pd G3 (63.6 mg, 0.08 mmol) was added to ( r )-4-(3-(4-bromophenyl)pyrrolidin-1-yl)-2-(trifluoro-methyl)benzonitrile (intermediate _65b ) (300 mg, 0.76 mmol), propane-1,3-diol (87 mg, 1.14 mmol) and Cs ₂ CO ₃ (742 mg, 2.28 mmol) in 1,4-dioxane (5 mL) at room temperature under N 2 . The resulting mixture was stirred at 100 °C for 16 h. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the material, which was further purified by FSC (gradient: 0-40% EtOAc in petroleum ether) to give the title compound (210 mg, 71%) as a yellow liquid; m/z ES ⁺ [M+H] ⁺ = 391.

Intermediate 65e: ( r )-4-(3-(4-(3-bromopropoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

PPh ₃ (282 mg, 1.08 mmol) was added to CBr ₄ (357 mg, 1.08 mmol) and ( r )-4-(3-(4-(3-hydroxypropoxy)-phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (210 mg, 0.54 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 16 h. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (135 mg, 55%) as a yellow liquid. ^1H NMR (300 MHz) 2.01-2.17 (1H, m), 2.24 (2H, p), 2.32-2.43 (1H, m), 3.32-3.44 (1H, m), 3.43-3.55 (2H, m), 3.60 (1H, d), 3.67 (2H, t), 3.86 (1 H, dd), 4.07 (2H, t), 6.87 (1H, dd), 6.93 (2H, d), 6.95 (1H, s), 7.28 (2H, d), 7.80 (1H, d); m/z ES ⁺ [M+H]+ = 453.

Example 65: 4-{(3r ) -3-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]piperazin-1-yl}propoxy)phenyl]pyrrolidin-1-yl}-2-(trifluoromethyl)benzonitrile (absolute configuration not yet established).

Intermediate 2c was reacted with intermediate 65e using the general synthetic method exemplified by Example 5 to give the title compound after purification by C18-flash chromatography (gradient: 5-50% MeCN in water (0.1% formic acid)); ¹ H NMR: (300 MHz) 1.85-2.15 (4H, m), 2.30-2.44 (2H, m), 2.52-2.67 (5H, m), 2.91 (1H, ddd), 3.31 (7H, d), 3.40-3.55 (2H, m), 3.55-3.68 (1H, m), 3.78-3.91 (1H, m), 4.02 (2H, t), 4.15-4.38 (2H, m), 5.05 (1H, dd), 6.83-6.98 (4H, m), 7.07 (2H, d), 7.26 (2H, d), 7.53 (1H, d), 7.80 (1H, d), 10.96 (1H, s); m/z ES ⁺ [M+H]+ = 701.2.

Intermediate 66a: 4-(4-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Under N _{2 ,} BrettPhos Pd G3 (177 mg, 0.20 mmol) was added 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (800 mg, 1.95 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (420 mg, 2.93 mmol) and Cs ₂ CO ₃ (1911 mg, 5.86 mmol) in 1,4-dioxa (30 mL). The resulting mixture was stirred at 100 °C for 3 h. The mixture was concentrated and diluted with EtOAc (50 mL). The solution was washed with water (50 mL x 2), dried (Na ₂ SO ₄ ), and concentrated. FSC (gradient: 0-10% MeOH in DCM) was performed to afford the title compound (750 mg, 81%) as a yellow solid; ¹ H NMR (CDCl ₃ ) 1.77 (2H, dd), 1.80-1.89 (4H, m), 1.99 (2H, d), 2.64-2.79 (1H, m), 3.07 (2H, t), 3.28-3.38 (4H, m), 4.00-4.02 (4H, m), 4.05 (2H, s), 6.92 (2H, d), 7.00 (1H, dd), 7.11 (2H, d), 7.17 (1H, d), 7.63 (1H, d).

Intermediate 66b: 4-(4-(4-(4-oxopiperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Formic acid (17.08 mL, 445.36 mmol) was added to 4-(4-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (700 mg, 1.48 mmol) in MeOH (20 mL). The resulting mixture was stirred at 60 °C for 2 days and then concentrated. The residue was dissolved in EtOAc (50 mL). The resulting solution was washed with saturated NaHCO ₃ (50 mL x 2), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (600 mg, 95%) as a yellow gum; m/z ES ⁺ [M+Na]+ = 450.

Example 66: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}piperidin-1-yl)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 66b using the general synthetic method exemplified by Example 2 to give the title compound after purification by C18-flash chromatography (0-100% MeCN in water); ^1H NMR: (300 MHz) 1.40-1.67 (4H, m), 1.73-2.02 (5H, m), 2.23-2.43 (3H, m), 2.54-2.78 (6H, m), 2.77-2.93 (1H, m), 3.02 (2H, t), 3.19-3.32 (5H) , m), 3.61-3.72 (2H, m), 4.10-4.39 (4H, m), 5.03 (1H, dd), 6.86 (2H, d), 7.00-7.11 (4H, m), 7.25 (1H, dd), 7.31 (1H, d), 7.50 (1H, d), 7.79 (1 H, d), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 740.4.

Intermediate 67a: 5-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

Ruphos Pd G3 (65.3 mg, 0.08 mmol) was _added to 5-(4-(4-bromophenyl)piperidin-1-yl)-3-(trifluoromethyl)-picolinonitrile (320 mg, 0.78 mmol), 4-(dimethoxymethyl)piperidine (124 mg, 0.78 mmol), Cs ₂ CO ₃ (254 mg, 0.78 mmol) and Ruphos (36.4 mg, 0.08 mmol) in 1,4-dioxane (5 mL) under N 2 at room temperature. The resulting solution was stirred at 100 °C for 10 h and then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (200 mg, 53%) as a yellow solid; ^1H NMR (300 MHz) 1.18-1.38 (2H, m), 1.55-1.72 (5H, m), 1.82 (2H, d), 2.50-2.59 (2H, m), 2.64-2.80 (1H, m), 3.08 (2H, t), 3.25 (6H, s), 3.61 ( 2H, d), 4.06 (1H, d), 4.19-4.32 (2H, m), 6.83 (2H, d), 7.06 (2H, d), 7.61 (1H, d), 8.63 (1H, d); m/z ES ⁺ [M+H]+ = 489.

Intermediate 67b: 5-(4-(4-(4-formylpiperidin-1-yl)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile

5-(4-(4-(4-(Dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-3-(trifluoromethyl)picolinonitrile (190 mg, 0.39 mmol) was stirred in formic acid (2 mL) at room temperature for 2 h. The mixture was then concentrated to dryness and the resulting residue was dissolved in EtOAc (25 mL). The solution was washed with saturated NaHCO ₃ (20 mL x 3), then saturated brine (20 mL x 2), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (140 mg, 81%) which was used in the next step without further purification; m/z ES ⁺ [M+H]+ = 443.2.

Example 67: 5-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-(trifluoromethyl)pyridine-2-carbonitrile

Intermediate 2c was reacted with intermediate 67b using the general synthetic method exemplified by Example 2 to give the title compound (as a formate salt) after purification by preparative HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 26 B to 40 B in 7 min; 254/220 nm; RT1: 5.55 and MeCN as eluent); ^1H NMR: (300 MHz) 1.29-1.46 (2H, m), 1.56-1.75 (2H, m), 1.80-1.92 (4H, m), 1.92-2.09 (2H, m), 2.26-2.47 (3H, m), 2.58-2.95 (5H, m), 3.04-3. 30 (9H, m), 3.96-4.08 (2H, m), 4.21-4.42 (5H, m), 5.08 (1H, dd), 6.98 (2H, d), 7.12-7.23 (4H, m), 7.58-7.66 (2H, m), 8.66 (1H, d), 10.97 (1H, s); m/z ES ⁺ [M+H]+ = 755.4.

Intermediate 68a: 4-(4-(5-bromopyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

5-Bromo-2-(piperidin-4-yl)pyridine (486 mg, 2.02 mmol) was added to 4-fluoro-2-(trifluoromethyl)-benzonitrile (400 mg, 2.12 mmol) and Cs ₂ CO ₃ (1.723 g, 5.29 mmol) in DMSO (5 mL) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The mixture was then diluted with EtOAc (50 mL), washed with water (50 mL x 3), then saturated brine (50 mL x 2), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) gave the title compound (224 mg, 31%) as a white solid; m/z ES ⁺ [M+H]+ = 410.

Intermediate 68b: 4-(4-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Ruphos Pd G3 (40.8 mg, 0.05 mmol) was added to 4-(dimethoxymethyl)piperidine (116 mg, 0.73 mmol), Cs ₂ CO ₃ (477 mg, 1.46 mmol) and 4-(4-(5-bromopyridin-2-yl ₎ piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (200 mg, 0.49 mmol) in dioxane (5 mL) under N 2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-80% EtOAc in petroleum ether) gave the title compound (0.160 g, 67%) as a yellow solid; ^1H NMR (300 MHz) 1.21-1.40 (2H, m), 1.59-1.77 (5H, m), 1.88 (2H, d), 2.61 (2H, dd), 2.83-2.98 (1H, m), 3.08 (2H, t), 3.26 (6H, s), 3.68 (2H, d) ), 4.08 (1H, d), 4.15 (2H, d), 7.10 (1H, d), 7.21-7.30 (2H, m), 7.31 (1H, d), 7.80 (1H, d), 8.17 (1H, d); m/z ES ⁺ [M+H]+ = 489.

Intermediate 68c: 4-(4-(5-(4-formylpiperidin-1-yl)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

4-(4-(5-(4-(Dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.31 mmol) was added formic acid (5 mL, 0.31 mmol) at room temperature, and the mixture was stirred for 4 h. The reaction was then quenched with saturated NaHCO ₃ and extracted with EtOAc. The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.160 g, 118%) as a yellow gum, which was used in the next step without further purification; ^1H NMR (300 MHz) 1.52-1.78 (6H, m), 1.84-1.93 (3H, m), 2.74-2.88 (2H, m), 3.08 (3H, t), 3.59 (2H, dt), 4.16 (2H, d), 7.11 (1H, d), 7.22-7.35 ( 3H, m), 7.81 (1H, d), 8.20 (1H, d), 9.63 (1H, s); m/z ES ⁺ [M+H]+ = 443.

Example 68: 4-(4-{5-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridin-2-yl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 68c using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 15 B to 25 B in 7 min; 254/220 nm; RT1:7.52); ^1H NMR: (300 MHz) 1.10-1.32 (2H, m), 1.66-1.97 (8H, m), 2.23 (2H, d), 2.37 (1H, dd), 2.59-2.77 (3H, m), 2.82-2.95 (2H, m), 3.09 (2H, t), -3.60 (8H, m), 3.69 (2H, d), 4.12-4.39 (4H, m), 5.06 (1H, dd), 7.04-7.15 (3H, m), 7.25-7.34 (3H, m), 7.53 (1H, d), 7.82 (1H, d), 8.20 (1H, d), 10.96 (1H, s); m/z ES ⁺ [M+H]+ = 755.4.

Intermediate 69a: 4-[(3 r )-3-[4-[4-(2,2-dimethoxyethyl)-1-piperidyl]phenyl]pyrrolidin-1-yl]-2-(trifluoro-methyl)benzonitrile

Ruphos Pd G3 (85 mg, 0.10 mmol) was added to Ruphos (47.2 mg, 0.10 mmol), 4-(2,2-dimethoxyethyl)-piperidine (259 mg, 1.49 mmol), Cs ₂ CO ₃ (989 mg, 3.04 mmol) and 4-[(3 r )-3-(4-bromophenyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (intermediate 65b) (400 mg, 1.01 mmol) in _1,4- dioxane (10 mL) under N 2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. The residue was purified by FSC (gradient: 0-25% EtOAc in petroleum ether) to give the title compound (0.140 g, 28%) as a yellow solid; ^1H NMR (300 MHz) 1.22-1.32 (3H, m), 1.46 (3H, d), 1.72 (2H, d), 1.99-2.10 (1H, m), 2.24-2.36 (1H, m), 2.49-2.63 (2H, m), 3.20 (6H, s), 3.51 (2H, m), 3.52-3.65 (3H, m), 3.74-3.86 (1H, m), 4.46 (1H, t), 6.80-6.93 (4H, m), 7.15 (2H, d), 7.77 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 488.

Intermediate 69b: ( r )-4-(3-(4-(4-(2-oxoethyl)piperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)-benzonitrile

4-[(3 r )-3-[4-[4-(2,2-Dimethoxyethyl)-1-piperidyl]phenyl]pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (140 mg, 0.29 mmol) was added to formic acid (5 mL) at room temperature, and the mixture was stirred for 2 h. After that, the reaction was quenched with saturated NaHCO ₃ , and the resulting mixture was extracted with EtOAc. The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.157 g, 124%) as a yellow solid, which was used directly in the next step; ^1H NMR (300 MHz) 1.23-1.32 (2H, m), 1.72 (2H, d), 1.89-2.12 (2H, m), 2.24-2.38 (1H, m), 2.40 (2H, dd), 2.56-2.71 (2H, m), 3.35-3.53 (2H, m), 3.53-3.67 (3H, m), 3.76-3.88 (1H, m), 4.22 (1H, t), 6.83-6.95 (4H, m), 7.17 (2H, d), 7.78 (1H, d), 9.70 (1H, t); m/z ES ⁺ , [M+H] ⁺ = 442.

Example 69: 4-[(3r ) -3-{4-[4-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]-piperazin-1-yl}ethyl)piperidin-1-yl]phenyl}pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Intermediate 2c was reacted with intermediate 69b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 20 B to 30 B in 7 min; 254/220 nm; RT1:8.33); ^1H NMR: 1.20-1.33 (2H, m), 1.30- 1.50 (3H, m), 1.77 (2H, d), 1.91-2.01 (1H, m), 2.01-2.11 (1H, m), 2.29-2.44 (5H, m), 2.52-2.66 (4H, m), 2 .91 (1H, ddd), 3.22-3.33 (8H, m), 3.40-3.80 (4H, m), 3.78-3.90 (1H, m), 4.21 (1H, d), 4.33 (1H, d), 5.05 (1H, dd), 6.82-6.96 (4H, m), 7.06 (2H) ,d), 7.17 (2H, d), 7.52 (1H, d), 7.79 (1H, d), 10.96 (1H, s); m/z ES ⁺ [M+H]+ = 754.3.

Intermediate 70a: ( s )-4-(3-(4-(3-hydroxypropoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

RockPhos Pd G3 (63.6 mg, 0.08 mmol) was added to ( s )-4-(3-(4-bromophenyl)pyrrolidin-1-yl)-2-(trifluoro-methyl)benzonitrile (intermediate _65c ) (300 mg, 0.76 mmol), propane-1,3-diol (87 mg, 1.14 mmol) and Cs ₂ CO ₃ (742 mg, 2.28 mmol) in 1,4-dioxane (5 mL) at room temperature under N 2 . The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) afforded the title compound (120 mg, 41%) as a white solid; ^1H NMR: 1.84 (2H, p), 2.06 (1H, ddd), 2.37 (1H, ddt), 3.32 (1H, s), 3.43-3.57 (4H, m), 3.60 (1H, ddd), 3.85 (1H, dd), 4.01 (2H, t), 4.53 (1H, t) ), 6.83-6.92 (3H, m), 6.94 (1H, d), 7.25 (2H, d), 7.79 (1H, d); m/z ES ⁺ [M+H] ⁺ = 391.

Intermediate 70b: ( s )-4-(3-(4-(3-bromopropoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

PPh ₃ (134 mg, 0.51 mmol) was added to DCM at room temperature. ( s )-4-(3-(4-(3-hydroxypropoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoro-methyl)benzonitrile (100 mg, 0.26 mmol) and CBr ₄ (170 mg, 0.51 mmol) were added to (3 mL). The mixture was stirred for 1 h and concentrated. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (101 mg, 87%) as a colorless gum; ^1H NMR: 2.01-2.14 (1H, m), 2.23 (2H, p), 2.37 (1H, dtd), 3.33-3.36 (1H, m), 3.41-3.56 (2H, m), 3.60 (1H, ddd), 3.66 (2H, t), 3.85 (1H, dd), 4 .06 (2H, t), 6.87 (1H, dd), 6.91-6.96 (3H, m), 7.27 (2H, d), 7.79 (1H, d); m/z ES ⁺ [M+H]+ = 453.

Example 70: 4-{(3s ) -3-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]piperazin-1-yl}propoxy)phenyl]pyrrolidin-1-yl}-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Intermediate 2c was reacted with intermediate 70b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 30 B to 40 B in 7 min; 254/220 nm; RT1:5.23); ^1H NMR: (300 MHz) 1.84-2.05 (3H, m), 2.10 (1H, dd), 2.26-2.40 (3H, m), 2.51-2.65 (4H, m), 2.91 (1H, m), 3.25-3.48 (9H, m), 3.60 (1H, ddd), 5 (1H, dd), 4.02 (2H, t), 4.21-4.33 (2H, m), 5.06 (1H, dd), 6.82-6.94 (4H, m), 7.07 (2H, d), 7.22-7.31 (2H, m), 7.53 (1H, d), 7.79 (1H, d), 10 .96 (1H, s); m/z ES ⁺ [M+H]+ = 701.3.

Intermediate 71a: ( r )-4-(3-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)-benzonitrile

Ruphos Pd G3 (85 mg, 0.10 mmol) was added Ruphos (47.2 mg, 0.10 mmol), 4-(dimethoxymethyl)-piperidine (259 mg, 1.49 mmol), Cs ₂ CO ₃ (989 mg, 3.04 mmol) and ( r )-4-(3-(4-bromophenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 65b) (400 mg, 1.01 mmol), which was then added to 1,4-dioxane (10 mL) (at room temperature). The resulting solution was stirred at 100 °C for 16 h. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (207 mg, 86%) as a yellow solid; ¹ H NMR (300 MHz) 0.85-0.97 (1H, m) 1.13-1.43 (3H, m), 1.70 (3H, d), 1.97-2.15 (1H, m), 2.36 (1H, d,), 2.60 (1H, d), 3.27 (6H, s), 3.46 (1H, d) , 3.54-3.67 (2H, m), 3.69 (1H, s), 3.77-3.89 (1H, m), 4.08 (1H, d), 6.85-6.91 (3H, m), 7.17 (2H, d), 7.79 (1H, d); m/z ES ⁺ [M+H] ⁺ = 474.

Intermediate 71b: ( r )-4-(3-(4-(4-formylpiperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

( r )-4-(3-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.38 mmol) was added formic acid (5 mL) at room temperature, and the mixture was stirred for 1 h. The reaction was then quenched with saturated NaHCO ₃ . The resulting mixture was extracted with EtOAc, and the organic extracts were dried (Na ₂ SO ₄ ) and concentrated to give the title compound (204 mg, 126%) as a yellow gum, which was used in the next step without further purification; ^1H NMR (300 MHz) 1.48-1.71 (3H, m), 1.86-1.97 (2H, m), 1.96-2.12 (1H, m), 2.26-2.41 (1H, m), 2.74-2.85 (2H, m), 3.35-3.53 (2H, m), 3.56 (3H, dt), 3.76-3.88 (1H, m), 4.22 (1H, t), 6.81-6.95 (4H, m), 7.18 (2H, d), 7.78 (1H, d), 9.63 (1H, s); m/z ES ⁺ [M+H] ⁺ = 428.

Example 71: 4-[(3r ) -3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]-piperazin-1-yl}methyl)piperidin-1-yl]phenyl}pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Intermediate 2c was reacted with intermediate 71b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A); ^1H NMR: (300 MHz) 1.11-1.34 (2H, m), 1.65-1.88 (3H, m), 1.94-2.14 (2H, m), 2.22-2.43 (4H, m), 2.52-2.73 (6H, m), 2.82-3.00 (1H, m), 3.40-3. 51 (7H, m), 3.54-3.74 (4H, m), 3.83 (1H, dd), 4.16-4.41 (2H, m), 5.06 (1H, dd), 6.83-6.97 (4H, m), 7.08 (2H, d), 7.18 (2H, d), 7.54 (1H, 7) .79 (1H, d), 10.96 (1H, s); m/z ES ⁺ [M+H]+ = 740.3.

Intermediate 72a: 4-(4-(4-(methylamino)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Cs ₂ CO ₃ (1194 mg, 3.67 mmol) was added to 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (500 mg, 1.22 mmol) in 1,4-dioxane (5.3 mL) and a solution of 2 M methanamine in THF (794 μL, 1.59 mmol). The reaction was degassed, and BrettPhos Pd G3 (55.4 mg, 0.06 mmol) and BrettPhos (32.8 mg, 0.06 mmol) were added. The resulting mixture was stirred at 80 °C under N ₂ for 18 h. The reaction was then quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL), and the combined organic solutions were dried (MgSO ₄ ) and concentrated. The residue was purified by FSC (gradient: 3:1 EtOAc/EtOH from 0 to 50% in EtOAc) to afford the title compound (318 mg, 72%) as a beige solid; ¹ H NMR: 1.58 (2H, qd), 1.82 (2H, d), 2.64 (3H, d), 2.65-2.7 (1H, m), 2.95-3.1 (2H, m), 4.15 (2H, d), 5.39 (1H, q), 6.47 (2H, d), 6.97 (2H, d), 7.26 (1H, dd), 7.31 (1H, d), 7.80 (1H, d); m/z : ES ⁺ [M+H] ⁺ 359.6.

Intermediate 72b: 5-(4-(3-(1,3-dioxolan-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride salt (250 mg, 0.66 mmol), 2-(3-bromopropyl)-1,3-dioxolane (0.134 mL, 0.99 mmol), KI (329 mg, 1.98 mmol), and DIPEA (0.461 mL, 2.64 mmol) were dissolved in MeCN (10 mL) and stirred at 70 °C for 4 h. After cooling to room temperature, water (10 mL) was added. The mixture was extracted with DCM (2 x 50 mL) and the combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0-10% MeOH in DCM) to give the title compound (220 mg, 73%) as a yellow solid; ^1H NMR (CDCl ₃ ) 1.62-1.68 (2H, m), 1.69-1.76 (2H, m), 2.07-2.18 (1H, m), 2.40-2.49 (2H, m), 2.55-2.63 (4H, m), 2.67-2.8 (1H, m), 2.8-2.94 (2 H, m), 3.40-3.46 (4H, m), 3.83-3.89 (2H, m), 3.95-4.01 (2H, m), 4.85-4.98 (2H, m), 7.05 (1H, dd), 7.28 (1H, d), 7.69 (1H, d), 8.00 (1H, s); m/z : ES ⁺ [M+H] ⁺ 457.4.

Intermediate 72c: 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butanal

At room temperature under air, formic acid (2 mL) was added to 5-(4-(3-(1,3-dioxolan-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (125 mg, 0.27 mmol). The resulting solution was stirred at 40 °C for 0.5 h and then diluted with toluene (3 mL). The solvent was removed under reduced pressure and the resulting residue was dissolved in toluene (3 mL), which was then concentrated again to give the title compound as a yellow gum (assumed 100% yield) which was used in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ 413.

Example 72: 4-(4-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butyl)(methyl)amino]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 72a was reacted with intermediate 72c using the general synthetic method exemplified by Example 2 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ^1H NMR: 1.52 (4H, d), 1.55-1.64 (2H, m), 1.83 (2H, d), 2.01 (1H, dd), 2.36 (2H, d), 2.50 (4H, s), 2.55-2.67 (1H, m), 2.67-2.74 (1H, m), 2.8 5 (3H, s), 2.86-2.94 (1H, m), 3.03 (2H, t), 3.30 (3H, t), 3.41-3.47 (4H, m), 4.15 (2H, d), 5.07 (1H, dd), 6.65 (2H, d), 7.04 (2H, d), 7.25 (2H) , dd), 7.32 (2H, dd), 7.68 (1H, d), 7.80 (1H, d), 8.16 (2H, s), 11.06 (1H, s); m/z ES ⁺ [M+H]+ = 756.0.

Example 73: 4-(4-{4-[4-({4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -Pyrrolo[3,4- b ]pyridin-2-yl]-piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 4c was reacted with intermediate 56k using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 25 B to 35 B in 7 min; 254/220 nm; RT1:6.95); ^1H NMR: (300 MHz) 1.22 (2H, q), 1.52-1.69 (3H, m), 1.77-1.87 (4H, m), 1.92-2.03 (1H, m), 2.21 (2H, d), 2.36 (1H, dd), 2.45 (3H, t), (4H, m), 2.82-3.10 (3H, m), 3.64 (7H, m), 4.04-4.34 (4H, m), 5.08 (1H, dd), 6.89 (3H, dd), 7.08 (2H, d), 7.23-7.36 (2H, m), 7.80 (2H, dd), 10 .96 (1H, s); m/z ES ⁺ [M+H]+ = 755.4.

Intermediate 74a: tert -Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-diazepane-1-carboxylate

Pd-PEPPSI Ipent (0.123 g, 0.15 mmol) was added to 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.00 g, 3.09 mmol), tert-butyl 1,4-diazepane-1 _- carboxylate (0.806 g, 4.02 mmol) and Cs ₂ CO ₃ (3.02 g, 9.28 mmol) in 1,4-dioxane (15 mL) at room temperature under N 2 . The resulting mixture was stirred at 90 °C for 16 h. After cooling, the mixture was poured into DCM (200 mL). The resulting solution was washed with 5% AcOH (200 mL), then water (200 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0–10% EtOH in EtOAc) to afford the title compound (0.400 g, 29%) as a white solid; m/z ES ⁺ [M+H] ⁺ = 443.

Intermediate 74b: 3-(5-(1,4-diazepan-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-diazepane-1-carboxylate (390 mg, 0.88 mmol) was added hydrochloric acid (0.134 mL, 4.41 mmol) in 1,4-dioxane (5 mL) at room temperature, and the mixture was stirred for 2 h. The mixture was then concentrated to give the title compound as a hydrochloride salt (300 mg, 99%) as a brown solid, which was used in the next step without further purification; ^1H NMR (300 MHz) 1.90-1.98 (1H, m), 2.03-2.15 (2H, m), 2.35 (1H, qd), 2.57 (1H, d), 2.89 (1H, ddd), 2.99-3.11 (2H, m), 3.14-3.26 (2H, m), 3.59 (2H, t), 3.80 (2H, t), 4.18 (1H, d), 4.30 (1H, d), 5.02 (1H, dd), 6.85-6.93 (2H, m), 7.50 (1H, d), 9.27 (1H, s), 10.92 (1H, s); m/z ES ⁺ [M+H] ⁺ = 343.

Example 74: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-1,4-diazepan-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 4c was reacted with intermediate 74b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 25 B to 35 B in 7 min; 254/220 nm; RT1:7.70); ¹ H NMR: (300 MHz) 1.02-1.21 (2H, m), 1.46-2.00 (11H, m), 2.20-2.40 (4H, m), 2.49-2.61 (3H, m), 2.63-2.77 (3H, m), 2.82-3.07 (3H, m), 3.48-3 .66 (6H, m), 4.15 (3H, d), 4.28 (1H, d), 5.01 (1H, dd), 6.76-6.85 (4H, m), 7.05 (2H, d), 7.20-7.34 (2H, m), 7.45 (1H, d), 7.79 (1H, d), 10.92 ( 1H, s); m/z ES ⁺ [M+H]+ = 768.4.

Intermediate 75a: 4-[(3 r )-3-[4-(4-hydroxybutoxy)phenyl]pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile

Rockphos Pd G3 (83.8 mg, 0.10 mmol) was added to Cs ₂ CO ₃ (975 mg, 2.99 mmol), butane-1,4-diol (135 mg, 1.50 mmol) and 4-[(3 r )-3-(4-bromophenyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (intermediate 65b) (400 mg, 1.01 mmol) in dioxane (10 mL). The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-25% EtOAc in petroleum ether) gave the title compound (0.204 g, 50%) as a yellow liquid; ^1H NMR: 1.51-1.59 (2H, m), 1.69-1.77 (2H, m), 2.02-2.14 (1H, m), 2.31-2.43 (1H, m), 3.39-3.53 (5H, m), 3.61 (1H, t), 3.85 (1H, dd), 3.96 (2 H, t), 4.23 (1H, t), 6.84-6.92 (3H, m), 6.94 (1H, d), 7.23-7.28 (2H, m), 7.80 (1H, d).

Intermediate 75b: ( r )-4-(3-(4-(4-oxobutoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

Dess-Martin periodinane (450 mg, 1.06 mmol) was added to (4-[(3 r )-3-[4-(4-hydroxybutoxy)phenyl]pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (203.8 mg, 0.50 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 1 h. The mixture was then quenched with saturated NaHCO ₃ . The resulting mixture was extracted with DCM, and the organic extracts were dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-25% EtOAc in petroleum ether) gave the title compound (0.094 g, 46%) as a brown liquid; ¹ H NMR: 1.91-2.02 (3H, m), 2.03-2.11 (1H, m), 2.37 (1H, dtd), 2.59 (2H, td), 3.41-3.55 (2H, m), 3.60 (1H, ddd), 3.84 (1H, dd), 3.96 (2H, t), 6.84-6.91 (3H, m), 6.94 (1H, d), 7.26 (2H, d), 7.79 (1H, d), 9.71 (1H, t); m/z ES ⁺ [M+H]+ = 403.

Example 75: 4-{(3R ) -3-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]pyrrolidin-1-yl}-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Intermediate 2c was reacted with intermediate 75b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A); ^1H NMR: 1.65 -1.75 (4H, m), 1.92-2.08 (2H, m), 2.32-2.41 (5H, m), 2.57-2.61 (7H, m), 2.91 (1H, m), 3.48-3.61 (5H, m), 3.85 (1H, m), 3.99 (2H) , t), 4.21 (1H, d), 4.33 (1H, d), 5.05 (1H, m), 6.83-6.95 (4H, m), 7.06-7.08 (2H, s), 7.22-7.30 (2H, m), 7.53 (1H, d), 7.80 (1H, d), 10.96 (1) H, s); m/z ES ⁺ [M+H]+ = 715.3.

Intermediate 76a: Methyl 4-(piperidin-4-yl)benzoate

At 0 °C under air, SOCl ₂ (24.15 g, 203.03 mmol) was added to 4-(1-( tert -Butoxycarbonyl)piperidin-4-yl)benzoic acid (12.40 g, 40.61 mmol) in MeOH (20 mL). The resulting solution was stirred at 70 °C for 15 h, and then concentrated to give the title compound (8.70 g, 39.7 mmol); ^1H NMR (CD ₃ OD) 1.86-2.04 (2H, m), 2.11 (2H, d), 3.02 (1H, tt), 3.17 (2H, t), 3.53 (2H, d), 3.91 (3H, s), 7.37-7.47 (2H, m), 7.95-8.05 (2H, m) ); m/z ES ⁺ , [M+H] ⁺ = 220.

Intermediate 76b: 4-(piperidin-4-yl)phenyl)methanol

LiAlH ₄ (2.5 M in THF, 176 mL, 198.35 mmol) was added to methyl 4-(piperidin-4-yl)benzoate (8.70 g, 39.67 mmol) in THF (90 mL) at 0 °C. The mixture was then stirred at room temperature for 2 h, after which it was quenched by the addition of Na ₂ SO ₄ .H ₂ O. The mixture was then filtered, and the filtrate was concentrated. Purification by FSC (gradient: 0-20% MeOH in DCM (containing 0.3% Et ₃ N)) gave the title compound (7.40 g, 97%) as a white solid; ¹ H NMR (CD ₃ OD, 300 MHz) 1.67 (2H, qd), 1.76-1.87 (2H, m), 2.65 (1H, dt), 2.70-2.80 (2H, m), 3.15 (2H, dt), 4.58 (2H, s), 7.23 (2H, d), 7.30 ( 2H, d); m/z ES ⁺ , [M+H] ⁺ = 192.

Intermediate 76c: 4-(4-(4-(hydroxymethyl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-Fluoro-2-(trifluoromethyl)benzonitrile (6.72 g, 35.55 mmol) was added to Cs ₂ CO ₃ (34.70 g, 106.65 mmol) and (4-(piperidin-4-yl)phenyl)methanol (6.80 g, 35.55 mmol) in DMF (50 mL) at room temperature under air, and the mixture was stirred for 15 h. The mixture was then diluted with EtOAc (150 mL), washed with saturated brine (100 mL x 3), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-60% EtOAc in petroleum ether) gave the title compound (9.20 g, 72%) as a white solid; ^1H NMR (CD ₃ OD, 300 MHz) 1.78 (2H, qd), 1.90-2.03 (2H, m), 2.76-2.91 (1H, m), 3.09 (2H, tt), 4.07-4.24 (2H, m), 4.58 (2H, s), 7.14-7.26 (3H, m), 7.27-7.35 (3H, m), 7.69 (1H, dd); m/z ES ⁺ , [M+H] ⁺ = 361.

Intermediate 76d: 4-(4-(4-formylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Dess-Martin periodinane (15.36 g, 36.21 mmol) was added to 4-(4-(4-(hydroxymethyl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (8.70 g, 24.14 mmol) in DCM (5 mL) at room temperature under air, and the mixture was stirred for 3 h. The mixture was then diluted with DCM (50 mL), washed with saturated brine (50 mL x 7), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (5.30 g, 61%) as a white solid; ^1H NMR (CD ₃ OD) 1.77-1.91 (2H, m), 2.01 (2H, ddd), 2.99 (1H, tt), 3.13 (2H, td), 4.20 (2H, dp), 7.23 (1H, dd), 7.32 (1H, d), 7.47-7.53 (2H, m), 7.72 (1H, d), 7.85-7.91 (2H, m), 9.96 (1H, s).

Intermediate 76e: tert -Butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carboxylate

NaBH(OAc) ₃ (3.23 g, 15.23 mmol) was added to 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.05 mmol), tert -butyl 4-oxopiperidine-1-carboxylate (0.607 g, 3.05 mmol) and Ti(OEt) ₄ (1.389 g, 6.09 mmol) in 1,2-dichloroethane (50 mL) at room temperature, and the mixture was stirred for 3 h. The mixture was then poured into water (100 mL), and the resulting mixture was filtered through celite. The filtrate was extracted with DCM (2 x 100 mL), and the combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0–10% MeOH in DCM) to afford the title compound (0.500 g, 32%) as a yellow solid; m/z ES ⁺ , [M+H] ⁺ = 512.

Intermediate 76f: 3-(1-oxo-5-(4-(piperidin-4-yl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

4 M HCl in 1,4-dioxane (1.955 mL, 7.82 mmol) was added dropwise over a period of 2 min to tert -butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carboxylate (400 mg, 0.78 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 2 h. It was then concentrated under reduced pressure to afford the title compound (300 mg, 79%) as the hydrochloride salt as a white solid; m/z ES ⁺ , [M+H] ⁺ = 412.

Example 76: 4-(4-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}piperidin-1-yl)methyl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 76d was reacted with intermediate 76f using the general synthetic method exemplified by Example 2 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). t; ^1H NMR: 1.43 (2H, q), 1.65 (2H, td), 1.75 (2H, d), 1.87 (2H, d), 1.91-2.01 (3H, m), 2.22 (1H, d), 2.36 (1H, qd), 2.62 (5H, t), 2.76-2.97 (4H, m), 3.00-3.11 (2H, m), 3.26 (4H, t), 3.45 (2H, s), 4.15-4.24 (3H, m), 4.32 (1H, d), 5.04 (1H, dd), 7.04 (2H, d), 7.21-7.27 (5H, m), 7.33 (1H) , d), 7.48-7.54 (1H, m), 7.82 (1H, d), 8.16 (1H, s), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 754.4.

Intermediate 77a: 3-(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.39 mmol) and 2-(2-(2-bromoethoxy)-ethoxy)ethan-1-ol (100 mg, 0.47 mmol) were added to DIPEA (0.067 mL, 0.39 mmol) in NMP (0.5 mL). The resulting mixture was stirred at 130 °C for 12 h, then concentrated to give the title compound as a brown dry film, which was used in the next step without further purification; ^1H NMR: 2.00-2.07 (1H, m), 2.27-2.36 (1H, m), 2.57-2.66 (1H, m), 2.86-3.00 (1H, m), 3.33 (2H, t), 3.36-3.64 (11H, m), 3.70-3.78 (1H, m), 4 .13 (1H, d), 4.25 (1H, d), 5.12 (1H, dd), 6.83 (1H, d), 6.96 (1H, d), 7.30 (1H, t), 11.02 (1H, s); m/z ES ⁺ [M+H]+ = 392.

Intermediate 77b: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl methanesulfonate

Methanesulfonic anhydride (89 mg, 0.51 mmol) was added 3-(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.26 mmol) and Et ₃ N (107 μL, 0.77 mmol) in DCM (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 1.5 h. The mixture was then diluted with DCM (20 mL), washed with water (20 mL), then saturated brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (120 mg, 100%) as a yellow gum, which was used in the next step without further purification; m / z ES ⁺ [M+H]+ = 470.

Example 77: 4-[4-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-4-yl]amino}-ethoxy)ethoxy]ethoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

4-(4-(4-Hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (90 mg, 0.26 mmol) was added to NaH (31.2 mg, 0.78 mmol) in DMF (1 mL) and stirred at room temperature for 2 h. Then 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-isoindolin-4-yl)amino)ethoxy)ethoxy)ethyl methanesulfonate (122 mg, 0.26 mmol) was added, and the mixture was stirred for 2 h. The residue was purified by preparative HPLC (SunFire Prep C18 OBD column, 30x150 mm 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: MeCN) to give the title compound (10 mg, 5%) as a white solid. ^1H NMR: 1.54-1.68 (2H, m), 1.84 (2H, d), 2.27 (1H, td), 2.55-2.64 (1H, m), 2.75 (1H, d), 2.92 (1H, ddd), 3.04 (2H, t), 3.59 (6H, qd), 3.68-3. 75 (2H, m), 4.00-4.06 (2H, m), 4.08-4.27 (4H, m), 5.11 (1H, dd), 5.60 (1H, q), 6.72-6.85 (1H, m), 6.81-6.91 (2H, m), 6.94 (1H, d), (2H, m), 7.19-7.31 (2H, m), 7.33 (1H, d), 7.82 (1H, d), 11.02 (1H, s); m/z ES ⁺ [M+H] ⁺ = 720.3.

Intermediate 78a: rac-4-(3-(4-bromophenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (5.79 mL, 33.17 mmol) was added to racemic 3-(4-bromophenyl)pyrrolidine (2.50 g, 11.06 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (2.09 g, 11.06 mmol) in MeCN (50 mL). The resulting mixture was stirred at 50 °C for 3 h. The mixture was concentrated to dryness, and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (100 mL x 2), then saturated brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 1-20% EtOAc in petroleum ether) gave the title compound (2.20 g, 50%) as a colorless oil which solidified on standing; m/z ES ⁺ [M+H] ⁺ = 395.

Intermediate 78b: 4-(3-(4-(4-((( tert -Butyldimethylsilyl)oxy)methyl)piperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

RuPhos Pd G3 (85 mg, 0.10 mmol) was _added to 4-(3-(4-bromophenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)-benzonitrile (400 mg, 1.01 mmol), 4-((( tert -butyldimethylsilyl)oxy)methyl)piperidine (348 mg, 1.52 mmol), RuPhos (47.2 mg, 0.10 mmol) and Cs ₂ CO ₃ (989 mg, 3.04 mmol) in 1,4-dioxane (5 mL) under N 2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (0-100% EtOAc in heptane) afforded the title compound (440 mg, 80%) as a yellow liquid; ^1H NMR (300 MHz) 0.02 (6H, s), 0.85 (9H, s), 1.25 (2H, dd), 1.53 (1H, s), 1.70 (2H, d), 2.05 (1H, q), 2.33 (1H, s), 2.51-2.65 (2H, m), 3.43 -3.45 (4H, m), 3.56 (1H, d), 3.64 (2H, d), 3.74-3.90 (1H, m), 6.80-6.96 (4H, m), 7.15 (2H, d), 7.30-7.37 (1H, m), 7.78 (1H, dd); m/z ES ⁺ [M+H] ⁺ = 544.

Intermediate 78c: 4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

Tetra- n -butylammonium fluoride (in THF, 2.94 mL, 2.94 mmol) was added 4-(3-(4-(4-((( tert -butyldimethyl-silyl)oxy)methyl)piperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (400 mg, 0.74 mmol) in THF (10 mL) at room temperature. The resulting solution was stirred at room temperature for 1.5 h. The mixture was then diluted with EtOAc, washed with water, then with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (239 mg, 75%) as a white solid; ^1H NMR (300 MHz) 1.22 (2H, qd), 1.55-1.43 (1H, m), 1.77-1.66 (2H, m), 2.07 (1H, q), 2.35 (1H, tt), 2.59 (3H, td), 3.28 (2H, dd), 3.45 (2H, td), 3.61-3.54 (1H, m), 3.64 (2H, dd), 3.82 (1H, dd), 4.47 (1H, t), 6.96-6.81 (4H, m), 7.21-7.12 (2H, m), 7.78 (1H, d); m/z ES ⁺ [M+H] ⁺ = 430.

Intermediate 78d: 4-(3-(4-(4-formylpiperidin-1-yl)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)-benzonitrile

Dess-Martin periodinane (415 mg, 0.98 mmol) was added to 4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)-phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (210 mg, 0.49 mmol) in DCM (5 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. The mixture was then diluted with DCM, washed with saturated NaHCO ₃ , then saturated brine, dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (75 mg, 36%) as a yellow solid; ^1H NMR (300 MHz) 1.57 (2H, dtd), 1.92 (2H, dd), 2.04 (1H, dd), 2.35 (1H, d), 2.54 (2H, s), 2.79 (2H, td), 3.27 (1H, s), 3.46 (3H, td), 3.56 (3 H, dt), 3.82 (1H, dd), 6.96-6.81 (4H, m), 7.23-7.13 (2H, m), 7.78 (1H, d), 9.63 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 428.

Example 78: 4-(3-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 78d using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (Column: SunFire C18 OBD Prep column, , 100Å, 5 μm, 19 mm x 250 mm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 25 mL/min; Gradient: from 30 B to 45 B in 7 min; 254/220 nm; RT1:6.50); ^1H NMR: (300MHz) 1.14-1.38 (2H, m), 1.82 (3H, d), 1.92-2.14 (2H, m), 2.18-2.44 (8H, m), 2.60-2.68 (6H, m), 2.82-3.01 (1H, m), 3.45-3.49 (4H, m), 3.62-3.65 (3H, m), 3.78-3.89 (1H, m), 4.21 (1H, d), 4.35 (1H, d), 5.06 (1H, dd), 6.85-6.98 (4H, m), 7.08 (2H, d), 7.18 (2H, d), 7.54 (1H, d), 7.80 (1H, d), 10.96 (1H, s); m/z ES ⁺ [M+H]+ = 740.4.

Intermediate 79a: ( s )-4-(3-(4-(4-hydroxybutoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

RockPhos Pd G3 (85 mg, 0.10 mmol) was added to ( s )-4-(3-(4-bromophenyl)pyrrolidin-1-yl)-2-(trifluoro-methyl)benzonitrile (intermediate _65c ) (400 mg, 1.01 mmol), 1,4-butanediol (137 mg, 1.52 mmol) and Cs ₂ CO ₃ (989 mg, 3.04 mmol) in 1,4-dioxane (10 mL) at room temperature under N 2 . The resulting mixture was stirred at 100 °C for 16 h and then concentrated. Purification by FSC (gradient: 0-25% EtOAc in petroleum ether) afforded the title compound (177 mg, 43%) as a yellow gum; ^1H NMR: 1.55 (2H, dq), 1.72 (2H, dq), 2.01-2.12 (1H, m), 2.29-2.42 (1H, m), 3.33-3.35 (1H, m), 3.41-3.53 (4H, m), 3.60 (1H, ddd), 3.84 (1H, dd), 3.95 (2H, t), 4.44 (1H, t), 6.83-6.93 (3H, m), 6.94 (1H, d), 7.25 (2H, d), 7.79 (1H, d).

Intermediate 79b: ( s )-4-(3-(4-(4-oxobutoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile

Dess-Martin periodinane (236 mg, 0.56 mmol) was added to ( s )-4-(3-(4-(4-hydroxybutoxy)phenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.37 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM, washed with saturated NaHCO ₃ then saturated brine, dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (127 mg, 85%) as a yellow gum; m / z ES ⁺ [M+H] ⁺ = 403.

Example 79: 4-{(3s ) -3-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]pyrrolidin-1-yl}-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Intermediate 2c was reacted with intermediate 79b using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (Column: SunFire C18 OBD Prep column, 100Å, 5 μm, 19 mm x 250 mm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 25 mL/min; Gradient: from 42% to 50% in 7 min; 254/220 nm; RT1:5.56); ^1H NMR: (300 MHz) 1.68-1.83 (4H, m), 1.90-2.11 (2H, m), 2.25-2.46 (5H, m), 2.51-2.65 (6H, m), 2.84-3.00 (2H, m), 3.41-3.66 (5H, m), 3.85 (1H) , dd), 3.99 (2H, d), 4.22 (1H, d), 4.35 (1H, d), 5.06 (1H, dd), 6.83-6.98 (4H, m), 7.05-7.17 (2H, m), 7.27 (2H, d), 7.56 (1H, d), 7.80 (1H, d), 10.97 (1H, s); m/z ES ⁺ [M+H]+ = 715.4.

Intermediate 80a: 4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), 4-(dimethoxy-methyl)piperidine (0.467 g, 2.93 mmol), RuPhos G3 (0.153 g, 0.18 mmol), RuPhos (0.086 g, 0.18 mmol), and sodium tert -butoxide (0.704 g, 7.33 mmol) were dissolved in anhydrous 1,4-dioxane (24.4 mL). The mixture was degassed under N ₂ and stirred at 100 °C overnight. The mixture was then cooled and concentrated. Water (10 mL) was added, and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.393 g, 33%) as a pale yellow solid; ^1H NMR (CDCl ₃ ) 1.45 (2H, qd), 1.67-1.8 (3H, m), 1.8-1.89 (2H, m), 1.97 (2H, d), 2.55-2.77 (3H, m), 3.05 (2H, td), 3.37 (6H, s), 3.67 (2H, d), 4.01 (2H, d), 4.08 (1H, d), 6.88-6.92 (2H, m), 6.98 (1H, dd), 7.06-7.12 (2H, m), 7.15 (1H, d), 7.61 (1H, d); m/z : ES ⁺ [M+H] ⁺ 488.4.

Intermediate 80b: tert -Butyl (3a R ,6a S )-5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1 H )-carboxylate

tert -Butyl ( 3aR , 6aS )-hexahydropyrrolo[3,4-c]pyrrole-2( 1H )-carboxylate (4.19 g, 19.72 mmol) was added 5-fluoroisobenzofuran-1( 3H )-one (3.00 g, 19.72 mmol), DIPEA (10.33 mL, 59.16 mmol) in DMSO (3 mL). The resulting solution was stirred at 120 °C for 40 h. Then the reaction mixture was poured into water. The precipitate was collected by filtration, washed with water (100 mL) and dried in vacuo. Purification by FSC (gradient: 0-40% EtOAc in DCM) gave the title compound (5.10 g, 75%) as a white solid; ^1H NMR (300 MHz) 1.39 (9H, s), 3.02 (2H, m), 3.19-3.33 (4H, m), 3.51-3.63 (4H, m), 5.22 (2H, s), 6.61 (1H, d), 6.69 (1H, m), 7.58 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 345.1.

Intermediate 80c: 4-((3a R ,6a S )-5-( tert -butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 H )-2-(hydroxymethyl)benzoic acid

NaOH (2.32 g, 58.07 mmol) was added to tert -butyl (3aR,6aS)-5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)hexa-hydropyrrolo[3,4- c ]pyrrole-2(1 H )-carboxylate (5.00 g, 14.52 mmol) in THF (10 mL), MeOH (10 mL) and water (10 mL). The resulting solution was stirred at room temperature for 2 h. The mixture was then diluted with water (50 mL) and washed with EtOAc (150 mL x 4). The combined organic solutions were dried (MgSO ₄ ) and concentrated to give the title compound, which was used in the next step without further purification; ^1H NMR (300 MHz) 1.39 (9H, s), 3.00 (2H, s), 3.15-3.24 (4H, m), 3.51-3.54 (4H, m), 4.78 (2H, s), 6.39-6.41 (1H, m), 6.84 (1H, d), 7.77 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 363.1.

Intermediate 80d: tert -Butyl (3a R ,6a S )-5-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)hexahydro-pyrrolo[3,4- c ]Pyrrole-2(1 H )-carboxylate

Trimethylsilyldiazomethane (20.69 mL, 41.39 mmol) was added in one portion to 4-((3a R ,6a S )-5-( tert -butoxycarbonyl)-hexahydropyrrolo[3,4- c ]pyrrole-2(1 H )-yl)-2-(hydroxymethyl)benzoic acid (5.00 g, 13.80 mmol) in MeOH (1 mL) and EtOAc (1 mL) at -10 °C. The resulting solution was stirred at -10 °C for 2 h. The mixture was then quenched with water (600 mL) and extracted with EtOAc (3 x 300 mL). The combined organic solutions were dried (MgSO ₄ ) and concentrated to give the title compound (4.90 g, 94%) as a brown oil which was used in the next step without further purification; m/z ES ⁺ , [M+H] ⁺ = 377.1.

Intermediate 80e: tert -Butyl (3a R ,6a S )-5-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)hexahydro-pyrrolo[3,4- c ]Pyrrole-2(1 H )-carboxylate

PPh ₃ (4.44 g, 16.92 mmol) was added simultaneously to tert -butyl (3a R ,6a S )-5-(3-(hydroxymethyl)-4-(methoxy-carbonyl)phenyl)hexahydropyrrolo[3,4- c ]pyrrole-2(1 H )-carboxylate (4.90 g, 13.02 mmol) and CBr ₄ (5.61 g, 16.92 mmol) in THF (80 mL) at room temperature. The resulting solution was stirred at room temperature for 16 h. The mixture was then filtered and the filtrate was concentrated. Purification by FSC (gradient: 0-40% EtOAc in DCM) gave the title compound (5.30 g, 93%) as a white solid; m / z ES ⁺ , [M + H] ⁺ = 439.0.

Intermediate 80f: tert -Butyl (3a R ,6aS})-2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-1,3,3a,4,6,6ahexahydropyrrolo[3,4-c]pyrrole-5-carboxylate

DIPEA (5.02 mL, 28.76 mmol) was added in one portion to tert -butyl (3aR,6aS)-2-(1-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperidin-4-yl)octahydrocyclopenta[ c ]pyrrole-5-carboxylate (5.00 g, 9.59 mmol) and 3-aminopiperidine-2,6-dione hydrochloride salt (2.37 g, 14.38 mmol) in MeCN (100 mL) at room temperature. The resulting solution was stirred at 80 °C for 35 h. Purification by FSC (gradient: 0-60% EtOAc in DCM) gave the title compound (4.00 g, 92%) as a green solid; m/z ES ⁺ , [M+H] ⁺ = 455.0.

Intermediate 80g: 3-(5-((3a R ,6a S )-hexahydropyrrolo[3,4- c ]Pyrrole-2(1 H )-1)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

tert -Butyl ( 3aR , 6aS )-2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-1,3,3a,4,6,6ahexahydro-pyrrolo[3,4- c ]pyrrole-5-carboxylate in formic acid (20.4 mL) (4.00 g, 8.80 mmol) was stirred at room temperature for 16 h. The solvent was then removed under reduced pressure to give the title compound (3.50 g, 89%) as a black waxy solid, which was used in the next step without further purification; m/z ES ⁺ , [M+H] ⁺ = 355.1.

Example 80: 4-{4-[4-(4-{[(3a R ,6a S )-5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]hexahydropyrrolo[3,4- c ]Pyrrole-2(1 H )-yl]methyl}piperidin-1-yl)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

At room temperature under air, formic acid (3 mL) was added 4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (70 mg, 0.14 mmol) and 3-(5-((3a R ,6a S )-hexahydropyrrolo[3,4- c ]pyrrole-2(1 H )-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50.9 mg, 0.14 mmol). The resulting solution was stirred at 40 °C for 0.5 h and then diluted with toluene (3 mL). The resulting mixture was concentrated to dryness and the residue was azeotroped with toluene to dryness. The residue was then dissolved in DCM (2 mL) and IPA (1 mL) and NaBH(OAc) ₃ (30.4 mg, 0.14 mmol) was added (at room temperature). The resulting suspension was stirred under air at room temperature for 0.5 h. The mixture was then diluted with EtOAc (20 mL) and washed with saturated NaHCO ₃ (2 x 5 mL), then saturated brine (5 mL), dried (MgSO ₄ ) and concentrated. Purification by preparative HPLC (column A, eluent A) was carried out. The fractions containing the desired compound were concentrated to remove MeCN and basified to pH 9 with saturated aqueous NaHCO ₃ . The solution was then extracted with DCM (4 x 20 mL) and the combined extracts were dried (MgSO ₄ ) and concentrated to dryness to give the title compound (26.0 mg, 23%) as a white solid; ^.1H NMR (CDCl ₃ ) 1.26 (1H, s), 1.28-1.38 (2H, m), 1.71 (1H, dd), 1.78 (1H, dd), 1.82-1.91 (2H, m), 1.92-1.99 (2H, m), 2.19 (1H, dtd), 2.28 (1 H, dd), 2.34 (2H, dd), 2.54 (2H, d), 2.61-2.67 (2H, m), 2.69 (2H, dt), 2.75 (1H, dd), 2.83 (1H, dd), 2.89 (1H, ddd), 2.94-3.09 (4H, m), 3.23 (2 H, d), 3.57 (2H, t), 3.63 (2H, d), 4.01 (2H, d), 4.24 (1H, d), 4.39 (1H, d), 5.18 (1H, dd), 6.57 (1H, s), 6.68 (1H, dd), 6.85-6.92 (2H, m), 6.98 (1 H, dd), 7.08 (2H, d), 7.15 (1H, d), 7.60 (1H, d), 7.71 (1H, d), 8.00 (1H, s); m/z ES ⁺ [M+H]+ = 780.0.

Intermediate 81a: tert -Butyl (1 R ,4 R )-5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

DIPEA (10.33 mL, 59.16 mmol) was added to (1 R ,4 R ) -tert -butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (4.69 g, 23.66 mmol) and 5-fluoroisobenzofuran-1(3 H )-one (3.00 g, 19.72 mmol) in DMSO (30 mL) at room temperature. The resulting mixture was stirred at 120 °C for 16 h. After cooling, the mixture was poured into water (100 mL), and the resulting mixture was filtered to give the title compound (5.00 g, 77%) as a white solid; ^1H NMR (300 MHz, CDCl ₃ ) 1.44 (9H, d), 2.01 (2H, s), 3.29 (1H, s), 3.45 (2H, d), 3.56-3.65 (1H, m), 4.51 (1H, s), 4.63 (1H, d), 5.17 (2H, s), 6.46 (1H, d), 6.59-6.68 (1H, m), 7.70 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 331.1.

Intermediate 81b: 4-((1 R ,4 R )-5-( tert -Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(hydroxymethyl)benzoic acid

NaOH (2.42 g, 60.54 mmol) was added to tert -butyl (1 R ,4 R )-5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.00 g, 15.13 mmol) in a mixture of MeOH (20 mL), THF (20 mL) and water (20 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was acidified with 2 M HCl. The mixture was then filtered to give the title compound (5.20 g, 99%) as a white solid; m / z ES ⁺ , [M+H] ⁺ = 349.1.

Intermediate 81c: tert -Butyl (1 R ,4 R )-5-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Trimethylsilyldiazomethane (21.5 mL, 43.05 mmol) was added in one portion to 4-((1 R ,4 R )-5-( tert -butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(hydroxymethyl)benzoic acid (5.00 g, 14.35 mmol) in MeOH (25 mL) and EtOAc (25 mL) at -10 °C. The resulting solution was stirred at -10 °C for 2 h, after which water (600 mL) was added. The mixture was extracted with EtOAc (3 × 300 mL) and the combined organic solutions were dried (MgSO ₄ ) and concentrated to give the title compound (5.00 g, 96%) as a brown oil which was used in the next step without further purification; m/z ES ⁺ , [M+H] ⁺ = 363.2.

Intermediate 81d: tert -Butyl (1 R ,4 R )-5-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Ph ₃ P (5.65 g, 21.53 mmol) was added to tert -butyl (1 R ,4 R )-5-(3-(hydroxymethyl)-4-(methoxycarbonyl)-phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.20 g, 14.35 mmol) and CBr ₄ (7.14 g, 21.53 mmol) in THF (50 mL) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was then filtered, and the filtrate was concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) gave the title compound (4.30 g, 71%) as a white solid; ^1H NMR (300 MHz, CDCl ₃ ) 1.44 (9H, d), 1.97 (2H, s), 3.16-3.47 (3H, m), 3.57 (1H, d), 3.87 (3H, s), 4.48 (1H, s), 4.96 (2H, s), 6.40-6.50 (1H , m), 6.54 (1H, d), 7.91 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 425.1.

Intermediate 81d: tert -Butyl (1 R ,4 R )-5-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

DIPEA (1.77 mL, 10.11 mmol) was added tert -butyl (1 R ,4 R )-5-(3-(bromomethyl)-4-(methoxycarbonyl)-phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (4.30 g, 10.11 mmol) and 3-aminopiperidine-2,6-dione hydrochloride salt (2.50 g, 15.16 mmol) in MeCN (20 mL) at -10 °C. The resulting solution was stirred at 80 °C for 2 h and then concentrated. Purification by FSC (gradient: 0-50% EtOAc in DCM) gave the title compound (2.20 g, 49%) as a green solid; ^1H NMR (300 MHz, CDCl ₃ ) 1.44 (9H, d), 1.57 (2H, d), 2.20 (1H, s), 2.22-2.42 (1H, m), 2.72-2.96 (2H, m), 3.17-3.33 (1H, m), 3.43 (2H, d), 3.61 ( 1H, d), 4.24 (1H, d), 4.34-4.50 (2H, m), 4.61 (1H, d), 5.13-5.25 (1H, m), 6.53 (1H, d), 6.57-6.68 (1H, m), 7.70 (1H, d), 8.41 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 441.2.

Intermediate 81e: 3-[5-[(1 R ,4 R )-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

tert -Butyl (1 R ,4 R )-5-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.2 g, 4.99 mmol) was stirred in formic acid (30 mL) at room temperature for 2 h. It was then concentrated under reduced pressure to give the title compound (1.50 g, 63%) as a white solid; ^1H NMR (300 MHz) 1.97 (2H, d), 2.13 (1H, d), 2.28-2.48 (1H, m), 2.52-2.66 (1H, m), 2.82-3.00 (1H, m), 3.05-3.19 (1H, m), 3.27 (1H, d), 3.36 (1 H, d), 3.53-3.70 (1H, m), 4.14-4.27 (1H, m), 4.27-4.40 (1H, m), 4.44 (1H, s), 4.74 (1H, s), 4.99-5.11 (1H, m), 6.70-6.84 (2H, m), 7.54 (1H) ,d), 8.26 (3H, s), 10.96 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 341.2.

Example 81: 4-(4-{4-[4-({(1 R ,4 R )-5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

At room temperature under air, formic acid (3 mL) was added 4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (70 mg, 0.14 mmol) and 3-[5-[(1 R ,4 R )-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (49 mg, 0.14 mmol). The resulting solution was stirred at 40 °C for 0.5 h and then diluted with toluene (3 mL). The resulting mixture was concentrated to dryness and the residue was azeotroped with toluene to dryness. The residue was then dissolved in DCM (2 mL) and IPA (1 mL), and NaBH(OAc) ₃ (60.9 mg, 0.29 mmol) was added (at room temperature). The resulting suspension was stirred under air at room temperature for 18 h. The mixture was then diluted with EtOAc (20 mL), washed with saturated NaHCO ₃ (2 x 5 mL), then saturated brine (5 mL), dried (MgSO ₄ ) and concentrated. The mixture was purified by preparative HPLC (column A, eluent A, basic workup A) to afford the title compound (41.0 mg, 37%) as a white solid; ^1H NMR: (CDCl ₃ ) 1.26 (2H, s), 1.32 (2H, td), 1.44 (1H, s), 1.71 (1H, dd), 1.75-1.8 (1H, m), 1.87 (2H, dd), 1.97 (2H, d), 2.19 (1H, dtd), 2.3 1 (1H, qd), 2.41 (2H, s), 2.55-2.67 (3H, m), 2.71 (1H, dt), 2.76-2.85 (1H, m), 2.85-2.95 (1H, m), 3.04 (3H, td), 3.31-3.46 (2H, m), 3.61 (3H) , dt), 4.01 (2H, d), 4.19-4.32 (2H, m), 4.38 (1H, d), 5.19 (1H, ddd), 6.51 (1H, s), 6.61 (1H, dd), 6.88 (2H, d), 6.98 (1H, dd), 7.08 (2H, d), 7.15 ( 1H, d), 7.60 (1H, d), 7.69 (1H, d), 7.95 (1H, s); m/z ES ⁺ [M+H]+ = 766.0.

Example 82a: tert -Butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]-undecane-3-carboxylate

Pd-PEPPSI-IPent (0.110 g, 0.14 mmol) was added to tert -butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.850 g, 3.34 mmol), 3-(5-bromo-1-oxoisoindolin- ₂ -yl)piperidine-2,6-dione (0.90 g, 2.79 mmol) and Cs ₂ CO ₃ (2.72 g, 8.36 mmol) in 1,4-dioxane (30 mL) at room temperature under N 2 . The resulting suspension was degassed under vacuum, backfilled with N ₂ , and stirred at 110 °C for 3 h. The mixture was then cooled to room temperature, diluted with DCM (100 mL), and washed with 5% AcOH in water (50 mL), then brine (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane, then 10% EtOH in EtOAc) gave the title compound (0.397 g, 29%) as a white solid. ^1H NMR (CDCl ₃ ) 1.46 (13H, s), 1.62-1.68 (4H, m), 2.14-2.23 (1H, m), 2.32 (1H, qd), 2.72-3.04 (2H, m), 3.37 (8H, dt), 4.24 (1H, d), 4.40 (1H, d), 5.19 (1H, dd), 6.87 (1H, d), 6.98 (1H, dd), 7.72 (1H, d), 8.00 (1H, s); m/z : ES ⁺ [M+H] ⁺ 497.4.

Example 82: 4-(4-{4-[4-({9-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-3,9-diaza-spiro[5.5]undecan-3-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 80a was reacted with intermediate 82a using the general synthetic method exemplified by Example 1 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: (CDCl ₃ ) 1.26-1.40 (4H, m), 1.28-1.4 (3H, m), 1.57 (3H, s), 1.63 (4H, s), 1.69-1.75 (1H, m), 1.79 (1H, d), 1.85 (2H, d), 1.94-2 (2H, m), 2.21 (2H, t), 2.26-2.35 (1H, m), 2.39 (3H, s), 2.6-2.74 (3H, m), 2.75-2.86 (1H, m), 2.86-2.95 (1H, m), 2.99-3.11 (2H, m), 3.25-3.37 (3 H, m), 3.64 (2H, d), 4.01 (2H, d), 4.24 (1H, d), 4.40 (1H, d), 5.19 (1H, dd), 6.82-6.93 (3H, m), 6.95-7.01 (2H, m), 7.09 (2H, d), 7.15 (1H, d), 1 (1H, d), 7.71 (1H, d), 7.86 (1H, s); m/z ES ⁺ [M+H]+ = 822.5.

Intermediate 83a: tert -Butyl methyl (1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4-yl)carbamate

DIPEA (6.89 mL, 39.44 mmol) was added simultaneously to 5-fluoroisobenzofuran-1(3 H )-one (3.00 g, 19.72 mmol) and tert -butyl methyl(piperidin-4-yl)carbamate (6.34 g, 29.58 mmol) in DMSO (20 mL) at room temperature. The resulting solution was stirred at 120 °C for 16 h. The mixture was then poured into water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic solutions were dried (MgSO ₄ ) and concentrated. Trituration with EtOAc and petroleum ether (1:5) gave a solid which was collected by filtration and dried in vacuo to give the title compound (5.82 g, 85%) as a white solid; ^1H NMR (CDCl ₃ ) 1.50 (9H, s), 1.76-1.84 (4H, m), 2.75 (3H, s), 2.95-3.07 (2H, m), 3.95-4.03 (2H, m), 4.26 (1H, s), 5.22 (2H, s), 6.84 (1H, s), 6.98-7.05 (1H, m), 7.75 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 347.2.

Intermediate 83b: 4-(4-(( tert -butoxycarbonyl)(methyl)amino)piperidin-1-yl)-2-(hydroxymethyl)benzoic acid

NaOH (0.716 g, 17.90 mmol) was added in one portion to tert -butyl methyl(1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4-yl)carbamate (6.20 g, 17.90 mmol) in a mixture of water (20 mL), MeOH (20 mL) and THF (20 mL) at -10 °C. The resulting solution was stirred at -10 °C for 2 h after which 1 M HCl (70 mL) was added. The mixture was extracted with EtOAc (3 x 300 mL) and the combined organic solutions were dried (MgSO ₄ ) and concentrated to give the title compound (6.20 g, 95%) as a brown oil which was used in the next step without further purification; ^1H NMR (300 MHz, CDCl ₃ ) 1.48 (9H, s), 1.74-1.81 (4H, m), 2.74 (3H, s), 2.92-3.12 (2H, m), 3.93-4.11 (2H, m), 4.27 (1H, s), 4.81 (2H, s), 6. 93 (2H, d), 7.98-8.07 (1H, m); m/z ES ⁺ , [M+H] ⁺ = 365.2.

Intermediate 83c: Methyl 4-(4-(( tert -Butoxycarbonyl)(methyl)amino)piperidin-1-yl)-2-(hydroxymethyl)benzoate

Trimethylsilyldiazomethane (25.5 mL, 51.04 mmol) was added to 4-(4-(( tert -butoxycarbonyl)-(methyl)-amino)piperidin-1-yl)-2-(hydroxymethyl)benzoic acid (6.20 g, 17.01 mmol) in MeOH (40 mL) and EtOAc (40 mL) in one portion at -10 °C. The resulting solution was stirred at -10 °C for 2 h, after which water (600 mL) was added. The mixture was extracted with EtOAc (3 x 300 mL) and the combined organic solutions were dried (MgSO ₄ ) and concentrated to give the title compound (5.50 g, 85%) as a brown oil which was used in the next step without further purification; ^1H NMR (300 MHz, CDCl ₃ ) 1.47 (9H, s), 1.70-1.76 (4H, m), 2.71 (3H, s), 2.84-2.95 (1H, m), 2.95 (1H, d), 3.86 (3H, s), 3.88-4.04 (2H, m), 4.2 8 (1H, s), 4.72 (2H, s), 6.70-6.87 (1H, m), 6.87 (1H, d), 7.91 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 379.2.

Intermediate 83d: Methyl 2-(bromomethyl)-4-(4-(( tert -Butoxycarbonyl)(methyl)amino)piperidin-1-yl)benzoate

PPh ₃ (4.96 g, 18.89 mmol) was added simultaneously to methyl 4-(4-(( tert -butoxycarbonyl)(methyl)amino)-piperidin-1-yl)-2-(hydroxymethyl)benzoate (5.50 g, 14.53 mmol) and CBr ₄ (6.27 g, 18.89 mmol) in THF (80 mL) at room temperature. The resulting solution was stirred at room temperature for 16 h, then filtered and concentrated. Purification by FSC (gradient: 0-40% EtOAc in DCM) gave the title compound (5.00 g, 78%) as a red oil; ^1H NMR (300 MHz, CDCl ₃ ) 1.49 (9H, s), 1.67-1.83 (4H, m), 2.74 (3H, s), 2.74-2.99 (2H, m), 3.89 (3H, s), 3.97 (2H, d), 4.21 (1H, s), 4.98 (2H) , s), 6.79-6.90 (1H, m), 6.91 (1H, d), 7.93 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 443.1.

Intermediate 83e: tert -Butyl (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)-(methyl)carbamate

DIPEA (5.94 mL, 33.99 mmol) was added in one portion to methyl 2-(bromomethyl)-4-(4-(( tert -butoxy-carbonyl)(methyl)amino)piperidin-1-yl)benzoate (5.00 g, 11.33 mmol) and 3-aminopiperidine-2,6-dione hydrochloride salt (2.80 g, 16.99 mmol) in MeCN (110 mL) at room temperature. The resulting solution was stirred at 80 °C for 2 days and then at room temperature overnight. The precipitate was collected by filtration, washed with MeCN (100 mL), and dried in vacuo. Purification by FSC (gradient: 0-50% EtOAc in DCM) gave the title compound (3.30 g, 64%) as a white solid; ^1H NMR (300 MHz) 1.41 (9H, s), 1.54-1.82 (4H, m), 1.89-2.03 (1H, m), 2.29-2.44 (1H, m), 2.54-2.64 (1H, m), 2.78-3.00 (3H, m), 3.08 (3H, s), 3.97 (3H, d), 4.21 (1H, d), 4.33 (1H, d), 5.00-5.12 (1H, m), 7.02-7.11 (2H, m), 7.52 (1H, d), 10.95 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 457.2.

Intermediate 83f: 3-(5-(4-(methylamino)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

4 M HCl in 1,4 _- dioxane (30 mL, 120.00 mmol) was added dropwise to butyl-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)(methyl)carbamate (3.30 g, 7.23 mmol) in 1,4-dioxane (10 mL) at room temperature under N 2 . The resulting mixture was stirred at room temperature for 16 h. The mixture was then diluted with EtOAc (120 mL). The precipitate was collected by filtration, washed with EtOAc (300 mL) and dried in vacuo to give the title compound (2.90 g, 93%) as a white solid; ^1H NMR (300 MHz) 1.73-1.93 (2H, m), 2.19 (2H, d), 2.32-2.45 (1H, m), 2.58 (2H, d), 2.79-2.98 (1H, m), 3.00-3.38 (3H, m), 3.56 (3H, s), 3.95 ( 2H, d), 4.25 (1H, d), 4.39 (1H, d), 5.01-5.13 (1H, m), 7.29-7.42 (2H, m), 7.62 (1H, d), 10.96 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 357.2.

Example 83: 4-{4-[4-(4-{[{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperidin-4-yl}(methyl)amino]methyl}piperidin-1-yl)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 80a was reacted with intermediate 83f using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: (CDCl ₃ ) 0.85-0.90 (2H, m), 1.28-1.34 (3H, m), 1.69-1.75 (2H, m), 1.78 (2H, dd), 1.86 (3H, s), 1.97 (2H, d), 2.19 (1H, dtd), 2.33 (5H) , dq), 2.57 (1H, d), 2.63-2.75 (3H, m), 2.85 (4H, tdd), 3.05 (2H, td), 3.65 (2H, d), 3.89 (2H, d), 4.01 (2H, d), 4.25 (1H, d), 4.40 (1H, d), 5.1 9 (1H, dd), 6.85-6.92 (3H, m), 6.98 (2H, d), 7.09 (2H, d), 7.15 (1H, d), 7.61 (1H, d), 7.72 (1H, d), 7.91 (1H, s); m/z ES ⁺ [M+H]+ = 782.5.

Intermediate 84a: tert -Butyl 4-((4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)-piperazin-1-yl)methyl)piperidine-1-carboxylate

BrettPhos Pd G3 (0.222 g, 0.24 mmol) was _added to 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (2.00 g, 4.89 mmol), tert -butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.524 g, 5.38 mmol) and Cs ₂ CO ₃ (4.78 g, 14.66 mmol) in 1,4-dioxane (20 mL) under N 2 at room temperature. The resulting solution was stirred at 100 °C for 2 h and then concentrated. Purification by FSC (gradient: 0-8% MeOH in DCM) gave the title compound (1.58 g, 53%) as a yellow solid; m/z ES ⁺ , [M+H] ⁺ = 612.

Intermediate 84b: 4-(4-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4 M HCl in 1,4-dioxane (12.26 mL, 49.04 mmol) was slowly added to tert -butyl 4-((4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (1.50 g, 2.45 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated. Flash C18-flash chromatography (gradient: 0-100% MeCN in water (0.1 NH ₄ OH)) gave the title compound (0.950 g, 76%) as a yellow solid; m/z ES ⁺ , [M+H] ⁺ = 512.

Example 84: 4-(4-{4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Under N _{2 ,} Pd-PEPPSI-IPent (107 mg, 0.14 mmol) was added to 4-(4-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (700 mg, 1.37 mmol), 3-(5-bromo-1-oxoisoindolin-2-yl)-piperidine-2,6-dione (442 mg, 1.37 mmol) and Cs ₂ CO ₃ (892 mg, 2.74 mmol) in DMF (20 mL). The resulting mixture was stirred at 100 °C for 15 h. The mixture was then filtered through Celite. The product was purified by flash C18-flash chromatography (Gradient: 0-90% MeCN in water (containing 0.5% formic acid)) to give the product, which was further purified by preparative HPLC (Column: Xselect CSH OBD column 30*150 mm 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 34% B to 44% B in 7 min; 254 nm) to give the title compound as its formate salt (71.0 mg, 7%) as a yellow solid; ^1H NMR: 1.19 (2H, q), 1.53-1.67 (2H, m), 1.81 (5H, t), 1.91-1.99 (1H, m), 2.20 (2H, d), 2.32-2.43 (1H, m), 2.50-2.53 (2H, m), 2.54-2.59 (2H) , m), 2.60-2.62 (1H, m), 2.65-2.75 (1H, m), 2.77-2.92 (3H, m), 2.98-3.11 (6H, m), 3.87 (2H, d), 4.13-4.23 (3H, m), 4.31 (1H, d), 5.04 (1H, dd) ), 6.86 (2H, d), 7.05-7.09 (4H, m), 7.26 (1H, dd), 7.32 (1H, d), 7.50 (1H, d), 7.81 (1H, d), 10.94 (1H, s); m/z ES ⁺ [M+H]+ = 754.4.

Example 85: 4-{4-[6-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)pyridin-3-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 56f was reacted with intermediate 63e using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: (CDCl ₃ ) 1.65-1.73 (2H, m), 1.76 (2H, dd), 1.79-1.9 (2H, m), 1.97 (2H, d), 2.08-2.18 (1H, m), 2.43-2.51 (2H, m), 2.56-2.64 (4H, m), 2 .67-2.74 (1H, m), 2.76 (1H, q), 2.77-2.86 (1H, m), 2.89 (1H, dd), 3.06 (2H, td), 3.3-3.5 (4H, m), 4.03 (2H, d), 4.31 (2H, t), 4.93 (1H, dd), 6 .70 (1H, d), 6.97-7.02 (1H, m), 7.05 (1H, dd), 7.16 (1H, d), 7.28 (1H, d), 7.43 (1H, dd), 7.62 (1H, d), 7.69 (1H, d), 7.95 (1H, s), 8.01 (1H, d); m/z ES ⁺ [M+H]+ = 744.0.

Example 86: 4-{4-[6-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)pyridin-3-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 56f using the general synthetic method exemplified by Example 2 to give the title compound after purification by HPLC (column A, eluent A, basic workup A); ^1H NMR: (CDCl ₃ ) 1.50-1.90 (6H, m), 1.97 (2H, d), 2.19 (1H, dtd), 2.32 (1H, qd), 2.47 (2H, t), 2.61 (4H, s), 2.69-2.8 (1H, m), 2.8-2.87 (1H, m) ), 2.91 (1H, ddd), 3.06 (2H, td), 3.29-3.36 (4H, m), 4.03 (2H, d), 4.25 (1H, d), 4.30 (2H, t), 4.41 (1H, d), 5.19 (1H, dd), 6.70 (1H, d), (1H, d), 6.99 (2H, dt), 7.16 (1H, d), 7.42 (1H, dd), 7.62 (1H, d), 7.73 (1H, d), 7.93 (1H, s), 8.01 (1H, d); m/z ES ⁺ [M+H] ⁺ = 730.5.

Example 87: 4-(4-{4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (0.319 mL, 1.82 mmol) was added to 4-(4-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride salt (200 mg, 0.36 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (101 mg, 0.36 mmol) in DMF (5 mL). The resulting mixture was stirred at 100 °C for 3 h. The mixture was then diluted with EtOAc (50 mL), washed with water (50 mL), then saturated brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by preparative HPLC (column A, eluent A) to give the title compound (30.0 mg, 11%) as a yellow solid; ^1H NMR: 1.11-1.24 (2H, m), 1.54-1.67 (2H, m), 1.77-1.89 (5H, m), 1.95-2.08 (1H, m), 2.12-2.26 (2H, m), 2.40-2.49 (2H, m), 2.52-2.63 (4H, m) ), 2.67-2.78 (1H, m), 2.80-2.90 (1H, m), 2.92-3.13 (8H, m), 4.05 (2H, d), 4.17 (2H, d), 5.06 (1H, dd), 6.87 (2H, d), 7.10 (2H, d), (2H, m), 7.32 (2H, s), 7.65 (1H, d), 7.81 (1H, d), 11.07 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 768.4.

Intermediate 88a: 4-(4-(6-((5-hydroxypentyl)oxy)pyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

4-(4-(6-chloropyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.50 g, 1.37 mmol), Cs ₂ CO ₃ (1.55 g, 4.78 mmol), and pentane-1,5-diol (0.72 mL, 6.83 mmol) were dissolved in toluene (15 mL) and degassed with N ₂ . Then Rockphos Pd G3 (0.057 g, 0.07 mmol) was added, and the mixture was heated at 90 °C for 2 h.

The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL), then saturated brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.375 g, 64%) as a pale yellow oil; ^1H NMR (CDCl ₃ ) 1.28 (1H, t), 1.53 (1H, s), 1.55-1.58 (1H, m), 1.61-1.7 (2H, m), 1.7-1.86 (4H, m), 1.92-2 (2H, m), 2.75 (1H, tt), 3.06 (2H, td ), 3.62-3.75 (2H, m), 4.03 (2H, d), 4.28 (2H, t), 6.69 (1H, d), 6.99 (1H, dd), 7.16 (1H, d), 7.42 (1H, dd), 7.62 (1H, d), 8.01 (1H, d); m/z : ES ⁺ [M+H] ⁺ 433.6.

Intermediate 88b: 4-(4-(6-((5-oxopentyl)oxy)pyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Dess-Martin periodinane (205 mg, 0.48 mmol) was added to 4-(4-(6-((5-hydroxypentyl)oxy)pyridin-3-yl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (190 mg, 0.44 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (15 mL) and poured into a mixture of saturated NaHCO ₃ (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 min and the layers were separated. The organic solution was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (190 mg, 100%) as a yellow dry film which was used in the next step without further purification; ^1H NMR (CDCl ₃ ) 1.75 (2H, td), 1.8-1.83 (3H, m), 1.98 (2H, d), 2.52 (2H, td), 2.75 (1H, ddt), 3.06 (2H, td), 3.93-4.09 (2H, m), 4.19-4.35 (2H, m), 6.69 (1H, d), 7.00 (1H, dd), 7.16 (1H, d), 7.42 (1H, dd), 7.62 (1H, d), 7.96-8.03 (2H, m), 9.79 (1H, t); m/z : ES ⁺ [M+H] ⁺ 432.2.

Example 88: 4-(4-{6-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}pentyl)oxy]pyridin-3-yl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 63e was reacted with intermediate 88b using the general synthetic method exemplified by Example 2 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ^1H NMR: (CDCl ₃ ) 1.51 (2H, p), 1.65-1.76 (3H, m), 1.76-1.86 (3H, m), 1.97 (2H, d), 2.14 (1H, ddq), 2.62-2.71 (2H, m), 2.71-2.74 (1H, m), 2.77 (1H, dd), 2.8-2.86 (1H, m), 2.89 (5H, dt), 3.06 (2H, td), 3.53-3.58 (4H, m), 3.71 (1H, s), 4.03 (2H, d), 4.27 (2H, t), 4.94 (1H, dd), 6.71 (1 H, s), 7.00 (1H, dd), 7.07 (1H, dd), 7.16 (1H, d), 7.30 (1H, d), 7.43 (1H, dd), 7.62 (1H, d), 7.72 (1H, d), 8.01 (1H, d), 8.16 (2H, s); m/z : ES ⁺ [M+H] ⁺ = 758.5.

Example 89: 4-(4-{6-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}pentyl)oxy]pyridin-3-yl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 88b using the general synthetic method exemplified by Example 2 to give the title compound (as a formate salt) after purification by HPLC (column A, eluent A). ¹ H NMR: (CDCl ₃ ) 1.53 (2H, p), 1.7-1.79 (2H, m), 1.82 (4H, dd), 1.97 (2H, d), 2.21 (1H, dtt), 2.34 (1H, qd), 2.74 (1H, dt), 2.78-2.88 (3H, m), 2.92 (1H, ddd), 3.08 (6H, dd), 3.54-3.59 (4H, m), 4.03 (2H, d), 4.25-4.3 (3H, m), 4.43 (1H, d), 5.20 (1H, dd), 6.70 (1H, d), 6.90 (1H, d), 7.00 (2H, dd), 7.16 (1H, d), 7.43 (1H, dd), 7.62 (1H, d), 7.76 (1H, d), 8.01 (2H, d), 8.16 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 743.9.

Intermediate 90a: tert -Butyl 4-(3-((5-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)pyridin-2-yl)oxy)propyl)piperazine-1-carboxylate

4-(4-(6-chloropyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 56d) (0.500 g, 1.37 mmol), Cs ₂ CO ₃ (1.56 g, 4.78 mmol) and tert -Butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (0.835 g, 3.42 mmol) were dissolved in toluene (15 mL) and degassed with N ₂ . Rockphos Pd G3 (0.057 g, 0.07 mmol) was added and the mixture was then heated at 90 °C for 18 h. The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL), then saturated brine (100 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.285 g, 36%) as a pale yellow solid; ^1H NMR (CDCl ₃ ) 1.46 (9H, s), 1.76 (2H, qd), 1.92-1.99 (4H, m), 2.31-2.45 (4H, m), 2.46-2.55 (2H, m), 2.75 (1H, tt), 3.06 (2H, td), 6 (4H, m), 4.03 (2H, d), 4.32 (2H, t), 6.69 (1H, d), 6.93-7.02 (1H, m), 7.16 (1H, d), 7.42 (1H, dd), 7.62 (1H, d), 8.01 (1H, d); m/z : ES ⁺ [M+H] + 574.0.

Intermediate 90b: 4-(4-(6-(3-(piperazin-1-yl)propoxy)pyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4 M HCl in 1,4-dioxane (1.24 mL, 4.97 mmol) was added tert -butyl 4-(3-((5-(1-(4-cyano-3-(trifluoromethyl)-phenyl)piperidin-4-yl)pyridin-2-yl)oxy)propyl)piperazine-1-carboxylate (285 mg, 0.50 mmol) in DCM (25 mL), and the mixture was stirred for 1 h. It was then concentrated under reduced pressure to give the title compound as a bis-hydrochloride salt (255 mg, 101%) as a white solid, which was used directly in the next step; ^1H NMR (CDCl ₃ ) 1.76 (3H, qd), 1.97 (4H, d), 2.61 (2H, s), 2.72-2.78 (5H, m), 3.00-3.11 (2H, m), 3.15-3.22 (4H, m), 4.03 (2H, d), 4.32 (2H, t) , 6.68 (1H, d), 7.00 (1H, dd), 7.16 (1H, d), 7.42 (1H, dd), 7.62 (1H, d), 8.00 (1H, d), 9.62 (1H, s); m/z : ES ⁺ [M+H] + 474.3.

Example 90: 4-{4-[6-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}propoxy)pyridin-3-yl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Cs ₂ CO ₃ (466 mg, 1.43 mmol) and Pd-PEPPSI I-pent (18.89 mg, 0.02 mmol) were added in _{one portion} to a degassed solution of 4-(4-(6-(3-(piperazin-1-yl)propoxy)pyridin-3-yl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (226 mg, 0.48 mmol) and 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (154 mg, 0.48 mmol) in 1,4-dioxane (8 mL) under N 2 . The resulting mixture was stirred at 90 °C for 5 h. The mixture was then cooled to room temperature, diluted with DCM (50 mL), washed with 5% AcOH in water (50 mL), then with water (50 mL), dried (MgSO ₄ ) and concentrated. Purification by preparative HPLC (column A, eluent A) was performed. The fractions containing the desired compound were combined, diluted with water (150 mL) and extracted with DCM (3 x 100 mL). The combined organic solutions were washed with brine (100 mL), dried (MgSO ₄ ) and concentrated. Further purification by preparative HPLC (column A, eluent A) gave the title compound (4.00 mg, 1%) as a formate salt as a colorless gum. ^1H NMR: (CDCl ₃ ) 1.76 (2H, qd), 1.98 (2H, d), 2.07 (2H, dt), 2.20 (1H, dtd), 2.33 (1H, qd), 2.73 (3H, dd), 2.77-2.81 (4H, m), 2.82-2.9 (2H, m), 2.93 (1H, dd), 2.98 (1H, s), 3.06 (3H, td), 3.34-3.45 (4H, m), 4.03 (2H, d), 4.26 (1H, d), 4.35 (2H, t), 4.42 (1H, d), 5.19 (1H, dd), 6.71 (1 H, d), 6.88 (1H, d), 6.99 (2H, dd), 7.16 (1H, d), 7.43 (1H, dd), 7.62 (1H, d), 7.74 (1H, d), 8.01 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 716.5.

Intermediate 91a: tert -Butyl 4-(2-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-ethyl)piperazine-1-carboxylate

Under N _{2 ,} RockPhos Pd G3 (0.102 g, 0.12 mmol) was added 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (1.00 g, 2.44 mmol), tert -butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.844 g, 3.67 mmol) and Cs ₂ CO ₃ (1.59 g, 4.89 mmol) in toluene (20 mL). The resulting mixture was stirred at 100 °C overnight and then concentrated. Purification by FSC (gradient: 0-70% EtOAc in petroleum ether) gave the title compound (0.80 g, 59%) as a yellow oil which solidified on standing; m/z ES ⁺ , [M+H] ⁺ = 559.

Intermediate 91b: 4-(4-(4-(2-(piperazin-1-yl)ethoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

4 M HCl in dioxane (10 mL, 40.00 mmol) was added tert -butyl 4-(2-(4-(1-(4-cyano-3-(trifluoromethyl)-phenyl)piperidin-4-yl)phenoxy)ethyl)piperazine-1-carboxylate (750 mg, 1.34 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the title compound as a brown solid (assumed 100% yield); m/z ES ⁺ , [M+H] ⁺ = 459.

Example 91: 4-{4-[4-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Pd-PEPPSI-IPent (4.32 mg, 5.45 μmol) was added to 4-(4-(4-(2-(piperazin-1-yl)ethoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (50 mg, _0.11 mmol), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (35.2 mg, 0.11 mmol) and Cs ₂ CO ₃ (107 mg, 0.33 mmol) in DMF (3 mL) at room temperature under N 2 . The resulting solution was stirred at 90 °C for 16 h. After that, the mixture was diluted with EtOAc (10 mL), washed with water (10 mL x 3), then saturated brine (10 mL x 2), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.1%NH ₃ .H ₂ O), mobile phase B: MeCN) to give the title compound (11 mg, 14%) as a white solid; ^1H NMR: 1.63 (2H, qd), 1.85 (2H, d), 1.92-2.00 (1H, m), 2.35-2.40 (1H, m), 2.56 (1H, s), 2.60-2.67 (3H, m), 2.71-2.81 (3H, m), 2.85-2.95 ( 1H, m), 3.05 (2H, t), 3.33 (5H, s), 4.10 (2H, t), 4.14-4.26 (3H, m), 4.33 (1H, d), 5.05 (1H, dd), 6.89 (2H, d), 7.07 (2H, d), 7.17 (2H, d), 7. 28 (1H, dd), 7.33 (1H, d), 7.52 (1H, d), 7.82 (1H, d), 10.95 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 701.3.

Intermediate 92a: Benzyl 4-(4-bromophenyl)piperidine-1-carboxylate

Benzyl carbonochloridate (4.26 g, 24.99 mmol) was added dropwise to 4-(4-bromophenyl)piperidine (5.00 g, 20.82 mmol) and DIPEA (10.91 mL, 62.46 mmol) in DCM (100 mL) over 5 min at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The mixture was then diluted with DCM (100 mL), washed with water (200 mL x 2), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (5.50 g, 71%) as a yellow oil which solidified on standing; ¹ H NMR (CDCl ₃ , 300 MHz) 1.37-1.72 (2H, m), 1.84 (2H, d), 2.54-2.75 (1H, m), 2.90 (2H, t), 4.34 (2H, br), 5.18 (2H, s), 7.04-7.24 (2H, m), 7. 26-7.61 (7H, m); m/z : ES ⁺ [M+H] ⁺ = 374.

Intermediate 92b: tert -Butyl 4-(3-(4-(1-((benzyloxy)carbonyl)piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate

RockPhos Pd G3 (0.336 g, 0.40 mmol) was _added to benzyl 4-(4-bromophenyl)piperidine-1-carboxylate (3.00 g, 8.02 mmol), tert -butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (1.96 g, 8.02 mmol) and Cs ₂ CO ₃ (5.22 g, 16.03 mmol) in toluene (60 mL) under N 2 . The resulting mixture was stirred overnight at 100 °C and then concentrated. Purification by FSC (gradient: 0-70% EtOAc in petroleum ether) gave the title compound (2.30 g, 53%) as a yellow oil which solidified on standing; m / z : ES ⁺ [M + H] ⁺ = 538.

Intermediate 92c: tert -Butyl 4-(3-(4-(piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate

tert -Butyl 4-(3-(4-(1-((benzyloxy)carbonyl)piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate (2.800 g, 5.21 mmol) and Pd(OH) ₂ (0.366 g, 0.26 mmol) in EtOAc (50 mL) were stirred under H ₂ (via balloon) at room temperature for 15 h. The mixture was then filtered through celite, and the filtrate was concentrated to dryness to afford the title compound (1.80 g, 86%) as a yellow solid; ^1H NMR (CDCl ₃ , 300 MHz) 1.48 (9H, s), 1.66-2.07 (6H, m), 2.41-2.43 (4H, m), 2.49-2.63 (2H, m), 2.58-2.84 (2H, m), 2.82-2.34 (1H, m), 3.30 ( 2H, d), 3.44-3.46 (4H, m), 3.51 (3H, s), 4.02 (2H, t), 6.82-6.92 (2H, m), 7.15 (2H, d) m/z : ES ⁺ [M+H] ⁺ = 404.

Intermediate 92d: tert -Butyl 4-(3-(4-(1-(3-bromo-4-cyanophenyl)piperidin-4-yl)phenoxy)propyl)-piperazine-1-carboxylate

Cs ₂ CO ₃ (1.45 g, 4.46 mmol) was added to tert -Butyl 4-(3-(4-(piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate (0.9 g, 2.23 mmol) and 2-bromo-4-fluorobenzonitrile (0.446 g, 2.23 mmol) in DMF (20 mL). The resulting mixture was stirred at 100 °C for 15 h. The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL), then saturated brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0-50% EtOAc in petroleum ether) to afford the title compound (0.850 g, 65%) as a yellow oil which solidified on standing; m/z : ES ⁺ [M+H] ⁺ = 583.

Intermediate 92e: tert -Butyl 4-(3-(4-(1-(4-cyano-3-cyclopropylphenyl)piperidin-4-yl)phenoxy)propyl)-piperazine-1-carboxylate

Under N _{2 ,} PdCl ₂ (dppf) (50.2 mg, 0.07 mmol) was added to a mixture of tert -butyl 4-(3-(4-(1-(3-bromo-4-cyanophenyl)-piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate (400 mg, 0.69 mmol), 2-cyclopropyl-4,4,5,5-tetra-methyl-1,3,2-dioxaborolane (173 mg, 1.03 mmol) and K ₃ PO ₄ (291 mg, 1.37 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 90 °C for 15 h. The mixture was then concentrated and the residue was dissolved in EtOAc (50 mL). The solution was washed with water (50 mL) and then with saturated brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0–50% EtOAc in petroleum ether) gave the title compound (280 mg, 75%) as a yellow solid; m/z : ES ⁺ [M+Na] ⁺ = 567.

Intermediate 92f: 2-Cyclopropyl-4-(4-(4-(3-(piperazin-1-yl)propoxy)phenyl)piperidin-1-yl)benzonitrile

4 M HCl in 1,4-dioxane (3.86 mL, 15.42 mmol) was added to tert -butyl 4-(3-(4-(1-(4-cyano-3-cyclopropyl-phenyl)piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate (280 mg, 0.51 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure to give the title compound (220 mg, 89%) as a yellow solid; m/z : ES ⁺ [M+H] ⁺ = 445.

Example 92: 2-Cyclopropyl-4-{4-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}propoxy)phenyl]piperidin-1-yl}benzonitrile

Intermediate 63c was reacted with intermediate 92f using the general synthetic method exemplified by Example 87 to give the title compound after purification by HPLC (column A, eluent A). ^1H NMR: 0.79-0.88 (2H, m), 0.98-1.08 (2H, m), 1.53-1.66 (2H, m), 1.81 (2H, d), 1.86-1.93 (2H, m), 1.98-2.12 (2H, m), 2.46 (3H, m), 2.51-2. 70 (7H, m), 2.70-2.80 (1H, m), 2.88 (3H, t), 3.41-3.45 (4H, m), 3.95-4.06 (4H, m), 5.07 (1H, dd), 6.46 (1H, d), 6.81-6.90 (3H, m), 7.11-7.18 (2H, m), 7.26 (1H, dd), 7.34 (1H, d), 7.47 (1H, d), 7.68 (1H, d), 11.08 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 701.4.

Intermediate 93a: tert -Butyl 4-(3-(4-(1-(4-cyano-3-(difluoromethyl)phenyl)piperidin-4-yl)phenoxy)-propyl)piperazine-1-carboxylate

Bis(dibenzylideneacetone)palladium (39.4 mg, 0.07 mmol) was added tert -butyl 4-(3-(4-(1-(3-bromo-4-cyanophenyl)piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate ( _intermediate 92d) (400 mg, 0.69 mmol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (73.8 mg, 0.14 mmol), and (1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl)(difluoromethyl)silver (377 mg, 0.69 mmol) in toluene (10 mL) under N 2 . The resulting solution was stirred at 80 °C for 18 h. The mixture was then concentrated and diluted with EtOAc (50 mL). The solution was then washed with water (50 mL x 2) and saturated brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (311 mg, 82%) as a yellow oil which solidified on standing; m / z : ES ⁺ [M + H] ⁺ = 555.

Intermediate 93b: 2-(difluoromethyl)-4-(4-(4-(3-(piperazin-1-yl)propoxy)phenyl)piperidin-1-yl)benzonitrile

4 M HCl in 1,4-dioxane (2.70 mL, 10.82 mmol) was added to tert -butyl 4-(3-(4-(1-(4-cyano-3-(difluoromethyl)-phenyl)piperidin-4-yl)phenoxy)propyl)piperazine-1-carboxylate (300 mg, 0.54 mmol) in DCM (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The solvent was then removed under reduced pressure to afford the title compound (253 mg, 95%) as the hydrochloride salt as a yellow solid; m/z : ES ⁺ [M+H] ⁺ = 455.

Example 93: 2-(Difluoromethyl)-4-{4-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}propoxy)phenyl]piperidin-1-yl}benzonitrile

Intermediate 63c was reacted with intermediate 93b using the general synthetic method exemplified by Example 87 to give the title compound after purification by HPLC (column A, eluent A). ^1H NMR: 1.55-1.69 (2H, m), 1.80-1.95 (4H, m), 1.98-2.05 (1H, m), 2.46 (2H, d), 2.51-2.63 (3H, m), 2.65 (1H, m), 2.77 (1H, d), 2.88 (1H, dd), 3.01 (2H, t), 3.30 (2H, m), 3.44 (4H, s), 3.99 (2H, t), 4.11 (2H, d), 5.07 (1H, dd), 6.86 (2H, d), 6.90-7.21 (4H, m), 7.22-7.41 (3H, m), 7.6 9 (2H, dd), 11.08 (1H, s); ¹⁹ F NMR: (376 MHz) -110.7; m/z : ES ⁺ [M+H] ⁺ = 711.4.

Intermediate 94a: tert -Butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

Sodium acetate (0.675 g, 8.22 mmol) was added in one portion to a stirred solution of tert -butyl 4-formyl-piperidine-1-carboxylate (0.643 g, 3.02 mmol) and 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (1.00 g, 2.74 mmol) in DCM (100 mL) at room temperature under air. The resulting suspension was stirred at room temperature for 1 h, after which NaBH(OAc) ₃ (0.871 g, 4.11 mmol) was added, and the mixture was stirred at room temperature for 1 h. The mixture was then diluted with water (20 mL). The organic phase was separated, washed with saturated NaHCO ₃ solution (20 mL) and saturated brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (1.44 g, 100%), which was used directly in the next step; m / z: ES ⁺ [MH] ^- 524.2.

Intermediate 94b: 3-(1-oxo-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

HCl (4 M in 1,4-dioxane) (6.85 mL, 27.40 mmol) was added to tert -butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (1.44 g, 2.74 mmol) in DCM (25 mL), and the mixture was stirred for 1 h. Concentration under reduced pressure gave the title compound as a bis-HCl salt (1.40 g, 103%) as a white solid, which was used directly in the next step; m/z: ES ⁺ [MH] ⁺ 426.0.

Example 94: 4-[4-(6-{4-[(4-{2-[(3 R )-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1 H -isoindole-5-yl}-piperazin-1-yl)methyl]piperidin-1-yl}pyridin-3-yl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Anhydrous DMF (5 mL) was added to a mixture of 4-(4-(6-chloropyridin-3-yl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile (intermediate 56d) (143 mg, 0.39 mmol), 3-(1-oxo-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (150 mg, 0.32 mmol), RuPhos (15.15 mg, 0.03 mmol), RuPhos Pd G3 (27.2 mg, 0.03 mmol), and sodium tert -butoxide (109 mg, 1.14 mmol). The mixture was degassed under N ₂ and stirred at 70 °C for 1 h. After cooling, the mixture was diluted with EtOAc (50 mL) and quenched with 5% AcOH in water (20 mL). The organics were separated, washed with saturated NaHCO ₃ solution (50 mL) and brine (50 mL), then dried (Na ₂ SO ₄ ) and concentrated. Preparative HPLC (column A, eluent A, basic workup A) gave the title compound (15.0 mg, 6%) as a white solid; ^1H NMR: (CDCl ₃ ) 1.30-1.45 (2H, m), 1.68-1.8 (3H, m), 1.85-1.99 (4H, m), 2.15-2.24 (1H, m), 2.27 (2H, d), 2.3-2.4 (1H, m), 2.53-2.64 (4H, m), 2.69 (1H, t), 2.76-2.87 (3H, m), 2.91 (1H, d), 3.05 (2H, t), 3.26-3.37 (4H, m), 4.01 (2H, d), 4.25 (3H, d), 4.41 (1H, d), 5.19 (1H, dd), (1H, d), 6.88 (1H, s), 6.99 (2H, dd), 7.16 (1H, d), 7.31 (1H, dd), 7.62 (1H, d), 7.73 (1H, d), 7.84 (1H, s), 8.06 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 755.0.

Example 95: 4-{4-[4-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 63c was reacted with intermediate 91b using the general synthetic method exemplified by Example 87 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 60 mL/min; Gradient: from 30 B to 50 B in 7 min; 254/220 nm; Rt1: 6.62). ^1H NMR: (300 MHz) 1.55-1.75 (2H, m), 1.83 (2H, d), 1.93-2.05 (2H, m), 2.51-2.64 (5H, m), 2.69-2.77 (3H, m), 2.78-2.96 (1H, m), 3.03 (2H, t), 3.37-3.48 (4H, m), 4.08 (2H, t), 4.16 (2H, d), 5.05 (1H, dd), 6.88 (2H, d), 7.15 (2H, d), 7.25 (2H, d), 7.32 (2H, d), 7.66 (1H, d), 7.80 (1H, d) , 11.06 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 715.4.

Intermediate 96a: tert -Butyl 4-(2-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)amino)ethyl)piperazine-1-carboxylate

Brettphos Pd G3 (0.222 g, 0.24 mmol) was _added to 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (1.00 g, 2.44 mmol), tert -butyl 4-(2-aminoethyl)piperazine-1-carboxylate (0.62 g, 2.69 mmol) and Cs ₂ CO ₃ (2.39 g, 7.33 mmol) in 1,4-dioxane (10 mL) at room temperature under N _{2 . The resulting mixture was stirred at 100 °C for 15 h under N 2} . The mixture was then diluted with EtOAc (75 mL) and washed with saturated brine (50 mL x 3). The organic solution was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0-50% EtOAc in 3-petroleum ether) to give the title compound (1.12 g, 82%) as a white solid; ^1H NMR (300 MHz) 0.84 (1H, q), 1.39 (9H, s), 1.57 (2H, td), 1.81 (2H, d), 2.35-2.67 (4H, m), 2.46 (1H, s), 2.65 (1H, t), 2.95-3.15 (4H, m), 3 .29 (2H, s), 4.15 (2H, d), 5.20 (1H, t), 6.51 (2H, d), 6.95 (2H, d), 7.25 (1H, dd), 7.31 (1H, d), 7.80 (1H, d); m/z ES ⁺ , [M+H] ⁺ = 558.

Intermediate 96b: 4-(4-(4-(2-(piperazin-1-yl)ethoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

tert -Butyl 4-(2-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)amino)ethyl)piperazine-1-carboxylate (200 mg, 0.36 mmol) was added to a solution of 4 M HCl in 1,4-dioxane (1.00 mL, 4.00 mmol) in MeOH (2 mL) at room temperature under air. The resulting mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give the title compound (159 mg, 97%) as a white solid; ^1H NMR (300 MHz) 1.61 (2H, dd), 1.82 (2H, d), 2.69 (1H, d), 3.03 (2H, t), 3.32 (2H, d), 3.52-3.54 (10H, m), 4.16 (2H, d), 6.71 (2H, d), 7.06 (2H) , d), 7.26 (1H, d), 7.31 (1H, d), 7.81 (1H, d), 9.76 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 458.

Example 96: 4-(4-{4-[(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethyl)amino]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 63c was reacted with intermediate 96b using the general synthetic method exemplified by Example 87 to give the title compound after purification by HPLC (column A, eluent B); ¹ H NMR: 1.51-1.65 (2H, m), 1.81 (2H, d), 1.95-2.07 (1H, m), 2.52-2.70 (8H, m), 2.88 (1H, ddd), 3.02 (2H, t), 3.14 (2H, t), 3.46 (4H, t), 4.15 (2H, d), 5.07 (1H, dd), 6.54 (2H, d), 6.96 (2H, d), 7.26 (2H, dt), 7.33 (2H, dd), 7.68 (1H, d), 7.80 (1H, d), 11.07 (1H, s); two protons below the solvent peak; m/z : ES ⁺ [M+H] ⁺ = 714.4.

Intermediate 97a: tert -Butyl 4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)piperazine-1-carboxylate

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.573 g, 1.40 mmol), tert-butyl piperazine-1-carboxylate (1 eq), sodium tert -butoxide (0.404 g, 4.20 mmol), RuPhos Pd G3 (0.117 g, 0.14 mmol), RuPhos (0.065 g, 0.14 mmol), and anhydrous THF (14 mL) were added to a microwave tube. The mixture was degassed, the tube was filled with N ₂ , and the mixture was stirred at 60 °C overnight. After cooling and concentration to dryness, water (10 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: hexane to 100% EtOAc) to afford the title compound (0.614 g, 85%) as a white solid; 1H NMR (500 MHz, CDCl ₃ ) 1.49 (9H, s), 1.70-1.85 (2H, m), 1.96-2.03 (2H, m), 2.65-2.80 (1H, m), 3.01-3.20 (6H, m), 3.48-3.77 (4H, m), 4.03 (2H, br d), 6.84-6.97 (2H, m), 7.00 (1H, dd), 7.10-7.19 (3H, m), 7.62 (1H, d); m/z: ES ⁺ , [M+H]+ = 515.

Intermediate 97b: 4-(4-(4-(piperazin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4 tert -Butyl 4-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)piperazine-1-carboxylate (1.71 g, 3.32 mmol) was dissolved in DCM (8 mL) and TFA (4 mL). The mixture was stirred at room temperature for 3 h. After concentration, DCM (20 mL) was added and the mixture was washed with saturated NaHCO ₃ (2 x 5 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness to give the title compound (1.37 g, 99%) as a dry film; ^1H NMR (500 MHz, CDCl ₃ ) 1.77 (2H, qd), 1.98 (2H, br d), 2.73 (2H, tt), 3.01-3.14 (6H, m), 3.20 (4H, dd), 4.03 (2H, br d), 6.90 (2H, d), 7.00 (1H, dd), 7.10-7.19 (3H, m), 7.62 (1H, d); m/z: ES ⁺ , [M+H] ⁺ = 415.

Intermediate 97c: 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione

NaOAc (0.50 g, 6.09 mmol) was added to 5-hydroxyisobenzofuran-1,3-dione (0.50 g, 3.05 mmol) and 3-aminopiperidine-2,6-dione (0.39 g, 3.05 mmol) in AcOH (3 mL) at room temperature. The resulting mixture was stirred at 120 °C for 3 h and then at room temperature overnight. The precipitate was then collected by filtration, washed with water (10 mL) and Et ₂ O (10 mL), and dried at 50 °C to give the title compound (0.60 g, 72%); ^1H NMR (500MHz) 2.08 (1H, dtd), 2.53-2.70 (2H, m), 2.90 (1H, ddd), 5.17 (1H, dd), 7.66-7.79 (1H, m), 7.86 (1H, dd), 8.02 (1H, dd), 11.21(1H, s) ; m/z : ES ⁺ , [M+H] ⁺ = 275.

Intermediate 97d: 2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxyethoxy)isoindoline-1,3-dione

DMF (0.5 mL) was added to a mixture of 2-bromoethane-1-ol (114 mg, 0.91 mmol), K ₂ CO ₃ (139 mg, 1.00 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (250 mg, 0.91 mmol). The resulting suspension was stirred at 50 °C for 5 h and then concentrated. Water (10 mL) was added and the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The mixture was purified by FSC (gradient: hexanes to EtOAc) to give the title compound (34 mg, 12%); ^1H NMR (500 MHz, CDCl ₃ ) 1.63-1.74 (1H, m), 2.13-2.20 (1H, m), 2.75-2.87 (2H, m), 4.01-4.09 (2H, m), 4.22 (2H, br d), 4.97 (1H, br dd), 7.25 (1H, d), 7.38 (1H, s), 7.81 (1H, br d), 8.02 (1H, s); m/z: ES ⁺ , [M+H] ⁺ = 319.

Intermediate 97e: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl methanesulfonate

Et ₃ N (0.030 mL, 0.21 mmol) was _added to a mixture of _{methanesulfonic} anhydride (22.33 mg, 0.13 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxyethoxy)isoindoline-1,3-dione (34 mg, 0.11 mmol) in anhydrous CH 2 Cl 2 (1 mL) at 0 °C, and the mixture was stirred overnight at room temperature. The mixture was then diluted with DCM (10 mL), washed with water (10 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (15 mg, 35%); ^1H NMR (500 MHz, CDCl ₃ ) 2.14-2.20 (1H, m), 2.72-2.93 (3H, m), 3.11 (3H, s), 4.37-4.43 (2H, m), 4.59-4.66 (2H, m), 4.97 (1H, dd), 7.19-7.25 (1 H, m), 7.37 (1H, d), 7.82 (1H, d), 8.11-8.25 (1H, m); m/z : ES ⁺ , [M+H] ⁺ = 397.

Example 97: 4-(4-{4-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]oxy}ethyl)piperazin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DMF (0.5 mL) was added to a mixture of NaI (6 mg, 0.04 mmol), DIPEA (0.020 mL, 0.11 mmol), 4-(4-(4-(piperazin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (16 mg, 0.04 mmol) and 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl methanesulfonate (15 mg, 0.04 mmol). The resulting solution was stirred at 60–90 °C for 3 h and then concentrated. DCM (10 mL) was added and the resulting solution was washed with water, saturated NaHCO ₃ (2 mL), dried (Na ₂ SO ₄ ) and concentrated. The title compound (7 mg, 23%) was purified by FSC (hexane~EtOAc); ^1H NMR: (500 MHz) 1.55-1.64 (2H, m), 1.79-1.85 (2H, m), 2.01-2.05 (1H, m), 2.55-2.65 (6H, m), 2.70 (1H, s), 2.82 (2H, s), 2.84-2.93 (1H, m) , 2.99-3.06 (2H, m), 3.06-3.11 (4H, m), 4.16 (2H, br d), 4.33 (2H, t), 5.11 (1H, dd), 6.86 (2H, d), 7.08 (2H, d), 7.25 (1H, dd), 7.31 (1H, d), 7.37 (1H, dd), 7.47 (1H, d), 7.81 (2H, dd), 11.09 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 715.3.

Intermediate 98a: 2-(2,6-dioxopiperidin-3-yl)-5-(4-hydroxypiperidin-1-yl)isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.200 g, 0.72 mmol) was dissolved in DMA (1 mL). Then DIPEA (0.253 mL, 1.45 mmol) and piperidin-4-ol (0.081 g, 0.80 mmol) were added. The mixture was stirred at 100 °C for 18 h and then concentrated. Purification by FSC (gradient: hexane~EtOAc) gave the title compound (0.200 g, 77%); ^1H NMR (500 MHz) 1.36-1.47 (2H, m), 1.73-1.84 (2H, m), 1.99-2.06 (1H, m), 2.52-2.63 (2H, m), 2.81-2.90 (1H, m), 3.18 (2H, ddd), 3.70-3.78 (1H , m), 3.81 (2H, br d), 4.74 (1H, d), 5.05 (1H, dd), 7.23 (1H, dd), 7.30 (1H, d), 7.64 (1H, d), 11.06 (1H, s); m/z : ES ⁺ , [M+H]+ = 358.

Intermediate 98b: 2-(2,6-dioxopiperidin-3-yl)-5-(4-oxopiperidin-1-yl)isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(4-hydroxypiperidin-1-yl)isoindoline-1,3-dione (25 mg, 0.07 mmol) was dissolved in DCM. Dess-Martin periodinane (59 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 2 h and then concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (18 mg, 72%); ^1H NMR (500 MHz, CDCl ₃ ) 2.61-2.64 (4H, m), 2.70-3.03 (4H, m), 3.82-3.85 (4H, m), 4.88-5.02 (1H, m), 7.10 (1H, dd), 7.30-7.34 (1H, m), 7.73-7. 76 (1H, m), 8.15 (1H, s); m/z : ES ⁺ , [M+H] ⁺ = 356.

Example 98: 4-{4-[4-(4-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperidin-4-yl}piperazin-1-yl)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 97b was reacted with intermediate 98b using the general synthetic method exemplified by Example 2 to give the title compound (as a formate salt) after purification by flash C-18 chromatography (eluent A); ^1H NMR: (500 MHz, CDCl ₃ ) 1.72-1.92 (4H, m), 1.97-2.02 (2H, m), 2.14-2.24 (4H, m), 2.71-2.97 (5H, m), 3.01-3.12 (7H, m), 3.41 (4H, br s), (4H, br t), 4.97 (1H, dd), 6.92 (2H, d), 7.01 (1H, br d), 7.10 (1H, br d), 7.13-7.19 (3H, m), 7.32 (1H, s), 7.64 (1H, d), 7.73 (1H, d), 8.00 (1H , br s), 8.10 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 754.4.

Intermediate 99a: 2-(2,6-dioxopiperidin-3-yl)-5-(4-hydroxybutoxy)isoindoline-1,3-dione

DMF (1 mL) was added to a mixture of 4-bromobutan-1-ol (112 mg, 0.73 mmol), K ₂ CO ₃ (111 mg, 0.80 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (200 mg, 0.73 mmol). The resulting suspension was stirred overnight at 50 °C and then concentrated. Water (10 mL) was then added, and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The mixture was purified by FSC (gradient: hexanes to EtOAc) and further purified using a 30 g C18 column (eluent A) to give the title compound (35 mg, 14%); ^1H NMR (500 MHz) 1.53-1.61 (2H, m), 1.78 (2H, quin), 2.01-2.11 (1H, m), 2.55-2.65 (2H, m), 2.83-2.93 (1H, m), 3.45 (2H, q), 4.18 (2H, t), 4.46 ( 1H, t), 5.07-5.15 (1H, m), 7.33 (1H, dd), 7.41 (1H, d), 7.82 (1H, d), 11.10 (1H, s); m/z: ES ⁺ , [M+H] ⁺ = 347.

Intermediate 99b: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl methanesulfonate

Et ₃ N (0.027 mL, 0.19 mmol) was added to a mixture of methanesulfonic anhydride (19.92 mg, 0.11 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(4-hydroxybutoxy)isoindoline-1,3-dione (33 mg, 0.10 mmol) in anhydrous DCM (1 mL) at 0 °C. The mixture was then stirred at room temperature for 0.5 h, diluted with DCM (10 mL), washed with water (1 mL), dried (Na ₂ SO ₄ ), and concentrated to provide the title compound; ^1H NMR (500 MHz, CDCl ₃ ) 1.50-1.55 (3H, m), 2.13-2.19 (1H, m), 2.72-2.96 (4H, m), 3.05 (3H, s), 4.13-4.20 (2H, m), 4.29-4.39 (2H, m), 4.97 (1H) , dd), 7.16-7.23 (1H, m), 7.35 (1H, d), 7.80 (1H, d), 7.96 (1H, br s); m/z : ES ⁺ , [M+H]+ = 425.

Example 99: 4-(4-{4-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]oxy}-butyl)piperazin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DMF (0.5 mL) was added to a mixture of NaI (12.71 mg, 0.08 mmol), DIPEA (0.044 mL, 0.25 mmol), 4-(4-(4-(piperazin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (35 mg, 0.08 mmol) and 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl methanesulfonate (36 mg, 0.08 mmol). The resulting solution was stirred at 60 °C for 1 h and then concentrated to dryness. DCM (10 mL) was added and the resulting mixture was washed with water, saturated NaHCO ₃ (2 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (eluent: hexane-EtOAc, then 5% MeOH in EtOAc) to give the title compound (12 mg, 19%); ^1H NMR: (500 MHz, CDCl ₃ ) 1.50-1.55 (2H, m), 1.76 (3H, qd), 1.90-2.01 (4H, m), 2.14-2.22 (1H, m), 2.46-3.29 (15H, m), 4.03 (2H, br d), 4.12-4.1 7 (2H, m), 4.97 (1H, dd), 6.90 (2H, d), 6.97-7.02 (1H, m), 7.11-7.15 (2H, m), 7.16 (1H, d), 7.20 (1H, dd), 7.34 (1H, d), 7.62 (1H, d), 7.79 (1H) ,d), 7.97 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 743.3.

Intermediate 100a: 2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxypropoxy)isoindoline-1,3-dione

DMF (0.5 mL) was added to a mixture of 3-bromopropan-1-ol (84 mg, 0.60 mmol), K ₂ CO ₃ (151 mg, 1.09 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (intermediate 97c) (150 mg, 0.55 mmol). The resulting suspension was stirred at 50 °C for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the phases were separated. The aqueous portion was extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by FSC (gradient: hexanes to EtOAc) to give the title compound (50.0 mg, 28%); ^1H NMR (500 MHz, CDCl ₃ ) 2.08-2.22 (3H, m), 2.71-2.94 (3H, m), 3.89 (2H, t), 4.26 (2H, t), 4.97 (1H, dd), 7.22 (1H, dd), 7.38 (1H, d), 7.80 (1H, d) ), 7.99 (1H, br s); m/z : ES ⁺ , [M+H] ⁺ = 333.

Intermediate 100b: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl 4-methyl-benzenesulfonate

DCM (1 mL) was added to a mixture of p -toluenesulfonyl chloride (33.6 mg, 0.18 mmol), 2-(2,6-dioxo-piperidin-3-yl)-5-(3-hydroxypropoxy)isoindoline-1,3-dione (45 mg, 0.14 mmol), DIPEA (0.047 mL, 0.27 mmol), and DMAP (16.54 mg, 0.14 mmol). The mixture was stirred at room temperature overnight. After diluted with DCM (5 mL), the resulting solution was washed with water, dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: hexanes to EtOAc) afforded the title compound (27 mg, 41%) as a sticky film; ^1H NMR (500 MHz, CDCl ₃ ) 2.12-2.26 (3H, m), 2.40 (3H, s), 2.72-2.95 (3H, m), 4.10 (2H, t), 4.26 (2H, t), 4.97 (1H, dd), 7.09 (1H, dd), 6 (1H, m), 7.28-7.32 (2H, m), 7.75-7.81 (3H, m), 8.05 (1H, br s); m/z : ES ⁺ , [M+H]+ = 487.

Example 100: 4-(4-{4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]oxy}-propyl)piperazin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DMF (0.5 mL) was added to a mixture of NaI (14 mg, 0.10 mmol), DIPEA (0.051 mL, 0.29 mmol), 4-(4-(4-(piperazin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 97b) (40 mg, 0.10 mmol), 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl 4-methylbenzenesulfonate (47 mg, 0.10 mmol). The resulting solution was stirred at 60 °C for 1 h. The mixture was then concentrated to dryness, after which DCM (10 mL) was added. The solution was washed with water and then saturated NaHCO ₃ (2 mL), dried (Na ₂ SO ₄ ), concentrated and purified by FSC (eluent: hexane-EtOAc then 5% MeOH in EtOAc) to give the title compound (39 mg, 54.0%); ^1H NMR: (500 MHz) 1.55-1.65 (2H, m), 1.79-1.87 (2H, m), 1.89-1.97 (2H, m), 2.01-2.07 (1H, m), 2.51-2.64 (7H, m), 2.68-2.75 (1H, m), 2.84-2. 91 (1H m), 2.98-3.12 (7H, m), 4.16 (2H, br d), 4.23 (2H, br t), 5.06-5.17 (1H, m), 6.85 (2H, br d), 7.08 (2H, br d), 7.23-7.28 (1H, m), 7.31 (1H, br s), 7.33-7.37 (1H, m), 7.43 (1H, br d), 7.75-7.86 (2H, m), 11.10 (1H, s), two protons below the solvent peak; m/z : ES ⁺ [M+H] ⁺ = 729.3.

Intermediate 101a: 5-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)pentyl 4-methylbenzenesulfonate

4-(4-(4-Hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.43 mmol), PPh ₃ (0.284 _g , 1.08 mmol) and 5-hydroxypentyl 4-methylbenzenesulfonate (0.168 g, 0.65 mmol) were dissolved in anhydrous DCM (4.3 mL) under N 2 . The mixture was cooled to 0 °C and di- tert -butyl (E)-diazen-1,2-dicarboxylate (0.199 g, 0.87 mmol) was added. The mixture was stirred at room temperature overnight and then washed with saturated NaHCO ₃ (2 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: hexane-DCM) to give the title compound (0.200 g, 79%) as a colorless oil; ^1H NMR (500 MHz, CDCl ₃ ) 1.48-1.55 (2H, m), 1.69-1.85 (6H, m), 1.99 (2H, br d), 2.45 (3H, s), 2.75 (1H, tt), 3.07 (2H, td), 3.90 (2H, t), .09 (4H, m), 6.83 (2H, d), 7.02 (1H, dd), 7.13 (2H, d), 7.19 (1H, d), 7.34 (2H, d), 7.57-7.69 (1H, m), 7.80 (2H, d); m/z : ES ⁺ , [M+H] ⁺ = 587.

Example 101: 4-(4-{4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}pentyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 63e was reacted with intermediate 101a using the general synthetic method exemplified by Example 12 to give the title compound after purification by FSC (gradient: 0-100% EtOAc in hexanes); ^1H NMR: (500 MHz) 1.38-1.46 (2H, m), 1.46-1.54 (2H, m), 1.55-1.66 (2H, m), 1.67-1.75 (2H, m), 1.83 (2H, br d), 1.98-2.04 (1H, m), 2.27-2.39 ( 3H, m), 2.51-2.66 (3H, m), 2.71-2.78 (1H, m), 2.81-2.92 (1H, m), 3.03 (2H, br t), 3.41 (4H, br s), 3.92 (2H, t), 4.16 (2H, br d), 4.97-5.20 (1 H, m), 6.84 (2H, d), 7.14 (2H, d), 7.21-7.28 (2H, m), 7.29-7.37 (2H, m), 7.66 (1H, d), 7.80 (1H, d), 11.05 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 757.3.

Example 102: 4-(4-{4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}pentyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 101a using the general synthetic method exemplified by Example 12 to give the title compound after purification by C-18 chromatography (eluent A, basic workup A); ^1H NMR: (500 MHz) 1.39-1.46 (2H, m), 1.47-1.54 (2H, m), 1.55-1.66 (2H, m), 1.67-1.76 (2H, m), 1.79-1.86 (2H, m), 1.91-2.01 (1H, m), 2.29-2. 39 (4H, m), 2.52-2.65 (2H, m), 2.72-2.79 (1H, m), 2.84-2.94 (1H, m), 3.03 (2H, br t), 3.22-3.28 (6H, m), 3.92 (2H, t), 4.11-4.22 (3H, m), 4.2 7-4.37 (1H, m), 5.03 (1H, dd), 6.84 (2H, br d), 7.00-7.08 (2H, m), 7.14 (2H, br d), 7.25 (1H, br d), 7.31 (1H, s), 7.51 (1H, d), 7.79 (1H, s), 10.92 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 743.4.

Intermediate 103a: tert -Butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butyl)carbamate

DMF (2 mL) was added to a mixture of tert -butyl (4-bromobutyl)carbamate (256 mg, 1.01 mmol), 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (370 mg, 1.01 mmol) and KI (168 mg, 1.01 mmol). The mixture was stirred at 90 °C for 24 h, then cooled to room temperature and the solvent was removed under reduced pressure. Purification by FSC (hexanes~DCM, then eluted with 10% MeOH in DCM) gave the title compound (340 mg, 67%); ¹ H NMR (500 MHz) 1.23-1.31 (2H, m), 1.32-1.46 (12H, m), 1.92-1.98 (1H, m), 2.36 (2H, qd), 2.53-2.64 (2H, m), 2.83-3.01 (4H, m), 3.08-3.18 (1 H, m), 3.31 (4H, br s), 4.12-4.24 (1H, m), 4.29-4.43 (1H, m), 5.04 (1H, dd), 6.84 (1H, br s), 7.10 (2H, br s), 7.43-7.67 (1H, m), 10.93 (1H, s); m/z : ES ⁺ , [M+H] ⁺ = 500.

Intermediate 103b: 3-(5-(4-(4-aminobutyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

4 M HCl in 1,4-dioxane (5.1 mL, 20.42 mmol) and DCM (10 mL) were added to tert -butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butyl)carbamate (340 mg, 0.68 mmol) to give a suspension. The resulting suspension was stirred at room temperature for 1 h and then concentrated to dryness. Et ₂ O (10 mL) was added to the residue to give a brown suspension. The solid was collected by filtration to give the title compound as a hydrochloride salt (270 mg, 91%); ^1H NMR (500 MHz) 1.59-1.69 (2H, m), 1.77-1.85 (2H, m), 1.93-2.03 (1H, m), 2.30-2.41 (1H, m), 2.54-2.66 (2H, m), 2.77-2.96 (3H, m), 3.06-3.2 3 (4H, m), 3.26-3.38 (2H, m), 3.96-4.04 (2H, m), 4.07-4.25 (2H, m), 4.32-4.40 (1H, m), 5.00-5.12 (1H, m), 7.08-7.25 (2H, m), 7.58 (1H, d), 7 .97 (3H, br s), 10.93 (1H, s); m/z: ES ⁺ , [M+H] ⁺ = 400.

Example 103: 4-(4-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butyl)amino]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (73 mg, 0.18 mmol), sodium tert -butoxide (78 mg, 0.81 mmol), 3-(5-(4-(4-aminobutyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione bis-hydrochloride salt (70 mg, 0.15 mmol), Brettphos Pd G3 (13 mg, 0.01 mmol) and anhydrous DMF (1.482 mL) were added to the flask. The mixture was degassed, the flask was filled with N ₂ , and then the mixture was stirred at 100 °C for 1.5 h. After cooling to room temperature, the reaction was quenched with AcOH (49 mg, 0.81 mmol) in MeCN (0.1 mL) to give a cloudy solution. DMSO (1 mL) was added and the mixture was filtered. Purification on a C-18 50 g column (0.1% formic acid in water to 0.1% formic acid in MeCN over 15 min) gave the title compound as a formate salt (20 mg, 17%); ^1H NMR: (500 MHz) 1.49-1.65 (7H, m), 1.79 (2H, br d), 1.92-2.00 (1H, m), 2.28-2.42 (4H, m), 2.54-2.68 (4H, m), 2.83-2.94 (2H, m), 2.95-3.30 ( 8H, m), 4.13 (2H, br d), 4.17-4.24 (1H, m), 4.28-4.41 (1H, m), 5.03 (1H, br dd), 6.49 (2H, br d), 6.93 (2H, br d), 7.00-7.08 (2H, m), 7.24 (1H, br d), 7.30 (1H, s), 7.51 (1H, d), 7.79 (1H, d), 8.02-8.18 (1H, m), 10.92 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 728.4.

Intermediate 104a: 4-(4-(4-((7-bromoheptyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-Hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.170 g, 0.49 mmol), PPh ₃ (0.283 g, 1.08 mmol) and 7-bromoheptan-1-ol (0.144 g, 0.74 mmol) were dissolved in anhydrous DCM (4.9 mL) under N ₂ and cooled to 0 °C. Di- tert -butyl ( E )-diazen-1,2-dicarboxylate (0.170 g, 0.74 mmol) was added dropwise. The mixture was then stirred at room temperature for 1 h. Additional di- tert -butyl ( E )-diazene-1,2-dicarboxylate (40 mg), PPh ₃ (40 mg) and 7-bromoheptan-1-ol (0.144 g, 0.74 mmol) were then added, and the mixture was stirred at room temperature overnight. The mixture was then washed with saturated NaHCO ₃ (2 mL) and dried (Na ₂ SO ₄ ). The mixture was purified by FSC (gradient: hexane~DCM) to give the title compound (0.170 g, 66%) as a white solid; ^1H NMR (500 MHz, CDCl ₃ ) 1.37-1.44 (2H, m), 1.45-1.52 (4H, m), 1.74-1.83 (4H, m), 1.88 (2H, dt), 1.96-2.02 (2H, m), 2.75 (1H, tt), 3.07 (2H, td) , 3.39-3.46 (2H, m), 3.95 (2H, t), 3.99-4.07 (2H, m), 6.82-6.89 (2H, m), 7.02 (1H, dd), 7.11-7.15 (2H, m), 7.18 (1H, d), 7.63 (1H, d); m/z: ES ⁺ , [M+H] ⁺ = 523.

Example 104: 4-(4-{4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}heptyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 104a using the general synthetic method exemplified by Example 12 to give the title compound as a formate salt after purification by C-18 chromatography (eluent A); ^1H NMR: (500 MHz) 1.28-1.45 (6H, m), 1.51-1.65 (4H, m), 1.69 (2H, dt), 1.82 (2H, br d), 1.92-1.99 (1H, m), 2.29-2.42 (2H, m), 2.54-2.62 (2H, m) ), 2.75 (2H, ddd), 2.85-2.95 (2H, m), 2.99-3.08 (3H, m), 3.29-3.35 (4H, m), 3.91 (2H, t), 4.13-4.24 (3H, m), 4.31 (1H, s), 5.04 (1H, dd), 6. 83 (2H, d), 7.05-7.11 (2H, m), 7.13 (2H, d), 7.25 (1H, dd), 7.31 (1H, d), 7.54 (1H, d), 7.80 (1H, d), 8.12 (1H, s), 10.93 (1H, s), four protons below the solvent peak; m/z : ES ⁺ [M+H] ⁺ = 771.5.

Example 105: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 63e using the general synthetic method exemplified by Example 5 to give the title compound as a formate salt after purification by C-18 chromatography (eluent A); ¹ H NMR: (500 MHz) 1.55-1.66 (4H, m), 1.68-1.78 (2H, m), 1.79-1.87 (2H, m), 1.95-2.04 (1H, m), 2.38 (2H, br t), 2.53-2.65 (2H, m), 2.68-2.80 (1H, m), 2.80-2.96 (1H, m), 2.98-3.08 (2H, m), 3.38-3.53 (4H, m), 3.95 (2H, t), 4.16 (2H, br d), 4.94-5.34 (1H, m), 6.85 (2H, d), 7.14 (2H, d), 7.21-7.28 (2H, m), 7.31 (2H, dd), 7.66 (1H, d), 7.80 (1H, d), 8.13 (1H, s), 11.06 (1H, s), three protons below the solvent peak; m/z : ES ⁺ [M+H] ⁺ = 743.3.

Intermediate 106a: 4-(4-(4-((6-bromohexyl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-Hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.170 g, 0.49 mmol), PPh ₃ (0.257 g, 0.98 mmol) and 6-bromohexan-1-ol (0.133 g, 0.74 mmol) were dissolved in anhydrous DCM (4.9 mL) under N ₂ and cooled to 0 °C. Di- tert -butyl ( E )-diazen-1,2-dicarboxylate (0.170 g, 0.74 mmol) was then added and the mixture was stirred at room temperature for 1 h. Afterwards, di- tert -butyl ( E )-diazene-1,2-dicarboxylate (40 mg), PPh ₃ (40 mg) and 6-bromohexan-1-ol (1 eq) were additionally added. The mixture was stirred at room temperature for 6 h, then washed with saturated NaHCO ₃ (2 mL) and dried (Na ₂ SO ₄ ). The mixture was purified by FSC (gradient: hexane~DCM) to give the title compound (0.150 g, 60%) as a white solid; ^1H NMR (500 MHz, CDCl ₃ ) 1.48-1.57 (4H, m), 1.77-1.94 (6H, m), 2.00 (2H, br d), 2.71-2.82 (1H, m), 3.03-3.14 (2H, m), 3.39-3.46 (2H, m), 3.96 (2 H, t), 4.02 (2H, br d), 6.86 (2H, d), 7.10 (1H, dd), 7.14 (2H, d), 7.22-7.25 (1H, m), 7.65 (1H, d); m/z : ES ⁺ , [M+H]+ = 509.

Example 106: 4-(4-{4-[(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}hexyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 63e was reacted with intermediate 106a using the general synthetic method exemplified by Example 5 to give the title compound (as a formate salt) after purification by C-18 chromatography (eluent A); ^1H NMR: (500 MHz) 1.30-1.38 (2H, m), 1.38-1.45 (2H, m), 1.45-1.52 (2H, m), 1.56-1.64 (2H, m), 1.65-1.74 (2H, m), 1.79-1.86 (2H, m), 1.98-2. 03 (1H, m), 2.30-2.37 (2H, m), 2.52-2.64 (4H, m), 2.71-2.79 (1H, m), 2.83-2.92 (1H, m), 2.99-3.06 (2H, m), 3.37-3.47 (4H, m), 3.91 (2H, t), 4.15 (2H, br d), 5.06 (1H, dd), 6.78-6.90 (2H, m), 7.13 (2H, d), 7.21-7.27 (2H, m), 7.31 (2H, dd), 7.66 (1H, d), 7.76-7.85 (1H, m), 8.12 (1H, s), (1H, s); m/z : ES ⁺ [M+H] ⁺ = 771.5.

Intermediate 107a: 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate

Et ₃ N (2.24 mL, 16.04 mmol) was slowly added to tert -butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (2.00 g, 8.02 mmol) and methanesulfonyl chloride (0.750 mL, 9.63 mmol) in DCM (20 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (100 mL) and washed with water (10 mL), followed by saturated brine (10 mL). The organic solution was then dried (Na ₂ SO ₄ ) and concentrated to afford the title compound (2.10 g, 80%) as a pale yellow oil; ^1H NMR (CDCl ₃ ) 1.36 (9H, s), 2.67 (4H, d), 4.36 (3H, s), 5.00 (6H, s), 5.29 (2H, s), 7.32 (1H, s); m/z ES ⁺ , [M+H] ⁺ = 328.

Intermediate 107b: 3-(5-(4-(2-(2-aminoethoxy)ethoxy)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione

Cs ₂ CO ₃ (1.79 g, 5.48 mmol) was added to 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (1.44 g, 4.39 mmol), 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (1.20 g, 3.65 mmol) and KI (0.728 g, 4.39 mmol) in DMF (12 mL). The resulting mixture was stirred at 65 °C for 2 h. Then the solvent was removed under reduced pressure. DCM (15 mL) was added to the residue, and the mixture was filtered. Then 4 M HCl in 1,4-dioxane (20 mL) was added dropwise to the filtrate, and the mixture was stirred at room temperature for 1 h. The residue was purified by flash C18-flash chromatography (eluent: 100% water) to give the title compound (0.699 g, 85%) as a light yellow solid; m/z ES ⁺ , [M+H] ⁺ = 460.

Example 107: 4-{4-[4-({2-[2-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]-piperazin-1-yl}ethoxy)ethoxy]ethyl}amino)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (65 mg, 0.16 mmol), sodium tert -butoxide (70 mg, 0.72 mmol), 3-(5-(4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione bis-hydrochloride salt (70 mg, 0.13 mmol), Brettphos Pd G3 (12 mg, 0.01 mmol), and anhydrous DMF (953 μL) were added to the flask. The mixture was degassed, the flask was filled with N ₂ , and then the mixture was stirred at 100 °C for 1.5 h. After cooling to room temperature, the mixture was quenched with 2 M AcOH in THF (362 μL, 0.72 mmol) to give a cloudy solution. THF was removed under reduced pressure. DMSO (1 mL) was added, and the mixture was filtered. Purification by C18 chromatography (0.1% formic acid in water to 0.1% formic acid in MeCN over 15 min) gave the title compound as a formate salt (20 mg, 17%); ^1H NMR: (500 MHz) 1.48-1.61 (2H, m), 1.73-1.80 (2H, m), 1.91-2.00 (1H, m), 2.32-2.41 (2H, m), 2.53-2.68 (4H, m), 2.84-2.95 (2H, m), 2.96-3. 05 (3H, m), 3.13-3.18 (3H, m), 3.52-3.67 (8H, m), 3.74-3.81 (2H, m), 4.12 (2H, br d), 4.19-4.25 (1H, m), 4.31 (1H, br s), 4.97-5.14 (1H, m), 6.52 (2H, br d), 6.93 (2H, br d), 7.07 (1H, br d), 7.10 (1H, br s), 7.23 (1H, br d), 7.29 (1H, br s), 7.56 (1H, br d), 7.79 (1H, br d), 8.12 (1H, s), 10.94 (1H, s), no exchangeable proton; m/z : ES ⁺ [M+H] ⁺ = 788.3.

Intermediate 108a: tert -Butyl (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate

DIPEA (4.79 mL, 27.41 mmol) was added to 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (3.00 g, 9.14 mmol) and tert -butyl (2-bromoethyl)carbamate (2.46 g, 10.96 mmol) in DMF (30 mL), and the mixture was stirred at room temperature for 40 h. The mixture was then diluted with EtOAc (100 mL) and washed with water (20 mL), followed by saturated brine (20 mL). The organic solution was then dried (Na ₂ SO ₄ ) and concentrated to give the title compound, which was used in the next step without further purification; m / z : ES ⁺ [M+H] ⁺ = 472.

Intermediate 108b: 3-(5-(4-(2-aminoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

tert -Butyl (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate (1.60 g, 3.39 mmol) was added to 4 M HCl in 1,4-dioxane (1 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the title compound (1.25 g, 99%) as a white solid; m/z : ES ⁺ [M+H] ⁺ = 372.

Example 108: 4-(4-{4-[(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethyl)amino]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (77 mg, 0.19 mmol), sodium tert -butoxide (91 mg, 0.95 mmol), 3-(5-(4-(2-aminoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione bis-hydrochloride salt (70 mg, 0.16 mmol) and Brettphos Pd G3 (14.28 mg, 0.02 mmol) were suspended in anhydrous DMF (1.103 mL). The mixture was degassed, filled with N ₂ and then stirred at 100 °C for 1.5 h. After cooling to room temperature, the reaction was quenched with AcOH (2 M in THF, 473 μL, 0.95 mmol) to give a cloudy solution. THF was removed under reduced pressure. DMSO (1 mL) was added, and the mixture was filtered. Purification by reverse phase (C18) chromatography (0.1% formic acid in water to 0.1% formic acid in MeCN over 15 min) gave the title compound as a formate salt (30 mg, 23%); ^1H NMR: (500 MHz) 1.54-1.65 (2H, m), 1.77-1.84 (2H, m), 1.83-1.91 (1H, m), 1.93-2.00 (1H, m), 2.34-2.42 (1H, m), 2.54-2.64 (3H, m), 2.65-2. 72 (2H, m), 2.85-2.95 (2H, m), 2.99-3.07 (3H, m), 3.42 (7H, br d), 4.15 (2H, br d), 4.20-4.27 (1H, m), 4.32-4.39 (1H, m), 5.05 (1H, dd), 2H, d), 6.99-7.03 (2H, m), 7.13-7.19 (2H, m), 7.23-7.27 (1H, m), 7.30-7.31 (1H, m), 7.58 (1H, d), 7.80 (1H, d), 8.12 (1H, s), 10.93 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 700.3.

Example 109: 4-(4-{4-[(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}hexyl)oxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 106a using the general synthetic method exemplified by Example 12 to give the title compound after purification by C-18 chromatography (eluent A); ^1H NMR: (500 MHz) 1.31-1.40 (2H, m), 1.41-1.49 (2H, m), 1.56-1.65 (2H, m), 1.68-1.75 (3H, m), 1.79-1.87 (2H, m), 1.93-2.00 (1H, m), 2.31-2. 42 (1H, m), 2.56-2.64 (2H, m), 2.71-2.80 (1H, m), 2.85-2.95 (1H, m), 3.00-3.07 (2H, m), 3.07-3.20 (6H, m), 3.54-3.64 (2H, m), 3.88-4.06 (4H) , m), 4.13-4.20 (2H, m), 4.20-4.27 (1H, m), 4.31-4.44 (1H, m), 4.98-5.12 (1H, m), 6.84 (2H, br d), 7.12-7.18 (3H, m), 7.26 (1H, br d), 7.31 (1H, br s), 7.57-7.60 (1H, m), 7.80 (1H, br d), 10.93 (1H, s); No exchangeables observed; m/z : ES ⁺ [M+H] ⁺ = 757.4.

Intermediate 110a: 6-(( tert -Butoxycarbonyl)amino)hexyl methanesulfonate

Et ₃ N (1.28 mL, 9.20 mmol) was slowly added to tert -butyl (6-hydroxyhexyl)carbamate (1.00 g, 4.60 mmol) and methanesulfonyl chloride (0.430 mL, 5.52 mmol) in DCM (15 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (50 mL) and washed with water (10 mL), followed by saturated brine (10 mL). The organic solution was then dried (Na ₂ SO ₄ ) and concentrated to give the title compound (1.350 g, 99%) as a colorless oil; ^1H NMR (300 MHz, CDCl ₃ ) 1.46 (15H, s), 1.76 (2H, dt), 3.03 (3H, s), 3.13 (2H, dd), 4.24 (2H, t), 4.54 (1H, s).

Intermediate 110b: tert -Butyl (6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)carbamate

Cs ₂ CO ₃ (4.47 g, 13.70 mmol) was added to 6-(( tert -butoxycarbonyl)amino)hexyl methanesulfonate (4.32 g, 14.62 mmol), 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (3.00 g, 9.14 mmol) and KI (2.43 g, 14.62 mmol) in DMF (15 mL). The resulting mixture was stirred at 65 °C for 3 h. Purification by FSC (gradient: 0-100% EtOAc in petroleum ether) gave the title compound (0.800 g, 17%) as a yellow solid; m/z ES ⁺ , [M+H] ⁺ = 528.

Intermediate 110c: 3-(5-(4-(6-aminohexyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

4 M HCl in 1,4-dioxane (15 mL, 1.52 mmol) was added dropwise to tert -butyl (6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)carbamate (800 mg, 1.52 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 h. The crude product was purified by C18-flash chromatography (eluent: 100% water) to give the title compound (425 mg, 66%) as a light yellow solid; m/z ES ⁺ , [M+H] ⁺ = 428.

Example 110: 4-(4-{4-[(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}hexyl)amino]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (68.7 mg, 0.17 mmol), sodium tert -butoxide (73.9 mg, 0.77 mmol), 3-(5-(4-(6-aminohexyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione bis-hydrochloride salt (70 mg, 0.14 mmol), Brettphos Pd G3 (12.68 mg, 0.01 mmol) were suspended in anhydrous DMF (1391 μL). The mixture was degassed, filled with N ₂ , and then stirred at 100 °C for 1.5 h. The mixture was then cooled to room temperature and quenched with 10% AcOH in MeCN (0.2 mL) to give a cloudy solution. DMSO (1 mL) was added and the mixture was filtered. The filtrate was directly loaded onto a C-18 50 g column (eluent: 0.1% formic acid in water to 0.1% formic acid in MeCN over 15 min) to give the title compound (41 mg, 37%) as a formate salt. ^1H NMR: (500 MHz) 1.28-1.43 (4H, m), 1.48-1.63 (5H, m), 1.67 (2H, br s), 1.71-1.86 (3H, m), 1.87-2.02 (1H, m), 2.33-2.42 (1H, m), 2.54-2.69 (3H, m), 2.84-3.20 (12H, m), 4.14 (2H, br d), 4.18-4.28 (1H, m), 4.34 (1H, br d), 5.05 (1H, dd), 6.48 (2H, br d), 6.94 (2H, d), 7.00-7.20 (2H, m) ), 7.22-7.26 (1H, m), 7.30 (1H, d), 7.58 (1H, d), 7.79 (1H, d), 8.12 (1H, s), 10.93 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 756.5.

Intermediate 111a: 5-(( tert -Butoxycarbonyl)amino)pentyl methanesulfonate

Et ₃ N (1.37 mL, 9.84 mmol) was added to tert -butyl (5-hydroxypentyl)carbamate (1.00 g, 4.92 mmol) and methanesulfonyl chloride (0.46 mL, 5.90 mmol) in DCM (12 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (50 mL) and washed with water (10 mL), followed by saturated brine (10 mL). The organic solution was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (1.35 g, 98%) as a colorless oil; ^1H NMR (300 MHz, CDCl ₃ ) 1.40-1.60 (13H, m), 1.80 (2H, p), 3.03 (3H, s), 3.09-3.21 (2H, m), 4.25 (2H, t), 4.57 (1H, s).

Intermediate 111b: tert-Butyl (5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentyl)carbamate

Cs ₂ CO ₃ (1.49 g, 4.57 mmol) was added to 5-(( tert -butoxycarbonyl)amino)pentyl methanesulfonate (1.71 g, 6.09 mmol) and 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (1.00 g, 3.05 mmol) in DMF (12 mL). The resulting mixture was stirred at 65 °C for 12 h. The crude product was purified by C-18 (eluent: water) to give the title compound (800 mg, 66%) as a brown oil; m / z : ES ⁺ [M + H] ⁺ = 514.

Intermediate 111c: 3-(5-(4-(5-aminopentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

4 M HCl in 1,4-dioxane (20 mL, 2.53 mmol) was added dropwise to tert -butyl (5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentyl)carbamate (1.30 g, 2.53 mmol) in DCM (15 mL). The resulting mixture was stirred at room temperature for 1 h. Flash C18-flash chromatography (eluent: 100% water) gave the title compound (1.00 g, 96%) as a pale yellow solid; ^1H NMR (CD ₃ OD) 1.54 (2H, p), 1.77 (2H, h), 1.97-1.86 (2H, m), 2.23-2.10 (1H, m), 2.50 (1H, qd), 2.85-2.70 (1H, m), 2.96-2.87 (1H, m), 2.99 ( 2H, q), 3.31-3.22 (4H, m), 3.37 (2H, s), 3.74 (2H, d), 7.71 (1H, d), 4.08 (2H, d), 4.53-4.37 (2H, m), 5.13 (1H, dd), 7.23-7.16 (2H, m); m/z : ES ⁺ [M+H] ⁺ = 414.

Example 111: 4-(4-{4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}pentyl)amino]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 4a was reacted with intermediate 111c using the general synthetic method exemplified by Example 110 to give the title compound (as a bis-formate salt) after purification by C-18 chromatography (eluent A). ^1H NMR: (500 MHz) 1.33-1.42 (2H, m), 1.45-1.61 (7H, m), 1.74-1.85 (2H, m), 1.91-2.00 (1H, m), 2.28-2.39 (4H, m), 2.53-2.68 (3H, m), 2.84-3. 07 (6H, m), 3.29-3.48 (3H, m), 4.09-4.17 (2H, m), 4.17-4.24 (1H, m), 4.28-4.40 (1H, m), 5.03 (1H, br d), 6.48 (2H, br d), 6.92 (2H, br d), 7.2 1-7.27 (1H, m), 7.30 (1H, br s), 7.51 (1H, br d), 7.79 (1H, br d), 8.14 (2H, s), 10.92 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 742.5.

Example 112: 4-{4-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}propoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 13a using the general synthetic method exemplified by Example 5 to give the title compound after purification by HPLC (column A, eluent A, basic workup A). ¹ H NMR: (500 MHz) 1.61 (2H, qd), 1.81-1.87 (2H, m), 1.87-1.92 (2H, m), 1.93-2.00 (1H, m), 2.31-2.40 (2H, m), 2.51-2.64 (7H, m), 2.71-2.80 (1 H, m), 2.84-2.93 (1H, m), 3.03 (2H, br t), 3.98 (2H, t), 4.12-4.23 (3H, m), 4.28-4.34 (1H, m), 5.03 (1H, d), 6.85 (2H, d), 7.00-7.10 (2H, m), 7.14 (2H, d), 7.22-7.29 (1H, m), 7.31 (1H, s), 7.51 (1H, d), 7.80 (1H, d), 10.92 (1H, s), three protons below the solvent peak; m/z : ES ⁺ [M+H] ⁺ = 715.3.

Example 113: 4-{4-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}propoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 13a was reacted with intermediate 63e using the general synthetic method exemplified by Example 5 to give the title compound after purification by FSC (eluent: 0-10% MeOH in EtOAc). ^1H NMR: (500 MHz) 1.56-1.67 (2H, m), 1.80-1.92 (4H, m), 1.97-2.05 (1H, m), 2.54-2.64 (4H, m), 2.71-2.80 (2H, m), 2.82-2.92 (2H, m), 3.00-3. 07 (2H, m), 3.43 (5H, br s), 3.96-4.03 (2H, m), 4.16 (2H, br d), 5.05 (1H, dd), 6.85 (2H, d), 7.14 (2H, d), 7.22-7.28 (2H, m), 7.31 (2H, br d), 7.66 (1H, d), 7.80 (1H, d), 11.05 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 729.4.

Example 114: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 2c was reacted with intermediate 4c using the general synthetic method exemplified by Example 2 to give the title compound after purification by flash alumina chromatography (eluent: 0-100% EtOAc in heptane, then 20% EtOH in EtOAc); ¹ H NMR: (CDCl ₃ ) 1.37 (2H, tt), 1.61-1.7 (1H, m), 1.76 (2H, qd), 1.89 (2H, d), 1.96 (2H, s), 2.20 (1H, ddq), 2.26-2.3 (2H, m), 2.3-2.38 (1H, m), 2.5 5-2.62 (4H, m), 2.64-2.77 (3H, m), 2.77-2.87 (1H, m), 2.87-2.96 (1H, m), 2.99-3.12 (2H, m), 3.24-3.37 (4H, m), 3.66 (2H, d), 4.01 (2H, d), 4 .25 (1H, d), 4.41 (1H, d), 5.19 (1H, dd), 6.84-6.93 (3H, m), 6.99 (2H, dt), 7.10 (2H, d), 7.15 (1H, d), 7.61 (1H, d), 7.73 (1H, d), 7.87 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 754.3.

Intermediate 115a: Benzyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate

3-(1-Oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (0.700 g, 1.92 mmol) was dissolved in a mixture of DCM (5 mL) and MeOH (5 mL). Benzyl (3-oxopropyl)carbamate (1.19 g, 5.76 mmol) was then added, and the mixture was stirred at room temperature for 10 min. NaBH(OAc) ₃ (1.63 g, 7.67 mmol) was then added, and the mixture was stirred at room temperature for 1 h. Additional benzyl (3-oxopropyl)carbamate (1.19 g, 5.76 mmol) was then added. The mixture was stirred at room temperature for 10 min, additional NaBH(OAc) ₃ (1.63 g, 7.67 mmol) was added and stirring was continued at room temperature for 1 h. After concentration under reduced pressure, EtOAc (20 mL) was added to the residue. The resulting solution was washed with saturated NaHCO ₃ solution (10 mL), brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: hexanes to DCM, then 10% MeOH in DCM) gave the title compound (0.800 g, 80%) as a colorless dry film; ^1H NMR (500 MHz, CDCl ₃ ) 1.76 (2H, br s), 2.14-2.26 (1H, m), 2.33 (1H, br dd), 2.49-2.57 (2H, m), 2.58-2.72 (4H, m), 2.78-2.87 (1H, m), 2.88-2. 96 (1H, m), 3.32 (6H, br s), 4.26 (1H, d), 4.42 (1H, d), 5.11 (2H, s), 5.18-5.25 (1H, m), 5.68 (1H, br s), 6.87 (1H, s), 6.98 (1H, br d), 7.3 5 (5H, br s), 7.74 (1H, d), 8.02-8.25 (1H, m); m/z ES ⁺ , [M+H] ⁺ =520.

Intermediate 115b: 3-(5-(4-(3-aminopropyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Benzyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propionyl)carbamate (0.800 g, 1.54 mmol) was dissolved in MeOH (30 mL). Pd on C (10% wet, 0.410 g, 0.38 mmol) was added, the suspension was degassed, filled with H ₂ (via balloon) and stirred at room temperature for 3 h. The mixture was then filtered through celite and washed with a mixture of MeCN/MeOH (1:1, 100 mL). The filtrate was concentrated to dryness to give the title compound (0.660 g, 94%); ^1H NMR (500 MHz) 1.93-2.03 (1H, m), 2.06-2.19 (2H, m), 2.34-2.45 (1H, m), 2.51 (1H, br s), 2.58-2.69 (1H, m), 2.88-3.03 (3H, m), 3.07-3.14 ( 1H, m), 3.20-3.30 (2H, m), 3.32-3.43 (2H, m), 3.52-3.62 (2H, m), 3.94-4.10 (2H, m), 4.20-4.30 (1H, m), 4.33-4.42 (1H, m), 5.07 (1H, dd), 7. 08-7.27 (2H, m), 7.60 (1H, d), 7.95-8.28 (3H, m), 10.95 (1H, s), 11.21-11.41 (1H, m); m/z ES ⁺ , [M+H] ⁺ =386.

Example 115: 4-(4-{4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}propyl)amino]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 4a was reacted with intermediate 115b using the general synthetic method exemplified by Example 110 to give the title compound after purification by C-18 chromatography (eluent A); the title compound was converted to the hydrochloride salt by mixing with 0.1 mL of a 1 N HCl aqueous solution and then concentrating the solution to dryness. ^1H NMR: (500 MHz) 1.55-1.69 (2H, m), 1.75-1.89 (2H, m), 1.91-1.99 (1H, m), 2.33-2.45 (2H, m), 2.54-2.65 (2H, m), 2.67-2.80 (1H, m), 2.83-2. 95 (1H, m), 2.99-3.11 (2H, m), 3.11-3.28 (5H, m), 3.75-4.11 (8H, m), 4.11-4.19 (3H, m), 4.19-4.27 (2H, m), 4.32-4.41 (1H, m), 4.98-5.12 (1H) , m), 7.02-7.22 (4H, m), 7.22-7.30 (1H, m), 7.29-7.36 (1H, m), 7.49-7.63 (1H, m), 7.70-7.86 (1H, m), 10.93 (1H, s); No two exchangeable protons observed; m/z : ES ⁺ [M+H] ⁺ = 714.5.

Example 116: 4-[4-[4-[4-[[4-[1-[2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]methyl]-1-piperidyl]phenyl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile

Intermediate 4b was reacted with intermediate 29g using the general synthetic method exemplified by Example 1 to give the title compound after purification by HPLC (column A, eluent A). ^1H NMR: (500 MHz) 1.55-1.69 (2H, m), 1.75-1.89 (2H, m), 1.91-1.99 (1H, m), 2.33-2.45 (2H, m), 2.54-2.65 (2H, m), 2.67-2.80 (1H, m), 2.83-2. 95 (1H, m), 2.99-3.11 (2H, m), 3.11-3.28 (5H, m), 3.75-4.11 (8H, m), 4.11-4.19 (3H, m), 4.19-4.27 (2H, m), 4.32-4.41 (1H, m), 4.98-5.12 (1H) , m), 7.02-7.22 (4H, m), 7.22-7.30 (1H, m), 7.29-7.36 (1H, m), 7.49-7.63 (1H, m), 7.70-7.86 (1H, m), 10.93 (1H, s); No two exchangeable protons observed; m/z : ES ⁺ [M+H] ⁺ = 769.3.

Intermediate 117a: 6-chloro-4-methoxy-2-methylnicotinic acid

To a stirred solution of ethyl 4,6-dichloro-2-methylnicotinate (2.00 g, 8.54 mmol) in DCM (30 mL) was added sodium methoxide (2.22 mL, 11.96 mmol) at 0 °C. The mixture was then stirred at room temperature for 16 h. Afterwards, the mixture was poured onto crushed ice, and the pH was adjusted to 4–5 with 2 N AcOH. The mixture was then extracted with DCM (50 mL x 2). The combined organic solutions were washed with water (30 mL), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (2.00 g) which was used in the next step without further purification; m / z : ES ⁺ [M+H] ⁺ = 202.2.

Intermediate 117b: Methyl 6-chloro-4-methoxy-2-methylnicotinate

To a stirred solution of 6-chloro-4-methoxy-2-methylnicotinic acid (2.50 g, 12.40 mmol) in DMF (30 mL) were added K ₂ CO ₃ (2.06 g, 14.88 mmol) and MeI (1.16 mL, 18.60 mmol) at room temperature. The mixture was then stirred at room temperature for 16 h. The mixture was then diluted with water (50 mL) and extracted with MTBE (50 mL x 3). The combined organic solutions were washed with brine (50 mL x 2), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure (bath temp.: 45 °C) to give the title compound (2.50 g, 7.04 mmol, 57% yield) as a yellow solid, which was used in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ = 216.1.

Intermediate 117c: Methyl 2-(bromomethyl)-6-chloro-4-methoxynicotinate

tert -Butyl acetate (30 mL) was added to methyl 6-chloro-4-methoxy-2-methylnicotinate (1.50 g, 6.96 mmol) under N ₂ at room temperature. Then NBS (1.610 g, 9.04 mmol) and AIBN (0.228 g, 1.391 mmol) were added at room temperature. The mixture was then stirred at 110 °C for 16 h. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 2). The combined organic solutions were washed with brine (30 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure (bath temp.: 45 °C) to give the title compound (2.00 g, 35% yield) as a brown liquid, which was used in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ = 294.

Intermediate 117d: 3-(2-chloro-4-methoxy-5-oxo-5,7-dihydro-6 H -Pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione

3-Aminopiperidine-2,6-dione hydrochloride salt (0.335 g, 2.037 mmol) and DIPEA (1.053 _g , 8.15 mmol) were added to a solution of methyl 2-(bromomethyl)-6-chloro-4-methoxynicotinate (2.00 g, 2.037 mmol) in MeCN (30 mL) at room temperature under N 2 . The mixture was then heated to 85 °C for 18 h. The mixture was then slowly cooled to room temperature and the resulting solid was collected by filtration, washed with MeCN (5 mL) and dried in vacuo to give the title compound (0.44 g, 66%) as a brown solid; ^1H NMR: 1.93-2.02 (1H, m), 2.32-2.41 (1H, m), 2.59 (1H, d), 2.83-2.97 (1H, m), 4.01 (3H, s), 4.22-4.29 (1H, m), 4.38-4.49 (1H, m), 5.09 (1 H, dd), 7.30 (1H, s), 10.99 (1H, s). m/z : ES ⁺ [M+H] ⁺ = 310.1.

Intermediate 117e: tert -Butyl 4-(6-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-oxo-6,7-dihydro-5 H -Pyrrolo[3,4- b ]pyridin-2-yl)piperazine-1-carboxylate

Pd-PEPPSI-IHept (Cl) (47.1 mg, 0.048 mmol) was added to tert -butyl piperazine-1-carboxylate (541 mg, 2.91 mmol), Cs ₂ CO ₃ (947 mg, 2.91 mmol) and 3-( ₂ -chloro-4-methoxy-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyridin-6-yl)piperidine-2,6-dione (300 mg, 0.969 mmol) in 1,4-dioxane (10 mL) at room temperature under N 2 . The resulting suspension was stirred at 120 °C for 2 h. The mixture was then diluted with DCM (20 mL) and washed with 5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ (20 mL), and then saturated brine (20 mL). The organic solution was then dried (Na ₂ SO ₄ ) and concentrated. EtOAc (4 mL) and washed with MTBE (16 mL) to give a solid which was collected by filtration and dried in vacuo to give the title compound (340 mg, 70% yield) as a brown powder; ^1H NMR: 1.43 (9H, s), 1.87-1.98 (1H, m), 2.28-2.37 (1H, m), 2.56-2.62 (1H, m), 2.84-2.95 (1H, m), 3.37-3.47 (4H, m), 3.62-3.70 (4H, m), 3 .90 (3H, s), 4.01 (1H, d), 4.12 (d, 1H), 5.00 (1H, dd), 6.29 (1H, s), 10.92 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 460.2.

Intermediate 117f: 3-(4-methoxy-5-oxo-2-(piperazin-1-yl)-5,7-dihydro-6 H -Pyrrolo[3,4- b ]pyridin-6-yl)piperidine-2,6-dione

To a stirred solution of tert -butyl 4-(6-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4-b]pyridin-2-yl)piperazine-1-carboxylate (340 mg, 0.740 mmol) in DCM (10 mL) was added 4 M HCl in 1,4-dioxane (3.70 mL, 14.80 mmol) at 0 °C. The mixture was then stirred at room temperature under N ₂ for 1 h. The mixture was then concentrated to afford the title compound (300 mg, 88%) as a hydrochloride salt as a brown solid; ^1H NMR: 1.88-1.99 (1H, m), 2.29-2.38 (1H, m), 2.59 (1H, br s), 2.84-2.96 (1H, m), 3.17-3.20 (4H, m), 3.92-4.00 (7H, s), 4.01-4.08 (1H, m) , 4.18 (1H, s), 5.02 (1H, dd), 6.41 (1H, s), 9.35 (2H, br s), 10.92 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 360.2.

Example 117: 4-(4-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 117f was reacted with intermediate 50a using the general synthetic method exemplified by Example 5 to give the title compound after purification by HPLC (column; Zorbax-C18, 5 μm; 50 x 21.2 mm, eluent C, basic workup A); ^1H NMR: 1.56-1.67 (4H, m), 1.69-1.79 (2H, m), 1.80-1.88 (2H, m), 1.88-1.96 (1H, m), 2.34-2.40 (3H, m), 2.40-2.45 (4H, m), 2.59 (1H, s), 2 .77 (1H, t), 2.84-2.95 (1H, m), 3.04 (2H, t), 3.60 -3.63 (4H, m), 3.89 (3H, s), 3.93-4.03 (3H, m), 4.10-4.23 (3H, m), 5.00 (1H, br dd), 1H, s), 6.86 (2H, d), 7.16 (2H, d), 7.23-7.36 (2H, m), 7.82 (1H, d), 10.91 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 760.2.

Intermediate 118a: tert -Butyl 9-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

4-(4-(4-Bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 4a) (0.500 g, 1.22 mmol), tert -Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.342 g, 1.34 mmol), RuPhos Pd G3 (0.102 g, 0.12 mmol), RuPhos (0.057 g, 0.12 mmol), and sodium 2-methylpropan-2-oleate (0.352 g, 3.67 mmol) were weighed and placed in a microwave vial. Anhydrous 1,4-dioxane (8 mL) was then added. The mixture was degassed by bubbling N ₂ through the mixture for 5 min and then heated and stirred in a microwave at 100 °C for 2 h. The mixture was then cooled to room temperature and water (20 mL) was added. A precipitate formed and was collected by filtration. The cake was washed with Et ₂ O (2 x 15 mL) to give the title compound (0.578 g, 81%) as a gray solid; ^1H NMR: 1.33-1.44 (13H, m), 1.5-1.69 (6H, m), 1.84 (2H, d), 2.68-2.78 (1H, m), 3-3.12 (6H, m), 3.29-3.38 (4H, m), 4.17 (2H, d), 6.86 (2H, d) , 7.08 (2H, d), 7.26 (1H, dd), 7.32 (1H, d), 7.81 (1H, d); m/z : ES ⁺ [M+H] ⁺ 583.3.

Example 118: 4-(4-(4-(9-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 118a was reacted with intermediate 27f using the general synthetic method exemplified by Example 1 to give the title compound after purification (column A, eluent A); ^1H NMR (CDCl ₃ ) 1.42 (2H, q), 1.62-1.88 (10H, m), 1.89-2.09 (5H, m), 2.12-2.23 (1H, m), 2.24-2.39 (1H, m), 2.65-2.78 (3H, m), 2.79-3.22 (13H , m), 3.81 (2H, d), 4.01 (2H, d), 4.24 (1H, d), 4.39 (2H, d), 5.16 (1H, dd), 6.78-6.92 (3H, m), 6.97 (2H, ddd), 7.07-7.2 (3H, m), 7.60 (1H, d), 7.70 (1H, d), 8.42 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 822.5.

Example 119: 4-[4-[4-[5-[4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazin-1-yl]pentoxy]phenyl]-1-piperidyl]-2-(trifluoromethyl)benzonitrile

Prepared from 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoro-methyl)benzonitrile (Intermediate 4a) using the general synthetic method exemplified by Example 12, except that pentane-1,5-diol was used to give the title compound after purification (column A, eluent A); ^1H NMR (CDCl ₃ ) 1.75 (2H, qd), 1.97 (2H, d), 2.13-2.34 (4H, m), 2.34-2.48 (2H, m), 2.64-2.93 (9H, m), 3.06 (2H, td), 3.29-3.39 (4H, m), 3.94 ( 3H, s), 4.02 (2H, d), 4.13-4.26 (3H, m), 4.36 (1H, d), 5.13 (1H, dd), 6.36 (1H, d), 6.46 (1H, s), 6.79-6.9 (2H, m), 6.99 (1H, dd), 7.09-7.1 9 (3H, m), 7.61 (1H, d), 7.89 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 773.5.

Intermediate 120a: 6-chloro-2-methoxy-4-methylnicotinic acid

To a stirred solution of sodium methoxide (10.3 mL, 55.8 mmol) in THF (25 mL) was added 2,6-dichloro-4-methylnicotinic acid (5.00 g, 24.27 mmol) in THF (25 mL) at 0 °C. The mixture was then heated at 70 °C for 16 h. After cooling to room temperature, the mixture was acidified with 1.5 N aqueous HCl to pH 3-4, then extracted with EtOAc (60 mL x 2). The combined organic solutions were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (4.00 g, 76%) which was used in the next step without further purification; ^1H NMR: 2.27 (3H, s), 3.87 (3H, s), 7.10 (1H, s), 13.43 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 202.1

Intermediate 120b: Methyl 6-chloro-2-methoxy-4-methylnicotinate

To a stirred solution of 6-chloro-2-methoxy-4-methylnicotinic acid (4.40 g, 20.19 mmol) in DMF (50 mL) was added K ₂ CO ₃ (3.35 g, 24.23 mmol) and MeI (1.89 mL, 30.3 mmol) at room temperature. The mixture was then stirred at room temperature for 16 h. The mixture was then diluted with water (50 mL) and extracted with MTBE (50 mL x 3). The combined organic solutions were washed with brine (50 mL x 2), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure (bath temp.: 45 °C) to afford the title compound (4.00 g, 76%) as a pale yellow solid; ¹ H NMR: 2.26 (3H, s), 3.84 (3H, s), 3.87 (3H, s), 7.13 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 216.1.

Intermediate 120c: Methyl 4-(bromomethyl)-6-chloro-2-methoxynicotinate

Under N ₂ tert -Butyl acetate (150 mL) was added to methyl 6-chloro-2-methoxy-4-methylnicotinate (8.00 g, 37.1 mmol). NBS (9.24 g, 51.9 mmol) and benzoyl peroxide (1.80 g, 7.42 mmol) were then added at room temperature. The mixture was stirred at 110 °C for 14 h. Additional NBS (2.64 g, 14.84 mmol) was then added and stirring was continued at 110 °C for 12 h. The mixture was then diluted with 10% NaHCO ₃ solution (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic solution was washed with brine (80 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (11.00 g, 27%) as a brown liquid which was used directly in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ = 294.

Intermediate 120d: 3-(6-chloro-4-methoxy-3-oxo-1,3-dihydro-2 H -Pyrrolo[3,4- c ]pyridin-2-yl)piperidine-2,6-dione

3-Aminopiperidine-2,6-dione hydrochloride salt (1.65 g, 10.01 mmol) and DIPEA (5.17 g, 40.0 mmol) were added to methyl 4-(bromomethyl)-6-chloro-2-methoxynicotinate (11.00 g, 10.01 mmol) in MeCN ₍ 80 mL) at room temperature under N 2 . The mixture was then stirred at 85 °C for 16 h and then slowly cooled to room temperature. The mixture was then diluted with DCM (200 mL) and washed with 5% AcOH in water (200 mL), water (200 mL), saturated NaHCO ₃ (200 mL), and then saturated brine (200 mL). The organic solution was dried (Na ₂ SO ₄ ) and concentrated. Dissolving the residue with EtOAc (10 mL) and washing with MTBE (30 mL) gave a solid which was collected by filtration and dried in vacuo to give the title compound (1.60 g, 44%) as a brown solid; ¹ H NMR: 1.89-2.02 (1H, m), 2.30-2.35 (1H, m), 2.50-2.59 (1H, m), 2.84-2.98 (1H, m), 3.99 (3H, s), 4.26-4.39 (1H, m), 4.40-4.53 (1H, m), 5.05 (1H, dd), 7.40 (1H, s), 10.99 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 310.2.

Intermediate 120e: tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1 H -Pyrrolo[3,4- c ]pyridin-6-yl)piperazine-1-carboxylate

Pd-PEPPSI-IHept (Cl) (47.1 mg, 0.048 mmol) was added to tert -butyl piperazine-1-carboxylate (541 mg, 2.91 mmol), Cs ₂ CO ₃ (947 mg, 2.91 mmol) and 3-( ₆ -chloro-4-methoxy-3-oxo-1,3-dihydro-2 H -pyrrolo[3,4- c ]pyridin-2-yl)piperidine-2,6-dione (300 mg, 0.969 mmol) in 1,4-dioxane (10 mL) at room temperature under N 2 . The resulting suspension was stirred at 120 °C for 2 h. After cooling, the reaction mixture was diluted with DCM (20 mL) and washed with 5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ (20 mL), then saturated brine (20 mL). The organic portion was dried (Na ₂ SO ₄ ) and concentrated. EtOAc (4 mL) and washed with MTBE (16 mL) to give a solid which was collected by filtration and dried in vacuo to give the title compound (260 mg, 50%) as a brown solid; ^1H NMR: 1.43 (9H, s), 1.88-2.00 (1H, m), 2.29-2.39 (1H, m), 2.58-2.68 (1H, m), 2.86-2.96 (1H, m), 3.34 -3.44 (4H, m), 3.53-3.63 (4H, m), 3 .90 (3H, s), 4.09-4.18 (1H, m), 4.24-4.34 (1H, m), 4.97 (1H, br dd), 6.50 (1H, s), 10.92 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 460.2.

Intermediate 120f: 3-(4-methoxy-3-oxo-6-(piperazin-1-yl)-1,3-dihydro-2 H -Pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione

To a stirred solution of tert -butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1 H -pyrrolo-[3,4- c ]pyridin-6-yl)piperazine-1-carboxylate (260 mg, 0.566 mmol) in DCM (10 mL) was added 4 M HCl in 1,4-dioxane (2.83 mL, 11.32 mmol) at 0 °C. The mixture was stirred at room temperature under N ₂ for 12 h. The mixture was then concentrated under reduced pressure to afford the title compound (240 mg, 63% yield) as the hydrochloride salt as a brown solid; m/z : ES ⁺ [M+H] ⁺ = 360.2.

Example 120: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4-c]pyridin-6-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 120f using the general synthetic method exemplified by Example 5 to give the title compound after purification (column: Zorbax-C18, 5 μm; 50 × 21.2 mm, eluent C, basic workup A); ^1H NMR: 1.55-1.69 (4H, m), 1.69-1.78 (2H, m), 1.81-1.95 (3H, m), 2.27-2.38 (3H, m), 2.46 (3H, br s), 2.57-2.68 (1H, m), 2.77 (1H, br t), 2. 83-2.97 (1H, m), 3.04 (2H, br t), 3.50-3.59 (4H, m), 3.84-3.93 (3H, m), 3.97 (2H, br t), 4.09-4.20 (3H, m), 4.22-4.31 (1H, m), 4.96 (1H, dd), 6.48 (1H, s), 6.86 (2H, d), 7.16 (2H, d), 7.27 (1H, d), 7.33 (1H, br s), 7.82 (1H, d), 10.91 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 760.2.

Intermediate 121a: tert -Butyl 4-(4-(4-bromobutoxy)-2-fluorophenyl)piperidine-1-carboxylate

K ₂ CO ₃ (421 mg, 3.05 mmol) and 1,4-dibromobutane (910 μL, 7.62 mmol) were added successively to a solution of tert -butyl 4-(2-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (Intermediate 38B) (450 mg, 1.52 mmol) in DMF (5 mL). The resulting mixture was stirred at 70 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and water (20 mL), then brine (20 mL). The organic fraction was collected, washed with additional portions of brine (3 × 20 mL), dried (MgSO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0-25% EtOAc in heptane) to afford the title compound (0.305 g, 47%) as a colorless oil; ¹ H NMR (CDCl ₃ ) 1.48 (9H, s), 1.55-1.67 (2H, m), 1.73-1.82 (2H, m), 1.88-1.98 (2H, m), 2-2.1 (2H, m), 2.81 (2H, td), 2.91 (1H, tt), 3.48 (2H, t), 3.96 (2H, t), 4.17-4.3 (2H, m), 6.58 (1H, dd), 6.63 (1H, dd), 7.07 (1H, t); m/z: ES ⁺ [MH-Boc] 330.0.

Intermediate 121b: tert -Butyl-4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)-2-fluorophenyl)piperidine-1-carboxylate

DIPEA (729 μL, 4.18 mmol) was added to a mixture of 3-(7-methoxy-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride salt (303 mg, 0.77 mmol) (intermediate 1f), tert -butyl 4-(4-(4-bromobutoxy)-2-fluorophenyl)piperidine-1-carboxylate (300 mg, 0.70 mmol) and KI (347 mg, 2.09 mmol) in DMSO (5 mL), and the resulting mixture was heated to 70 °C for 4 h. The mixture was cooled to room temperature and diluted with water (20 mL) and EtOAc (20 mL). The organic portion was collected and the aqueous portion was washed with additional EtOAc (20 mL). The combined organics were washed with water (2 x 20 mL), brine (2 x 20 mL), dried (MgSO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0–10% MeOH in DCM) to give the title compound (0.200 g, 41%) as a pale yellow liquid; ^1H NMR (CDCl ₃ ) 1.48 (9H, s), 1.53-1.67 (6H, m), 1.72-1.81 (3H, m), 1.86 (2H, s), 2.13-2.24 (1H, m), 2.31 (1H, dd), 2.73-2.98 (6H, m), 3.06 -3.78 (6H, m), 3.94 (3H, s), 3.95-4.02 (2H, m), 4.16-4.29 (3H, m), 4.36 (1H, d), 5.12 (1H, dd), 6.36 (1H, s), 6.48 (1H, s), 6.58 (1H, dd), 6.63 (1H, dd), 7.07 (1H, t), 7.98 (1H, s); m/z: ES ⁺ [M+H] + 708.6.

Intermediates 121c and 121d: 3-(5-(4-(4-(3-fluoro-4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)-7-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(4-chloro-5-(4-(4-(3-fluoro-4-(piperidin-4-yl)phenoxy)butyl)piperazin-1-yl)-7-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione

4 M HCl in 1.4-dioxane (706 μL, 2.83 mmol) was added in one portion to tert -butyl-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)-2-fluorophenyl)piperidine-1-carboxylate (200 mg, 0.28 mmol) in DCM (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to afford a mixture of the title compounds 121c and by-product 121d (ratio 1:2) as a light brown solid, which was used in the next step without further manipulation.

Example 121: 4-(4-(4-(4-(4-(4-chloro-2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)-2-fluorophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Using the general synthetic method exemplified by Example 16, a (1:2) mixture of intermediates 121c and 121d was reacted with 4-fluoro-2-(trifluoromethyl)benzonitrile to give the title compound (as a formate salt) after purification (column A, eluent A); ^1H NMR (CDCl ₃ ) 1.79 (6H, ddd), 1.95 (2H, d), 2.14-2.24 (1H, m), 2.27-2.41 (1H, m), 2.76-2.94 (4H, m), 2.96-3.14 (7H, m), 3.31-3.33 (4H, m), 3 .89-4.07 (7H, m), 4.21 (1H, d), 4.36 (1H, d), 5.13 (1H, dd), 6.13 (1H, s), 6.54-6.67 (3H, m), 6.98 (1H, dd), 7.07 (1H, t), 7.15 (1H, d), (1H, d), 8.33 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 811.6.

Example 122: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)-2-fluorophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Using the general synthetic method exemplified by Example 16, a (1:2) mixture of intermediates 121c and 121d was reacted with 4-fluoro-2-(trifluoromethyl)benzonitrile to give the title compound as a formate salt after purification (column A, eluent A); ^1H NMR (CDCl ₃ ) 1.71-1.89 (6H, m), 1.95 (2H, d), 2.1-2.22 (1H, m), 2.30 (1H, qd), 2.64-2.73 (2H, m), 2.76-2.94 (6H, m), 2.98-3.16 (3H, m), 3. 41-3.51 (4H, m), 3.94 (3H, s), 3.95-4.08 (4H, m), 4.20 (1H, d), 4.36 (1H, d), 5.13 (1H, dd), 6.36 (1H, d), 6.47 (1H, s), 6.57-6.69 (2H, m), 6.99 (1H, dd), 7.07 (1H, t), 7.15 (1H, d), 7.62 (1H, d), 7.96 (1H, s), 8.19 (0.5H, s); m/z : ES ⁺ [M+H] ⁺ = 777.4.

Intermediate 123a: tert -Butyl 4-(4-hydroxy-2-methylphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

Na ₂ CO ₃ (3.11 g, 29.4 mmol) was added to a stirred solution of 4-bromo-3-methylphenol (1.83 g, 9.78 mmol) and tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (3.63 g, 11.74 mmol) in toluene (20 mL), EtOH (10 mL), and water (5 mL), and the flask was purged with N ₂ for 20 min. Then PdCl ₂ (dppf)-DCM (0.799 g, 0.978 mmol) was added at room temperature under N ₂ , and the mixture was then stirred at 110 °C for 16 h. After cooling, the mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a rubbery mass, which was dissolved in EtOAc (100 mL). The solution was washed with water (30 mL) and brine (30 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 5-17% EtOAc in hexanes) gave the title compound (2.27 g, 72%) as a pale yellow solid; ^1H NMR: 1.43 (9H, s), 2.15 (3H, s), 3.33 (2H, s), 3.50 (2H, br t), 3.93 (2H, br s), 5.47 (1H, br s), 6.51-6.56 (1H, m), 6.58 (1H, d), (1H, d), 9.21 (1H, s); m/z : ES ⁺ [M-Boc] ⁺ 190.4.

Intermediate 123b: tert -Butyl 4-(4-hydroxy-2-methylphenyl)piperidine-1-carboxylate

A solution of tert -butyl 4-(4-hydroxy-2-methylphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate (2.25 g, 7.78 mmol) in EtOAc (40 mL) was bubbled with N ₂ gas for a period of 10 min. Then Pd on C (10% (dry basis), 0.80 g, 7.52 mmol) was added under N ₂ . The mixture was then stirred at room temperature for 24 h under H ₂ . The mixture was then filtered through celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (2.22 g, 95%) as a yellowish white solid; ^1H NMR: 1.42 (9H, s), 1.57-1.66 (4H, m), 2.21 (3H, s), 2.74 (1H, br t), 3.57 (4H, br s), 6.54 (2H, s), 6.93-6.96 (1H, m), 8.94-9.16 (1H, m ); m/z : ES ⁺ [M-Boc] ⁺ 192.2.

Intermediate 123c: 3-Methyl-4-(piperidin-4-yl)phenol

4 M HCl in 1,4-dioxane (10 mL, 40.0 mmol) was _added to a mixture of tert -butyl 4-(4-hydroxy-2-methyl-phenyl)piperidine-1-carboxylate (500 mg, 1.72 mmol) in DCM (5 mL) at room temperature under N 2 . The mixture was then stirred at room temperature for 24 h. The solvent was then removed under reduced pressure to afford the title compound (390 mg, 96%) as the hydrochloride salt as an off-white solid; m / z : ES ⁺ [M + H] ⁺ 192.2.

Intermediate 123d: 4-(4-(4-hydroxy-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

DIPEA (3.95 mL, 22.61 mmol) was added (at room temperature under air for 18 h) to a mixture of 3-methyl-4-(piperidin-4-yl)phenol hydrochloride salt (1.03 g, 4.52 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (1.00 g, 5.29 mmol) in DMSO (10 mL). The mixture was then poured into water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (0.880 g, 54%) as a yellow solid; ^1H NMR: 1.59 (2H, qd), 1.75 (2H, d), 2.26 (3H, s), 2.91 (1H, ddd), 3-3.14 (2H, m), 4.17 (2H, d), 6.44-6.64 (2H, m), 6.94 (1H, d), 7.22-7.37 ( 2H, m), 7.81 (1H, d), 9.01 (1H, s); m/z: ES ⁺ [M+H]+ 361.1.

Intermediate 123e: 4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

2-(3-Bromopropyl)-1,3-dioxolane (0.364 mL, 2.69 mmol) was added simultaneously to 4-(4-(4-hydroxy-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile ( _0.88 g, 2.44 mmol) and K ₂ CO ₃ (1.012 g, 7.33 mmol) in MeCN (10 mL) under N 2 at room temperature. The resulting suspension was stirred at 80 °C for 24 h. The mixture was then cooled to room temperature and filtered. The filtrate was diluted with water (50 mL), and the resulting yellow precipitate was collected by filtration to give the title compound (1.10 g, 95%); ^1H NMR: 1.55-1.66 (2H, m), 1.67-1.73 (2H, m), 1.73-1.8 (4H, m), 2.31 (3H, s), 2.86-3.01 (1H, m), 3.08 (2H, t), 3.74-3.81 (2H, m), 3.87-3. 91 (2H, m), 3.94 (2H, t), 4.18 (2H, d), 4.84 (1H, t), 6.69 (1H, dd), 6.73 (1H, d), 7.06 (1H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d); m/z : ES ⁺ [M+H] ⁺ 475.4.

Example 123: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)-2-methylphenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 123e was reacted with intermediate 1e using the general synthetic method exemplified by Example 1 to give the title compound after purification (column A, eluent A, basic workup A); ^1H NMR: 0.84-0.93 (4H, m), 0.97-1.05 (4H, dt), 1.12-1.25 (1H, m), 1.35 (3H, d), 1.59 (5H, d), 1.65 (2H, t), 1.84 (1H, d), 2.09-2.28 (2H, m), 2.35 (2H, t), 3.11 (3H, s), 3.22 (2H, t), 3.33-3.58 (4H, m), 4.23 (1H, dd), 5.75 (1H, s), 5.87 (1H, s), 5.92-6.06 (2H, m), 6.33 (1H, d), 6 .53 (1H, dd), 6.59 (1H, s), 7.08 (1H, d), 10.15 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 773.3.

Intermediate 124a: 4-(4-(4-(4-hydroxybut-1-yn-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile

_But -3-yn-1-ol (154 mg, 2.20 mmol) and diethylamine (357 mg, 4.89 mmol) were added to a mixture of 4-(4-(4-bromophenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 4a) (500 mg, 1.222 mmol) and DMF (5 mL) at room temperature under N ₂ . Then bis(triphenylphosphine)palladium(II) chloride (42.9 mg, 0.061 mmol), PPh ₃ (22.43 mg, 0.086 mmol) and CuI (11.63 mg, 0.061 mmol) were added under N 2 . The mixture was then stirred at 80 °C for 16 h. After cooling, the mixture was filtered through celite and washed with DCM (20 mL x 3). The filtrate was then concentrated under reduced pressure and then diluted with DCM (50 mL). The solution was washed with water (20 mL x 2) and brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 5–40% EtOAc in hexanes) gave the title compound (220 mg, 29%) as a yellow solid; m/z : ES ⁺ [M+H] ⁺ 399.0.

Intermediate 124b: 4-(4-(4-(4-hydroxybutyl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

A solution of 4-(4-(4-(4-hydroxybut-1-yn-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (200 mg, 0.502 mmol) in EtOH (10 mL) was bubbled with N ₂ gas for a period of 10 min. Then 10% Pd on C (150 mg, 1.410 mmol) under N ₂ was added. The mixture was then stirred at room temperature for 5 h under H ₂ . The mixture was then filtered through celite and washed with EtOH. The filtrate was concentrated to give the title compound (160 mg, 46%) as a gummy mass; m / z : ES ⁺ [M + H] ⁺ 403.4.

Intermediate 124b: 4-(4-(4-(4-bromobutyl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

PPh ₃ (201 mg, 0.765 mmol) and CBr ₄ (254 mg, 0.765 mmol) were added to a solution of 4-(4-(4-(4-hydroxy-butyl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (154 mg, 0.383 mmol) in DCM (5 mL) at 0 °C, and the mixture was then stirred at room temperature for 3 h. The reaction was then quenched with water (10 mL). The mixture was extracted with DCM (15 mL x 2), and the combined organic solutions were washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FSC (Snap-Ultra silica-gel, 100–200 mesh size, gradient: 5–15% EtOAc in hexane) to afford the title compound (71 mg, 32% yield) as a brown gummy liquid; m/z : ES ⁺ [M+H] ⁺ 467.

Example 124: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butyl)phenyl)-piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 124c was reacted with intermediate 2c using the general synthetic method exemplified by Example 5 to give the title compound after purification (column B, eluent A, basic workup A); ^1H NMR: 1.48-1.68 (6H, m), 1.87 (2H, br d), 1.94-1.99 (1H, m), 2.33-2.40 (3H, m), 2.57 (5H, br s), 2.80-2.95 (2H, m), 3.06 (2H, br t), 3.27 ( 6H, br s), 4.16-4.23 (3H, m), 4.29-4.36 (1H, m), 5.05 (1H, dd), 7.04-7.07 (2H, m), 7.13-7.19 (4H, m), 7.28 (1H, dd), 7.33 (1H, s), 7.52 (1H) , d), 7.82 (1H, d), 10.94-10.96 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 713.0.

Intermediate 125a: ((1r,3r)-3-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)methyl)-cyclobutyl)methyl methanesulfonate

To a stirred solution of 4-(4-(4-(((1r,3r)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 36b) (90 mg, 0.202 mmol) in DCM (2 mL) was added Et ₃ N (41.0 mg, 0.405 mmol) and methanesulfonyl chloride (46.4 mg, 0.405 mmol) at 0 °C. The mixture was then stirred at room temperature for 1 h. The reaction was then quenched with water (25 mL). Afterwards, the mixture was extracted with DCM (30 mL x 2), and the combined organic solutions were washed with brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (100 mg, 92% yield), which was used directly in the next step without further purification; m / z : ES ⁺ [M + H] ⁺ = 523.0.

Example 125: 4-[4-(4-{[(1r,3r)-3-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)cyclobutyl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 125a was reacted with intermediate 1f using the general synthetic method exemplified by Example 12 to give the title compound after purification (column B, eluent A, basic workup A); ^1H NMR: 1.56-1.69 (2H, m), 1.77-1.98 (7H, m), 2.33 (2H, d), 2.41-2.47 (4H, m), 2.61-2.70 (2H, m), 2.77 (1H, t), 2.84-2.95 (1H, m), 3.05 (2H) , t), 3.27-3.29 (4H, m), 3.83 (3H, s), 3.98 (2H, d), 4.07-4.30 (4H, m), 4.96 (1H, dd), 6.48 (1H, s), 6.60 (1H, s), 6.87 (2H, d), 7.16 (2H, d) ), 7.28 (1H, dd), 7.33 (1H, d), 7.82 (1H, d), 10.90 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 785.4.

Intermediate 126a: ((1s,3s)-3-((4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-methyl)cyclobutyl)methyl methanesulfonate

To a stirred solution of 4-(4-(4-(((1s,3s)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 36c) (100 mg, 0.225 mmol) in DCM (2 mL) was added Et ₃ N (0.063 mL, 0.450 mmol) and methanesulfonyl chloride (0.035 mL, 0.450 mmol) at 0 °C, and then stirred at room temperature for 1 h. The reaction was then quenched with water (25 mL) and extracted with DCM (30 mL x 2). The combined organic solution was washed with brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated to give the title compound (100 mg, 83%), which was used directly in the next step without further purification; m/z : ES ⁺ [M+H] ⁺ = 523.0.

Example 126: 4-[4-(4-{[(1s,3s)-3-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)cyclobutyl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 126a was reacted with intermediate 1f using the general synthetic method exemplified by Example 12 to give the title compound after purification (column B, eluent A, basic workup A); ^1H NMR: 1.48-1.70 (5H, m), 1.81-1.96 (3H, m), 2.14-2.26 (2H, m), 2.37-2.42 (2H, m), 2.58-2.72 (2H, m), 2.74-2.95 (2H, m), 3.00-3.13 (2H, m) ), 3.27-3.31 (3H, m), 3.82-3.87 (5H, m), 4.04-4.25 (4H, m), 4.96 (1H, dd), 6.48 (1H, s), 6.60 (1H, s), 6.84 (2H, d), 7.15 (2H, d), 7.27 (1H) , dd), 7.33 (1H, d), 7.82 (1H, d), 10.90 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 785.0.

Intermediate 127a: tert -Butyl 5-(4-(benzyloxy)phenyl)-2,3,4,7-tetrahydro-1 H -Azepine-1-carboxylate

To a stirred solution of 1-(benzyloxy)-4-bromobenzene (4.00 g, 15.20 mmol) in THF (40 mL) was added n -BuLi (1.6 M in hexanes, 14.25 mL, 22.80 mmol) at -78 °C, and the mixture was then stirred at -78 °C for 1 h. tert -Butyl 4-oxoazepane-1-carboxylate (3.89 g, 18.24 mmol) was then added at -78 °C. The mixture was stirred at -78 °C for 2 h and then at room temperature for 1 h. The reaction was quenched with saturated NH ₄ Cl solution and extracted with EtOAc (2 x 20 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 20-30% EtOAc in hexanes) to afford the title compound (3.50 g, 55%) as a pale yellow liquid; ¹ H NMR: 1.42 (9H, d), 1.63-1.92 (4H, m), 2.01-2.14 (1H, m), 3.10-3.29 (2H, m), 3.39-3.62 (3H, m), 4.89 (1H, s), 5.08 (2H, s), 6.94 (2H, dd), 7.10-7.35 (3H, m), 7.36-7.42 (2H, m), 7.42-7.49 (2H, m).

Intermediate 127b: 5-(4-(benzyloxy)phenyl)-2,3,4,7-tetrahydro-1 H -Azepine

To a solution of tert -butyl 5-(4-(benzyloxy)phenyl)-2,3,4,7-tetrahydro-1 H -azepine-1-carboxylate (3.00 g, 7.91 mmol) in DCM (30 mL) was added TFA (2.70 g, 23.72 mmol) at 0 °C, and the reaction was stirred for 2 h while slowly warming to room temperature. Concentrated under reduced pressure and washed with MTBE to give the title compound as a TFA salt (2.98 g, 100% yield); ^1H NMR: 1.19-1.38 (1H, m), 1.58-1.98 (2H, m), 2.69-2.91 (2H, m), 2.96-3.39 (5H, m), 5.10-5.17 (3H, m), 6.05 (1H, s), 6.98 (2H, d), 7.20-8 .26 (7H, m), 8.47-9.08 (2H, m).

Intermediate 127c: 4-(5-(4-(benzyloxy)phenyl)-2,3,4,7-tetrahydro-1 H -Azepin-1-yl)-2-(trifluoromethyl)-benzonitrile

To a stirred solution of 5-(4-(benzyloxy)phenyl)-2,3,4,7-tetrahydro-1 H -azepine (3.0 g, 7.97 mmol) in DMSO (30 mL) was added DIPEA (5.15 g, 39.9 mmol) and 4-fluoro-2-(trifluoro-methyl)benzonitrile (1.809 g, 9.56 mmol) at room temperature. The mixture was then stirred at 100 °C for 16 h. After cooling, the mixture was poured into ice-cold water and extracted with EtOAc (100 mL x 2). The combined organic solutions were washed with brine (100 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (gradient: 25-35% EtOAc in hexanes) gave the title compound (2.30 g, 64%) as an off-white solid; ^1H NMR: 1.90-2.08 (1H, m), 2.54-2.66 (2H, m), 2.78-2.89 (1H, m), 3.68-3.92 (3H, m), 4.22 (1H, d), 5.09 (2H, s), 5.85-6.27 (1H, m), 6.94 (2 H, d), 7.06-7.18 (2H, m), 7.21-7.53 (7H, m), 7.63-8.02 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 449.0.

Intermediates 127d and 127e: 4-(4-(4-hydroxyphenyl)azepan-1-yl)-2-(trifluoromethyl)benzonitrile (Enantiomer 1 and Enantiomer 2)

A solution of 4-(5-(4-(benzyloxy)phenyl)-2,3,4,7-tetrahydro-1 H -azepin-1-yl)-2-(trifluoromethyl)benzonitrile (2.3 g, 5.13 mmol) in MeOH (25 mL) was bubbled with N ₂ for 5 min. 10% Pd on C (1.092 g, 10.26 mmol) was added to the mixture under N ₂ . The mixture was then stirred at room temperature under H ₂ using a H ₂ bladder for 3 h. The mixture was then filtered through Celite and washed with MeOH (150 mL). The filtrate was concentrated to give a pale yellow sticky liquid. Elution with MTBE gave the title compound (1.80 g, 92%) as a racemic mixture, which was separated by chiral SFC (column: LUX A3, (LUXA3_MeOH_3-40_CHIRALHPLC-SFCME), eluent CO ₂ /MeOH) to give enantiomer 1 (first elution) (500 mg) and enantiomer 2 (500 mg);

Enantiomer 1 (127d) : ¹ H NMR: 1.43-1.64 (1H, m), 1.68-1.85 (3H, m), 1.89-2.03 (2H, m), 2.52-2.70 (2H, m), 3.48-3.61 (2H, m), 3.63-3.83 (2H, m), 6.64 (2H, d), 6.95 (2H, d), 7.03-7.12 (2H, m), 7.07 (2H, s), 7.78 (1H, d) ), 8.98-9.34 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 361.0.

Enantiomer 2 (127e) : ¹ H NMR: 1.46-1.61 (1H, m), 1.63-1.80 (3H, m), 1.88-2.04 (2H, m), 2.54-2.75 (2H, m), 3.40-3.62 (2H, m), 3.65-3.85 (2H, m), 6.64 (2H, d), 6.96 (2H, d), 7.02-7.17 (2H, m), 7.78 (1H, d), 9.12 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 361.0.

Intermediate 127f: 4-(4-(4-(4-bromobutoxy)phenyl)azepan-1-yl)-2-(trifluoromethyl)benzonitrile Mirror image 1

To a stirred solution of 4-(4-(4-hydroxyphenyl)azepan-1-yl)-2-(trifluoromethyl)benzonitrile ( enantiomer 1, 127d ) (300 mg, 0.832 mmol) in MeCN (3 mL) were added K ₂ CO ₃ (230 mg, 1.67 mmol) and 1,4-dibromobutane (270 mg, 1.249 mmol) at room temperature, and the mixture was stirred at 70 °C for 6 h. The mixture was then quenched with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic solutions were washed with brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0-20% EtOAc in hexanes) to afford the title compound (255 mg, 60%) as a pale yellow gummy material; ¹ H NMR: 1.53-1.65 (1H, m), 1.73-1.85 (5H, m), 1.90-2.03 (4H, m), 2.57-2.69 (1H, m), 3.46-3.63 (4H, m), 3.64-3.83 (2H, m), 3.95 (2H, t), 6.81 (2H, d), 6.99-7.20 (4H, m), 7.79 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 496.9.

Example 127: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazin-1-yl}butoxy)phenyl]azepan-1-yl}-2-(trifluoromethyl)benzonitrile ( isomer 1) (absolute stereochemistry not determined)

Intermediate 127e was reacted with intermediate 2c using the general synthetic method exemplified by Example 5 to give the title compound after purification (column B, eluent A, basic workup A); ^1H NMR: 1.53-1.65 (3H, m), 1.70-1.81 (5H, m), 1.92-2.05 (3H, m), 2.38 (2H, d), 2.54-2.79 (5H, m), 2.83-2.94 (1H, m), 3.27 (4H, d), 3.46-3. 61 (2H, m), 3.65-3.82 (2H, m), 3.95 (2H, t), 4.15-4.27 (1H, m), 4.29-4.40 (1H, m), 5.05 (1H, d), 6.82 (2H, d), 6.99-7.18 (6H, m), 7.52 (1H, d) , 7.78 (1H, d), 10.95 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 743.2.

Intermediate 128a: 4-(4-(4-(4-bromobutoxy)phenyl)azepan-1-yl)-2-(trifluoromethyl)benzonitrile (enantiomer 2)

K ₂ CO ₃ (345 mg, 2.50 mmol) and 1,4-dibromobutane (270 mg, 1.249 mmol) were added to a stirred solution of 4-(4-(4-hydroxyphenyl)azepan-1-yl)-2-(trifluoromethyl)benzonitrile ( enantiomer 2, 127e ) (300 mg, 0.832 mmol) in MeCN (3 mL) at room temperature, and the mixture was then stirred at 70 °C for 6 h. The mixture was then quenched with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic solutions were washed with brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FSC (gradient: 0-20% EtOAc in hexanes) to afford the title compound (250 mg, 58% yield) as a pale yellow gummy substance; ¹ H NMR: 1.59 (1H, q), 1.68-1.84 (5H, m), 1.92-2.02 (4H, m), 2.61 (1H, t), 3.50-3.63 (4H, m), 3.64-3.82 (2H, m), 3.95 (3H, t), 6.81 (2H, d), 6.97-7.24 (4H, m), 7.63-7.84 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 496.8.

Example 128: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]azepan-1-yl}-2-(trifluoromethyl)benzonitrile

(Isomers 2) (absolute stereochemistry not confirmed)

Intermediate 128a was reacted with intermediate 2c using the general synthetic method exemplified by Example 5 to give the title compound after purification (column B, eluent A, basic workup A); ^1H NMR: 1.53-1.65 (3H, m), 1.70-1.81 (5H, m), 1.92-2.05 (3H, m), 2.38 (2H, d), 2.54-2.79 (5H, m), 2.83-2.94 (1H, m), 3.27 (4H, d), 3.46-3. 61 (2H, m), 3.65-3.82 (2H, m), 3.95 (2H, t), 4.15-4.27 (1H, m), 4.29-4.40 (1H, m), 5.05 (1H, d), 6.82 (2H, d), 6.99-7.18 (6H, m), 7.52 (1H, d) , 7.78 (1H, d), 10.95 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 743.2.

Intermediate 129a: tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2 H )-carboxylate

tert -Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (574 mg, 1.86 mmol) and Cs ₂ CO ₃ (1008 mg, 3.09 mmol) were added to a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.55 mmol) in 1,4-dioxane (10 mL), which was purged with N ₂ for 15 min. PdC _l2 (dppf)-CH ₂ Cl ₂ adduct (126 mg, 0.155 mmol) was then added, and the mixture was stirred at 120 °C for 5 h. After cooling, the crude mixture was diluted with DCM and filtered through Celite. The filtrate was washed with water. The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (600 mg, 38%) as a brown rubbery liquid; m / z : ES ⁺ [M + H] ⁺ = 426.1.

Intermediate 129b: 3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

4 M HCl in 1,4-dioxane (2.0 mL, 8.00 mmol) was added to a solution of tert -butyl-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (200 mg, 0.47 mmol) in DCM (5 mL) at 0 °C. After stirring for 2 h, the solvent was removed under reduced pressure to give the title compound as a hydrochloride salt (140 mg, 80%) which was used directly in the next step; m/z : ES ⁺ [M+H] ⁺ = 326.2.

Example 129: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2 H )-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 129b using the general synthetic method exemplified by Example 5 to give the title compound after purification (column B, eluent C, basic workup A); ^1H NMR: 1.43-1.69 (5H, m), 1.69-1.90 (4H, m), 1.97-2.06 (1H, m), 2.30-2.41 (1H, m), 2.59-2.67 (3H, m), 2.70-2.84 (1H, m), 2.84-3.15 (5H, m) ), 3.97 (2H, t), 4.17 (2H, d), 4.27-4.47 (2H, m), 5.04-5.20 (1H, m), 6.32 (1H, s), 6.87 (2H, d), 7.15 (2H, d), 7.24-7.36 (2H, m), 7.59 (1H, d) ), 7.63-7.71 (2H, m), 7.82 (1H, d), 10.83-11.22 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 726.4.

Intermediate 130a: tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate

10% Pd on C (75 mg, 0.705 mmol) was added to a solution of tert -butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (Intermediate 129a) (150 mg, 0.353 mmol) in MeOH (5 mL), and the mixture was stirred under H ₂ for 16 h. The solvent was removed under reduced pressure to give the title compound (140 mg, 93%) which was used directly in the next step without further purification; m / z : ES ⁺ [M-Boc] ⁺ = 328.0.

Intermediate 130b: 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride

To a solution of tert -butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (150 mg, 0.351 mmol) in DCM (5 mL) was added 4 M HCl in 1,4-dioxane (2 mL, 8.00 mmol), and the mixture was stirred for 1 h. Concentration under reduced pressure gave the title compound (120 mg, 85%), which was used directly in the next step.

Example 130: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 130b using the general synthetic method exemplified by Example 5 to give the title compound after purification by C-18 chromatography (eluent C, basic workup A); ^1H NMR: 1.58-1.87 (11H, m), 1.94-2.04 (3H, m), 2.32-2.42 (3H, m), 2.58-2.92 (4H, m), 2.97-3.11 (4H, m), 3.93-4.01 (2H, m), 4.12-4.21 (2H, m), 4.24-4.47 (2H, m), 5.00-5.14 (1H, m), 6.80-6.93 (2H, m), 7.12-7.18 (2H, m), 7.24-7.30 (1H, m), 7.32 (1H, s), 7.35-7.42 (1H, m), 7.49 ( 1H, s), 7.58-7.70 (1H, m), 7.82 (1H, d), 10.82 (1H, bs); m/z : ES ⁺ [M+H] ⁺ = 728.2.

Intermediate 131a: Methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate

NBS (3.24 g, 18.22 mmol) was added to a stirred solution of methyl 4-bromo-2-chloro-6-methylbenzoate (3.00 g, 11.38 mmol) and AIBN (0.374 g, 2.28 mmol) in CHCl ₃ (72 mL), and the reaction was stirred under reflux at 80 °C. After 3 h, additional NBS (1.62 g, 9.11 mmol) and AIBN (0.187 mg, 1.14 mmol) were added, and heating was continued at reflux for an additional 0.5 h. The mixture was then cooled to room temperature. Water (150 mL) was added. The mixture was extracted with DCM (2 x 150 mL). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated to give the title compound, which was used without further purification; ¹ H NMR (500 MHz, CDCl ₃ ) 3.99 (3H, s), 4.44 (2H, s), 7.49 (1H, d), 7.54 (1H, d).

Intermediate 131b: 3-(5-bromo-7-chloro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

At room temperature under air, DIPEA (6.08 mL, 34.14 mmol) was added in one portion to a stirred solution of methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (3.90 g, 11.38 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (2.060 g, 12.52 mmol) in MeCN (120 mL). The resulting mixture was stirred at 80 °C for 20 h and then cooled to room temperature with stirring. The resulting solid was collected by filtration, washed with MeCN (2 x 10 mL), and dried to afford the title compound (1.49 g, 37%) as a gray/purple solid; ^1H NMR (500 MHz) 2.02 (1H, ddd), 2.39 (1H, ddd), 2.60 (1H, d), 2.91 (1H, ddd), 4.34 (1H, d), 4.45 (1H, d), 5.09 (1H, dd), 7.83 (1H, d), 7.88 (1H, d) , 11.01 (1H, s); m/z : ES ⁺ [M+H] ⁺ 356.8.

Intermediate 131c: tert -Butyl-4-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

tert -Butyl piperazine-1-carboxylate (40.1 mg, 0.22 mmol), 3-(5-bromo-7-chloro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.20 mmol) and oven-dried Cs ₂ CO ₃ (191 mg, 0.59 mmol) were placed in an oven-dried microwave vial, and the tube was flushed with N ₂ . DMF (1.75 mL) was added, and the mixture was purged with N ₂ . diMeiHept-Cl-Pd(cinnamyl)Cl (10.45 mg, 9.79 μmol) was added, and the mixture was again purged with N ₂ . The tube was sealed, and the mixture was heated at 100 °C for 4 h, and then cooled to room temperature. The mixture was diluted with DCM (50 mL), poured into 5% AcOH in water (50 mL) and shaken. Saturated brine (5 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (30 mL) and the extracts were combined with the organic layer. The combined organic fractions were washed with water (2 x 50 mL) and filtered through a phase separator. The crude product was purified by preparative HPLC (column A, eluent A). The fractions containing the desired compound were concentrated to a volume such that MeCN was removed. The resulting aqueous suspension was basified to pH 7 and extracted with DCM (3 x 15 mL). The combined DCM extracts were dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.028 g, 27%) as a white solid; ^1H NMR (500 MHz) 1.43 (9H, s), 1.93-2.01 (1H, m), 2.31-2.42 (1H, m), 2.59 (1H, d), 2.90 (1H, ddd), 3.33-3.37 (4H, m), 3.42-3.51 (4H, m), 4.20 (1H, d), 4.32 (1H, d), 5.02 (1H, dd), 7.01 (1H, d), 7.04 (1H, s), 10.96 (1H, s); m/z : ES ⁺ [M+H] ⁺ 463.0.

Example 131: 4-{4-[4-(4-{4-[7-chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Example 1h) (28.8 mg, 0.06 mmol) and tert -butyl-4-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (29 mg, 0.06 mmol) were heated in formic acid (2 mL) at 60 °C for 1 h. The mixture was then concentrated and then diluted in NMP (2 mL) (at room temperature under air). After 5 min, NaBH(OAc) ₃ (33.2 mg, 0.16 mmol) was added all at once, and the resulting suspension was stirred at room temperature for 18 h. The mixture was purified by preparative HPLC (column A, eluent A) to give the title compound (0.034 g, 67%) as a formate salt as a beige solid; ^1H NMR: 1.64-1.89 (6H, m), 1.97 (2H, d), 2.09-2.22 (1H, m), 2.31 (1H, qd), 2.66-3 (9H, m), 3.07 (2H, d), 3.26-3.57 (4H, m), 3.93-4.14 (4H, m) ), 4.20 (1H, d), 4.33 (1H, d), 5.12 (1H, dd), 6.75 (1H, s), 6.78-6.88 (3H, m), 6.95-7.04 (1H, m), 7.06-7.18 (3H, m), 7.60 (1H, d), 8.28 (1H, s), 8.54-8.94 (1H, m); m/z : ES ⁺ [M+H] ⁺ 763.2.

Intermediate 132a: 4-Bromo-2-hydroxy-6-methylbenzoic acid

Powdered NaOH (2.06 g, 51.49 mmol) was added to a solution of 4-bromo-2-fluoro-6-methylbenzoic acid (3.00 g, 12.87 mmol) in 1,3-dimethylimidazolidin-2-one (33.4 mL, 308.96 mmol). The mixture was heated to 120 °C for 3 h. The mixture was then cooled to room temperature and poured into water (400 mL). The mixture was acidified to pH 3 with 2 M HCl while stirring. The resulting solid was collected by filtration, washed with water and dried in vacuo to give the title compound (2.13 g, 72%) as a white solid; ¹ H NMR (500 MHz) 2.29 (3H, s), 6.92-6.94 (2H, m), 11.19 (1H, br.s.), 13.00 (1H, br.s.); m/z: ES-[MH] ^-229 .

Intermediate 132b: Methyl 4-bromo-2-hydroxy-6-methylbenzoate

Sulfuric acid (1.04 mL, 19.48 mmol) was added to a solution of 4-bromo-2-hydroxy-6-methylbenzoic acid (1.50 g, 6.49 mmol) in MeOH (40 mL). The mixture was heated to 80 °C, stirred for 5 days, and then concentrated to a volume of 15 mL. The mixture was diluted with EtOAc (100 mL), and ice (100 g) was added, followed by saturated NaHCO ₃ solution (60 mL). The mixture was shaken; the organic layer was separated, washed with saturated NaHCO ₃ solution (60 mL) and saturated brine (30 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (20% EtOAc in heptane) afforded the title compound (1.43 g, 90%) as a beige crystalline solid; ^1H NMR (500 MHz) 2.19 (3H, s), 3.80 (3H, s), 6.92 (1H, dd), 6.94 (1H, dd), 10.36 (1H, s); m/z: ES-[MH] ^-243 .

Intermediate 132c: Methyl 4-bromo-2-(difluoromethoxy)-6-methylbenzoate

8.2 M KOH solution (7.07 mL, 57.94 mmol) was added dropwise to a suspension of methyl 4-bromo-2-hydroxy-6-methylbenzoate (1.42 g, 5.79 mmol) in MeCN (7 mL) at -35 °C under N ₂ . The biphasic mixture was stirred at -35 °C for 10 min, after which time diethyl(bromodifluoromethyl)phosphonate (2.06 mL, 11.59 mmol) was added dropwise, maintaining the temperature at -35 °C. The cooling bath was removed, and the resulting solution was warmed with stirring. A rapid exotherm began at -10 °C; the cooling bath was reapplied at 5 °C, and a maximum temperature of 32 °C was reached. The mixture was then stirred at room temperature for an additional 90 min. TLC showed almost complete conversion to the new product. The reaction was quenched with water (125 mL) and adjusted to pH=2 with 2 M HCl. The mixture was extracted with EtOAc (2 x 125 mL); the combined organic solutions were washed with saturated brine (75 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-10% EtOAc in heptane) gave the title compound (1.16 g, 68%) as a white crystalline solid; ¹ H NMR (500 MHz) 2.27 (3H, s), 3.86 (3H, s), 7.30 (1H, t), 7.42 (1H, d), 7.49 (1H, dd).

Intermediate 132d: Methyl 4-bromo-2-(bromomethyl)-6-(difluoromethoxy)benzoate

NBS (1.16 g, 6.51 mmol) was added to a stirred solution of methyl 4-bromo-2-(difluoromethoxy)-6-methylbenzoate (1.20 g, 4.07 mmol) and AIBN (134 mg, 0.81 mmol) in t -butyl acetate (45 mL), and the reaction was stirred at 100 °C for 35 min. The mixture was then cooled to room temperature. Water (50 mL) was added. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic solutions were washed with brine (50 mL), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (1.52 g, 100%) as a beige gum, which was used without further purification; ^1H NMR (500 MHz, CDCl ₃ ) 3.97 (3H, s), 4.51 (2H, s), 6.49 (1H, t), 7.36 (1H, d), 7.48 (1H, d).

Intermediate 132e: 3-(5-bromo-7-(difluoromethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

At room temperature under air, DIPEA (2.17 mL, 12.21 mmol) was added in one portion to a stirred solution/suspension of methyl 4-bromo-2-(bromomethyl)-6-(difluoromethoxy)benzoate (1.522 g, 4.07 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.737 g, 4.48 mmol) in MeCN (45 mL). The resulting mixture was stirred at 80 °C for 16 h. The mixture was then cooled to room temperature and concentrated to a volume of 10 mL. Diethyl ether (30 mL) was added, followed by stirring and sonication to cause a dark solid to precipitate. The solid was collected by filtration and washed with MeCN. The filtrate was concentrated to give a brown gum. The gum was treated with DCM (30 mL), warmed, and sonicated. A brown precipitate remained in the solution. It was collected by filtration and washed with DCM to give the product as a brown solid. The filtrate was purified by FSC (gradient: 0-3% MeOH in DCM) to give the title compound (1.145 g, 72%) as a brown solid; ¹ H NMR (500 MHz) 1.98 (1H, qd), 2.38 (1H, ddd), 2.60 (1H, dd), 2.90 (1H, ddd), 4.36 (1H, d), 4.48 (1H, d), 5.07 (1H, dd), 7.45 (1H, t), 7.53 (1H, s), 7.78 (1H, s), 11.01 (1H, s); m/z : ES ⁺ [M+H] ⁺ 389.

Intermediate 132f: tert -Butyl-4-(7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

Pd-PEPPSI-IHept.Cl (11.25 mg, 0.01 mmol) was added to a N 2 -purged mixture of 3-(5-bromo- _7- (difluoro-methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.23 mmol), tert -butyl piperazine-1-carboxylate (129 mg, 0.69 mmol) and 1,4-dioxane (7.5 mL) and heated at 90 °C for 5 h. The mixture was then diluted with DCM (100 mL) and washed with 5% AcOH in water (100 mL), water (100 mL), and then saturated brine (50 mL). The organic solution was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC (gradient: 0-3% MeOH in DCM) (after concentration and azeotropic mixing with MeCN) to give the title compound (0.090 g, 32%) as a gray solid; ^1H NMR (500 MHz) 1.43 (9H, s), 1.97 (1H, ddd), 2.37 (1H, ddd), 2.59 (1H, d), 2.89 (1H, ddd), 3.33-3.37 (4H, m), 3.43-3.50 (4H, m), 4.24 (1H, d), 4.35 (1H, d), 5.01 (1H, dd), 6.74 (1H, d), 6.96 (1H, d), 7.42 (1H, t), 10.96 (1H, s); m/z : ES ⁺ [M+H] ⁺ 495.1.

Example 132: 4-{4-[4-(4-{4-[7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

4-(4-(4-(3-(1,3-dioxolan-2-yl)propoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (Example 1h) (50 mg, 0.11 mmol) and tert -butyl-4-(7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (62.2 mg, 0.12 mmol) were heated in formic acid (2 mL) at 60 °C for 0.5 h. The mixture was then concentrated and the crude residue was stirred in NMP (2 mL) (at room temperature under air). NaBH(OAc) ₃ (57.5 mg, 0.27 mmol) was then added all at once after 5 min, and the resulting suspension was stirred at room temperature for 2 h. The residue was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5 μm silica, 30 mm diameter, 100 mm length) using a decreasingly polar mixture of water (containing 0.1% formic acid) and MeCN as the eluent, to give the title compound (0.073 g, 85%) as a white solid; ¹ H NMR: 1.55-1.69 (4H, m), 1.69-1.8 (2H, m), 1.85 (2H, d), 1.91-2.03 (1H, m), 2.36-2.46 (2H, m), 2.53-2.64 (2H, m), 2.77 (1H, tt), 2.89 (1H, ddd), 3.05 (2H, td), 3.26-3.37 (8H, m), 3.97 (2H, t), 4.17 (2H, d), 4.23 (1H, d), 4.34 (1H, d), 5.00 (1H, dd), 6.72 (1H, d), 6.83-6.9 (2H, m), 6.93-6.98 (1H, m), 7.12-7.19 (2H, m), 7.27 (1H, dd), 7.32 (1H, d), 7.41 (1H, t), 7.81 (1H, d), 10.94 (1H, s); m/z : ES ⁺ [M+H] ⁺ 795.3.

Intermediate 133a: Methyl 4-bromo-3-methoxy-2-methylbenzoate

To a stirred solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (1.00 g, 4.08 mmol) in MeCN (10 mL) were added K ₂ CO ₃ (1.69 g, 12.24 mmol) and MeI (0.38 mL, 6.12 mmol) at 0 °C. The mixture was then stirred at room temperature for 16 h. The reaction was then quenched with water (10 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic solutions were washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. Purification by FSC (eluent: EtOAc-hexane 20%∼35%) afforded the title compound (600 mg, 57%) as a yellowish white solid; ^1H NMR (CDCl ₃ ) 2.58 (3H, s), 3.83 (3H, s), 3.91 (3H, s), 7.46 (1H, d), 7.53 (1H, d).

Intermediate 133b: Methyl 4-bromo-2-(bromomethyl)-3-methoxybenzoate

Under N _{2 ,} CHCl ₃ (80 mL) was added to ethyl 4-bromo-3-methoxy-2-methylbenzoate (4.10 g, 15.82 mmol). Then NBS (3.94 g, 22.15 mmol) and AIBN (520 mg, 3.16 mmol) were added at room temperature, and the mixture was stirred at 75 °C for 3 h. The mixture was then diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic solutions were washed with brine (100 mL), dried (Na ₂ SO ₄ ), and concentrated to give the title compound (5.00 g, 86%) as a brown liquid, which was used directly without further purification; ^1H NMR: 3.88 (3H, s), 3.92 (3H, s), 5.01 (2H, s), 7.60 (1H, d), 7.80 (1H, d).

Intermediate 133c: 3-(5-bromo-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Methyl 4-bromo-2-(bromomethyl)-3-methoxybenzoate (5.70 g, 16.86 mmol) was dissolved in MeCN (60 mL). 3-Aminopiperidine-2,6-dione hydrochloride salt (2.78 g, 16.86 mmol) and DIPEA (11.78 mL, 67.5 mmol) were added at room temperature under N ₂ . The mixture was then stirred at 85 °C for 16 h under N ₂ . The mixture was then slowly cooled to room temperature and the solid was collected by filtration, washed with MeCN (20 mL) and dried under vacuum to give the title compound (4.00 g, 62%) as an off-white solid; ^1H NMR: 1.96-2.07 (1H, m), 2.40-2.49 (1H, m), 2.58-2.62 (1H, m), 2.85-3.00 (1H, m), 4.00 (3H, s), 4.52-4.61 (1H, m), 4.68-4.74 (1H, m), 5 .12 (1H, dd), 7.36 (1H, d), 7.77 (1H, d), 11.02 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 355.

Intermediate 133d: tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

Pd-PEPPSI-IHeptCl (83 mg, 0.085 mmol) was added to tert -butyl piperazine-1-carboxylate (949 mg, 5.10 mmol), Cs ₂ CO ₃ (1661 mg, 5.10 mmol) and 3-(5-bromo- ₄ -methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (600 mg, 1.699 mmol) in 1,4-dioxane (20 mL) at room temperature under N 2 . The resulting suspension was stirred at 120 °C for 2 h. The mixture was then diluted with DCM (20 mL) and washed with 5% AcOH in water (20 mL), water (20 mL), saturated NaHCO ₃ (20 mL), and then saturated brine (20 mL). The organic solution was dried (Na ₂ SO ₄ ), concentrated, diluted with EtOAc (8 mL) and washed with MTBE (25 mL) to give a solid which was collected by filtration and dried in vacuo to give the title compound (700 mg, 77%) as a dark brown solid; ^1H NMR: 1.43 (9H, s), 1.88-2.06 (1H, m), 2.40-2.48 (1H, m), 2.58 (1H, br d), 2.76-3.00 (1H, m), 3.00-3.09 (4H, m), 3.41-3.58 (4H, m), 3.89 (3H, s), 4.26-4.34 (1H, m), 4.47 (1H, br d), 5.05 (1H, dd), 7.09 (1H, d), 7.40 (1H, d), 10.98 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 459.2.

Intermediate 133e: 3-(4-methoxy-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

To a stirred solution of tert -butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (700 mg, 1.527 mmol) in DCM (10 mL) was added 4 M HCl in 1,4-dioxane (7.63 mL, 30.5 mmol) at 0 °C. The mixture was stirred at room temperature under N ₂ for 2 h. The mixture was then concentrated to give the title compound (600 mg, 78%) as a brown solid; ^1H NMR: 1.94-2.03 (1H, m), 2.43-2.47 (2H, m), 2.58-2.69 (1H, m), 2.85-2.97 (1H, m), 3.22-3.37 (8H, m), 3.90 (3H, s), 4.35-4.38 (1H, m), 4 .51 (1H, d), 4.46-4.54 (1H, m), 5.08 (1H, dd), 7.14 (1H, d), 7.43 (1H, d), 9.42 (2H, br s), 10.98 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 359.

Example 133: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 133e was reacted with intermediate 50a using the general synthetic method exemplified by Example 5 to give the title compound after purification by HPLC (column: Zorbax-C18, 5 μm; 50 x 21.2 mm, eluent C, basic workup A); ^1H NMR: 1.55-1.69 (4H, m), 1.74 (2H, d), 1.84 (2H, d), 1.91-2.03 (1H, m), 2.39 (2H, d), 2.54-2.64 (5H, m), 2.71-2.82 (1H, m), 2.84-2.96 (1H , m), 2.98-3.15 (6H, m), 3.85 (3H, s), 3.97 (2H, t), 4.18 (2H, d), 4.27 (1H, d), 4.39-4.51 (1H, m), 5.07 (1H, dd), 6.87 (2H, d), 7.07 (1H, d), 7.16 (2H, d), 7.27 (1H, d), 7.33 (1H, s), 7.39 (1H, d), 7.82 (1H, d), 10.96 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 759.

Intermediate 134a: 1-Bromo-4-iodo-2-methoxy-5-methylbenzene

THF (10 mL) was added to 4-bromo-5-methoxy-2-methylaniline (1.00 g, 4.63 mmol), followed by water (2.4 mL) and HCl (37%, 2.40 mL) (at room temperature). The mixture was stirred at room temperature for 1 h and then cooled to 0 °C. A solution of sodium nitrite (0.734 g, 10.64 mmol) in water (10 mL) was then added dropwise, followed by a solution of KI (1.306 g, 7.87 mmol) in water (2 mL). The mixture was then slowly warmed to room temperature and stirred for 16 h. The reaction was then quenched with saturated Na ₂ CO ₃ solution and the pH was adjusted to 7–8. The mixture was then extracted with DCM (20 mL x 3). The combined organic solution was washed with brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FSC using hexane (100%) as the eluent to give the title compound (1.07 g, 62%) as a yellow solid; ¹ H NMR: 2.29 (3H, s), 3.82 (3H, s), 7.45 (1H, s), 7.54 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 328.2.

Intermediate 134b: 4-Bromo-5-methoxy-2-methylbenzoic acid

THF (10 mL) was added to 1-bromo-4-iodo-2-methoxy-5-methylbenzene (1.05 g, 3.21 mmol), followed by the dropwise addition of iPrMgCl (4.82 mL, 9.63 mmol) (at -78 °C). The mixture was stirred at -50 °C to -20 °C for 40 min. Solid carbon dioxide (excess) was added, and the mixture was then slowly warmed to room temperature and stirred for 1 h. The reaction was then quenched with 1.5 M HCl solution (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic solutions were washed with water (10 mL) and brine (10 mL), then dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.80 g, 74%) as a brown solid; m/z : ES ⁺ [M+H] ⁺ = 245.9.

Intermediate 134c: Methyl 4-bromo-5-methoxy-2-methylbenzoate

DMF (3 mL) was added to 4-bromo-5-methoxy-2-methylbenzoic acid (750 mg, 3.06 mmol). Then K ₂ CO ₃ (846 mg, 6.12 mmol) and MeI (0.287 mL, 4.59 mmol, dropwise) were added at room temperature, and then the mixture was stirred at room temperature for 24 h. The reaction was then quenched with ice-cold water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give the title compound (730 mg, 92%); ^1H NMR (CDCl ₃ ) 2.58 (3H, s), 3.83 (3H, s), 3.91 (3H, s), 7.46 (1H, d), 7.53 (1H, d).

Intermediate 134d: Methyl 4-bromo-2-(bromomethyl)-5-methoxybenzoate

Under N _{2 ,} CHCl ₃ (10 mL) was added to methyl 4-bromo-5-methoxy-2-methylbenzoate (720 mg, 2.78 mmol), followed by addition of NBS (692 mg, 3.89 mmol) and AIBN (91 mg, 0.556 mmol) at 0 °C. The mixture was then stirred at 75 °C for 32 h, after which it was quenched with saturated bicarbonate solution (5 mL). The pH was adjusted to 6~7, and the mixture was extracted with DCM (15 mL x 2). The combined organic extracts were washed with brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a brown liquid; ^1H NMR: 3.89 (3H, s), 3.93-4.00 (3H, m), 4.97 (2H, s), 7.48 (1H, s), 7.90 (1H, s).

Intermediate 134e: 3-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)piperidine-2,6-dione

Under N _{2 ,} MeCN (10 mL) was added to methyl 4-bromo-2-(bromomethyl)-5-methoxybenzoate (860 mg, 2.54 mmol). Then 3-aminopiperidine-2,6-dione hydrochloride (419 mg, 2.54 mmol) and DIPEA (1.78 mL, 10.18 mmol) were added at room temperature, and the mixture was stirred at 85 °C for 16 h. After cooling to room temperature, the precipitate was collected by filtration, washed with 5 mL of MeCN, and then dried under reduced pressure to give the title compound (430 mg, 31%) as a gray solid; ^1H NMR: 1.95-2.09 (2H, m), 2.31-2.45 (2H, m), 3.95 (3H, s), 4.17-4.30 (2H, m), 4.36-4.42 (1H, m), 7.37 (1H, s), 7.90 (1H, s), 11.24-11. 31 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 355.0.

Intermediate 134f: tert -Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

1,4-Dioxane (20 mL) was added to 3-(5-bromo-6-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (430 mg, 1.22 mmol) under N ₂ . To this mixture at room temperature under N ₂ , tert -Butyl piperazine-1-carboxylate (680 mg, 3.65 mmol) and Cs ₂ CO ₃ (1.19 g, 3.65 mmol) were added. To this mixture was charged Pd-PEPPSI-IHeptCl (71.1 mg, 0.073 mmol) under N ₂ , and then the mixture was stirred at 120 °C for 2 h. The mixture was then diluted with DCM (20 mL) and washed with 5% AcOH in water (25 mL), water (25 mL), saturated NaHCO ₃ (25 mL), and then saturated brine (20 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. EtOAc (5 mL) and washed with MTBE (20 mL) to give a solid which was collected by filtration and dried in vacuo to give the title compound (253 mg, 36% yield) as a green solid; ^1H NMR: 1.43 (9H, s), 1.90-2.06 (1H, m), 2.35-2.44 (1H, m), 2.56-2.69 (2H, m), 2.85-2.96 (1H, m), 3.01 (3H, br d), 3.48 (4H, br s), 3.83-3 .95 (3H, m), 4.12-4.44 (2H, m), 5.07 (1H, dd), 7.10 (1H, s), 7.20-7.25 (1H, m), 10.92-11.02 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 459.0.

Intermediate 134g: 3-(6-methoxy-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride

DCM (2 mL) was added tert -butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-methoxy-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (250 mg, 0.545 mmol), then 4 M HCl in 1,4-dioxane (2.73 mL, 10.90 mmol) was added at 0 °C, and then the mixture was stirred at room temperature for 2 h. The organic solvent was then removed under reduced pressure to give the title compound (250 mg, 99%) as a gray solid; ^1H NMR: 1.24 (1H, d), 1.95-2.03 (1H, m), 2.33-2.35 (2H, m), 2.67-2.71 (2H, m), 3.26 (8H, br s), 3.89 (3H, s), 4.18-4.38 (2H, m), 5.05-5.1 2 (1H, m), 7.17 (1H, s), 7.25 (1H, s), 10.94-11.00 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 359.

Example 134: 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-methoxy-1-oxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 50a was reacted with intermediate 134 g using the general synthetic method exemplified by Example 5 to give the title compound after purification (column: X Select C18 150 x 21.1, eluent C, basic workup A); ^1H NMR: 1.55-1.67 (4H, m), 1.68-1.78 (2H, m), 1.84 (2H, br d), 1.92-2.00 (1H, m), 2.29-2.43 (4H, m), 2.61-2.77 (2H, m), 2.81-2.92 (1H, m), 2.99-3.14 (6H, m), 3.86 (3H, s), 3.97 (2H, t), 4.14-4.24 (3H, m), 4.26-4.36 (1H, m), 5.07 (1H, dd), 6.86 (2H, d), 7.07 (1H, s), 3H, m), 7.22-7.36 (2H, m), 7.82 (1H, d), 10.90-11.00 (1H, m); m/z : ES ⁺ [M+H] ⁺ = 759.3.

Example 135: 4-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1 H -Pyrrolo[3,4- c ]pyridin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 4b was reacted with intermediate 120e using the general synthetic method exemplified by Example 1 to give the title compound after purification (column A, eluent A); ^1H NMR: 1.14-1.34 (3H, m), 1.53-1.75 (4H, m), 1.75-1.95 (6H, m), 2.21 (2H, d), 2.43-2.47 (4H, m), 2.56-2.77 (2H, m), 2.82-2.95 (1H, m), 3. 04 (2H, t), 3.61 (6H, s), 3.89 (3H, s), 4.08-4.22 (3H, m), 4.27 (1H, d), 4.95 (1H, dd), 6.48 (1H, s), 6.86 (2H, d), 7.08 (2H, d), 7.26 (1H, dd), 7.32 (1H, d), 7.80 (1H, d), 10.88 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 785.3.

Intermediate 136a: tert -Butyl 9-(4-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3-azaspiro[5.5]undecane-3-carboxylate

PPh ₃ (757 mg, 2.89 mmol) was added to 4-(4-(4-hydroxyphenyl)piperidin-1-yl)-2-(trifluoromethyl)-benzonitrile (Example 1g) (500 mg, 1.44 mmol), tert -Butyl 9-hydroxy- ₃ -azaspiro[5.5]undecane-3-carboxylate (467 mg, 1.73 mmol) and DIAD (365 μL, 1.88 mmol) in THF (16 mL) at room temperature under N 2 . The resulting mixture was stirred at room temperature for 16 h. Concentrated and purified by FSC (gradient: 0-20% EtOAc in petroleum ether) to give the title compound (0.560 g, 65%) as a yellow gum; ^1H NMR: 1.12-1.15 (5H, m), 1.23-1.36 (3H, m), 1.39 (9H, s), 1.47-1.55 (2H, m), 1.55-1.72 (3H, m), 1.76-1.87 (3H, m), 2.76 (1H, t), 2.98-3 .09 (2H, m), 3.27-3.29 (6H, m), 4.24-4.33 (1H, m), 6.85 (2H, d), 7.14 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.82 (1H, d); m/z ES ⁺ [M-Boc] = 498.3.

Example 136: 4-(4-(4-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)oxy)phenyl)piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 27f was reacted with intermediate 136a using the general synthetic method exemplified by Example 1 to give the title compound after purification by preparative TLC (DCM:MeOH, 15:1); ^1H NMR: 1.12-1.29 (4H, m), 1.35-1.65 (10H, m), 1.70-1.88 (7H, m), 1.92-1.99 (1H, m), 2.12-2.16 (2H, m), 2.24-2.40 (5H, m), 2.59 (1H, d), 2 .71-2.93 (4H, m), 3.04 (2H, t), 3.86 (2H, d), 4.15-4.24 (3H, m), 4.24-4.36 (2H, m), 5.05 (1H, dd), 6.85 (2H, d), 7.00-7.07 (2H, m), 7.14 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.50 (1H, d), 7.82 (1H, d), 10.96 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 837.3.

Intermediate 137a: 2-[3-(3-bromo-4-iodophenoxy)propyl]-1,3-dioxolane

3-Bromo-4-iodophenol (5.0 g, 16.73 mmol) was added to 2-(3-bromopropyl)-1,3-dioxolane (4.7 g, 24.33 mmol) and K ₂ CO ₃ (6.3 g, 45.62 mmol) in MeCN (100 mL). The mixture was stirred at 80 °C for 1 h, cooled to room temperature, filtered through silica, and the solvent was evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-20% DCM in MeOH) to give the title compound (5.0 g, 80%) as a colorless oil; ^1H NMR: δ 1.65-1.73 (2H, m), 1.7-1.8 (2H, m), 1.76-1.95 (1H, m), 3.7-3.99 (5H, m), 4.8-4.87 (1H, m), 6.69-6.79 (1H, m), 7.26-7.33 (1H, m), 7.71-7.8 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 413.0.

Intermediate 137b: tert -Butyl 4-{2-bromo-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}-3,6-dihydropyridine-1(2 H )-carboxylate

At room temperature under nitrogen, PdCl ₂ (dtbpf) (0.472 g, 0.65 mmol) was added K ₂ CO ₃ (2.20 g, 16.14 mmol), 2-[3-(3-bromo-4-iodophenoxy)propyl]-1,3-dioxolane (4.00 g, 9.68 mmol) and tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (1.99 g, 6.46 mmol) in 1,4-dioxane:water (4:1, 50 mL). The mixture was stirred at 80 °C for 1 h, cooled to room temperature, filtered through Celite® and the solvent was evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-60% EtOAc in _Et2O ) to give the title compound (2.3 g, 76%) as a yellow oil; ¹ H NMR: δ 1.43 (9H, s), 1.65-1.84 (4H, m), 2.31 (2H, s), 3.52 (2H, t), 3.71-3.84 (2H, m), 3.84-3.93 (2H, m), 3.94 (2H, s), 3.96-4.08 (2H, m), 4.85 (1H, t), 5.75 (1H, s), 6.88-6.98 (1H, m), 7.11-7.18 (2H, m); m/z: ES ⁺ [M+H] ⁺ = 468.1.

Intermediate 137c: tert -Butyl 4-{2-bromo-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-carboxylate

Rhodium on carbon (5%, 2.1 g, 1.02 mmol) and tert -butyl 4-{2-bromo-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}-3,6-dihydropyridine-1(2 H )-carboxylate (2.1 g, 4.48 mmol) in EtOAc (10 mL) and MeOH (1 mL) were stirred under hydrogen atmosphere at room temperature for 3 h. The reaction mixture was filtered through Celite® and the solvent was evaporated to give the title compound (1.7 g, 81%) which was used without further purification; ^1H NMR: δ 1.42 (9H, s), 1.53-1.65 (1H, m), 1.65-1.74 (4H, m), 1.71-1.86 (2H, m), 1.91 (1H, s), 2.60 (1H, s), 2.9-3.02 (1H, m), 3.35-3.4 7 (1H, m), 3.71-3.8 (2H, m), 3.84-3.9 (2H, m), 3.94-4.01 (2H, m), 4.09 (2H, d), 4.75-4.87 (1H, m), 6.91 (1H, dd), 7.14 (1H, d), 7.23 (1H, d).

Intermediate 137d: tert -Butyl 4-{2-cyano-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-carboxylate

Copper(I) cyanide (0.38 g, 4.34 mmol) was added tert -butyl 4-{2-bromo-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-carboxylate (1.7 g, 3.61 mmol) in NMP (14 mL) at room temperature. The mixture was stirred at 150 °C for 3 h. The reaction was cooled to room temperature, diluted with EtOAc (100 mL), washed with water (50 mL), saturated brine (50 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-30% EtOAc in Et ₂ O) to give the title compound (0.500 g, 33.2%) as a yellow gum; ^1H NMR: δ 1.42 (9H, s), 1.55 (1H, d), 1.70 (6H, d), 1.77 (2H, d), 2.94 (1H, t), 3.73-3.83 (2H, m), 3.83-3.93 (2H, m), 3.99-4.11 (5H, m), 4. 84 (1H, t), 7.22 (1H, dd), 7.34 (1H, d), 7.42 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 417.2.

Intermediate 137e: 5-[3-(1,3-dioxolan-2-yl)propoxy]-2-(piperidin-4-yl)benzonitrile

TMS-I (327 μl, 2.40 mmol) was added to tert-butyl 4-{2-cyano-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidine-1-carboxylate (500 mg, 1.20 mmol) in MeCN (1 mL). The mixture was stirred at room temperature for 1 min. The solvent was removed under reduced pressure to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-20% EtOAc in DCM) to give the title compound (0.350 g, 92%) as a yellow solid; m/z: ES ⁺ [M+H] ⁺ = 317.2.

Intermediate 137f: 4-(4-{2-cyano-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

Copper(I) cyanide (61.3 mg, 0.68 mmol) was added to 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene (170 mg, 0.65 mmol) in NMP (2 mL) at room temperature and stirred at 150 °C for 3 h. DIPEA (228 μl, 1.30 mmol) and 5-[3-(1,3-dioxolan-2-yl)propoxy]-2-(piperidin-4-yl)benzonitrile (206 mg, 0.65 mmol) were added and the reaction was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), washed with water (10 mL), saturated brine (10 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-50% EtOAc in _Et2O ) to give the title compound (0.150 g, 45.7%) as a yellow solid; ¹ H NMR: δ 1.67-1.74 (1H, m), 1.76-1.8 (3H, m), 1.84-1.89 (4H, m), 3.05-3.09 (3H, m), 3.71-3.8 (4H, m), 3.8-3.93 (2H, m), 4.04 (2H, t), 4.85 (1H, t), 7.24 (1H, dd), 7.37 (1H, d), 7.44-7.53 (2H, m), 7.83 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 504.3.

Example 137: 4-{4-[2-cyano-4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)phenyl]piperidin-1-yl}-3-fluoro-2-(trifluoromethyl)benzonitrile

4-(4-{2-Cyano-4-[3-(1,3-dioxolan-2-yl)propoxy]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (152 mg, 0.30 mmol) was stirred in formic acid (1 mL) at 60 °C for 2 h. The reaction was cooled to room temperature and evaporated to dryness. tert -Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazine-1-carboxylate (intermediate 2b) (160 mg, 0.30 mmol) was stirred in formic acid (2 mL) at 40 °C for 1 h. The solvent was evaporated to dryness. The above two residues were dissolved in NMP (1.5 mL), and the solution was stirred at room temperature for 16 h. The reaction mixture was purified by C18-flash chromatography (elution gradient: 5-100% MeCN in water (1% NH ₄ HCO ₃ )) to give the title compound (78 mg, 33%) as a white solid; ¹ H NMR: δ 1.56-1.66 (2H, m), 1.7-1.81 (2H, m), 1.85 (4H, s), 1.92-2 (1H, m), 2.29-2.44 (3H, m), 2.49 (3H, s), 2.53-2.56 (1H, s), 2.59 (1 H, d), 2.84-2.97 (1H, m), 2.97-3.13 (3H, m), 3.21-3.3 (4H, m), 3.74 (2H, d), 4.06 (2H, t), 4.21 (1H, d), 4.33 (1H, d), 5.06 (1H, dd), 7.01-7. 08 (2H, m), 7.25 (1H, dd), 7.38 (1H, d), 7.43-7.55 (3H, m), 7.82 (1H, d), 10.96 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 772.3.

Intermediate 138a: tert -Butyl 4-(4-bromo-2,6-difluorophenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

The title compound was obtained by reacting tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate with 5-bromo-1,3-difluoro-2-iodobenzene using a general synthetic method exemplified by intermediate 9a; ¹ H NMR (CDCl ₃ ): δ 1.49 (9H, s), 2.37 (2H, d), 3.62 (2H, t), 4.03 - 4.12 (2H, m), 5.81 (1H, s), 7.05 - 7.12 (2H, m); m/z: ES ⁺ [M- t Bu] ⁺ = 318.0

Intermediate 138b: 4-(4-bromo-2,6-difluorophenyl)-1,2,3,6-tetrahydropyridine

Using the general synthetic method exemplified by intermediate 26c, reaction of tert -butyl 4-(4-bromo-2,6-difluorophenyl)-3,6-dihydropyridine-1(2 H )-carboxylate gave the title compound as its HCl salt which was used without further purification; ¹ H NMR: δ 2.76 (2H, s), 3.45 (2H, d), 3.87 - 3.99 (2H, m), 5.87 (1H, s), 7.01 - 7.17 (2H, m), 10.11 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 274.0.

Intermediate 138c: 4-[4-(4-bromo-2,6-difluorophenyl)-3,6-dihydropyridine-1(2 H )-1]-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reaction of 4-(4-bromo-2,6-difluorophenyl)-1,2,3,6-tetrahydropyridine with 4-fluoro-2-(trifluoromethyl)benzonitrile using a general synthetic method exemplified by intermediate 4a; ¹ H NMR: δ 2.57 - 2.64 (2H, m), 3.68 (2H, t), 4.04 (2H, q), 6.00 (1H, s), 6.96 (1H, dd), 7.08 - 7.16 (3H, m), 7.62 - 7.68 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 443.0.

Intermediate 138d: 4-[4-{4-[4-(dibutoxymethyl)piperidin-1-yl]-2,6-difluorophenyl}-3,6-dihydropyridine-1(2 H )-1]-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 4-[4-(4-bromo-2,6-difluorophenyl)-3,6-dihydropyridin-1(2 H )-yl]-2-(trifluoromethyl)benzonitrile with 4-(dibutoxymethyl)piperidine (intermediate 27e) using a general synthetic method exemplified by intermediate 27c; ¹ H NMR: δ 0.93 (6H, t), 1.35 - 1.47 (4H, m), 1.53 - 1.6 (6H, m), 1.72 - 1.89 (3H, m), 2.25 (2H, ddd), 2.65 - 2.77 (2H, m), 3.43 (2H, dt), 3.53 - 3.72 (5H, m), 3.80 (1H, dt), 3.91 (1H, s), 4.17 (1H, d), 5.03 (1H, d), 6.37 (2H, d), 6.67 (1H, dd), 7.03 (1H, dd), 7.19 (1H, d), 7.61 - 1H, m); m/z: ES ⁺ [M+H] ⁺ = 606.3.

Intermediate 138e: 4-(4-{4-[4-(dibutoxymethyl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

The title compound was obtained by hydrogenation of 4-[4-{4-[4-(dibutoxymethyl)piperidin-1-yl]-2,6-difluorophenyl}-3,6-dihydropyridin-1(2 H )-yl]-2-(trifluoromethyl)benzonitrile using a general synthetic method exemplified by intermediate 9b; ¹ H NMR: δ 0.93 (6H, t), 1.36 - 1.44 (6H, m), 1.53 - 1.61 (4H, m), 1.72 - 1.92 (6H, m), 2.07 - 2.19 (2H, m), 2.68 (2H, td), 3.04 (2H, q), 3.43 ( 2H, dt), 3.64 (4H, ddd), 4.00 (2H, d), 4.17 (1H, d), 6.38 (2H, t), 6.98 (1H, td), 7.15 (1H, dd), 7.61 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 608.4.

Example 138: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

4-(4-{4-[4-(Dibutoxymethyl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (65 mg, 0.11 mmol) and tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)piperazine-1-carboxylate (intermediate 120e) (54.1 mg, 0.12 mmol) were heated in formic acid (1 mL, 26.51 mmol) at 60 °C for 2 h. The reaction mixture was cooled to room temperature, evaporated and the residue was suspended in NMP (2 mL). The reaction mixture was stirred for 5 minutes, then sodium triacetoxyhydroborate (56.7 mg, 0.27 mmol) was added. The suspension was stirred at room temperature for 2 hours. The residue was purified by preparative HPLC (column A, eluent A) to give the title compound (25 mg, 28.5%) as a formate salt as a yellow solid; ¹ H NMR: δ 1.07 - 1.22 (2H, m), 1.7 - 1.82 (5H, m), 1.85 - 2 (3H, m), 2.16 - 2.23 (2H, m), 2.32 - 2.35 (1H, m), 2.42 - 2.47 (4H, m), 2.67 - (2H, m), 2.83 - 2.95 (1H, m), 2.99 - 3.1 (2H, m), 3.57 - 3.65 (4H, m), 3.72 (2H, d), 3.89 (3H, s), 4.1 - 4.22 (3H, m), 4.28 (1H, d), 4.96 (1H, dd), 6.49 (1H, s), 6.54 - 6.59 (1H, m), 7.27 (1H, dd), 7.33 (1H, d), 7.79 - 7.89 (1H, m), 8.19 (1H, s), 10.91 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 821.5.

Intermediate 139a: Benzyl (2 S )-4-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-2-methylpiperazine-1-carboxylate

The title compound was provided by reaction of benzyl ( 2S )-2-methylpiperazine-1-carboxylate with 4-fluoro-2-(trifluoromethyl)benzonitrile using a general synthetic method exemplified by intermediate 137f; ^1H NMR: δ 1.24 (3H, d), 2.92-3.04 (1H, m), 3.07-3.16 (1H, m), 3.28 (1H, d), 3.48 (1H, d), 3.54 (1H, d), 3.86-3.96 (1H, m), 4.26-4.35 (1H, m) , 5.06-5.18 (2H, m), 7.3-7.35 (1H, m), 7.38 (5H, d), 7.42 (1H, d), 7.83 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 422.2.

Intermediate 139b: 3-Fluoro-4-[(3 S )-3-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reacting benzyl (2 S )-4-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-2-methylpiperazine-1-carboxylate with hydrogen gas using a general synthetic method exemplified by intermediate 123b; ¹ H NMR: δ 1.03 (3H, d), 2.37-2.51 (2H, m), 2.67-2.84 (2H, m), 2.95 (1H, d), 3.86 (2H, t), 7.22 (1H, d), 7.28 (1H, s), 7.80 (1H, d), one proton exchanged; m/z: ES ⁺ [M+H] ⁺ = 288.2.

Intermediate 139c: 3-Fluoro-4-[(3 S )-3-methyl-4-(4-nitrophenyl)piperazin-1-yl]-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reaction of 3-fluoro-4-[( 3S )-3-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile with 1-fluoro-4-nitrobenzene using a general synthetic method exemplified by intermediate 29a; ¹ H NMR: δ 1.24 (3H, d), 3.17-3.28 (1H, m), 3.3-3.47 (2H, m), 3.62 (1H, dt), 3.74 (1H, d), 3.85-3.95 (1H, m), 4.38-4.45 (1H, m), 6.99-7.07 (2H, m), 7.45 (1H, t), 7.84 (1H, d), 8.05-8.14 (2H, m); m/z: ES ⁺ [M+H] ⁺ = 409.2.

Intermediate 139d: 4-[(3 S )-4-(4-aminophenyl)-3-methylpiperazin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reacting 3-fluoro-4-[( 3S )-3-methyl-4-(4-nitrophenyl)piperazin-1-yl]-2-(trifluoromethyl)benzonitrile with iron and ammonium chloride using a general synthetic method exemplified by intermediate 29b; ^1H NMR: δ 0.85-0.95 (3H, m), 2.54 (1H, s), 2.98-3.05 (2H, m), 3.08-3.17 (1H, m), 3.33-3.42 (2H, m), 3.45 (1H, d), 4.71-4.78 (2H, m), 6.49 -6.6 (2H, m), 6.74-6.85 (2H, m), 6.95 (1H, s), 7.41-7.52 (1H, m), 7.82 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 379.2.

Intermediate 139e: 4-[(3 S )-4-(4-bromophenyl)-3-methylpiperazin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

Copper bromide (682 mg, 4.76 mmol) was added to 4-[(3 S )-4-(4-aminophenyl)-3-methylpiperazin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile (600 mg, 1.59 mmol) and tert -butylnitrite (491 mg, 4.76 mmol) in MeCN (15 mL) at room temperature and stirred at room temperature for 3 h. The reaction mixture was diluted with DCM, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-30% EtOAc in Et ₂ O) to give the title compound (130 mg, 18.5%) as a yellow solid; ^1H NMR: δ 1.06 (3H, d), 3.09-3.21 (2H, m), 3.25-3.32 (1H, m), 3.41-3.48 (1H, m), 3.5-3.58 (1H, m), 3.6-3.65 (1H, m), 4.09-4.15 (1H, m), 6. 87-6.98 (2H, m), 7.34-7.4 (2H, m), 7.47 (1H, t), 7.84 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 442.1.

Intermediate 139f: 4-[(3 S )-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-3-methylpiperazin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

Pd( t -Bu ₃ P) ₂ (0.11 g, 0.02 mmol) was added to 4-[(3 S )-4-(4-bromophenyl)-3-methylpiperazin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile (0.1 g, 0.03 mmol), 4-(1,3-dioxolan-2-yl)piperidine (0.039 g, 0.25 mmol), Cs ₂ CO ₃ (0.147 g, 0.45 mmol), and tri- tert -butylphosphonium tetrafluoroborate (0.006 g, 0.02 mmol) in 1,4-dioxane (3 mL) under nitrogen and stirred at 100 °C for 2 h. 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% EtOAc in _Et2O ) to give the title compound (0.80 g, 68%) as a yellow solid; ^1H NMR δ 0.94 (3H, d), 1.15 (1H, d), 1.39 (2H, s), 1.4-1.46 (1H, m), 1.58 (2H, s), 1.73 (2H, d), 2.54 (1H, d), 3.06-3.12 (1H, m), 3.15 (1H, s), 3.28-3.39 (2H, m), 3.45-3.52 (1H, m), 3.56 (2H, d), 3.72-3.76 (2H, m), 3.74-3.92 (4H, m), 4.61 (1H, d), 6.87 (4H, s), 7.46 (1H, t), 7. 83 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 519.3.

Example 139: 4-[(3 S )-4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}-3-methylpiperazin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

Using a general synthetic method exemplified by Example 137, 4-[( 3S )-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-3-methylpiperazin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile was reacted with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (Intermediate 1e) and purified by flash silica chromatography (elution gradient: 0-8% MeOH in DCM) to give the title compound; ¹ H NMR: δ 0.95 (3H, d), 1.17 - 1.31 (3H, m), 1.57 - 1.73 (1H, m), 1.81 (2H, d), 1.88 - 1.95 (1H, m), 2.23 (2H, d), 2.27 - 2.38 (1H, m), 2.50 (7 H, s), 2.52 - 2.62 (4H, m), 2.82 - 2.96 (1H, m), 3.03 - 3.21 (2H, m), 3.22 - 3.30 (1H, m), 3.31 - 3.43 (1H, m), 3.45 - 3.57 (3H, m), 3.70 - 8 (1H, m), 3.83 (3H, s), 4.17 (2H, dd), 4.96 (1H, dd), 6.46 - 6.51 (1H, m), 6.61 (1H, s), 6.88 (4H, s), 7.46 (1H, t), 7.83 (1H, d), 10.89 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 817.3.

Intermediate 140a: Benzyl 4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methylpiperazine-1-carboxylate

DIPEA (2.09 mL, 12.02 mmol) was added to benzyl 3-methylpiperazine-1-carboxylate (1.12 g, 4.81 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (1.0 g, 5.29 mmol) in NMP (12 mL) and stirred at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with water (50 mL), saturated brine (20 mL), dried over MgSO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-40% EtOAc in Et ₂ O) to give the title compound (1.5 g, 77%) as a yellow solid; ^1H NMR: δ 1.05 (3H, d), 3.21 (3H, s), 3.77 (1H, s), 3.84 (1H, dt), 4.00 (1H, dd), 4.33 (1H, s), 5.13 (2H, d), 7.19 (1H, dd), 7.25 (1H, d), 7.28 - 7.43 (5H, m), 7.86 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 404.2.

Intermediate 140b: 4-[2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reacting benzyl 4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methylpiperazine-1-carboxylate with hydrogen gas using the general synthetic method exemplified by intermediate 123b; ¹ H NMR: δ 1.08 - 1.19 (3H, m), 2.57 - 2.70 (1H, m), 2.75 - 2.88 (2H, m), 2.90 - 3.03 (2H, m), 3.56 - 3.65 (1H, m), 4.12 - 4.20 (1H, m), 7.12 - 7.19 (1H, m), 7.19 - 7.27 (1H, m), 7.76 - 7.87 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 270.1.

Intermediate 140c: 1-(4-bromophenyl)-4-(1,3-dioxolan-2-yl)piperidine

Under nitrogen, Pd ₂ (dba) ₃ (175 mg, 0.19 mmol) was added Xantphos (110 mg, 0.19 mmol), Cs ₂ CO ₃ (3.1 g, 9.54 mmol), 1-bromo-4-iodobenzene (1.1 g, 4.20 mmol) and 4-(1,3-dioxolan-2-yl)piperidine (600 mg, 3.82 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 80 °C for 3 h and then cooled to room temperature. The solvent was evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-55% EtOAc in Et ₂ O) to give the title compound (0.30 g, 25.2%) as a yellow solid; ¹ H NMR δ 1.30 - 1.44 (2H, m), 1.59 - 1.76 (3H, m), 2.58 - 2.69 (2H, m), 3.66 - 3.74 (2H, m), 3.74 - 3.84 (2H, m), 3.81 - 3.93 (2H, m), 4.56 - 4 .63 (1H, m), 6.84 - 6.91 (2H, m), 7.27 - 7.36 (2H, m); m/z: ES ⁺ [M+H] ⁺ = 312.1.

Intermediate 140d and Intermediate 141a: 4-[(2 R* )-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile and 4-[(2 S *)-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Using the general synthetic method exemplified by intermediate 139f, 1-(4-bromophenyl)-4-(1,3-dioxolan-2-yl)piperidine was reacted with 4-[2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile to give the racemate, which was purified by preparative chiral-HPLC on the following column: CHIRALPAK IH, 3*25 cm, 5 μm; Mobile phase A: CO ₂ , Mobile phase B: MEOH (0.1% 2M NH ₃ -MeOH); Flow rate: 100 mL/min; Gradient: isocratic 40% B;

Intermediate 140d (isomer 1) eluted first: ¹ H NMR: δ 1.21 (3H, d), 1.37 - 1.48 (2H, m), 1.57 (1H, s), 1.73 (2H, d), 2.67 - 2.74 (1H, m), 2.86 (1H, d), 3.26 - 3.30 (2H, m), 3.43 (1H, d), 3.54 (4H, d), 3.76 - 3.80 (2H, m), 3.83 - 3.90 (3H, m), 4.42 (1H, s), 4.60 (1H, d), 6.87 (4H, s), 7.25 (1H, d), 7.29 (1H, s), 7.85 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 501.3, >99% ee.

Intermediate 141a (isomer 2): ¹ H NMR: δ 1.21 (4H, d), 1.41 (2H, q), 1.58 (1H, s), 1.73 (2H, d), 2.55 (1H, s), 2.71 (1H) , d), 2.86 (1H, d), 3.43 (1H, d), 3.54 (3H, d), 3.79 (2H, d), 3.87 (3H, s), 4.42 (1H, s), 4.57-4.63 ( 1H, m), 6.87 (3H, d), 7.24 (1H, d), 7.29 (1H, s), 7.85 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 501.3, >99% ee.

Example 140: 4-[(2 R *)-4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}-2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

The title compound was provided by reaction of 4-[(2 R *)-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (Intermediate 1e) using a general synthetic method exemplified by Example 137; ^1H NMR: δ 1.19-1.32 (5H, m), 1.58-1.73 (1H, m), 1.82 (2H, d), 1.88-1.95 (1H, m), 2.23 (2H, d), 2.26-2.38 (1H, m), 2.46-2.51 (4H, m), 2.53 ( 1H, d), 2.58 (3H, d), 2.64-2.76 (1H, m), 2.83-2.95 (2H, m), 3.23-3.33 (4H, m), 3.43 (1H, d), 3.48-3.59 (3H, m), 3.81-3.93 (4H, m), 4.11 (1H, d), 4.24 (1H, d), 4.4-4.44 (1H, m), 4.97 (1H, dd), 6.53 (2H, d), 6.88 (4H, s), 7.1-7.37 (2H, m), 7.86 (1H, d), 10.90 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 799.4.

Example 141: : 4-[(2S * )-4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}-2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

The title compound was provided by reaction of 4-[( 2S *)-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-2-methylpiperazin-1-yl]-2-(trifluoromethyl)benzonitrile with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (Intermediate 1e) using a general synthetic method exemplified by Example 137; ^1H NMR: δ 1.18-1.29 (6H, m), 1.66 (1H, s), 1.81 (2H, d), 1.88-1.95 (1H, m), 2.17-2.28 (2H, m), 2.31 (2H, dd), 2.46-2.5 (4H, m), (2H, m), 2.82-2.95 (2H, m), 3.32 (3H, s), 3.43 (2H, d), 3.48-3.55 (3H, m), 3.76-3.93 (5H, m), 4.11 (1H, d), 4.23 (1H, d), 4.42 (1H, s), 6 (1H, dd), 6.49 (1H, s), 6.61 (1H, s), 6.88 (4H, s), 7.21-7.27 (1H, m), 7.30 (1H, d), 7.85 (1H, d), 10.90 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 799.4.

Intermediate 142a: 3-Fluoro-4-(3-methyl-4-oxopiperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Copper(I) cyanide (1.80 g, 20.12 mmol) was added to 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene (5.0 g, 19.16 mmol) in NMP (2 mL) and stirred at 150 °C for 3 h and then cooled to 100 °C. DIPEA (6.69 mL, 38.32 mmol) and 3-methylpiperidin-4-one (2.16 g, 19.16 mmol) were added and stirred for an additional 1 h. The reaction was cooled to room temperature, diluted with EtOAc (200 mL) and water (200 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-30% EtOAc in Et ₂ O) to give the title compound (3.3 g, 57.4%) as a white solid; ¹ H NMR (CDCl ₃ ): δ 1.12 (3H, d), 2.51 - 2.64 (1H, m), 2.65 - 2.89 (2H, m), 3.04 (1H, t), 3.28 - 3.43 (1H, m), 3.75 - 3.94 (2H, m), 7.14 (1H, t), 7.52 (1H, d).

Intermediate 142b: 1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate

Lithium bis(trimethylsilyl)amide (15.0 mL, 14.99 mmol) was added to 3-fluoro-4-(3-methyl-4-oxopiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.5 g, 5.00 mmol) in THF (30 mL) at -65 °C under nitrogen for 1 h. N-(5-Chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.92 g, 9.99 mmol) was added and stirring was continued at -65 °C for 2 h. The reaction mixture was quenched with MeOH and evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-20% EtOAc in Et ₂ O) to afford the title compound (0.410 g, 18.98%) as a yellow solid; ¹ H NMR (CDCl ₃ ): δ 1.30 (3H, t), 2.81 - 2.86 (1H, m), 3.33 (1H, dd), 3.62 (1H, dd), 3.86 - 3.95 (2H, m), 5.76 - 6.08 (1H, m), 7.11 (1H, t), 7.51 - 7.58 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 433.1.

Intermediate 142c: 4-(1,3-dioxolan-2-yl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine

The title compound was provided by reaction of 4-(1,3-dioxolan-2-yl)piperidine with 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using a general synthetic method exemplified by intermediate 139f; ¹ H NMR (CDCl3): δ 1.35 (12H, s), 1.50 - 1.64 (2H, m), 1.69 - 1.77 (1H, m), 1.83 - 1.90 (2H, m), 2.77 (2H, t), 3.83 - 3.87 (2H, m), 3.87 - 3.92 ( 2H, m), 3.92 - 4.02 (2H, m), 4.69 (1H, d), 6.92 (2H, d), 7.71 (2H, d); m/z: ES ⁺ [M+H] ⁺ = 360.2.

Intermediate 142d: 4-[4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-3-methyl-3,6-dihydropyridine-1(2 H )-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reaction of 1-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate with 4-(1,3-dioxolan-2-yl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine using a general synthetic method exemplified by intermediate 92e; ¹ H NMR (CDCl ₃ ): δ 1.18 (3H, d), 1.59 - 1.73 (2H, m), 1.83 - 1.93 (3H, m), 2.70 - 2.80 (3H, m), 2.96 - 3.02 (1H, m), 3.34 - 3.46 (1H, m), 3.62 - 3.81 (4H, m), 3.85 - 3.93 (5H, m), 3.95 - 4.03 (2H, m), 4.69 (1H, d), 5.88 (1H, t), 6.90 - 6.96 (2H, m), 7.08 (1H, t), 7.29 (2H, d), 7.48 (1H, d) ; m/z: ES ⁺ [M+H] ⁺ = 516.3.

Intermediate 143a and Intermediate 142e: 4-[(3S * ,4S * )-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-3-methylpiperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile and 4-[(3R * ,4R * )-4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-3-methylpiperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Using the general synthetic method exemplified by intermediate 9b, 3-ethenyl-4-fluoro-2-(trifluoromethyl)benzonitrile was reacted with hydrogen gas to give the title compound as a racemic mixture, which was purified by preparative chiral-HPLC on the following column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2 M NH ₃ -MeOH), Mobile phase B: EtOH--HPLC; Flow rate: 15 mL/min; Gradient: from 50% B to 50% B in 20 min;

Intermediate 142e (cis-isomer 1) (first eluted): ¹ H NMR (CDCl ₃ ): δ 0.76 (3H, d), 1.15 (1H, s), 1.45 (2H, s), 1.73 (3H, dd), 2.06 (1H, s), 2.12 - 2.28 (1H, m), 2.57 (2H, t), 2.78 - 2.95 (2H, m), 3.00 - 3.10 (1H, m), 3.56 (4H, dd), 3.72 - 3.93 (4H, m), 4.59 (1H, d), 6.82 (2H, d), 6.93 - 7.06 (3H, m), 7.38 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 518.2. >99% ee.

Intermediate 143a (cis-isomer 2): ¹ H NMR (CDCl ₃ ): δ 0.76 (3H, d), 1.15 (1H, s), 1.45 (2H, s), 1.56 (2H, d), 1.78 (2H, d), 2.08 - 2.27 (1H, m), 2.57 (2H, t), 2.77 - 2.95 (2H, m), 3.05 (1H, dd), 3.51 (1H, d), 3.61 (3H, d), 3.71 - 3.93 (4H, m), 4.59 (1H, d), 6.82 (2H, d), 6.93 - 7.06 (3H, m), 7.38 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 518.2. >99% ee.

Example 142: 4-[(3S * ,4S * )-4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}-3-methylpiperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Intermediate 142e was reacted with intermediate 1e using the general synthetic method exemplified by Example 137 to provide the title compound; ¹ H NMR (CDCl ₃ ): δ 0.89 (3H, d), 1.43 (2H, s), 1.93 (2H, s), 2.11 - 2.38 (6H, m), 2.70 (6H, dd), 2.79 - 3.07 (5H, m), 3.18 (1H, d), 3.35 (4H, s), 3.53 - 3.79 (5H, m), 3.96 (3H, s), 4.15 - 4.54 (2H, m), 5.16 (1H, dd), 6.28 - 6.55 (2H, m), 6.95 (2H, d), 7.12 (3H, t), 7.50 (1H, d), (1H, s); m/z: ES ⁺ [M+H] ⁺ = 816.4.

Example 143: 4-[(3R * ,4R * )-4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro- 1H -isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}-3-methylpiperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet determined)

Intermediate 143a was reacted with intermediate 1e using the general synthetic method exemplified by Example 137 to provide the title compound; ¹ H NMR (CDCl ₃ ): δ 0.89 (3H, d), 1.43 (2H, s), 1.93 (2H, s), 2.09 - 2.46 (6H, m), 2.53 - 2.85 (6H, m), 2.78 - 2.93 (2H, m), 2.87 - 3.10 (3H, m) , 3.18 (1H, d), 3.36 (4H, s), 3.59 - 3.75 (5H, m), 3.97 (3H, s), 4.22 (1H, d), 4.39 (1H, d), 5.16 (1H, dd), 6.44 (2H, d), 6.95 (2H, d), 3H, t), 7.50 (1H, d), 7.96 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 816.4.

Intermediate 144a: 4-Fluoro-3-iodo-2-(trifluoromethyl)benzonitrile

Lithium diisopropylamide (2.91 mL, 5.82 mmol) was added to 4-fluoro-2-(trifluoromethyl)benzonitrile (1.0 g, 5.29 mmol) in THF (20 mL) and cooled to -78 °C over a period of 10 min under nitrogen. I ₂ (1.47 g, 5.82 mmol) was added and the resulting mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated NH ₄ Cl solution (25 mL), extracted with EtOAc (3 × 25 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to afford the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-50% EtOAc in Et ₂ O) to afford the title compound (1.00 g, 60.0%) as a yellow solid; ¹ H NMR (CDCl ₃ ): δ 7.31 - 7.41 (1H, m), 7.81 - 7.95 (1H, m).

Intermediate 144b: 3-Ethenyl-4-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reaction of 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile with 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using a general synthetic method exemplified by intermediate 35a; ¹ H NMR (CDCl ₃ ): δ 5.70 - 5.87 (2H, m), 6.68 (1H, m), 7.40 (1H, t), 7.74 (1H, dd).

Intermediate 144c: 3-Ethyl-4-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reacting 3-ethenyl-4-fluoro-2-(trifluoromethyl)benzonitrile with hydrogen gas using a general synthetic method exemplified by intermediate 9b; ¹ H NMR (CDCl ₃ ): δ 1.23 (3H, t), 2.72 - 2.95 (2H, m), 7.23 - 7.40 (1H, m), 7.71 (1H, dd).

Intermediate 144d: Benzyl 4-(4-bromophenyl)piperidine-1-carboxylate

Benzyl carbonochloridate (14.27 mL, 96.17 mmol) was added dropwise 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) at 0 °C over 5 min. The resulting mixture was stirred at room temperature for 24 h and then quenched with water (250 mL). The layers were separated, and the organic layer was washed with water (250 mL), NaCl solution (50 mL), dried with MgSO ₄ , filtered, and evaporated to give 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 h. The resulting solid was collected by filtration, washed with water (2 x 20 mL) and dried under vacuum at 50 °C for 16 h to afford the title compound (32.9 g, 91%) as a white solid; ¹ H 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).

Intermediate 144e: Benzyl 4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}piperidine-1-carboxylate

To a solution of 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 Cs ₂ CO ₃ (56.6 g, 173.67 mmol) in 1,4-dioxane (325 mL) under nitrogen was added tri- tert -butylphosphonium tetrafluoroborate (2.52 g, 8.68 mmol). The mixture was degassed with nitrogen, and then Pd( t -Bu ₃ P) ₂ (2.21 g, 4.34 mmol) was added. The resulting mixture was stirred at 100 °C for 20 h, cooled to room temperature, and the solid was filtered under vacuum. The solid was washed with 1,4-dioxane (3x 65 mL) and the filtrate was evaporated to give a pale yellow solid. The solid was suspended in cyclopentyl methyl ether:heptane (1:10, 300 mL) and stirred at 50 °C for 30 min, then allowed to cool to room temperature for an additional 2 h. The solid was filtered to give the title compound (28.9 g, 73.9%) as a cream 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 - 3.93 (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.

Intermediate 144f: 4-(1,3-dioxolan-2-yl)-1-[4-(piperidin-4-yl)phenyl]piperidine

Benzyl 4-{4-[4-(1,3-dioxolan-2-yl)piperidin-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 was stirred under hydrogen atmosphere at 4 bar for 16 h. The catalyst was then filtered off through a pad of Celite®, and the solvent was removed under reduced pressure and azeotroped with excess MeCN. The product was dried in a vacuum oven for 2 h to give 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.

Intermediate 144g: 4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-ethyl-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 3-ethyl-4-fluoro-2-(trifluoromethyl)benzonitrile with 4-(1,3-dioxolan-2-yl)-1-[4-(piperidin-4-yl)phenyl]piperidine using a general synthetic method exemplified by intermediate 140a; ¹ H NMR (CDCl ₃ ): δ 1.10 - 1.74 (8H, m), 1.77 - 2.05 (6H, m), 2.63 (1H, dd), 2.77 - 3.00 (4H, m), 3.15 (2H, d), 3.70 (2H, d), 3.83 - 4.05 (4H, m), 4.69 (1H, d), 6.94 (2H, s), 7.17 (2H, d), 7.37 (1H, d), 7.65 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 514.3.

Example 144: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-ethyl-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-ethyl-2-(trifluoromethyl)benzonitrile with intermediate 2b using a general synthetic method exemplified by Example 137; ¹ H NMR: δ 1.05 - 1.29 (5H, m), 1.59 - 2.00 (8H, m), 2.20 (2H, d), 2.29 - 2.41 (5H, m), 2.50 - 2.67 (4H, m), 2.79 - 2.92 (5H, m), 3.09 (2H, d), 3.27 (4H, t), 3.61 (2H, d), 4.03 - 4.40 (2H, m), 5.04 (1H, dd), 6.87 (2H, d), 6.99 - 7.15 (4H, m), 7.51 (1H, d), 7.60 (1H, d), 7.92 (1H, d), 10. 93 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 782.0.

Intermediate 145a: 4-{4-[4-(4-bromobutoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 38d (1.0 g, 2.74 mmol), K ₂ CO ₃ (0.759 g, 5.49 mmol) and 1,4-dibromobutane (1.63 mL, 13.72 mmol) were suspended in MeCN (20 mL) and stirred at 70 °C for 6 h. The reaction mixture was cooled to room temperature and filtered under vacuum. The filtrate was evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-30% EtOAc in heptane) to give the title compound (1.03 g, 75%) as a yellow oil which solidified on standing; ¹ H NMR (CDCl ₃ ): δ 1.79 (2H, qd), 1.89 - 2 (4H, m), 2.06 (2H, dtd), 3 - 3.13 (3H, m), 3.48 (2H, t), 3.96 (2H, t), 4.02 (2H, d), 6.56 - 6.67 (2H, m) ), 6.99 (1H, dd), 7.07 (1H, t), 7.16 (1H, d), 7.56 - 7.68 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 499.1.

Intermediate 145b: tert -Butyl 4-(4-nitro-1 H -Indol-1-yl)piperidine-1-carboxylate

4-Nitro-1 H -indole (5x 95.0 g, 585 mmol), tert -Butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (5x 409.0 g, 1.46 mol) and Cs ₂ CO ₃ (5x 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 h. Water (10.0 L) was added to each mixture and the batches were combined by extraction with EtOAc (6.0 L). The organic layer was washed with NaCl solution (10.0 L x3) and dried over Na ₂ SO ₄ . The solvent was evaporated and the crude product was purified by recrystallization from MTBE:Et ₂ O (1:4, 500.0 mL) at room temperature for 20 min. The solid was filtered and dried in vacuo to give 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 = 8.4 Hz, 1H), 7.92 (d, J = 3.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H).

Intermediate 145c: tert -Butyl 4-(4-amino-1 H -Indol-1-yl)piperidine-1-carboxylate

tert -Butyl 4-(4-nitro-1 H -indol-1-yl)piperidine-1-carboxylate (7x 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 h. The seven batches were combined by filtering off the Pd/C and evaporating the solvent. The resulting solid was used without further purification to afford the title compound (770.0 g, 86%) as a brown solid; ^1H NMR δ 1.43 (s, 9H), 1.86-1.98 (m, 4H), 3.46-3.82 (m, 2H), 4.12 (d, J = 10.4 Hz, 2H), 4.59 (t, J = 3.6 Hz, 1H), 5.36 (s, 2H), 6.34 (d, J = 3.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 3.6 Hz, 1H).

Intermediate 145d: tert -Butyl 4-{4-[(3-methoxy-3-oxopropyl)amino]-1 H -Indol-1-yl}piperidine-1-carboxylate

tert -Butyl 4-(4-amino-1 H -indol-1-yl)piperidine-1-carboxylate (5x 175.0 g, 555 mmol) was added to five separate portions of MeOH (1.2 L). AcOH (5x 499.0 g, 8.32 mol, 476 mL) was added to each mixture followed by methyl acrylate (471.0 g, 5.47 mol, 4923 mL) and stirred at 80 °C for 18 h. The batches were combined and the solvent was evaporated to give the crude product which was extracted with EtOAc (10.0 L) and washed with NaHCO ₃ (15.0 L). The aqueous layer was back-extracted with EtOAc (5.0 L x3). The combined organics were washed with NaCl solution and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (1.08 kg, crude material) as a black oil, which was used without further purification; ^1H NMR δ 1.79 (s, 9H), 1.89-1.91 (m, 2H), 1.98 (s, 1H), 2.65 (t, 6.8 Hz, 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, 7.2 Hz, 1H), 6.39-6.54 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.77-6.89 (m, 1H), (s, 1H), 11.89 (s, 1H).

Intermediate 145e: tert -Butyl 4-{4-[carbamoyl(3-methoxy-3-oxopropyl)amino]-1 H -Indol-1-yl}piperidine-1-carboxylate

tert -Butyl 4-{4-[(3-methoxy-3-oxopropyl)amino]-1 H -indol-1-yl}piperidine-1-carboxylate (6x 200 g, 498 mmol) was added to DCM (6x 1.0 L). AcOH (6x 2.1 kg, 34.97 mol, 2.0 L) in DCM (6x 1.0 L) was added to the mixture, followed by potassium cyanate (6x 40.4 g, 498 mmol) and stirred at room temperature for 2 h. The six batches were combined and water (5.0 L) was added to the mixture. DCM (8 L x2) was added to the extracts, which were washed with NaCl solution. The organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography (elution gradient: 30:1 to 1:1 Et ₂ O:EtOAc) to give 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 = 8.4 Hz, 2H), .78 (m, 1H), 5.36 (s, 2H), 6.34 (d, J = 3.2 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 8.4 Hz, 1 H), 7.56 (t, J = 4 Hz, 2H).

Intermediate 145f: tert -Butyl 4-[4-(2,4-dioxo-1,3-diazin-1-yl)-1 H -Indol-1-yl]piperidine-1-carboxylate

tert -Butyl 4-{4-[carbamoyl(3-methoxy-3-oxopropyl)amino]-1 H -indol-1-yl}piperidine-1-carboxylate (3x 105.0 g, 236 mmol) in MeOH (3x 779.0 g, 24.3 mol, 3x 984 mL) was added to three separate containers of MeOH (1.0 L), followed by addition of MeONa/MeOH (42.5 g, 236 mmol, 30% purity). The reaction was stirred at room temperature for 2 h and the combined solids were collected by filtration. The filtrate was evaporated and purified by column chromatography (elution gradient: 10:1 DCM:MeOH) to afford 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 = 6.8 Hz, 2H), 2.7 5 (s, 2H), 3.37-3.77 (m, 2H), 4.12 (d, J = 5.6 Hz, 2H), 0 (m, 1H), 6.41 (d, J = 3.2 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.52-7.54 (m, 2 H), 10.3 (s, 1H).

Intermediate 145g: 1-[1-(piperidin-4-yl)-1 H -Indole-4-yl]-1,3-diazinane-2,4-dione TsOH

tert -Butyl 4-[4-(2,4-dioxo-1,3-diazinan-1-yl)-1 H -indol-1-yl]piperidine-1-carboxylate (140.0 g, 339.41 mmol) in MeCN solution (300 mL) was added dropwise to p -toluenesulfonic acid hydrate (82.6 g, 434 mmol) in MeCN (560 mL) at room temperature. The reaction was stirred at 60 °C for 1 h. Additional p -toluenesulfonic acid hydrate (6.46 g, 33.9 mmol) was added to the mixture and stirring was continued at 60 °C for an additional 1 h. The reaction was then filtered and dried in vacuo to afford 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 = 6.8 Hz, 2H), 3.19-3.45 (m, 2H), 3.45-3.48 (m, 3H), 3.77 (t, J = 6.4 Hz, 2H), -4.79 (m, 1H), 6.46 (d, J = 3.2 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 44.0 Hz, 2H), 7.14 (t, J = 14.0 Hz, 1H), 7.40 (d, J = 3.6 Hz, 1H) , 7.52 (d, J = 8.0 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2H), 8.41 (d, J = 10.0 Hz, 1H), 8.68 (d, J =10.0 Hz, 1 H), 10.3 (s, 1H); m/z : ES ⁺ [M+H] ⁺ = 313.1.

Example 145: 4-{4-[4-(4-{4-[4-(2,4-dioxo-1,3-diazin-1-yl)-1 H -Indol-1-yl]piperidin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

1-[1-(Piperidin-4-yl)-1 H -indol-4-yl]-1,3-diazinane-2,4-dione TsOH (0.040 g, 0.13 mmol), 4-{4-[4-(4-bromobutoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile (0.067 g, 0.13 mmol), potassium iodide (0.043 g, 0.26 mmol) and DIPEA (0.089 mL, 0.51 mmol) were dissolved in MeCN (2 mL) and stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, filtered under vacuum and the filtrate was evaporated to dryness to give the crude product. The crude product was purified by preparative HPLC (column A, eluent A) to give the title compound (0.03 g, 32.1%) as a yellow solid; ¹ H NMR: δ 1.62 - 1.87 (8H, m), 2.04 - 2.21 (4H, m), 2.61 (1H, s), 2.77 (2H, t), 3.01 - 3.15 (4H, m), 3.33 - 3.47 (4H, m), 3.78 (2H, t), 4.03 ( 2H, s), 4.19 (2H, d), 4.59 (1H, s), 6.45 (1H, d), 6.7 - 6.89 (2H, m), 6.99 (1H, d), 7.20 (2H, dt), 7.27 (1H, dd), 7.33 (1H, d), 7.43 - 2 H, m), 7.83 (1H, d), 10.33 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 731.4.

Intermediate 146a: tert -Butyl 4-[(3-amino-5-bromopyridin-2-yl)ethynyl]piperidine-1-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (1.39 g, 1.20 mmol) was added to 5-bromo-2-iodopyridin-3-amine (3.0 g, 10.04 mmol), tert -butyl 4-ethynylpiperidine-1-carboxylate (2.1 g, 10.04 mmol) and copper(I) iodide (0.229 g, 1.20 mmol) in triethylamine (17 mL) under nitrogen at room temperature. The mixture was stirred at 80 °C for 16 h, cooled to room temperature, and the solvent was evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-20% EtOAc in DCM) to give the title compound (3.0 g, 79%) as a yellow solid; ^1H NMR (CDCl ₃ ) δ 1.46 (9H, s), 1.70 (2H, m), 1.90 (2H, m), 2.86 (1H, tt), 3.19 (2H, m), 3.72-3.85 (2H, m), 4.33 (2H, s), 7.17 (1H, d), 7.98 ( 1H, d); m/z : ES ⁺ [M+H] ⁺ = 380.0.

Intermediate 146b: tert -Butyl 4-(6-bromo-1 H -Pyrrolo[3,2-b]pyridin-2-yl)piperidine-1-carboxylate

Dichlorobis(MeCN)palladium(II) (0.409 g, 1.58 mmol) was added to tert -butyl 4-[(3-amino-5-bromopyridin-2-yl)ethynyl]piperidine-1-carboxylate (3.0 g, 7.89 mmol) in DMF (30 mL) at room temperature under nitrogen. The resulting mixture was stirred at 120 °C for 16 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (75 mL), washed with NaHCO ₃ solution (100 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash alumina chromatography (elution gradient: 0-50% EtOAc in Et ₂ O) to give the title compound (1.5 g, 50.0%) as a yellow oil; ^1H NMR δ 1.42 (9H, s), 1.96 (2H, d), 2.73 (2H, s), 2.89 (2H, s), 4.02-4.1 (3H, m), 6.35 (1H, s), 7.85 (1H, s), 8.30 (1H, s), 11.41 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 380.0.

Intermediate 146c: tert -Butyl 4-(6-bromo-1-methyl-1 H -Pyrrolo[3,2-b]pyridin-2-yl)piperidine-1-carboxylate

Under nitrogen at 0 °C, sodium hydride (60% in mineral oil, 0.22 g, 5.52 mmol) was added to tert -butyl 4-(6-bromo-1 H -pyrrolo[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (1.4 g, 3.68 mmol) in DMF (15 mL). After 15 min, iodomethane (0.229 mL, 3.68 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (1 mL) and diluted with EtOAc (50 mL). The organic layer was washed with water (150 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-20% EtOAc in DCM) to give the title compound (0.62 g, 42.7%) as a yellow solid; ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, d), 1.64-1.78 (2H, m), 1.99 (2H, d), 2.84-2.94 (3H, m), 3.72 (3H, d), 4.30 (2H, s), 6.46 (1H, s), 7.74 (1H, s), 8.45 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 394.0.

Intermediate 146d: tert -Butyl 4-[6-(2,4-dioxo-1,3-diazin-1-yl)-1-methyl-1 H -Pyrrolo[3,2-b]pyridin-2-yl]piperidine-1-carboxylate

Under nitrogen, Ephos Pd G4 (280 mg, 0.30 mmol) was added to tert -butyl 4-(6-bromo-1-methyl-1 H -pyrrolo[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (600 mg, 1.52 mmol), Cs ₂ CO ₃ (992 mg, 3.04 mmol), EPhos (163 mg, 0.30 mmol) and 1,3-diazinane-2,4-dione (521 mg, 4.56 mmol) in 1,4-dioxane (8 mL). The mixture was stirred at 100 °C for 2 h, cooled to room temperature and evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-4% MeOH in DCM) to give the title compound (400 mg, 61.5%) as a red solid; ¹ H NMR δ 1.43 (9H, s), 1.96 (2H, d), 2.77 (2H, t), 3.33 (5H, s), 3.83 (2H, t), 5.76 (1H, s), 6.40 (1H, s), 8.25 (1H, d), 10.42 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 428.3.

Intermediate 146e: 4-[4-(4-bromophenyl)piperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reaction of 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene with 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene and copper cyanide using a general synthetic method exemplified by intermediate 137f; ¹ H NMR: δ 1.76 (2H, qd), 1.84 - 1.92 (2H, m), 2.78 (1H, tt), 2.98 - 3.10 (2H, m), 3.68 - 3.77 (2H, m), 7.22 - 7.30 (2H, m), 7.42 - 7.54 (3H, m), 7.81 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 427.1.

Intermediate 146f: 4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 4-[4-(4-bromophenyl)piperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile with 4-(1,3-dioxolan-2-yl)piperidine using a general synthetic method exemplified by intermediate 139f; ¹ H NMR: δ 1.27 - 1.47 (2H, m), 1.52 - 1.68 (1H, m), 1.65 - 1.78 (4H, m), 1.78 - 1.88 (2H, m), 2.49 - 2.71 (3H, m), 2.94 - 3.08 (2H, m), 3.60 - 3.73 (4H, m), 3.74 - 3.89 (4H, m), 4.59 (1H, d), 6.80 - 6.89 (2H, m), 7.04 - 7.13 (2H, m), 7.44 (1H, t), 7.78 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 504.3.

Example 146: 4-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinane-1-yl)-1-methyl-1 H -pyrrolo[3,2-b]pyridin-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (100 mg, 0.20 mmol) was added tert -butyl 4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1 H -pyrrolo[3,2-b]pyridin-2-yl]piperidine-1-carboxylate (85 mg, 0.20 mmol) in formic acid (2 mL) at 60 °C over a period of 1 h. The solvent was evaporated to obtain a residue. The residue was diluted with NMP (2 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (10 mL), washed with saturated NaHCO ₃ solution (20 mL), saturated brine (10 mL), dried over MgSO ₄ , filtered and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-11% MeOH in DCM) and then preparative TLC (DCM:MeOH, 10:1) to give the title compound (0.065 g, 42%) as a white solid; ¹ H NMR (100 °C): δ 1.17 - 1.32 (2H, m), 1.61 - 1.76 (5H, m), 1.76 - 1.96 (6H, m), 2.08 - 2.26 (4H, m), 2.60 - 2.86 (6H, m), 2.90 - 2.99 (4H, m), 3.05 (2H, td), 3.58 (2H, dt), 3.69 (2H, s), 3.73 (1H, t), 3.80 (2H, t), 6.34 (1H, s), 6.80 - 6.88 (2H, m), 7.04 - 7.11 (2H, m), 7.39 (1H, t), 7.65 - 7.74 (2H, m), 8.22 (1H, d), 9.96 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 771.3.

Intermediate 147a: tert -Butyl 4-(4-bromo-2,6-difluorophenyl)piperidine-1-carboxylate

Intermediate 138a was reacted with hydrogen gas using the general synthetic method exemplified by intermediate 137c to give the title compound; ¹ H NMR (CDCl ₃ ): δ 1.48 (9H, s), 1.65 (2H, d), 1.98 (2H, qd), 2.76 (2H, s), 3.08 (1H, qt), 4.23 (2H, s), 7 - 7.09 (2H, m).

Intermediate 147b: 4-(4-bromo-2,6-difluorophenyl)piperidine

The title compound was obtained by reaction of tert -butyl 4-(4-bromo-2,6-difluorophenyl)piperidine-1-carboxylate with HCl using a general synthetic method exemplified by intermediate 24d; ¹ H NMR: δ 1.83 (2H, d), 2.16 (2H, q), 3.01 (2H, q), 3.25 (1H, td), 3.31 (2H, s), 7.41 - 7.52 (2H, m), 8.86 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 276.0.

Intermediate 147c: 4-[4-(4-bromo-2,6-difluorophenyl)piperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was obtained by reaction of 4-(4-bromo-2,6-difluorophenyl)piperidine with 4-(4-bromophenyl)piperidine and copper cyanide using the general synthetic method exemplified by Example 137d; ¹ H NMR (CDCl ₃ ): δ 1.78 - 1.91 (2H, m), 2.30 (2H, td), 2.98 (2H, t), 3.19 (1H, dtt), 3.69 - 3.83 (2H, m), 7.02 - 7.17 (3H, m), 7.49 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 463.0.

Intermediate 147d: 4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 4-[4-(4-bromo-2,6-difluorophenyl)piperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile with 4-(1,3-dioxolan-2-yl)piperidine using a general synthetic method exemplified by intermediate 139f; ¹ H NMR (CDCl ₃ ): δ 1.50 (2H, qd), 1.67 - 1.88 (5H, m), 2.25 (2H, qd), 2.72 (2H, td), 2.97 (2H, t), 3.07 (1H, tt), 3.6 - 3.79 (4H, m), 3.79 - 2 (4H, m), 4.67 (1H, d), 6.26 - 6.5 (2H, m), 7.11 (1H, t), 7.48 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 540.2.

Example 147: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

Using the general synthetic method exemplified by Example 138, 4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile was reacted with intermediate 1e and purified by preparative HPLC (column A, eluent D) to give the title compound; ¹ H NMR: δ 1.16 (2H, d), 1.71 - 1.82 (5H, m), 1.88 - 1.97 (1H, m), 2.06 (2H, d), 2.21 (2H, d), 2.26 - 2.33 (1H, m), 2.52 - 2.53 (4H, m), 2.57 (1 H, d), 2.73 (2H, d), 2.82 - 2.96 (1H, m), 3.04 (3H, t), 3.37 (4H, s), 3.64 - 3.77 (4H, m), 3.84 (3H, s), 4.11 (1H, d), 4.24 (1H, d), 4.97 (1H, dd), 6.49 (1H, s), 6.54 - 6.64 (3H, m), 7.46 (1H, t), 7.81 (1H, d), 10.90 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 838.4.

Intermediate 148a: Benzyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

The title compound was obtained by reaction of 4-bromo-2-fluoro-1-iodobenzene with benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate using a general synthetic method exemplified by intermediate 35a; ¹ H NMR: δ 2.11 (2H, dt), 3.42 (2H, s), 3.96 (2H, s), 4.08 (2H, s), 5.10 (4H, d), 5.76 (1H, s), 6.03 (2H, s), 6.40 (1H, s), 7.54 (1H, dd); m/z: ES ⁺ [M+H] ⁺ = 390.1.

Intermediate 148b: Benzyl 4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]-2-fluorophenyl}-3,6-dihydropyridine-1(2 H )-carboxylate

Pd-PEPPSI-IHept ^Cl (0.312 g, 0.32 mmol) was added to benzyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.5 g, 6.41 mmol), 4-(1,3-dioxolan-2-yl)piperidine (1.1 g, 7.05 mmol) and Cs ₂ CO ₃ (5.2 g, 16.02 mmol) in dioxane (50 mL) under nitrogen and stirred at 80 °C for 24 h. The reaction was cooled to room temperature, and the solvent was evaporated to dryness to obtain the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-35% EtOAc in _Et2O , then 0-10% EtOAc in DCM) to give the title compound (0.950 g, 31.8%) as a yellow solid; ¹ H NMR: δ 1.28 - 1.42 (2H, m), 1.61 - 1.75 (3H, m), 2.22 - 2.26 (1H, m), 2.35 - 2.43 (1H, m), 2.67 (2H, td), 3.58 (2H, s), 3.70 (1H, t), - 3.83 (4H, m), 3.80 - 3.92 (2H, m), 4.59 (1H, d), 5.04 - 5.15 (3H, m), 5.88 (1H, s), 6.64 - 6.75 (2H, m), 7.14 (1H, t), 7.37 - 7.40 (5H, m); m/z: ES ⁺ [M+H] ⁺ = 467.3.

Intermediate 148c: 4-(1,3-dioxolan-2-yl)-1-[3-fluoro-4-(piperidin-4-yl)phenyl]piperidine

Benzyl 4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]-2-fluorophenyl}-3,6-dihydropyridine-1(2H)-carboxylate was reacted with hydrogen gas to give the title compound using a general synthetic method exemplified by intermediate 9b; ¹ H NMR: δ 1.08 - 1.27 (1H, m), 1.28 - 1.42 (2H, m), 1.42 - 1.67 (4H, m), 1.70 (2H, d), 2.24 (1H, t), 2.52 - 2.66 (3H, m), 2.62 - 2.76 (1H, m), 2.87 - 3.02 (2H, m), 3.20 - 3.56 (2H, m), 3.69 (2H, d), 3.73 - 3.92 (4H, m), 4.60 (1H, d), 6.60 - 6.72 (2H, m), 7.06 (1H, t); m/z: ES ⁺ [M+H] ⁺ = 335.3.

Intermediate 148d: 4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]-2-fluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 4-(1,3-dioxolan-2-yl)-1-[3-fluoro-4-(piperidin-4-yl)phenyl]piperidine with 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene and copper cyanide using a general synthetic method exemplified by Example 137f; ¹ H NMR: δ 1.27 - 1.43 (2H, m), 1.61 - 1.75 (3H, m), 1.77 - 1.84 (4H, m), 2.58 - 2.68 (2H, m), 2.88 - 2.96 (1H, m), 3.03 - 3.07 (2H, m), 3.74 (4 H, dd), 3.75 - 3.84 (2H, m), 3.84 - 3.91 (2H, m), 4.60 (1H, d), 6.62 - 6.74 (2H, m), 7.13 (1H, t), 7.45 (1H, t), 7.81 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 522.2.

Example 148: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 4-(4-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]-2-fluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile with intermediate 1e using the general synthetic method exemplified by Example 146; ¹ H NMR: δ 1.18 - 1.27 (2H, m), 1.72 - 1.82 (8H, m), 1.91 (1H, s), 2.20 (2H, d), 2.25 - 2.36 (1H, m), 2.56 - 2.64 (2H, m), 2.70 (1H, dd), - 2.96 (2H, m), 3.00 - 3.06 (2H, m), 3.30 (8H, s), 3.61 - 3.74 (4H, m), 3.82 (3H, s), 4.15 (2H, q), 4.94 (1H, dd), 6.47 (1H, s), 6.59 (1H, s) ), 6.62 - 6.73 (2H, m), 7.12 (1H, t), 7.44 (1H, t), 7.79 (1H, d), 10.88 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 820.4.

Intermediate 149a: 7-Ethenyl-1-methyl-1,3-dihydro-2 H -Benzimidazole-2-one

Under nitrogen, Pd(dppf) ₂ Cl ₂ -DCM (0.575 g, 0.70 mmol) was added to 7-bromo-1-methyl-1,3-dihydro-2 H -benzimidazol-2-one (2.0 g, 8.81 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.03 g, 13.21 mmol) and K ₂ CO ₃ (3.04 g, 22.02 mmol) in 1,4-dioxane:water (4:1, 48 mL). The resulting mixture was stirred at 80 °C for 18 h. The reaction was cooled to room temperature and evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-50% EtOAc in _Et2O ) to afford the title compound (1.1 g, 71.7%) as a white solid; ¹ H NMR δ 3.36 (3H, s), 5.24 (1H, dd), 5.57 (1H, dd), 6.74 - 6.94 (2H, m), 7.00 (1H, m), 7.26 (1H, dd), 10.80 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 175.2.

Intermediate 149b: 3-Methyl-2-oxo-2,3-dihydro-1 H -Benzimidazole-4-carbaldehyde

Potassium osmate dihydrate (0.212 g, 0.57 mmol) was added to 7-ethenyl-1-methyl-1,3-dihydro-2 H -benzimidazol-2-one (1.0 g, 5.74 mmol), sodium meta periodate (3.68 g, 17.22 mmol), and 2,6-lutidine (1.33 mL, 11.48 mmol) in 1,4-dioxane:water (3:1, 40 mL) at room temperature and stirred for 2 h. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (3 x 100 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-4% MeOH in DCM) to give the title compound (0.95 g, 94%) as a gray solid; ¹ H NMR δ 3.58 (3H, s), 7.11 (1H, t), 7.19 - 7.28 (1H, m), 7.51 (1H, dd), 10.34 (1H, s), 11.30 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 177.2.

Intermediate 149c: 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -Benzimidazole-4-carbaldehyde

Under nitrogen at 0 °C, LHMDS (153 mL, 153.26 mmol) was added 3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazole-4-carbaldehyde (9.0 g, 51.09 mmol) in THF (80 mL). The resulting mixture was stirred at room temperature for 1 h. This mixture was added dropwise to a solution of 3-bromopiperidine-2,6-dione (19.62 g, 102.17 mmol) in THF (80 mL) at room temperature. The mixture was stirred at 60 °C for 3 h, then cooled to 10 °C, quenched with saturated NH ₄ Cl solution (20 mL), water (200 mL), and the resulting solid was collected by filtration. The solid was washed with water (50 mL) and EtOAc (50 mL). The aqueous one was extracted with EtOAc (300 mL) and the solvent was evaporated to give a brown solid. The brown solid was eluted with water to give a solid which was collected by filtration and dried in vacuo to give the crude product. The two solid batches were combined, eluted with Et ₂ O, collected by filtration and dried in vacuo to give the title compound (10.0 g, 68.1%) as a gray solid; ¹ H NMR δ 2.64 (2H, d), 2.89 (2H, d), 3.54 (3H, s), 5.39 - 5.48 (1H, m), 7.07 (1H, d), 7.13 (1H, t), 7.27 (1H, d), 9.27 (1H, s), 10.41 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 288.2.

Intermediate 149d: tert -Butyl 4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -Benzimidazol-4-yl]methyl}piperazine-1-carboxylate

Sodium triacetoxyborohydride (3.69 g, 17.40 mmol) was added to 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazole-4-carbaldehyde (2.0 g, 3.48 mmol) and tert -butyl piperazine-1-carboxylate (1.94 g, 10.44 mmol) in DCM:MeOH (1:2, 24 mL) and stirred at room temperature for 16 h. The solvent was reduced in volume, poured into NaCl solution (25 mL), extracted with EtOAc (300 mL), and the layers were separated. The organic layer was dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 50-100% EtOAc in _Et2O ) to give the title compound (0.800 g, 50.2%) as a yellow solid; ¹ H NMR δ 1.40 (9H, s), 1.95 - 2.08 (1H, m), 2.29 - 2.41 (4H, m), 2.56 - 2.95 (3H, m), 3.24 - 3.32 (4H, m), 3.59 - 3.65 (2H, m), 3.68 (3H, s), 5.30 - 5.44 (1H, m), 6.86 - 6.93 (1H, m), 6.94 - 7.01 (1H, m), 7.06 - 7.12 (1H, m), 11.11 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 458.3.

Intermediate 149e: 3-{3-Methyl-2-oxo-4-[(piperazin-1-yl)methyl]-2,3-dihydro-1 H -Benzimidazol-1-yl}piperidine-2,6-dione

TFA (2.5 mL) was added to tert -butyl 4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-4-yl]methyl}piperazine-1-carboxylate (750 mg, 1.64 mmol) in DCM (10 mL) and stirred at room temperature for 1 h. Evaporation of the solvent gave the title compound (1.1 g, 96%) as a yellow oil which was used without further purification; ¹ H NMR δ 1.92 - 2.06 (2H, m), 2.62 - 2.94 (9H, m), 3.65 (3H, s), 3.83 - 4.13 (3H, m), 5.36 - 5.45 (1H, m), 6.96 - 7.02 (2H, m), 7.15 (1H, d), 11.11 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 358.2.

Example 149: 4-[4-(4-{4-[(4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-4-yl]methyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of 3-{3-methyl-2-oxo-4-[(piperazin-1-yl)methyl]-2,3-dihydro-1 H -benzimidazol-1-yl}piperidine-2,6-dione with intermediate 146f using the general synthetic method exemplified by Example 138; ¹ H NMR (CDCl ₃ ): δ 1.44 (2H, qd), 1.75 - 2.04 (8H, m), 2.13 - 2.28 (1H, m), 2.58 - 3.12 (17H, m), 3.55 - 3.84 (9H, m), 5.22 (1H, dd), 6.79 (1H, d ), 6.86 - 6.93 (3H, m), 6.94 - 7 (1H, m), 7.07 - 7.16 (3H, m), 7.48 (1H, d), 8.38 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 801.5.

Intermediate 150a: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1 H -Benzimidazol-1-yl)piperidine-2,6-dione

Lithium bis(trimethylsilyl)amide (1 M in THF, 11.01 mL, 11.01 mmol) was added dropwise over 5 min to a suspension of 7-bromo-1-methyl-1,3-dihydro-2 H -benzimidazol-2-one (1.0 g, 4.40 mmol) in THF (5.00 mL) at room temperature under nitrogen for 20 min. This solution was then added portionwise over 5 min to a separate flask containing a solution of 3-bromopiperidine-2,6-dione (1.78 g, 8.81 mmol) in THF (10 mL) and stirred at 60 °C for 4 h. The reaction was cooled to room temperature and diluted with saturated NH ₄ Cl solution (10 mL), water (10 mL), saturated brine solution (5 mL), dried over MgSO ₄ and evaporated to dryness to give the crude product. The crude product was diluted with IPA:heptane (1:1 20 mL) and heated to 50 °C for 30 min. The mixture was cooled to room temperature and filtered in vacuo to give the title compound (743 mg, 50%) as a gray solid; ¹ H NMR (CDCl ₃ ): δ 2.23 (1H, m), 2.67 - 3 (3H, m), 3.79 (3H, s), 5.19 (1H, dd), 6.73 (1H, dd), 6.92 (1H, t), 7.24 (1H, dd), 8.08 (1H, s); m/z : ES ⁺ [M+H] ⁺ = 338.0.

Intermediate 150b: tert -Butyl 4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -Benzimidazol-4-yl]piperazine-1-carboxylate

3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl)piperidine-2,6-dione (2.21 g, 6.55 mmol), Pd-PEPPSI-IPent (0.550 g, 0.65 mmol), tert -butyl piperazine-1-carboxylate (3.05 g, 16.37 mmol) and sodium tert -butoxide (1.88 g, 19.64 mmol) were suspended in 1,4-dioxane (60 mL) under nitrogen. The reaction was stirred at 50 °C for 1 h. The reaction was cooled to room temperature, diluted with DCM (100 mL) and washed with NH ₄ Cl solution (50 mL), water (50 mL), NaHCO ₃ solution (50 mL) and NaCl solution (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The crude product was diluted with hexane:EtOAc (1:1, 100 mL) and filtered under vacuum. The solid was then slurried in EtOH (50 mL) for 20 min, filtered under vacuum and then slurried in MeCN (50 mL). The solid was filtered under vacuum to give the title compound (1.48 g, 51.2%) as a beige solid; ¹ H NMR: δ 1.42 (9H, s), 1.98 (1H, br t), 2.56 - 2.76 (4H, m), 2.79 - 2.96 (2H, m), 2.96 - 3.20 (4H, m), 3.62 (3H, s), 3.94 (1H, br s), 5.30 - 5.40 (1H, m), 6.88 - 6.94 (2H, m), 6.94 - 7.00 (1H, m), 11.09 (1H, br s); m/z : ES ⁺ [M+Na] = 466.1.

Intermediate 150c: 3-[3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1 H -Benzimidazol-1-yl]piperidine-2,6-dione

Using the general synthetic method exemplified by intermediate 34d, tert -butyl 4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-4-yl]piperazine-1-carboxylate was reacted with HCl to give the title compound which was isolated as the HCl salt; ¹ H NMR: δ 1.95 - 2.04 (1H, m), 2.59 - 2.77 (2H, m), 2.84 - 2.96 (1H, m), 2.99 - 3.30 (7H, m), 3.33 - 3.41 (2H, m), 3.63 (3H, s), 5.33 - 5.43 ( 1H, m), 6.89 - 7.09 (3H, m), 11.11 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 344.3.

Example 150: 4-(4-{4-[4-({4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-4-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

Using the general synthetic method exemplified by Example 138, 3-[3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzimidazol-1-yl]piperidine-2,6-dione was reacted with intermediate 146f and purified by preparative HPLC (column A, eluent D) to give the title compound; ¹ H NMR (CDCl ₃ ): δ 1.44 (2H, qd), 1.74 - 2.05 (7H, m), 2.12 - 2.3 (1H, m), 2.47 - 3.3 (18H, m), 3.67 (2H, d), 3.71 - 3.8 (5H, m), 5.21 (1H, dd), 6.61 (1H, dd), 6.88 - 7.04 (4H, m), 7.08 - 7.19 (3H, m), 7.48 (1H, d), 8.32 (1H, s), 8.57 - 8.77 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 787.5.

Intermediate 151a: tert -Butyl 3-{[(methanesulfonyl)oxy]methyl}azetidine-1-carboxylate

Methanesulfonyl chloride (9.1 mL, 117.50 mmol) was dissolved in DCM (40 mL) and added to a solution of tert -butyl 3-(hydroxymethyl)azetidine-1-carboxylate (20.0 g, 106.82 mmol), triethylamine (22.33 mL, 160.22 mmol), and DMAP (0.652 g, 5.34 mmol) in DCM (236 mL) at 0 °C and stirred at room temperature for 2 h. The reaction was then washed with citric acid (1 M, 2x 100 mL), saturated NaHCO ₃ solution (100 mL), saturated brine (100 mL), dried over MgSO ₄ and evaporated to dryness to give the title compound (28.0 g, 99%) as a pale brown oil which was used without further purification; ¹ H NMR (CDCl ₃ ): δ 1.44 (9H, s), 2.93 (1H, dddd), 3.05 (3H, s), 3.72 (2H, dd), 3.98 - 4.11 (2H, m), 4.35 (2H, d).

Intermediate 151b: tert -Butyl 3-[(4-{1-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-yl}phenoxy)methyl]azetidine-1-carboxylate

Intermediate 1 g (1.9 g, 4.50 mmol) was stirred with K ₂ CO ₃ (1.865 g, 13.49 mmol) and tert -butyl 3-{[(methanesulfonyl)oxy]methyl}azetidine-1-carboxylate (1.45 g, 5.5 mmol) in MeCN (45.0 mL) at room temperature for 48 h. The reaction was then cooled to room temperature and evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-40% EtOAc in heptane) to give the title compound (2.2 g, 95%) as a colorless gum; ¹ H NMR (CDCl ₃ ): δ 1.45 (9H, s), 1.76 (2H, qd), 1.98 (2H, d), 2.75 (1H, tt), 2.95 (1H, dddd), 3.06 (2H, td), 3.78 (2H, dd), 3.95 - 4.11 (6H, m), 6.84 - 6.89 (2H, m), 6.99 (1H, dd), 7.11 - 7.18 (3H, m), 7.61 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 516.3.

Intermediate 151c: 4-(4-{4-[(azetidin-3-yl)methoxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

TFA (0.6 mL, 7.79 mmol) was added to tert -butyl 3-[(4-{1-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-yl}phenoxy)methyl]azetidine-1-carboxylate (230 mg, 0.45 mmol) in DCM (6 mL) and stirred at room temperature for 2 h. The solvent was evaporated to dryness to give the title compound (0.23 g, 97%) as a yellow oil, which was used without further purification; ¹ H NMR (CDCl ₃ ): δ 1.80 (2H, qd), 1.95 - 2.07 (2H, m), 2.71 - 2.87 (1H, m), 3.09 (2H, td), 3.31 - 3.46 (1H, m), 4.02 - 4.10 (2H, m), 4.13 (2H, d) , 4.20 - 4.32 (2H, m), 4.34 - 4.52 (2H, m), 6.96 (2H, d), 7.04 (1H, dd), 7.15 - 7.24 (3H, m), 7.66 (1H, d), 8.21 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 416.0.

Intermediate 151d: 4-[4-(4-{[1-(2,2-dimethoxyethyl)azetidin-3-yl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

2-Bromo-1,1-dimethoxyethane (0.206 mL, 1.74 mmol), 4-(4-{4-[(azetidin-3-yl)methoxy]phenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.602 g, 1.45 mmol) and DIPEA (0.631 mL, 3.63 mmol) were stirred in NMP (10 mL) at room temperature under nitrogen for 8 h. The reaction mixture was purified by preparative HPLC (column A, eluent D). The product was extracted with DCM (300 mL), dried on a phase separation cartridge and evaporated to give the title compound (0.055 g, 6.37%) as a dry film; ¹ H NMR (CDCl ₃ ): δ 1.76 (2H, qd), 1.98 (2H, d), 2.75 (1H, tt), 3.01 - 3.12 (3H, m), 3.16 - 3.28 (1H, m), 3.43 (6H, s), 3.76 (2H, dd), 3.97 - 4. 13 (6H, m), 4.61 (1H, t), 6.84 - 6.9 (2H, m), 6.99 (1H, dd), 7.14 (3H, dd), 7.61 (1H, d), 8.48 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 504.4.

Example 151: 4-[4-(4-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}ethyl)azetidin-3-yl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

4-[4-(4-{[1-(2,2-Dimethoxyethyl)azetidin-3-yl]methoxy}phenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile (55 mg, 0.11 mmol) was stirred in 2-MeTHF (1 mL) and HCl (1 M, 1 mL) at 60 °C for 1 h, cooled to room temperature and evaporated to dryness. The residue was redissolved in NMP (1 mL) and intermediate 2c (47.8 mg, 0.13 mmol) was added, followed by sodium triacetoxyborohydride (57.9 mg, 0.27 mmol) and stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC (column A, eluent A) to give the title compound (0.013 g, 14.59%) in the form of a formate salt as a colorless film; ¹ H NMR (CDCl ₃ ): δ 1.76 (2H, qd), 1.98 (2H, d), 2.19 (1H, ddq), 2.32 (1H, qd), 2.63 - 2.7 (4H, m), 2.72 (2H, t), 2.75 - 2.86 (2H, m), 2.90 (1H, d) dd), 3.06 (2H, td), 3.24 (2H, t), 3.28 - 3.41 (5H, m), 3.88 - 3.99 (2H, m), 3.99 - 4.07 (4H, m), 4.25 (1H, d), 4.32 (2H, t), 4.40 (1H, d), (1H, dd), 6.82 - 6.93 (3H, m), 6.98 (2H, ddd), 7.14 - 7.2 (3H, m), 7.62 (1H, d), 7.72 (1H, d), 8.39 (2H, s); m/z: ES ⁺ [M+H] ⁺ = 770.4.

Intermediate 152a: 6-chloro-2-methoxy-4-methylpyridine-3-carboxylic acid

To a stirred solution of sodium methoxide (20.67 mL, 112 mmol) in THF (50.0 mL) was added 2,6-dichloro-4-methylpyridine-3-carboxylic acid (10.0 g, 48.5 mmol) in THF (50.0 mL) at 0 °C, and then stirred at 70 °C for 16 h. The reaction was then cooled to room temperature, acidified with HCl (2 M, aq.) to pH 3–4, and then extracted with EtOAc (160 mL). The organic layer was washed with water (100 mL), NaCl solution (100 mL), dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the title compound (8.0 g, 78% yield), which was used without further purification; ^1H NMR δ 2.27 (3H, s), 3.87 (3H, s), 7.10 (1H, s), 13.42 (1H, s).

Intermediate 152b: Methyl 6-chloro-2-methoxy-4-methylpyridine-3-carboxylate

To a stirred solution of 6-chloro-2-methoxy-4-methylpyridine-3-carboxylic acid (8.0 g, 39.7 mmol) in DMF (80 mL) were added K ₂ CO ₃ (6.58 g, 47.6 mmol) and methyl iodide (8.45 g, 59.5 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with MTBE (240 mL). The organic layer was washed with NaCl solution (160 mL), dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the title compound (8.5 g, 37.1 mmol, 93% yield) as a pale yellow solid; ^1H NMR δ 2.26 (3H, s), 3.84 (3H, s), 3.87 (3H, s), 7.13 (1H, s).

Intermediate 152c: Methyl 4-(bromomethyl)-6-chloro-2-methoxypyridine-3-carboxylate

Methyl 6-chloro-2-methoxy-4-methylpyridine-3-carboxylate (8.0 g, 37.1 mmol) was added to tert -butyl acetate (150 mL) under nitrogen. NBS (9.24 g, 51.9 mmol) and benzoyl peroxide (1.79 g, 7.42 mmol) were added at room temperature and stirred at 110 °C for 14 h. Additional NBS (2.64 g, 14.84 mmol) was added and stirring was continued at 110 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with NaHCO ₃ solution (10%, 50 mL) and extracted with EtOAc (120 mL). The organic layer was washed with NaCl solution (80 mL), dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the title compound (11.0 g, 10.01 mmol, 27.0% yield) as a brown liquid which was used without further purification; m / z : ES ⁺ [M + H] ⁺ = 294.0.

Intermediate 152d: 3-(6-chloro-4-methoxy-3-oxo-1,3-dihydro-2 H -Pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione

Methyl 4-(bromomethyl)-6-chloro-2-methoxypyridine-3-carboxylate (11.0 g, 10.01 mmol) was dissolved in MeCN (80 mL). 3-Aminopiperidine-2,6-dione hydrochloride (1.65 g, 10.01 mmol) and DIPEA (5.17 g, 40.0 mmol) were added, and the reaction was stirred at 85 °C for 16 h. The reaction mixture was then cooled to room temperature, diluted with DCM (200 mL), washed with AcOH (5%, aq. 200 mL), water (200 mL), NaHCO ₃ solution (200 mL), NaCl solution (200 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was diluted with EtOAc (10 mL) and washed with MTBE (30 mL) to give a solid which was collected by filtration and dried in vacuo to afford the title compound (1.6 g, 4.35 mmol, 43.5% yield) as a brown solid; ¹ H NMR δ 1.89 - 2.02 (1H, m), 2.30 - 2.35 (1H, m), 2.50 - 2.59 (1H, m), 2.84 - 2.98 (1H, m), 3.99 (3H, s), 4.26 - 4.39 (1H, m), 4.40 - 4.53 (1H, m), 5.05 (1H, dd), 7.40 (1H, s), 10.99 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 310.2.

Intermediate 152e: tert -Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1 H -Pyrrolo[3,4-c]pyridin-6-yl]piperazine-1-carboxylate

At room temperature under nitrogen, Pd-PEPPSI-IPent (47.1 mg, 0.048 mmol) was added to tert -butyl piperazine-1-carboxylate (541 mg, 2.91 mmol), Cs ₂ CO ₃ (947 mg, 2.91 mmol) and 3-(6-chloro-4-methoxy-3-oxo-1,3-dihydro-2 H -pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione (300 mg, 0.969 mmol) in 1,4-dioxane (10 mL). The resulting suspension was stirred at 120 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with DCM (20 mL), washed with AcOH (5%, aq. 20 mL), water (20 mL), NaHCO ₃ solution (20 mL), NaCl solution (20 mL), dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The crude product was diluted with EtOAc (4 mL) and washed with MTBE (16 mL) to give a solid which was collected by filtration and dried in vacuo to give the title compound (260 mg, 0.485 mmol, 50.1% yield) as a brown solid; ¹ H NMR: δ 1.43 (9H, s), 1.88 - 2.00 (1H, m), 2.29 - 2.39 (1H, m), 2.58 - 2.68 (1H, m), 2.86 - 2.96 (1H, m), 3.34 -3.44 (4H, m), 3.53 - 3.63 (4 H, m), 3.90 (3H, s), 4.09 - 4.18 (1H, m), 4.24 - 4.34 (1H, m), 4.97 (1H, br dd), 6.50 (1H, s), 10.92 (1H, br s); m/z : ES ⁺ [M+H] ⁺ = 460.2.

Example 152: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of tert -butyl 4-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihydro-1 H -pyrrolo[3,4-c]pyridin-6-yl]piperazine-1-carboxylate with intermediate 146f using the general synthetic method exemplified by Example 138; ¹ H NMR (CDCl ₃ ): δ 1.38 (2H, qd), 1.63 - 2 (7H, m), 2.12 - 2.34 (4H, m), 2.51 - 2.59 (4H, m), 2.6 - 2.75 (3H, m), 2.76 - 2.93 (2H, m), 2.98 (2H, t d), 3.61 - 3.81 (8H, m), 4.02 (3H, s), 4.17 (1H, d), 4.35 (1H, d), 5.14 (1H, dd), 6.15 (1H, s), 6.92 (2H, d), 7.07 - 7.16 (3H, m), 7.49 (1H, d) ), 7.86 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 803.4.

Intermediate 153a: tert -Butyl 4-[(2-amino-4-bromophenyl)ethynyl]piperidine-1-carboxylate

Under nitrogen, PdCl ₂ (PPh ₃ ) ₂ (3.36 g, 4.78 mmol) was added 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 dark brown solution was stirred at room temperature for 18 h. The reaction mixture was diluted with water (150 mL) and extracted with MTBE (150 mL). The organic layer was washed with water (150 mL), NaCl solution (50 mL), dried over MgSO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 5-20% EtOAc in heptane) to give the title compound (24.1 g, 70%) as an orange oil; ¹ H NMR (CDCl ₃ ): 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, d); m/z : ES ⁺ [M+H] ⁺ = 379.1.

Intermediate 153b: tert -Butyl 4-(6-bromo-1-methyl-1 H -Indol-2-yl)piperidine-1-carboxylate

Potassium tert -butoxide (13.3 g, 118.48 mmol) was added to tert -butyl 4-[(2-amino-4-bromophenyl)ethynyl]piperidine-1-carboxylate (21.4 g, 39.49 mmol) in NMP (200 mL) at room temperature and stirred for 3 h. Iodomethane (7.38 mL, 118.48 mmol) was then added to the reaction flask over 10 min while maintaining the internal temperature below 35 °C and then left to stir for 1 h. The reaction mixture was quenched with NH ₄ Cl solution (100 mL) and water (100 mL). The product was extracted with 2-MeTHF (400 mL), washed with water (2 x 100 mL), NaCl solution (100 mL), dried over MgSO ₄ , filtered and evaporated to give the crude material. The crude product was purified by flash silica chromatography (elution gradient: 0-50% EtOAc in heptane) to give the title compound (13.74 g, 88%) as a white solid; ¹ H NMR (CDCl ₃ ): 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, d), 6.24 (1H, s), 7.19 (1H, dd), 7 .39 - 7.44 (1H, m), 7.45 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 393.3.

Intermediate 153c: tert -Butyl 4-[6-(2,4-dioxo-1,3-diazin-1-yl)-1-methyl-1 H -Indol-2-yl]piperidine-1-carboxylate

tert -Butyl 4-(6-bromo-1-methyl-1 H -indol-2-yl)piperidine-1-carboxylate (10.82 g, 27.51 mmol) was dissolved in 1,4-dioxane (180 mL) and added to a flask containing 1,3-diazinane-2,4-dione (9.42 g, 82.53 mmol), K ₂ CO ₃ (11.41 g, 82.53 mmol) and tert -butylBrettPhos (1.33 g, 2.75 mmol). The mixture was degassed with nitrogen and tert -butylBrettPhos Pd G3 (2.35 g, 2.75 mmol) was then added. The mixture was stirred at 100 °C for 42 h and then cooled to room temperature. Water (180 mL) and 2-MeTHF (180 mL) were added and stirred for 5 min. The layers were separated and the organic layer was washed with water (180 mL), NaCl solution (50 mL), dried over MgSO ₄ , filtered and evaporated to give the crude product. The crude product was slurried in EtOAc (30 mL), the resulting brown suspension was filtered and the solid was washed with EtOAc (10 mL) to give the title compound (6.59 g, 56.2%) as a light brown solid; ^1H NMR: δ 1.43 (11H, s), 1.94 (2H, d), 2.73 (2H, t), 2.82 - 3.07 (3H, m), 3.70 (3H, s), 3.79 (2H, t), 4.06 (2H, dd), 6.24 (1H, s), 6.94 (1H , dd), 7.37 (1H, d), 7.43 (1H, d), 10.26 (1H, s).

Example 153: 4-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinane-1-yl)-1-methyl-1 H -Indol-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

The title compound was provided by reaction of tert -butyl 4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1 H -indol-2-yl]piperidine-1-carboxylate with intermediate 138e using the general synthetic method exemplified by Example 138; ¹ H NMR (CDCl ₃ ): δ 1.22 - 1.36 (2H, m), 1.62 - 1.98 (9H, m), 2.03 - 2.19 (4H, m), 2.25 (2H, d), 2.53 - 2.81 (3H, m), 2.86 (2H, t), 2.96 - 3.07 (4 H, m), 3.12 (1H, tt), 3.6 - 3.67 (2H, m), 3.69 (3H, s), 3.90 (2H, t), 4.00 (2H, d), 6.28 (1H, s), 6.31 - 6.44 (2H, m), 6.92 - 6.99 (2H, m), 7. 14 (1H, d), 7.23 (1H, d), 7.40 (1H, s), 7.55 (1H, d), 7.61 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 788.5.

Example 154: 4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2,6-difluorophenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

Intermediate 138e was reacted with intermediate 1e using the general synthetic method exemplified by Example 138 to provide the title compound; ¹ H NMR (CDCl ₃ ): δ 1.24 - 1.38 (2H, m), 1.68 - 1.79 (1H, m), 1.86 (3H, dd), 2.05 - 2.22 (3H, m), 2.23 - 2.38 (3H, m), 2.62 - 2.67 (4H, m), 2.7 - 2.94 (5H, m), 3.03 (2H, t), 3.13 (1H, tt), 3.3 - 3.43 (4H, m), 3.64 (2H, d), 3.94 (3H, s), 4.00 (2H, d), 4.20 (1H, d), 4.36 (1H, d), 5.14 (1H, dd), 6.32 - 6.41 (3H, m), 6.47 (1H, s), 6.97 (1H, dd), 7.14 (1H, d), 7.61 (1H, d), 7.99 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 820.5.

Example 155: 4-(4-{4-[4-({4-[6-(2,4-dioxo-1,3-diazinane-1-yl)-1-methyl-1 H -Indol-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

Intermediate 146f was reacted with intermediate 153c using the general synthetic method exemplified by Example 138 and purified by preparative HPLC (column A, eluent D) to provide the title compound; ¹ H NMR (CDCl ₃ ): δ 1.36 (2H, qd), 1.62 - 1.71 (1H, m), 1.74 - 2.02 (10H, m), 2.04 - 2.14 (2H, m), 2.27 (2H, d), 2.58 - 2.76 (4H, m), 2.86 (2H, t) , 2.94 - 3.07 (4H, m), 3.61 - 3.79 (7H, m), 3.90 (2H, t), 6.28 (1H, s), 6.89 - 6.97 (3H, m), 7.07 - 7.16 (3H, m), 7.23 (1H, d), 7.44 (1H, s), 7.48 (1H, d), 7.55 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 770.5.

Intermediate 156a: Methyl 2-(bromomethyl)-6-chloropyridine-3-carboxylate

AIBN (88 mg, 0.54 mmol) was added to methyl 6-chloro-2-methylpyridine-3-carboxylate (1.0 g, 5.39 mmol) and NBS (1.05 g, 5.93 mmol) in chloroform (12 mL) and stirred at 80 °C for 6 h. The reaction was cooled to room temperature, filtered through Celite®, and evaporated to give the crude product. The crude product was purified by silica gel chromatography (0-8% EtOAc/hexanes) to give the title compound (0.350 g, 24.5%); m/z: ES ⁺ [M+H] ⁺ = 264.0.

Intermediate 156b: 3-(2-chloro-5-oxo-5,7-dihydro-6 H -Pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione

DIPEA (475 μL, 2.72 mmol) was added to methyl 2-(bromomethyl)-6-chloropyridine-3-carboxylate (240 mg, 0.91 mmol) and 3-aminopiperidine-2,6-dione, HCl (119 mg, 0.73 mmol) in DMF (2 mL). The mixture was stirred at 40 °C for 2 h and then at 100 °C for 16 h. The reaction was cooled to room temperature and evaporated to dryness to give the crude product. The crude product was purified by silica gel chromatography (0-10% MeOH:DCM), followed by crystallization from EtOAc to give the title compound (0.140 g, 55.2%) as a purple solid; ^1H NMR: δ 2.02 - 2.08 (1H, m), 2.43 (1H, br dd), 2.62 (1H, br d), 2.91 - 2.97 (1H, m), 4.36 - 4.46 (1H, m), 4.56 (1H, br d), 5.18 (1H, br dd), 7. 69 (1H, d), 8.21 (1H, dd), 11.03 (1H, br s); m/z: ES ⁺ [M+H] ⁺ = 280.0.

Intermediate 156c: tert -Butyl 4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -Pyrrolo[3,4-b]pyridin-2-yl]piperazine-1-carboxylate

DIPEA (1.27 mL, 7.15 mmol) was added 3-(2-chloro-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (1.0 g, 3.58 mmol) and tert -butyl piperazine-1-carboxylate (0.66 g, 3.58 mmol) in DMSO (8 mL). The mixture was stirred at 120 °C for 5 h and then poured into ice water. The precipitate was collected by filtration and dried in vacuo for 48 h to give the title compound (1.06 g, 69.5%) as a beige solid; ¹ H NMR: δ 1.43 (9H, s), 1.91 - 2.04 (1H, m), 2.3 - 2.44 (1H, m), 2.55 - 2.65 (1H, m), 2.91 (1H, ddd), 3.39 - 3.54 (4H, m), 3.62 - 3.74 (4H, m), 4.12 (1H, d), 4.29 (1H, d), 5.08 (1H, dd), 6.91 (1H, d), 7.80 (1H, d), 10.93 (1H, s); m/z: ES ^- [MH] ^- = 428.4.

Intermediate 156d: 3-[5-oxo-2-(piperazin-1-yl)-5,7-dihydro-6 H -Pyrrolo[3,4-b]pyridin-6-yl]piperidine-2,6-dione

HCl (4 M in dioxane, 2 mL, 8.00 mmol) was added to tert -butyl 4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4-b]pyridin-2-yl]piperazine-1-carboxylate (92 mg, 0.21 mmol) at room temperature and stirred for 2 h. The reaction was evaporated to dryness to give the title compound as an HCl salt, which was used without further purification.

Example 156: 4-(4-{4-[4-({4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

Intermediate 146f (0.075 g, 0.13 mmol) was stirred in formic acid (2 mL) at 60 °C for 2 h. The mixture was evaporated and the residue was redissolved in NMP (2 mL) together with 3-[5-oxo-2-(piperazin-1-yl)-5,7-dihydro-6 H -pyrrolo[3,4-b]pyridin-6-yl]piperidine-2,6-dione (0.060 g, 0.17 mmol) at room temperature. After 5 min sodium triacetoxyborohydride (0.067 g, 0.32 mmol) was added and the suspension was stirred at room temperature for 10 min. The reaction mixture was purified by preparative HPLC (column A, eluent A) to afford the title compound (0.054 g, 51.9%) in the form of a formate salt as a pale solid; ¹ H NMR (CDCl ₃ ): δ 1.29 - 1.5 (2H, m), 1.81 - 2.02 (6H, m), 2.16 - 2.25 (2H, m), 2.26 - 2.4 (3H, m), 2.55 - 2.75 (7H, m), 2.76 - 3.03 (4H, m), 3. 6 - 3.84 (8H, m), 4.18 (1H, d), 4.32 (1H, d), 5.20 (1H, dd), 6.66 (1H, d), 6.87 - 6.96 (2H, m), 7.08 - 7.16 (3H, m), 7.49 (1H, d), 7.86 (1H, d), 7.92 (1H, s), 8.09 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 773.4.

Intermediate 157a: 1-[1-methyl-2-(piperidin-4-yl)-1 H -Indole-6-yl]-1,3-diazinane-2,4-dione

Intermediate 153c was reacted with TFA using the general synthetic method exemplified by intermediate 149e to give the title compound in the form of a TFA salt, which was used without further purification; ¹ H NMR: δ 1.71 - 1.87 (2H, m), 2.07 - 2.15 (2H, m), 2.69 - 2.77 (2H, m), 3.02 - 3.23 (3H, m), 3.41 (2H, d), 3.71 (3H, s), 3.75 - 3.83 (2H, m), 6.25 (1H, s), 6.92 - 6.99 (1H, m), 7.38 (1H, s), 7.46 (1H, d), 10.28 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 327.1.

Example 157: 4-{4-[4-(4-{4-[6-(2,4-dioxo-1,3-diazinane-1-yl)-1-methyl-1 H -Indol-2-yl]piperidin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 12, 1-[1-methyl-2-(piperidin-4-yl)-1 H -indol-6-yl]-1,3-diazinane-2,4-dione was reacted with intermediate 145a to give the title compound; ¹ H NMR: δ 1.62 - 1.88 (10H, m), 2.04 (2H, d), 2.74 (3H, t), 2.9 - 3 (1H, m), 3.01 - 3.15 (3H, m), 3.31 (5H, s), 3.70 (3H, s), 3.79 (2H, t), 4 .02 (2H, t), 4.18 (2H, d), 6.24 (1H, s), 6.75 (1H, dd), 6.80 (1H, dd), 6.95 (1H, dd), 7.22 (1H, t), 7.27 (1H, dd), 7.35 (2H, dd), 7.44 (1H, d), 7.82 (1H, d), 10.28 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 745.4.

Intermediate 158a: tert -Butyl 4-(5-bromo-1 H -Indol-1-yl)piperidine-1-carboxylate

tert -Butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (534 g, 1912.81 mmol) and potassium tert -butoxide (258 g, 2295.37 mmol) were added portionwise to 5-bromo-1 H -indole (150 g, 765.12 mmol) in heptane (2400 mL) and stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and diluted with MTBE. The solid was filtered and the filtrate was evaporated to dryness. The residue was redissolved in EtOAc, washed with water, dried over Na ₂ SO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-30% EtOAc in Et ₂ O) to give a colorless foam, which was crystallized from MTBE:Et ₂ O (1:5) to give the title compound (85 g, 29.3%) as a white solid; ¹ H NMR (CDCl ₃ ) δ 1.36 - 1.42 (9H, s), 1.69 - 1.89 (2H, m), 1.92 - 2.02 (2H, d), 2.73 - 2.89 (2H, m), 4.14 - 4.29 (3H, m), 6.33 - 6.40 (1H, m), 7.04 - 7.12 (1H, d), 7.09 - 7.23 (2H, m), 7.60 - 7.69 (1H, m); m/z : ES ⁺ [M-tBu] ⁺ = 323.0.

Intermediate 158b: tert -Butyl 4-[5-(2,4-dioxo-1,3-diazin-1-yl)-1 H -Indol-1-yl]piperidine-1-carboxylate

Under nitrogen at room temperature, [Pd(cinnamyl)Cl] ₂ (0.913 g, 1.65 mmol) was added to tert -Butyl 4-(5-bromo-1 H -indol-1-yl)piperidine-1-carboxylate (25 g, 65.91 mmol), 1,3-diazinane-2,4-dione (15.04 g, 131.82 mmol), tert -ButylBrettPhos (1.59 g, 3.30 mmol), and Cs ₂ CO ₃ (43 g, 131.82 mmol) in 1,4-dioxane (750 mL). The resulting mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (2 L) and water (2 L). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The crude product was purified by crystallization from MTBE to give the title compound (44.0 g, 57.1%) as a white solid; ¹ H NMR (CDCl ₃ ) δ 1.49 - 1.54 (9H, s), 1.85 - 2.00 (2H, qd), 2.04 - 2.13 (2H, m), 2.84 - 3.00 (4H, m), 3.88 - 3.95 (2H, m), 4.32 - 4.44 (3H, m), 6.52 - 6.58 (1H, m), 7.12 - 7.19 (1H, m), 7.22 - 7.27 (1H, d), 7.38 - 7.46 (2H, m), 7.52 - 7.57 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 413.0.

Intermediate 158c: 1-[1-(piperidin-4-yl)-1 H -Indole-5-yl]-1,3-diazinane-2,4-dione

The title compound was prepared using the method described in Intermediate 145g using tert -butyl 4-[5-(2,4-dioxo-1,3-diazinan-1-yl)-1 H -indol-1-yl]piperidine-1-carboxylate to afford the title compound as the tosylate salt (73 g, 82%) as a white solid; ¹ H NMR δ 2.05 - 2.20 (4H, m), 2.27 - 2.32 (3H, d), 2.69 - 2.77 (2H, m), 3.15 - 3.20 (2H, s), 3.44 - 3.51 (2H, d), 3.73 - 3.81 (2H, m), 4.71 - 4.75 (1H, s), 6.48 - 6.54 (1H, m), 7.08 - 7.16 (3H, m), 7.39 - 7.47 (1H, m), 7.47 - 7.53 (3H, m), 7.53 - 7.63 (1H, m), 8.37 - 8.42 (1H, s), 8. 61 - 8.65 (1H, s), 10.24 - 10.29 (1H, d); m/z : ES ⁺ [M+H] ⁺ = 313.0.

Example 158: 4-{4-[4-(4-{4-[5-(2,4-dioxo-1,3-diazin-1-yl)-1 H -Indol-1-yl]piperidin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 12, 1-[1-(piperidin-4-yl)-1 H -indol-5-yl]-1,3-diazinane-2,4-dione was reacted with intermediate 145a to give the title compound; ¹ H NMR: δ 1.62 - 1.86 (8H, m), 2 - 2.16 (5H, m), 2.73 (3H, t), 2.78 - 3.14 (5H, m), 3.31 (3H, s), 3.77 (2H, t), 4.02 (2H, t), 4.18 (2H, d), 4. 44 - 4.61 (1H, m), 6.49 (1H, d), 6.75 (1H, dd), 6.80 (1H, dd), 7.10 (1H, dd), 7.22 (1H, t), 7.26 - 7.3 (1H, m), 7.33 (1H, d), 7.46 - 7.52 (2H, m) , 7.56 (1H, s), 7.82 (1H, d), 8.14 (0H, s), 10.26 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 731.4.

Intermediate 159a: tert -Butyl 4-[(2-amino-4-bromo-6-fluorophenyl)ethynyl]piperidine-1-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (1.46 g, 1.27 mmol) was added to 5-bromo-3-fluoro-2-iodoaniline (4.0 g, 12.66 mmol), tert -butyl 4-ethynylpiperidine-1-carboxylate (2.91 g, 13.93 mmol) and copper(I) iodide (0.241 g, 1.27 mmol) in triethylamine (60 mL) under nitrogen at room temperature. The mixture was stirred at 100 °C for 2 h, cooled to room temperature and then evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-35% EtOAc in Et ₂ O) to give the title compound (4.0 g, 80%) as a yellow solid; ¹ H NMR: δ 1.40 (9H, s), 1.49 - 1.62 (2H, m), 1.77 - 1.88 (2H, m), 2.84 - 2.95 (1H, m), 3.10 (2H, t), 3.60 - 3.70 (2H, m), 5.85 (2H, s), (1H, dd), 6.69 - 6.74 (1H, m); m/z: ES ⁺ [M- t Bu] ⁺ = 341.1.

Intermediate 159b: tert -Butyl 4-(6-bromo-4-fluoro-1 H -Indol-2-yl)piperidine-1-carboxylate

Under nitrogen, bis(MeCN)palladium(II) chloride (0.496 g, 1.91 mmol) was added to tert -butyl 4-[(2-amino-4-bromo-6-fluorophenyl)ethynyl]piperidine-1-carboxylate (3.8 g, 9.56 mmol) in DMF (40 mL). The mixture was stirred at 120 °C for 3 h and then cooled to room temperature. The mixture was diluted with water (125 mL), and EtOAc (300 mL), washed with saturated brine (100 mL), dried over MgSO ₄ , filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-35% EtOAc in Et ₂ O) to give the title compound (1.35 g, 35.5%) as a yellow solid; ¹ H NMR: δ 1.42 (9H, d), 1.48 - 1.62 (2H, m), 1.92 - 2.02 (2H, m), 2.85 - 2.96 (3H, m), 4.01 - 4.09 (2H, m), 6.26 (1H, s), 6.96 (1H, d), 7.32 ( 1H, s), 11.47 (1H, s); m/z: ES ⁺ [M-tBu+H] ⁺ = 343.1.

Intermediate 159c: tert -Butyl 4-(6-bromo-4-fluoro-1-methyl-1 H -Indol-2-yl)piperidine-1-carboxylate

Under nitrogen at 0 °C, NaH (60% in mineral oil, 0.196 g, 4.91 mmol) was added to tert -Butyl 4-(6-bromo-4-fluoro-1 H -indol-2-yl)piperidine-1-carboxylate (1.3 g, 3.27 mmol) in THF (20 mL). After 15 min iodomethane (0.204 mL, 3.27 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was quenched with water (1 mL), diluted with EtOAc (50 mL), washed with water (3x 50 mL), dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-100% EtOAc in _Et2O ) to afford the title compound (1.15 g, 85%) as a red solid; ¹ H NMR: δ 1.42 (9H, s), 1.44 - 1.55 (2H, m), 1.92 (2H, d), 2.89 - 3.00 (3H, m), 3.73 (3H, s), 4.03 - 4.13 (2H, m), 6.32 (1H, s), 7.01 (1H, dd), 7.57 (1H, s); m/z: ES ⁺ [M-tBu] ⁺ = 355.0.

Intermediate 159d: tert -Butyl 4-[6-(2,4-dioxo-1,3-diazin-1-yl)-4-fluoro-1-methyl-1 H -Indol-2-yl]piperidine-1-carboxylate

The title compound was obtained by reaction of tert -butyl 4-(6-bromo-4-fluoro-1-methyl-1 H -indol-2-yl)piperidine-1-carboxylate using a general synthetic method exemplified by intermediate 146d; m/z: ES ⁺ [M-tBu+H] ⁺ = 389.3.

Intermediate 159e: 1-[4-fluoro-1-methyl-2-(piperidin-4-yl)-1 H -Indole-6-yl]-1,3-diazinane-2,4-dione

tert -Butyl 4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-4-fluoro-1-methyl-1 H -indol-2-yl]piperidine-1-carboxylate (500 mg, 1.12 mmol) was added to formic acid (1 mL) and stirred at room temperature for 1 h. The reaction mixture was purified by ion exchange chromatography using a SCX column. The desired product was eluted from the column using 7 M NH ₃ /MeOH to give the title compound (0.300 g, 77%) as a yellow solid; ¹ H NMR: δ 1.44 - 1.52 (1H, m), 1.50 - 1.58 (1H, m), 1.86 (2H, d), 2.61 - 2.77 (4H, m), 2.86 - 2.91 (1H, m), 3.00 - 3.07 (2H, m), 3.70 (3H, s), 3.80 (2H, t), 6.24 (1H, s), 6.82 (1H, dd), 7.26 (1H, t), 10.33 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 345.3.

Intermediate 159f: 4-{4-[4-(3-bromopropoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

Intermediate 1 g (2.0 g, 5.77 mmol) was added to 1,3-dibromopropane (3.5 g, 17.32 mmol) and K ₂ CO ₃ (1.59 g, 11.55 mmol) in MeCN (30 mL) at room temperature. The mixture was stirred at 80 °C for 16 h, then cooled to room temperature and evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-25% EtOAc in Et ₂ O) to give the title compound (1.9 g, 70.4%) as a white solid; ¹ H NMR: δ 1.52 - 1.72 (2H, m), 1.79 - 1.90 (2H, m), 2.23 (2H, p), 2.70 - 2.83 (1H, m), 2.96 - 3.12 (2H, m), 3.66 (2H, t), 4.05 (2H, t), 4.18 (2 H, d), 6.82 - 6.93 (2H, m), 7.11 - 7.22 (2H, m), 7.22 - 7.36 (2H, m), 7.81 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 467.2.

Example 159: 4-{4-[4-(3-{4-[6-(2,4-dioxo-1,3-diazinane-1-yl)-4-fluoro-1-methyl-1 H -Indol-2-yl]piperidin-1-yl}propoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 12, 4-{4-[4-(3-bromopropoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile was reacted with 1-[4-fluoro-1-methyl-2-(piperidin-4-yl)-1H-indol-6-yl]-1,3-diazinane-2,4-dione to give the title compound; ¹ H NMR: δ ¹ H NMR: δ 1.55 - 1.69 (4H, m), 1.78 - 1.97 (6H, m), 2.07 (4H, s), 2.74 (4H, q), 2.95 - 3.09 (4H, m), 3.70 (3H, s), 3.79 (2H, t), 3. 99 (2H, t), 4.17 (2H, d), 6.28 (1H, s), 6.84 (3H, dd), 7.16 (2H, d), 7.26 (2H, s), 7.32 (1H, d), 7.81 (1H, d), 10.34 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 731.4.

Intermediate 160a: tert -Butyl 4-[(2-amino-4-bromo-5-fluorophenyl)ethynyl]piperidine-1-carboxylate

The title compound was obtained by reaction of 5-bromo-4-fluoro-2-iodoaniline and tert -butyl 4-ethynylpiperidine-1-carboxylate using a general synthetic method exemplified by intermediate 159a; ¹ H NMR: δ 1.40 (9H, s), 1.46 - 1.64 (2H, m), 1.75 - 1.90 (2H, m), 2.80 - 2.94 (1H, m), 3.01 - 3.20 (2H, m), 3.60 - 3.73 (2H, m), 5.36 (2H, s), 6.95 (1H, d), 7.11 (1H, d); m/z: ES ⁺ [M- t Bu] ⁺ = 341.1.

Intermediate 160b: tert -Butyl 4-(6-bromo-5-fluoro-1 H -Indol-2-yl)piperidine-1-carboxylate

The title compound was obtained by reaction of tert -butyl 4-[(2-amino-4-bromo-5-fluorophenyl)ethynyl]piperidine-1-carboxylate using a general synthetic method exemplified by intermediate 159b; ¹ H NMR: δ 1.42 (9H, s), 1.46 - 1.61 (2H, m), 1.90 - 2.02 (2H, m), 2.71 - 3.00 (3H, m), 3.99 - 4.09 (2H, m), 6.20 (1H, d), 7.38 (1H, d), 7.52 (1H, d), 11.20 (1H, s); m/z: ES ⁺ [M- t Bu] ⁺ = 341.1.

Intermediate 160c: tert -Butyl 4-(6-bromo-5-fluoro-1-methyl-1 H -Indol-2-yl)piperidine-1-carboxylate

The title compound was obtained by reaction of tert -butyl 4-(6-bromo-5-fluoro-1 H -indol-2-yl)piperidine-1-carboxylate using a general synthetic method exemplified by intermediate 159c; ¹ H NMR: δ 1.42 (9H, s), 1.42 - 1.53 (2H, m), 1.91 (2H, d), 2.92 - 3.04 (1H, m), 3.17 (1H, d), 3.31 (1H, s), 3.71 (3H, s), 4.00 - 4.12 (2H, m), 6.25 (1H, s), 7.39 (1H, d), 7.77 (1H, d); m/z: ES ⁺ [M- t Bu] ⁺ = 355.1.

Intermediate 160d: tert -Butyl 4-[6-(2,4-dioxo-1,3-diazinane-1-yl)-5-fluoro-1-methyl-1 H -Indol-2-yl]piperidine-1-carboxylate

The title compound was obtained by reaction of tert -butyl 4-(6-bromo-5-fluoro-1-methyl-1 H -indol-2-yl)piperidine-1-carboxylate using a general synthetic method exemplified by intermediate 146d; ¹ H NMR: δ 1.44 (9H, s), 1.73 - 1.84 (3H, m), 1.84 - 1.91 (1H, m), 2.87 (3H, s), 3.16 - 3.28 (4H, m), 3.33 (1H, s), 4.04 - 4.12 (2H, m), 4.5 4 - 4.60 (2H, m), 7.07 - 7.17 (1H, m), 7.46 - 7.57 (1H, m), 7.67 (1H, s); m/z: ES ⁺ [M- t Bu] ⁺ = 389.2.

Intermediate 160e: 1-[5-fluoro-1-methyl-2-(piperidin-4-yl)-1 H -Indole-6-yl]-1,3-diazinane-2,4-dione

The title compound was obtained by reacting tert -butyl 4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1 H -indol-2-yl]piperidine-1-carboxylate using a general synthetic method exemplified by intermediate 80g; ¹ H NMR: δ 1.69 - 1.77 (2H, m), 2.03 (2H, d), 2.76 (2H, d), 2.95 (2H, t), 3.07 - 3.12 (1H, m), 3.29 (2H, d), 3.63 - 3.80 (5H, m), 6.25 (1H, s), 7.34 (1H, d), 7.48 - 7.54 (1H, m), 8.35 (1H, s), 10.44 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 345.2.

Example 160: 4-{4-[4-(3-{4-[6-(2,4-dioxo-1,3-diazinane-1-yl)-5-fluoro-1-methyl-1 H -Indol-2-yl]piperidin-1-yl}propoxy)phenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 12, intermediate 159f was reacted with 1-[5-fluoro-1-methyl-2-(piperidin-4-yl)-1 H -indol-6-yl]-1,3-diazinane-2,4-dione to give the title compound; ¹ H NMR: δ 1.58 - 1.65 (4H, m), 1.84 - 1.92 (6H, m), 2.03 - 2.13 (2H, m), 2.69 - 2.85 (5H, m), 2.90 - 3.15 (5H, m), 3.66 - 3.75 (5H, m), 3.98 (2 H, t), 4.17 (2H, d), 6.24 (1H, s), 6.82 - 6.89 (2H, m), 7.12 - 7.19 (2H, m), 7.22 - 7.34 (3H, m), 7.45 - 7.51 (1H, m), 7.81 (1H, d), 10.41 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 731.3.

Example 161: 4-{4-[4-(4-{4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 138, intermediate 156d was reacted with intermediate 38e to provide the title compound in the form of a formate salt; ¹ H NMR (CDCl ₃ ): δ 1.7 - 1.88 (6H, m), 1.95 (2H, d), 2.21 (1H, ddq), 2.33 (1H, qd), 2.74 - 2.97 (8H, m), 3 - 3.13 (3H, m), 3.79 - 3.98 (6H, m), 4 .02 (2H, d), 4.19 (1H, d), 4.32 (1H, d), 5.20 (1H, dd), 6.60 (1H, dd), 6.64 (1H, dd), 6.69 (1H, s), 6.99 (1H, dd), 7.07 (1H, t), 7.16 (1H, d), 7.61 (1H, d), 7.89 (1H, d), 8.19 - 8.44 (2H, m); m/z: ES ⁺ [M+H] ⁺ = 748.4.

Intermediate 162a: tert -Butyl 4-(2,6-difluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

In a general synthetic method exemplified by intermediate 9a, tert -Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate was reacted with 4-bromo-3,5-difluorophenol to give the title compound; ¹ H NMR: δ 1.43 (9H, s), 2.26 (2H, brs), 3.50 (2H, t), 3.96 (2H, br s), 5.75 (1H, brs), 6.4 - 6.5 (2H, m), 10.33 (1H, s); m/z: ES ⁺ [M- t Bu] ⁺ = 256.1.

Intermediate 162b: tert -Butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperidine-1-carboxylate

In a general synthetic method exemplified by intermediate 9b, tert -butyl 4-(2,6-difluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2 H )-carboxylate was reacted with hydrogen gas to give the title compound; ¹ H NMR (CDCl ₃ ): δ 0.96 (1H, d), 1.15 (2H, d), 1.26 (2H, d), 1.48 (9H, s), 1.57 - 1.69 (2H, m), 1.69 - 1.86 (2H, m), 1.86 - 2.03 (3H, m), 2.32 - 2.46 (1H, m), 2.69 - 2.8 (2H, m), 3.00 (1H, tt), 4.21 (2H, d), 6.32 (2H, d); m/z: ES ⁺ [M- t Bu] ⁺ = 258.1.

Intermediate 162c: 3,5-Difluoro-4-(piperidin-4-yl)phenol

tert -Butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperidine-1-carboxylate (130 mg, 0.41 mmol) was suspended in DCM (2 mL) and TFA (317 μl, 4.15 mmol) and stirred at room temperature for 1 h. The solution was evaporated to dryness to obtain the crude product. The crude product was purified by ion exchange chromatography using a SCX column. The desired product was eluted from the column using 1 M NH ₃ /MeOH to give the title compound (0.083 g, 94%) as a white solid; m/z: ES ⁺ [M+H] ⁺ = 214.1.

Intermediate 162d: 4-[4-(2,6-difluoro-4-hydroxyphenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

3,5-Difluoro-4-(piperidin-4-yl)phenol (83 mg, 0.39 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (77 mg, 0.41 mmol) and DIPEA (74.6 μl, 0.43 mmol) (in NMP (1 mL)) were stirred at 100 °C for 1 h. The reaction was cooled to room temperature and diluted with EtOAc (10 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried over MgSO ₄ , filtered and evaporated to dryness to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-40% EtOAc in heptane) to give the title compound (0.143 g, 96%) as a white solid; ¹ H NMR: δ 1.78 - 1.89 (2H, m), 1.99 - 2.07 (2H, m), 2.07 - 2.21 (2H, m), 2.40 (2H, t), 2.86 (3H, t), 2.96 - 3.08 (2H, m), 3.14 (1H, ddd), 3.36 - 3.45 (2H, m), 3.93 - 4.04 (2H, m), 6.35 - 6.44 (2H, m), 6.97 (1H, dd), 7.05 (1H, s), 7.15 (1H, d), 7.57 - 7.64 (1H, m); m/z: ES ^- [MH] ^- = 381.2.

Intermediate 162e: 4-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]-2,6-difluorophenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile

To a solution of 4-[4-(2,6-difluoro-4-hydroxyphenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile (140 mg, 0.37 mmol) in MeCN (5 mL) were added K ₂ CO ₃ (253 mg, 1.83 mmol) and 2-(3-bromopropyl)-1,3-dioxolane (99 μl, 0.73 mmol). The reaction was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography (elution gradient: 0-40% EtOAc in heptane) to give the title compound (0.127 g, 69.9%) as a white solid; ¹ H NMR: δ 1.61 - 1.82 (6H, m), 1.85 - 2.01 (2H, m), 3.06 (2H, t), 3.12 - 3.22 (1H, m), 3.73 - 3.8 (2H, m), 3.85 - 3.92 (2H, m), 3.99 (2H, t), 4 .11 - 4.24 (2H, m), 4.84 (1H, t), 6.67 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.81 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 497.4.

Example 162: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-2,6-difluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 138, 4-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]-2,6-difluorophenyl}piperidin-1-yl)-2-(trifluoromethyl)benzonitrile was reacted with intermediate 2b to give the title compound in the form of a formate salt; ¹ H NMR (CDCl ₃ ): δ 1.77 - 1.92 (6H, m), 2.07 - 2.26 (3H, m), 2.35 (1H, qd), 2.69 - 2.99 (8H, m), 3.06 (2H, t), 3.18 (1H, ddd), 3.43 - 3.56 (4H, m) , 3.9 - 3.99 (2H, m), 3.99 - 4.07 (2H, m), 4.29 (1H, d), 4.44 (1H, d), 5.22 (1H, dd), 5.29 - 5.98 (1H, m), 6.43 (2H, d), 6.87 - 6.95 (1H, m), 6. 96 - 7.06 (2H, m), 7.17 (1H, d), 7.64 (1H, d), 7.78 (1H, d), 8.11 (1H, s), 8.24 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 765.4.

Example 163: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-2,6-difluorophenyl]piperidin-1-yl}-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 138, intermediate 162e was reacted with intermediate 1e to provide the title compound in the form of a formate salt; ¹ H NMR (CDCl ₃ ): δ 1.75 - 1.9 (6H, m), 2.05 - 2.21 (3H, m), 2.29 (1H, qd), 2.68 - 2.78 (2H, m), 2.78 - 2.88 (2H, m), 2.88 - 2.97 (4H, m), 3.03 (2 H, t), 3.09 - 3.22 (1H, m), 3.39 - 3.52 (4H, m), 3.88 - 3.98 (5H, m), 4.01 (2H, d), 4.20 (1H, d), 4.35 (1H, d), 5.12 (1H, dd), 5.9 - 6.28 (1H, m) , 6.41 (4H, dd), 6.97 (1H, dd), 7.14 (1H, d), 7.61 (1H, d), 8.13 - 8.34 (2H, m); m/z: ES ⁺ [M+H] ⁺ = 795.3.

Intermediate 164a: 3-Fluoro-4-[4-(2-fluoro-4-hydroxy-phenyl)-1-piperidyl]-2-(trifluoromethyl)benzonitrile

Intermediate 38c was reacted with 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene in a general synthetic method exemplified by intermediate 137f to give the title compound; ¹ H NMR (CDCl ₃ ): δ 1.85 - 1.97 (4H, m), 2.92 - 3.11 (3H, m), 3.68 - 3.8 (2H, m), 6.54 - 6.65 (2H, m), 7.09 (2H, dt), 7.46 - 7.53 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 383.2.

Intermediate 164b: 4-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]-2-fluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by intermediate 38e, 3-Fluoro-4-[4-(2-fluoro-4-hydroxy-phenyl)-1-piperidyl]-2-(trifluoromethyl)benzonitrile was reacted with 2-(3-bromopropyl)-1,3-dioxolane to give the title compound; m/z: ES ⁺ [M+H] ⁺ = 497.3.

Example 164: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-3-fluoro-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 138, 4-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]-2-fluorophenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile was reacted with intermediate 2b to give the title compound in the form of a formate salt; ¹ H NMR (CDCl ₃ ): δ 1.68 - 1.79 (2H, m), 1.8 - 1.98 (6H, m), 2.19 (1H, dtd), 2.32 (1H, qd), 2.49 - 2.57 (2H, m), 2.65 - 2.72 (4H, m), 2.75 - 3.1 ( 5H, m), 3.29 - 3.47 (4H, m), 3.73 (2H, d), 3.97 (2H, t), 4.25 (1H, d), 4.41 (1H, d), 5.19 (1H, dd), 6.61 (1H, dd), 6.67 (1H, dd), 6.88 (1H, d), 6.99 (1H, dd), 7.11 (2H, td), 7.49 (1H, d), 7.73 (1H, d), 7.99 - 8.11 (1H, m); m/z: ES ⁺ [M+H] ⁺ = 765.4.

Intermediate 165a: 3-Fluoro-4-[4-(4-hydroxy-2-methylphenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile

Intermediate 123c was reacted with 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene in a general synthetic method exemplified by intermediate 137f to give the title compound; ¹ H NMR: δ 1.64 - 1.8 (4H, m), 2.25 (3H, s), 2.78 - 2.91 (1H, m), 3 - 3.13 (2H, m), 3.72 (2H, d), 6.53 - 6.58 (2H, m), 7.01 (1H, d), 7.46 (1H, t), 7.80 (1H, d), 9.02 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 379.2.

Intermediate 165b: 4-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]-2-methylphenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by intermediate 38e, 3-fluoro-4-[4-(4-hydroxy-2-methylphenyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile was reacted with 2-(3-bromopropyl)-1,3-dioxolane to give the title compound; ¹ H NMR: δ 1.63 - 1.83 (8H, m), 2.30 (3H, s), 2.79 - 2.94 (1H, m), 3.01 - 3.13 (2H, m), 3.66 - 3.8 (4H, m), 3.85 - 3.98 (4H, m), 4.84 (1H, t), 6.67 - 6.75 (2H, m), 7.11 (1H, d), 7.45 (1H, t), 7.80 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 493.3.

Example 165: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-2-methylphenyl]piperidin-1-yl}-3-fluoro-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 138, 4-(4-{4-[3-(1,3-dioxolan-2-yl)propoxy]-2-methylphenyl}piperidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile was reacted with intermediate 2b to give the title compound in the form of a formate salt; ¹ H NMR (CDCl3): δ 1.8 - 1.97 (8H, m), 2.15 - 2.27 (1H, m), 2.27 - 2.43 (4H, m), 2.75 - 2.97 (5H, m), 2.97 - 3.08 (6H, m), 3.45 - 3.56 (4H, m), 3. 72 - 3.83 (2H, m), 4.00 (2H, t), 4.29 (1H, d), 4.44 (1H, d), 5.22 (1H, dd), 6.75 (2H, d), 6.92 (1H, d), 7.02 (1H, dd), 7.14 (2H, t), 7.52 (1H, d) , 7.77 (1H, d), 8.21 (1H, s), 8.27 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 761.5.

Example 166: 4-{4-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}butoxy)-2-fluorophenyl]piperidin-1-yl}-3-fluoro-2-(trifluoromethyl)benzonitrile

In a general synthetic method exemplified by Example 138, intermediate 164b was reacted with intermediate 1e to provide the title compound in the form of a formate salt; ¹ H NMR (CDCl ₃ ): δ 1.66 - 2.01 (8H, m), 2.1 - 2.22 (1H, m), 2.30 (1H, qd), 2.48 - 2.6 (2H, m), 2.64 - 2.7 (4H, m), 2.75 - 3.1 (5H, m), 3.27 - 2 (4H, m), 3.74 (2H, d), 3.94 (3H, s), 3.97 (2H, t), 4.20 (1H, d), 4.36 (1H, d), 5.13 (1H, dd), 6.36 (1H, d), 6.45 - 6.49 (1H, m), 6.61 (1H, dd) , 6.66 (1H, dd), 7.12 (2H, td), 7.49 (1H, d), 7.84 (1H, s), 8.09 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 795.3.

Intermediate 167a: tert -Butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2 H )-carboxylate

In a general synthetic method exemplified by intermediate 8a, 4-bromo-2-fluoro-1-iodobenzene was reacted with tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate to give the title compound; ¹ H NMR: δ 1.43 (9H, s), 2.41 (2H, br s), 3.52 (2H, t), 3.99 (2H, br s), 6.02 (1H, br s), 7.30 - 7.35 (1H, m), 7.39 - 7.43 (1H, m), 7.54 (1H, dd).

Intermediate 167b: tert -Butyl 4-{4-[4-(ethoxycarbonyl)piperidin-1-yl]-2-fluorophenyl}-3,6-dihydropyridine-1(2 H )-carboxylate

To a solution of tert -butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2 H )-carboxylate (1.0 g, 2.81 mmol) in toluene (30 mL) was added ethyl piperidine-4-carboxylate (0.883 g, 5.61 mmol) and sodium tert -butoxide (0.540 g, 5.61 mmol) at room temperature, degassed for 5 min, then Pd ₂ (dba) ₃ (0.129 g, 0.140 mmol) and BINAP (0.175 g, 0.281 mmol) were added. The mixture was stirred at 120 °C for 6 h, then cooled to room temperature and quenched with water. The product was extracted with EtOAc (200 mL), washed with saturated brine (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the crude product. The crude product was purified by flash column chromatography using EtOAc:hexane (0∼20%) to give the title compound (0.5 g, 37%) as a yellow solid; m/z: ES ⁺ [M+H] ⁺ = 433.2.

Intermediate 167c: tert -Butyl 4-{4-[4-(ethoxycarbonyl)piperidin-1-yl]-2-fluorophenyl}piperidine-1-carboxylate

In a general synthetic method exemplified by intermediate 123b, tert -butyl 4-{4-[4-(ethoxycarbonyl)piperidin-1-yl]-2-fluorophenyl}-3,6-dihydropyridine-1(2 H )-carboxylate was reacted with hydrogen gas to give the title compound; m/z: ES ⁺ [M+H] ⁺ = 435.0.

Intermediate 167d: Ethyl 1-[3-fluoro-4-(piperidin-4-yl)phenyl]piperidine-4-carboxylate

To a solution of tert -butyl 4-{4-[4-(ethoxycarbonyl)piperidin-1-yl]-2-fluorophenyl}piperidine-1-carboxylate (0.4 g, 0.920 mmol) in DCM (20 mL) was added HCl (4 M in dioxane, 10 mL, 40.0 mmol) dropwise at 0 °C. The reaction was stirred at room temperature for 4 h and then evaporated to dryness to give the crude product. The crude product was diluted with MTBE (30 mL) and filtered under vacuum to give the title compound as an HCl salt which was used without further purification; m/z: ES ⁺ [M+H] ⁺ = 335.5.

Intermediate 167e: Ethyl 1-{4-[1-(4-cyano-3-cyclopropylphenyl)piperidin-4-yl]-3-fluorophenyl}piperidine-4-carboxylate

To a solution of ethyl 1-[3-fluoro-4-(piperidin-4-yl)phenyl]piperidine-4-carboxylate hydrochloride (0.518 g, 1.396 mmol) in DMSO (7 mL) were added K ₂ CO ₃ (0.386 g, 2.79 mmol) and 2-cyclopropyl-4-fluorobenzonitrile (0.15 g, 0.931 mmol) and stirred at 120 °C for 16 h. The reaction was then cooled to room temperature and quenched with water. The product was extracted with EtOAc (200 mL), washed with saturated brine (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the crude product. The crude product was purified by flash column chromatography using EtOAc:hexane (0∼20%) to give the title compound (0.3 g, 66.4%) as a yellow solid; m/z: ES ⁺ [M+H] ⁺ = 476.0.

Intermediate 167f: 2-Cyclopropyl-4-(4-{2-fluoro-4-[4-(hydroxymethyl)piperidin-1-yl]phenyl}piperidin-1-yl)benzonitrile

To a solution of ethyl 1-{4-[1-(4-cyano-3-cyclopropylphenyl)piperidin-4-yl]-3-fluorophenyl}piperidine-4-carboxylate (0.3 g, 0.631 mmol) in methanol (15 mL) was added NaBH ₄ (0.239 g, 6.31 mmol) at 0 °C and stirred for 4 h at room temperature. The reaction was quenched with saturated NH ₄ Cl solution and extracted with DCM (10 mL). The organic layer was washed with saturated brine (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the crude product. The crude product was purified by flash column chromatography using EtOAc:hexane (0∼50%) to give the title compound (0.1 g, 35.8%) as a white solid; ¹ H NMR: δ 0.76 - 0.92 (2H, m), 0.97 - 1.11 (2H, m), 1.11 - 1.28 (2H, m), 1.45 - 1.56 (1H, m), 1.61 - 1.83 (6H, m), 2.08 (1H, tt), 2.55 - 2.72 ( 2H, m), 2.81 - 3.00 (3H, m), 3.19 - 3.41 (2H, m), 3.68

(2H, d), 4.03 (2H, d), 4.46 (1H, t), 6.46 (1H, d), 6.62 - 6.72 (2H, m), 6.85 (1H, dd), 6.98 - 7.16 (1H, m) ), 7.48 (1H, d); m/z: ES ⁺ [M+H] ⁺ = 434.0.

Intermediate 167g: 2-Cyclopropyl-4-{4-[2-fluoro-4-(4-formylpiperidin-1-yl)phenyl]piperidin-1-yl}benzonitrile

In a general synthetic method exemplified by intermediate 53b, 2-cyclopropyl-4-(4-{2-fluoro-4-[4-(hydroxymethyl)piperidin-1-yl]phenyl}piperidin-1-yl)benzonitrile was reacted with Dess-Martin periodinane to give the title compound, which was isolated crude and used without further purification.

Example 167: 2-Cyclopropyl-4-(4-{4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1 H -isoindole-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorophenyl}piperidin-1-yl)benzonitrile

To a solution of intermediate 1f (0.16 g, 0.405 mmol) and 2-cyclopropyl-4-{4-[2-fluoro-4-(4-formylpiperidin-1-yl)phenyl]piperidin-1-yl}benzonitrile (0.175 g, 0.405 mmol) in DCM (10 mL) was added sodium acetate (0.066 g, 0.810 mmol), stirred at room temperature for 3 h, and then sodium triacetoxyborohydride (0.172 g, 0.810 mmol) was added. The mixture was stirred at room temperature for 16 h and extracted with DCM (80 mL). The solution was washed with water (100 mL), dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. Purification by preparative HPLC (column A, eluent A) was performed and the fractions containing the product were evaporated, then neutralized with saturated NaHCO ₃ solution and extracted with DCM (2x 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the title compound (0.025 g, 7.81%) as a white solid; ¹ H NMR: δ 0.80 - 0.90 (2H, m), 0.98 - 1.09 (2H, m), 1.15 - 1.25 (2H, m), 1.65 - 1.83 (7H, m), 2.06 - 2.12 (1H, m), 2.22 (1H, d), 2.30 - 2.36 (3 H, m), 2.59 - 2.71 (7H, m), 2.90 (4H, t), 3.43 (4H, br s), 3.68 (2H, d), 3.84 (3H, s), 3.98 - 4.09 (3H, m), 4.19 - 4.27 (1H, m), 4.97 (1H, dd), 6.44 - 6.52 (2H, m), 6.61 (1H, s), 6.65 - 6.73 (2H, m), 6.85 (1H, dd), 7.01 - 7.13 (1H, m), 7.48 (1H, d), 10.91 (1H, s); m/z: ES ⁺ [M+H] ⁺ = 774.5.

LNCaP Androgen Receptor Imaging Analysis

This cell-based imaging assay uses immunofluorescence to measure both cell counts and endogenous nuclear AR staining in the prostate cancer cell line LNCaP (expressing full-length AR). The objective of this assay is to identify compounds that modulate AR protein levels, following the protocol outlined in the steps below.

All work was performed in a sterile tissue culture hood until cell fixation. LNCaP cells were cultured at 6–8 x10 ⁶ per T175 flask and seeded every 3–4 days. Medium: RPMI 1640 (VWR Sigma) containing 10% FCS and 1% glutamine. Cells were plated in assay-ready plates at a density of 12,000 cells per well at 40 μL using a Multidrop (ThermoFisher) (Cedex ^TM Cell counter, Beckmann & Coulter).

Test compounds were diluted in DMSO and administered to cells using an Echo 555 ^TM (Labcyte), to a final concentration of DMSO in the wells of 0.3%. A neutral control (DMSO) and a positive AR degrader control (a prior art AR PROTAC) at 3 μM were included. The Echo utilizes acoustic technology to perform direct microplate-to-microplate transfer of DMSO compound solutions into the assay plates. The system can be programmed to deliver volumes as small as 2.5 nL in multiple increments between microplates, thereby generating a serial dilution of the compound in the assay plate, which is then backfilled to normalize DMSO concentration across the dilution range. Compounds were dispensed into cell plates using a compound source plate prepared as above, using an Integrated Echo workcell to generate a 12-point dose-response curve using 3-fold dilutions and one final 10-fold dilution and a peak concentration of 3 or 30 μM. The plates were incubated at 37°C/5% _CO2 for 24 h, then fixed and stained as described below.

40 μL of 8% paraformaldehyde solution (v/v) in phosphate buffered saline (PBS) was added to the top of the media already in the wells using a Multidrop to secure the plates to give a final concentration of 4% PFA (v/v) for 20–30 min (maintained inside a fume hood to minimize PFA exposure). After 20–30 min, the plates were washed 3 x with PBS using a BioTek washer.

Cells were incubated with mouse monoclonal anti-AR antibody AR441 (DAKO M3562) (1:1000) diluted in modified blocking buffer (PBS+1% BSA+0.1% TritonX) (15 μL/well, for 2 h at room temperature). The plates were then washed 3x with PBS using a BioTek washer. Cells were then incubated with goat anti-mouse secondary antibody 488 (Invitrogen A11001) (1:500) and nuclear stain, DRAQ5 (Abcam Ab108410) (1:2000), diluted in modified blocking buffer (for 45 min at room temperature, 15 μL/well). The plates were then washed 3x with PBS using a BioTek washer and sealed with a black plate seal.

The plates are read using Cellomics Cellinsight to measure androgen receptor levels in each well. The data is exported to Genedata for curve fitting analysis. All data are normalized to % of positive control, and any data points corresponding to the hook of the curve are masked prior to fitting. Downregulation of AR is expressed as DC ₅₀ values, and the compound concentration required to provide 50% of the maximal degradation of AR is determined by calculating the curve fit for that compound. The maximum degradation observed for each compound is expressed as D _max . AR degradation data for compounds are illustrated in the table below and may be from a single experiment or an average of two or more experiments.

LNCaP Androgen Receptor L702H Imaging Analysis

Although treatment with AR antagonists has been shown to be beneficial for patients, most cancers eventually progress to castration-resistant prostate cancer (CRPC). At this stage, anti-androgen therapy is largely ineffective due to AR amplification, overexpression, or point mutations. One of the point mutations observed in the patient population is L702H in the AR ligand binding domain. LNCAP cells were engineered to introduce the mutant L702H into the AR gene using CRISPR/Cas9. A previously described imaging-based AR assay monitors nuclear AR(L702H) levels in these cells to identify compounds that modulate AR(L702H). Downregulation of AR(L702H) is expressed as a DC ₅₀ value, and the concentration of compound required to provide 50% of the maximal degradation of AR(L702H) is determined by calculating the concentration of compound based on curve fitting for that compound. The maximum degradation observed for each compound is expressed as D _max . AR and AR(L702H) degradation data for the compounds are illustrated in the table below and may be the results from a single experiment or the average of two or more experiments.

declaration

1. A compound of the following chemical formula I, or a pharmaceutically acceptable salt thereof:

[Chemical Formula I]

[Here,

X ¹ is C and 0, 1 or 2 of X ² , X ³ and X ⁴ are N, otherwise they are C;

or

X ³ and X ⁴ are both C, and - X ⁵ = X ⁶ - X ⁷ = X ⁸ - (where X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ ) are substituted, where one or two of X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ are N, otherwise they are C;

p is 1 or 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -); otherwise p is 0, 1, or 2;

Each R ¹ is ^a substituent on any C atom in X ¹ , X ² , X ³ and X ⁴ (or in X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ when X ³ and X 4 are substituted such that - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), and is independently selected from F, Cl, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy may be optionally substituted independently with one or more F;

n is 0, 1, or 2;

m is 0 or 1;

Q is CH or N (if both n and m are non-zero), otherwise Q is CH;

R ^2a and R ^2b are substituents on the same or different C atoms other than Q , each independently selected from H, F and C _1-3 alkyl, or R ^2a and R ^2b together form a -(CH ₂ ) _r - group, wherein r is 1, 2 or 3;

Zero, one, or two of Y ¹ , Y ² , Y ^{3 ,} and Y ⁴ are N, otherwise they are C;

Each R ³ is a substituent on any C atom in Y ¹ , Y ² , Y ³ and Y ⁴ , and is independently selected from F, Cl, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy may be optionally substituted independently with one or more F;

q is 0, 1, or 2;

The linker is a saturated or partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has a minimum length of 6 to 26 atoms between the terminal attachment points 'a' and 'b' and 'a' and 'b'; the framework may comprise one or more straight and/or branched chains and/or rings, and is optionally substituted with one or more F on any available C atom(s);

W is the E3 ubiquitin ligase cereblon binder unit].

2. In statement 1, the linker is a compound of formula I, which is a saturated or partially unsaturated framework, or a pharmaceutically acceptable salt thereof.

3. In statement 1 or statement 2, the linker is a compound of formula I comprising C and H atoms and at least two heteroatoms, or a pharmaceutically acceptable salt thereof.

4. In statement 1 or statement 2, the linker is a compound of formula I comprising C and H atoms and one or more nitrogen heteroatoms in the form of a secondary or tertiary amine, or a pharmaceutically acceptable salt thereof.

5. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein in statement 1 or statement 2, the linker comprises 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 units, wherein A ¹ and A ² are each independently selected from N and O.

6. In any one of statements 1 to 5, the linker is a compound of formula I, or a pharmaceutically acceptable salt thereof, having the following formula:

'a' - Q ^A - Q ^B - Q ^C - 'b'

[Here,

' a ' and ' b ' indicate terminal attachment points;

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O-, -O- or -N( R ^J )- (wherein R ^J is H or C _1-3 alkyl);

Q ^C is -Q ^H -G- or -(C _1-5 alkylene)- G -;

Each G is independently a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Each Q ^H is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A , Q ^B and Q ^C are chosen such that the linker does not contain NN or NO bonds.

7. In statement 6, a compound of formula I, wherein Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O- or -N( R ^J )- (wherein R ^J is C _1-3 alkyl), or a pharmaceutically acceptable salt thereof.

8. A compound of formula I, wherein in statement 6 or statement 7, Q ^C is -Q ^H -G- or -(C _1-2 alkylene)- G -, or a pharmaceutically acceptable salt thereof.

9. In any one of statements 6 to 8, each Q ^H is independently selected from the group consisting of piperazine-1,4-diyl, azetidine-1,3-diyl, piperidine-1,4-diyl, 1,4-diazepane-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl, pyrrolidine-1,3-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c ]pyrrole-2,5-diyl, 3,6-dihydro-2 H -pyridine-1,4-diyl and A compound of formula I, selected from 9-azaspiro[5.5]undecane-3,9-diyl, or a pharmaceutically acceptable salt thereof.

10. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein in any one of statements 1 to 9, the linker is selected from any one of linkers 1 to 46 or 1 to 48 as exemplified in the description.

11. A PROTAC compound comprising an AR binding unit of the following formula Ia and an E3 ubiquitin ligase cereblon binder unit, or a pharmaceutically acceptable salt thereof:

[Chemical formula Ia]

(where R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q are as defined in Statement 1).

12. A PROTAC compound containing an AR binding unit of formula Ia and an E3 ubiquitin ligase cereblon binder unit of formula Ib below in statement 11, or a pharmaceutically acceptable salt thereof:

[Chemical formula Ib]

[Here,

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.]

13. A PROTAC compound containing an AR binding unit of formula Ia and an E3 ubiquitin ligase cereblon binder unit of formula Ic below in statement 12, or a pharmaceutically acceptable salt thereof:

[Chemical formula Ic]

[Here,

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O-, -O- or -N( R ^J )- (wherein R ^J is H or C _1-3 alkyl);

Each Q ^H is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A and Q ^B are chosen so that the chemical formula Ic does not contain NN or NO bonds.

14. In statement 12 or statement 13,

Q ^A is - G ^A - Q ^HA - or - G ^A -(C _1-5 alkylene)-,

G ^A is selected from a direct bond, -CH ₂ -, -O- or -N( R ^G )-;

R ^G is H or C _1-3 alkyl;

Q ^HA is a 4- to 11-membered nitrogen-containing saturated heterocyclic group, a PROTAC compound, or a pharmaceutically acceptable salt thereof.

15. A compound of the following chemical formula II, or a salt thereof:

[Chemical Formula II]

[Here,

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^H is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

Q ^D is C _1-2 alkylene which is directly bonded or optionally substituted with one or more F (e.g., 1 or 2 F);

(i) R ^L1 and R ^L2 together form “=O” and R ^L3 is H or C _1-6 alkoxy; or

(ii) R ^L1 and R ^L2 are each independently C _1-6 alkoxy, and R ^L3 is H;

(iii) R ^L1 and R ^L2 together form -O-(CH ₂ ) _k -O- (wherein k is 2 or 3), and R ^L3 is H; or

(iv) R ^L1 is OH or LG ¹ (wherein LG ¹ is a leaving group), and R ^L2 and R ^L3 are both H;

Here, if Q ^D is a direct bond and Q ^A is - G - Q ^H - , the value of Q ^H is chosen so that Q ^D is connected to the C atom of Q ^H ;

[ R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , Q , R ^2a , R ^2b , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q are as defined in Statement 1].

16. In statement 15, LG ¹ is a compound of formula II, or a salt thereof, selected from Cl, Br, I, trifluoromethanesulfonate and C _1-7 hydrocarbylsulfonate.

17. A compound of the following chemical formula IV, or a salt thereof:

[Chemical Formula IV]

[Here,

J is H or PG ² (wherein PG ² is a nitrogen protecting group (e.g., tert -butoxycarbonyl group));

Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));

Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;

Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O-, -O- or -N( R ^J )- (wherein R ^J is H or C _1-3 alkyl);

Each Q ^H (including the " Q ^H ring " attached to J ) is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of Q ^A , Q ^B and Q ^H rings are chosen such that formula IV does not contain NN or NO bonds; R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q are as defined in statement 1].

18. In statement 17, a compound of formula IV, or a salt thereof, wherein PG ² is C _1-6 alkoxycarbonyl.

19. A compound of the following chemical formula V, or a salt thereof:

[Chemical formula V]

[Here,

X ^X is selected from:

(i) N substituted with J (wherein J is H) or PG ³ (wherein PG ³ is a protecting group); and

(ii) C substituted with oxo or substituted with R ^U1 and R ^U2 (wherein R ^U1 and R ^U2 are each C _1-6 alkoxy; or R ^U1 and R ^U2 together represent -O-(CH ₂ ) _u -O- (wherein u is 2 or 3);

G is a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);

Q ^H ring is a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;

The values of G and Q ^H ring are chosen such that formula V does not contain NN or N O bonds; R ¹ , p , X ¹ , X ² , X ³ , X ⁴ , n , m , R ^2a , R ^2b , Q , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ and q are as defined in statement 1].

20. In statement 19, a compound of formula V, wherein PG ³ is C _1-6 alkoxycarbonyl, or a salt thereof.

21. In any one of statements 1 to 10, W is W1 , which is - Z -( R ^A ) _h

, and here, Z is And,

represents a single covalent bond or a double covalent bond;

Zero, one, or two of X ^A , X ^B , X ^C , X ^D , X ^E , and X ^F are N (provided that not both X ^E and X ^F are N), otherwise they are C;

One of X ^G , X ^H and X ^J is C(O);

One of X ^G , X ^{H ,} and X ^J is N-(2,6-dioxopiperidin-3-yl)( Y );

One of X ^G , X ^H and X ^J is selected from C( R ^T ) ₂ , -CH ₂ CH ₂ -, C(O), N(C _1-3 alkyl), -O- and -N= (wherein each R ^T is selected from H, F, Me or forms a cycloprop-1,1-diyl group together with the carbon of C( R ^T ) ₂ ;

X ^G , X ^H and X ^J are selected such that no two C(O) groups exist at adjacent positions and N-(2,6-dioxopiperidin-3-yl) is not at a position adjacent to N(C _1-3 alkyl) or O;

Each R ^A is independently a substituent on any available C atom in X ^A , X B , X ^C or X ^D selected from F, ^Cl , C _1-3 alkyl, C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy are independently optionally substituted with one or more F;

h is 0, 1, or 2;

The linker is attached to any C atom in X ^A , X ^B , X ^C or X ^D .

22. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein in statement 21, each R ^A is a substituent on any available C in X ^A , X ^B , X ^C or X ^D selected from F, Cl and C _1-3 alkoxy (optionally substituted with one or more F).

23. In statement 21 or statement 22, X ^G - X ^H - X ^J

(i) X ^G -N Y -C(O) (wherein, X ^G is -CH ₂ -, -CH ₂ CH ₂ -, =N-, or C(O));

(ii) X ^G -C(O)-N Y (wherein, X ^G is -O- or N(C _1-3 alkyl); or

(iii) C(O)-N Y -CH ₂

A compound of formula I, or a pharmaceutically acceptable salt thereof.

24. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein in any one of statements 21 to 23, - Z -( R ^A ) _h together represent any one of groups 1 to 21 as exemplified in the description.

25. In any one of statements 1 to 10, W is is W2 ;

Z ^A is And,

Here,

represents a single covalent bond or a double covalent bond;

One of X ^A2 , X ^B2 , X ^{C2 ,} and X ^D2 is C and is covalently bonded to Y ;

Zero, one, or two of X ^A2 , X ^B2 , X ^C2 , X ^D2 , X ^E2 , and X ^F2 are N (provided that not both X ^E2 and X ^F2 are N), otherwise they are C;

One or two of X ^G2 , X ^H2 and X ^J2 N; otherwise, they are C;

Each R ^AA is a substituent on any available C or N atom of Z , independently selected from R ^AA1 optionally substituted with one or more R ^AA2 in each case; when R ^AA is a substituent on an available C atom of Z ^A , R ^AA is additionally selected from R ^AA2 ;

Each R ^AA1 is independently C _1-4 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxyC _1-3 alkyl, carboxyC _1-3 alkyl, C _5-7 carbocyclyl or 4- to 6-membered heterocyclyl;

Each R ^AA2 is independently selected from 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 (wherein said C _1-3 alkyl is optionally substituted with one or more F);

v is 0, 1, or 2;

A compound of formula I, wherein Y is N-(2,6-dioxopiperidin-3-yl), or a pharmaceutically acceptable salt thereof.

26. In statement 25,

One of X ^A2 and X ^B2 is C and covalently bonded to Y, and the other of X ^A2 and X ^B2 is C;

Zero or one of X ^C2 and X ^D2 is N, otherwise they are C;

One of X ^G2 and X ^J2 N and the other of X ^G2 and X ^J2 is C;

X ^H2 , X ^E2 and X ^F2 are Any compound or salt thereof, which is C.

27. In statement 25, W is W2-1

And,

Here,

X ^K and X ^L are N-linker and CH or NMe and C-linker, respectively;

One of X ^M and X ^O is N-(2,6-dioxopiperidin-3-yl)( Y );

Zero or one of X ^M and X ^N is CF;

X ^N can be N if X ^M is not CF;

A compound, or a salt thereof, wherein the remainder of X ^N , X ^M and X ^O are CH.

28. In statement 27, W represents any one of groups 22 to 26 exemplified below, a compound, or a salt thereof:

.

29. A compound, or a salt thereof, in any of the preceding statements, wherein X ¹ is C and zero or one of X ² , X ³ and X ⁴ is N and otherwise they are C; or both X ³ and X ⁴ are C and - X ⁵ = X ⁶ - X ⁷ = X ⁸ - is substituted such that X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ , wherein one of X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ is N and otherwise they are C.

30. A compound, or a salt thereof, wherein in any of the preceding statements, R ^2a and R ^2b are substituents on the same or different C atoms adjacent to Q.

31. A compound, or a salt thereof, wherein in any of the preceding statements, R ^2a and R ^2b are substituents on the same or different C atoms, each independently selected from H and C _1-3 alkyl.

32. In any of the above statements, Y ¹ , Y ² , Y ³ and Y ⁴ are each selected from (C, C, C, C), (N, C, C, C), (C, N, C, C) and (N, C, N, C), a compound or a salt thereof.

33. A compound, or a salt thereof, wherein in any of the preceding statements, q is 0, 1 or 2 and R ³ (if present) is a substituent on any C atom in Y ¹ , Y ² , Y ³ and Y ⁴ selected from F and C _1-3 alkyl.

34. A compound, or a salt thereof, wherein in any of the preceding statements, p is 1; X ³ and X ⁴ are not substituted by - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ , X ² , X ³ and X ⁴ are all C and R ¹ is CF ₃ as a substituent on X ¹ .

35. A compound, or a salt thereof, wherein in any one of statements 1 to 33, p is 2; X ³ and X ⁴ are not substituted with - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ , X ² , X ³ and X ⁴ are all C; and one R ¹ substituent is CF ₃ as a substituent on X ¹ , and the other R ¹ substituent is F or ethyl as a substituent on X ² .

36. A compound, or a salt thereof, wherein in any of the preceding statements, n is 1, m is 1, Q is CH, R ^2a is H and R ^2b is H.

37. A compound or a salt thereof, wherein in any of the above statements, zero or one of Y ¹ , Y ² , Y ³ and Y ⁴ is N, and otherwise they are C.

38. A compound, or a salt thereof, in any of the preceding statements, wherein Y ¹ , Y ² , Y ³ and Y ⁴ are all C.

39. A compound, or a salt thereof, in any of the preceding statements, wherein q is 0.

40. A compound, or a salt thereof, in any one of statements 1 to 38, wherein q is 1, R ³ is attached to C in Y ¹ , and R ³ is selected from F, CN, and Me.

41. A compound, or a salt thereof, wherein in any one of statements 1 to 38, q is 2, and each R ³ group is F, which is attached to C in Y ¹ and Y ³ .

42. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient.

43. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

44. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of a solid tumor.

45. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of an AR sensitive tumor type.

46. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumor type having one or more mutant forms of the androgen receptor.

47. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer.

48. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of castration-resistant prostate cancer.

49. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of metastatic castration-resistant prostate cancer.

50. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the treatment of AR mutant cancer.

51. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use as a medicine.

52. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use in therapy.

53. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body by therapy.

54. A compound of formula I according to any one of statements 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in producing an antiproliferative effect in a warm-blooded animal such as a human.

55. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for producing an antiproliferative effect in a warm-blooded animal such as a human.

56. A method for producing an antiproliferative effect in a warm-blooded animal, such as a human, in need of an antiproliferative effect, comprising administering to said animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

57. A compound of formula I or a PROTAC of formula Ia according to any one of claims 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use as an anti-invasive agent in the blockade and/or treatment of solid tumor diseases.

58. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as an anti-invasive agent in the blockade and/or treatment of solid tumor diseases.

59. A method for producing an anti-invasive effect by blockade and/or treatment of a solid tumor disease in a warm-blooded animal such as a human, comprising administering to said animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

60. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of cancer.

61. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of cancer.

62. A method for preventing or treating cancer in a warm-blooded animal, such as a human, in need of treatment, such as prevention or treatment of cancer, comprising administering to said animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

63. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of solid tumor(s).

64. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of solid tumor(s).

65. A method for preventing or treating solid tumor(s) in a warm-blooded animal, such as a human, in need of treatment, such as prevention or treatment of solid tumor(s), comprising administering to said animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

66. A compound of formula I according to any one of claims 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of tumor types sensitive to androgen receptor degradation.

67. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of tumor types sensitive to androgen receptor degradation.

68. A method for preventing or treating a type of tumor in a warm-blooded animal, such as a human, in need of such treatment, such as prevention or treatment of a type of tumor sensitive to degradation of the androgen receptor, comprising administering to said animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

69. A compound of formula I according to any one of statements 1 to 14 or 21 to 41 or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof, for use in providing a degradative effect on the androgen receptor in a warm-blooded animal such as a human.

70. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for providing a degradative effect on the androgen receptor in a warm-blooded animal such as a human.

71. A method for providing said effect in a warm-blooded animal, such as a human, in need of a degradative effect on the androgen receptor, comprising administering to said animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

72. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use in providing a selective degradative effect on androgen receptors in a warm-blooded animal such as a human.

73. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for providing a selective degrading effect on the androgen receptor in a warm-blooded animal such as a human.

74. A method for providing said effect in a warm-blooded animal, such as a human, in need of a selective degrading effect on the androgen receptor, comprising administering an effective amount of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof.

75. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumor type harboring an androgen receptor mutation.

76. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of a tumor type carrying an androgen receptor mutation.

77. A method for preventing or treating a tumor type in a warm-blooded animal, such as a human, having an androgen receptor mutation, comprising administering to the animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

78. A compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC).

79. Use of a compound of formula I or a PROTAC of formula Ia according to any one of statements 1 to 14 or 21 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer (e.g. castration-resistant prostate cancer (CRPC), e.g. metastatic CRPC).

80. A method for treating prostate cancer (e.g., castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC)) in a warm-blooded animal, such as a human, in need thereof, comprising administering to said animal an effective amount of a compound of formula I according to any one of statements 1 to 14 or 21 to 41, or a PROTAC of formula Ia, or a pharmaceutically acceptable salt thereof.

Claims (28)

A compound of the following formula I, or a pharmaceutically acceptable salt thereof:
[Chemical Formula I]

[Here,
X ¹ is C and 0, 1 or 2 of X ² , X ³ and X ⁴ are N, otherwise they are C;
or
X ³ and X ⁴ are both C, and - X ⁵ = X ⁶ - X ⁷ = X ⁸ - (where X ⁵ is attached to X ³ and X ⁸ is attached to X ⁵ ) are substituted, where one or two of X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ are N, otherwise they are C;
p is 1 or 2 and X ¹ is C attached to R ¹ (unless X ³ and X ⁴ are substituted - X ⁵ = X ⁶ - X ⁷ = X ⁸ -); otherwise p is 0, 1, or 2;
Each R ¹ is ^a substituent on any C atom in X ¹ , X ² , X ³ and X ⁴ (or in X ¹ , X ² , X ⁵ , X ⁶ , X ⁷ and X ⁸ when X ³ and X 4 are substituted such that - X ⁵ = X ⁶ - X ⁷ = X ⁸ -), and is independently selected from F, Cl, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy may be optionally substituted independently with one or more F;
n is 0, 1, or 2;
m is 0 or 1;
Q is CH or N (if both n and m are non-zero), otherwise Q is CH;
R ^2a and R ^2b are substituents on the same or different C atoms other than Q , each independently selected from H, F and C _1-3 alkyl, or R ^2a and R ^2b together form a -(CH ₂ ) _r - group, wherein r is 1, 2 or 3;
Zero, one, or two of Y ¹ , Y ² , Y ^{3 ,} and Y ⁴ are N, otherwise they are C;
Each R ³ is a substituent on any C atom in Y ¹ , Y ² , Y ³ and Y ⁴ , and is independently selected from F, Cl, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy may be optionally substituted independently with one or more F;
q is 0, 1, or 2;
The linker is a saturated or partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has a minimum length of 6 to 26 atoms between the terminal attachment points 'a' and 'b' and 'a' and 'b'; the framework may comprise one or more straight and/or branched chains and/or rings, and is optionally substituted with one or more F on any available C atom(s);
W is the E3 ubiquitin ligase cereblon binder unit]. In claim 1, the linker is a compound of formula I, or a pharmaceutically acceptable salt thereof, having the following chemical formula:
'a' - Q ^A - Q ^B - Q ^C - 'b'
[Here,
' a ' and ' b ' indicate terminal attachment points;
Q ^A is - G - Q ^H - or - G -(C _1-5 alkylene)-;
Q ^B is a direct bond, - Q ^B1 - Q ^B2 - Q ^B3 - or C _1-3 alkylene (optionally substituted with one or more F (e.g. 1 or 2));
Q ^B1 and Q ^B3 each independently represent a direct bond or C _1-2 alkylene;
Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O-, -O- or -N( R ^J )- (wherein R ^J is H or C _1-3 alkyl);
Q ^C is -Q ^H -G- or -(C _1-5 alkylene)- G -;
Each G is independently a direct bond, -CH ₂ -, -O-, or -N( R ^G )- (wherein R ^G is H or C _1-3 alkyl);
Each Q ^H is independently a 4- to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;
The values of Q ^A , Q ^B and Q ^C are chosen such that the linker does not contain NN or NO bonds. In the second paragraph, a compound of formula I, wherein Q ^B2 is Q ^H , -O-CH ₂ CH ₂ -O- or -N( R ^J )- (wherein R ^J is C _1-3 alkyl), or a pharmaceutically acceptable salt thereof. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein in claim 2 or 3, Q ^C is -Q ^H -G- or -(C _1-2 alkylene)- G -. In any one of claims 2 to 4, each Q ^H is independently selected from piperazine-1,4-diyl, azetidine-1,3-diyl, piperidine-1,4-diyl, 1,4-diazepane-1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecane-3,9-diyl, pyrrolidine-1,3-diyl, 3,9-diazaspiro[5.5]undecane-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptane-2,5-diyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c ]pyrrole-2,5-diyl, 3,6-dihydro-2 H -pyridine-1,4-diyl and A compound of formula I, selected from 9-azaspiro[5.5]undecane-3,9-diyl, or a pharmaceutically acceptable salt thereof. In claim 1, the linker is a compound of formula I, selected from any one of linkers 1 to 46 or 1 to 48, or a pharmaceutically acceptable salt thereof:


. In any one of claims 1 to 6, W is a compound of formula I, which is W1 , which is -Z- ( R ^A ) _h , or a pharmaceutically acceptable salt thereof.
[Here, Z is And,
represents a single covalent bond or a double covalent bond;
Zero, one, or two of X ^A , X ^B , X ^C , X ^D , X ^E , and X ^F are N (but not both X ^E and X ^F are N), otherwise they are C;
One of X ^G , X ^H and X ^J is C(O);
One of X ^G , X ^{H ,} and X ^J is N-(2,6-dioxopiperidin-3-yl)( Y );
One of X ^G , X ^H and X ^J is selected from C( R ^T ) ₂ , -CH ₂ CH ₂ -, C(O), N(C _1-3 alkyl), -O- and -N= (wherein each R ^T is selected from H, F, Me or forms a cycloprop-1,1-diyl group together with the carbon of C( R ^T ) ₂ ;
X ^G , X ^H and X ^J are selected such that no two C(O) groups exist at adjacent positions and N-(2,6-dioxopiperidin-3-yl) is not at a position adjacent to N(C _1-3 alkyl) or O;
Each R ^A is independently a substituent on any available C atom in X ^A , X B , X ^C or X ^D selected from F, ^Cl , C _1-3 alkyl, C _1-3 alkoxy, wherein said C _1-3 alkyl and C _1-3 alkoxy are independently optionally substituted with one or more F;
h is 0, 1, or 2;
The linker is attached to any C atom in X ^A , X ^B , X ^C or X ^D . A compound of formula I, or a pharmaceutically acceptable salt thereof, in claim 7, wherein each R ^A is any available substituent on C in X ^A , X ^B , X ^C or X ^D selected from F, Cl and C _1-3 alkoxy (optionally substituted with one or more F). In paragraph 7 or statement 22, X ^G - X ^H - X ^J
(i) X ^G -N Y -C(O) (wherein, X ^G is -CH ₂ -, -CH ₂ CH ₂ -, =N-, or C(O));
(ii) X ^G -C(O)-N Y (wherein, X ^G is -O- or N(C _1-3 alkyl); or
(iii) C(O)-N Y -CH ₂
A compound of formula I, or a pharmaceutically acceptable salt thereof. In any one of claims 1 to 6, W is a compound of formula I, which is any one of groups 1 to 21, or a pharmaceutically acceptable salt thereof:
. In any one of claims 1 to 6, W is is W2 ;
Z ^A is And,
Here,
represents a single covalent bond or a double covalent bond;
One of X ^A2 , X ^B2 , X ^{C2 ,} and X ^D2 is C and is covalently bonded to Y ;
Zero, one, or two of X ^A2 , X ^B2 , X ^C2 , X ^D2 , X ^E2 , and X ^F2 are N (provided that not both X ^E2 and X ^F2 are N), otherwise they are C;
One or two of X ^G2 , X ^H2 and X ^J2 N; otherwise, they are C;
Each R ^AA is a substituent on any available C or N atom of Z , independently selected from R ^AA1 optionally substituted with one or more R ^AA2 in each case; when R ^AA is a substituent on an available C atom of Z ^A , R ^AA is additionally selected from R ^AA2 ;
Each R ^AA1 is independently C _1-4 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxyC _1-3 alkyl, carboxyC _1-3 alkyl, C _5-7 carbocyclyl or 4- to 6-membered heterocyclyl;
Each R ^AA2 is independently selected from 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 (wherein said C _1-3 alkyl is optionally substituted with one or more F);
v is 0, 1, or 2;
A compound of formula I, wherein Y is N-(2,6-dioxopiperidin-3-yl), or a pharmaceutically acceptable salt thereof. In Article 11,
One of X ^A2 and X ^B2 is C and covalently bonded to Y, and the other of X ^A2 and X ^B2 is C;
Zero or one of X ^C2 and X ^D2 N, otherwise they are C;
One of X ^G2 and X ^J2 N and the other of X ^G2 and X ^J2 is C;
X ^H2 , X ^E2 and X ^F2 are Any compound or salt thereof, which is C. In Article 11, W is W2-1
And,
Here,
X ^K and X ^L are N-linker and CH or NMe and C-linker, respectively;
One of X ^M and X ^O is N-(2,6-dioxopiperidin-3-yl)( Y );
Zero or one of X ^M and X ^N is CF;
X ^N can be N if X ^M is not CF;
A compound, or a salt thereof, wherein the remainder of X ^N , X ^M and X ^O are CH. In any one of claims 1 to 6, W represents any one of groups 22 to 26 exemplified below, a compound, or a salt thereof:
. A compound, or a salt thereof, in any one of claims 1 to 14, wherein R ^2a and R ^2b are substituents on the same or different C atoms adjacent to Q. A compound, or a salt thereof, in any one of claims 1 to 15, wherein R ^2a and R ^2b are substituents on the same or different C atoms, and are each independently selected from H and C _1-3 alkyl. A compound according to any one of claims 1 to 16, wherein p is 1; X ³ and X ⁴ are not substituted with - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ , X ² , X ³ and X ⁴ are all C and R ¹ is CF ₃ as a substituent on X ¹ , or a salt thereof. A compound according to any one of claims 1 to 16, wherein p is 2; X ³ and X ⁴ are not substituted with - X ⁵ = X ⁶ - X ⁷ = X ⁸ -; X ¹ , X ² , X ³ and X ⁴ are all C; and one R ¹ substituent is CF ₃ as a substituent on X ¹ , and the other R ¹ substituent is F or ethyl as a substituent on X ² , or a salt thereof. A compound according to any one of claims 1 to 18, wherein n is 1, m is 1, Q is CH, R ^2a is H and R ^2b is H, or a salt thereof. A compound, or a salt thereof, in any one of claims 1 to 19, wherein Y ¹ , Y ² , Y ³ and Y ⁴ are all C. A compound, or a salt thereof, according to any one of claims 1 to 20, wherein q is 0. A compound according to any one of claims 1 to 20, or a salt thereof, wherein q is 1, R ³ is attached to C in Y ¹ , and R ³ is selected from F, CN and Me. A compound according to any one of claims 1 to 21, wherein q is 2, and each R ³ group is F, which is attached to C in Y ¹ and Y ³ , or a salt thereof. In claim 1, a compound of the following chemical formula VI or a pharmaceutically acceptable salt thereof, a compound, or a salt thereof:
[Chemical Formula VI]

(Here,
R ^Z1 is H or F;
R ^Z2 is H or F;
R ^Z3 is H or F;
L ^Z is a linker selected from 1, 3, 45 and 47:


W ^Z is selected from 1, 2, 3, 10, 16, 22, 23, 24 and 26:


Y is N-(2,6-dioxopiperidin-3-yl)). In claim 1, a compound of the following chemical formula VI-1 or a pharmaceutically acceptable salt thereof, a compound, or a salt thereof:
[Chemical Formula VI-1]

(Here,
R ^Z1 is H or F;
L ^Z is a linker selected from 1 and 3:

W ^Z is selected from 1, 2 and 10:

Y is N-(2,6-dioxopiperidin-3-yl)). In claim 1, a compound of the following chemical formula VI-2 or a pharmaceutically acceptable salt thereof, a compound, or a salt thereof:
[Chemical Formula VI-2]

(Here,
R ^Z1 is H or F;
R ^Z2 is H or F;
R ^Z3 is H or F;
L ^Z is a linker selected from 3, 45 and 47:

W ^Z is selected from 1, 3, 16, 22, 23, 24 and 26:


Y is N-(2,6-dioxopiperidin-3-yl)). A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient. A compound of formula I according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for use in the prevention or treatment of tumor types sensitive to the degradation of the androgen receptor, or in the treatment of prostate cancer (e.g. castration-resistant prostate cancer (CRPC), e.g. metastatic CRPC).