WO2023139199A1 - Compounds and their use in treating cancer - Google Patents

Compounds and their use in treating cancer Download PDF

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Publication number
WO2023139199A1
WO2023139199A1 PCT/EP2023/051344 EP2023051344W WO2023139199A1 WO 2023139199 A1 WO2023139199 A1 WO 2023139199A1 EP 2023051344 W EP2023051344 W EP 2023051344W WO 2023139199 A1 WO2023139199 A1 WO 2023139199A1
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compound
formula
mmol
pharmaceutically acceptable
diyl
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PCT/EP2023/051344
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French (fr)
Inventor
Martin John Packer
Coura Rosalie DIENE
Charlene FALLAN
Sharanjeet Kaur Bagal
James Scott
Doyle Joseph CASSAR
Johannes Wilhelmus Maria Nissink
Lakshmaiah GINGIPALLI
Sameer Pralhad Kawatkar
Qing Ye
Peter Astles
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Astrazeneca Ab
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Publication of WO2023139199A1 publication Critical patent/WO2023139199A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • This specification relates to certain Proteolysis Targeting Chimera (PROTAC) compounds and, as a minimum, their ability to degrade the Androgen Receptor (AR) and therefore their use for the treatment of diseases or disorders dependent on the androgen receptor in mammals.
  • Degradation of androgen receptors may provide, for example, an anti-tumour effect and accordingly this specification relates in part to the use of such compounds for the treatment of cancer and to pharmaceutical compositions containing them. It also relates to intermediate compounds that may be useful in the preparation of such PROTACs.
  • PROTAC molecules are often described as having three parts - (1) a part that is capable of binding to the target protein to be degraded, (2) a second part that is capable of binding to an E3 ubiquitin ligase, and finally, a linker that connects (1) and (2) together.
  • the PROTAC binds to both the target protein and E3 ubiquitin ligase simultaneously to form 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 labelling the target protein for degradation by the cell’ s proteasome machinery.
  • a PROTAC can then dissociate from the target protein and initiate another cycle of this process in a catalytic manner. Meanwhile, the ubiquitinated target proteins are recognized and degraded by the cell’s proteasome machinery.
  • This PROTAC-mediated approach may be valuable as a method of treating certain diseases where the targeted degradation of specific bodily proteins may be beneficial, for example in the treatment of cancer.
  • One such cancer-related target is the androgen receptor.
  • the androgen receptor belongs to the steroid hormone group of nuclear receptors and is a ligand-dependent transcription factor which controls the expression of a range of genes involved in growth and survival of prostate cells.
  • AR is composed of four distinct domains: the N-terminal domain (NTD), DNA binding domain (DBD), a hinge region which 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 dimerise and translocate from the cytoplasm into the nucleus.
  • NTD N-terminal domain
  • DBD DNA binding domain
  • LBD C-terminal ligand binding domain
  • DHT dihydrotestosterone
  • nucleus receptor dimers bind to androgen response elements (AREs) in the promoters of androgen responsive genes such as PSA and FKBP5.
  • AREs androgen response elements
  • the AR signalling pathway is critical for normal prostate development and male sexual differentiation fails to occur in the absence of androgens or without a functioning AR.
  • abiraterone acetate is an androgen biosynthesis inhibitor which targets cytochrome p450 enzyme 17R-hydroxlase-17,20-lyase (CYP17).
  • CYP17 cytochrome p450 enzyme 17R-hydroxlase-17,20-lyase
  • Testosterone is processed in the testes and adrenal glands by CYP17 and therefore inhibition of this enzyme inhibits prostate tumour growth by decreasing circulating androgen levels.
  • AR PROTACs which bind the ligand binding domain of the androgen receptor and simultaneously recruit an E3 ligase such as cereblon leading to ubiquitination and degradation of AR via the proteasome, could offer therapeutic benefit to patients with prostate cancer, particularly metastatic CRPC.
  • AR PROTACs may also be useful against AR+ breast cancer.
  • WO2018/071606 describes certain PROTAC compounds said to be AR degraders.
  • binders and PROTACs alike there is always the issue of “off- target” activity in vivo which can be important to avoid in the development of safe and effective drug treatments.
  • a given binding unit may be very potent against the intended target, but if it is inadvertently potent against other unintended biological targets in the human body, it may cause unacceptable toxicities, side effects and so on.
  • PROTACs Other properties of interest during pharmaceutical discovery and development of such PROTACs may relate to selectivity profile, absorption/bioavailability, distribution, metabolism, elimination, toxicity and side-effect profile, stability, manufacturability and so on.
  • the compounds of this specification provide, as a minimum, potent AR binding units suitable for incorporation into PROTAC compounds, and to PROTAC compounds containing such AR binding units together with an E3 ubiquitin ligase cereblon binder unit at the other end of the PROTAC molecule.
  • Certain AR binding units are advantageously configured to degrade not only the wild-type AR, but also one or more clinically relevant mutant forms of AR too, for example L702H.
  • Certain PROTAC compounds of this specification also have a surprisingly beneficial combination of properties, e.g. relating to AR degradation and selectivity/safety profile in combination.
  • This specification relates to the above-mentioned AR-binding units and to PROTAC compounds (and pharmaceutically acceptable salts thereof) that incorporate such AR binding units together with an E3 ubiquitin ligase cereblon binder unit (the two units being linked by a linker).
  • This specification also relates to pharmaceutical compositions containing such PROTACs (and pharmaceutically acceptable salts thereof) and their use in methods of treatment in the human or animal body, for example in the treatment or prevention of cancer.
  • This specification also relates to processes and intermediate compounds (and salts thereof) involved in the preparation of said PROTACs.
  • X 1 is C & 0, 1 or 2 of X 2 , X 3 & X 4 is/are N, and are otherwise C: or
  • each R 1 is a substituent on any C atom at X 1 , X 2 , X 3 & X 4 , (or at X 1 , X 2 , X s , X 6 , X 7
  • Ci-aalkyl and Ci-aalkoxy are independently selected from F, Cl, Ci-aalkyl and Ci-aalkoxy, wherein said Ci-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F; n is 0, 1 or 2; m is 0 or 1 ;
  • Q is CH or N when n & m are both other than 0 and otherwise Q is CH;
  • R 2a and R 2b are substituents on the same or different C atoms other than at Q, each independently selected from H, F and Ci-aalkyl, or R 2a & R 2b together form a -(CH2) r - group where r is 1 , 2 or 3 ;
  • each R 3 is a substituent on any C atom at Y 1 , Y 2 , Y 3 & Y 4 , and is/are independently selected from F, Cl, CN, C i-aalkyl and Ci-aalkoxy, wherein said C i-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F ; q is 0, 1 or 2;
  • Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and a minimum length of from 6 to 26 atoms between ‘a’ and ‘b’; wherein said framework may include one or more straight and/or branched chains and/or rings and is optionally substituted on any available C atom(s) by one or more F; and
  • W is an E3 ubiquitin ligase cereblon binder unit.
  • composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • This specification also describes, in part, a method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the present researchers have not just developed a range of beneficial AR binding units, but gained an understanding about where such binding units can incorporate a linker (leading to an E3 ubiquitin ligase cereblon binder unit) without it interfering with their AR binding capability. Accordingly the present researchers understand that when incorporating their AR binding units into a PROTAC, the linker of said PROTAC should not attach at the left or central rings in Formula (I) shown hereinabove, but may suitably attach at the specified position on the right-hand ring in the compound of Formula (I) as shown herein.
  • a PROTAC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la): 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 may take any of the values defined herein for each of these integers respectively.
  • Formula (la) indicates a point of connection via a single covalent bond to the remainder of the PROTAC compound.
  • PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of Formula (la) as described herein.
  • the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 6 to 26 atoms, said atoms being linked by single covalent bonds and each selected from carbon or a heteroatom (i.e. O, N or S).
  • the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 7 to 14 atoms, said atoms being linked by single covalent bonds and each selected from carbon or a heteroatom (i.e. O, N or S).
  • the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 6 to 26 atoms, said atoms being linked by single covalent bonds and each selected from C, N or O.
  • the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 7 to 14 atoms, said atoms being linked by single covalent bonds and each selected from C, N or O.
  • the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length of from 0.9 nm to 4 nm.
  • the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length of from 1.0 nm to 2.2 nm.
  • the link between androgen receptor binding unit of Formula (la) [as described above] and an E3 ubiquitin ligase cereblon binder unit is a Linker as defined according to any embodiment or claim herein, where the point of attachment shown in Formula (la) above connects to the ‘a’ point of connection on any Linker as defined herein.
  • a pharmaceutically acceptable salt of a compound of Formula (I) or PROTAC compound described herein may be, for example, an acid-addition salt when said compound contains a basic functional group, such as an amine.
  • An acid-addition salt may be formed using an inorganic acid or an organic acid.
  • a pharmaceutically acceptable salt of said compound may be, for example, a base-addition salt when said compound contains an acidic functional group, such as a carboxylic acid.
  • An acid-addition salt may be formed using an inorganic base or an organic base. “Pharmaceutically acceptable salt” is used to specify that the salt is suitable for use in the human or animal body. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H.
  • a pharmaceutically acceptable salt of a compound of Formula (I) or PROTAC compound includes such salts that may be formed within the human or animal body after administration of said compound to said human or animal body.
  • alkyl includes straight chain, branched chain and cyclic alkyl groups and combinations thereof having the specified number of carbon atoms. Therefore, C i.vilkvl includes methyl, ethyl, w-propyl, isopropyl and cyclopropyl; and Ci.galkyl would include (4-isopropylcyclohexyl)methyl.
  • alkoxy includes straight chain, branched chain and/or cyclic alkoxy groups having the specified number of carbon atoms. Therefore, Ci-aalkoxy includes methoxy, ethoxy, w-propoxy, isopropoxy and cyclopropoxy.
  • methyl optionally substituted by one or more F includes -CI L. -CH 2 F, -CHF 2 and -CF 3 .
  • substituted means that one or more hydrogens on the designated atom or group is replaced by the indicated substituent(s) provided that any atom(s) bearing such substituent(s) maintains its permitted valency where the skilled person understands that the standard valencies of carbon, nitrogen and oxygen are 4, 3 and 2 respectively. Therefore, “substituted on any available C atom(s)” is to be understood to mean that the substituent(s) is/are limited in their positioning (and/or potentially in their number) according to whether there are any hydrogen atoms remaining on the designated atom or group which could be replaced by said substituent(s).
  • the dashed bonds included in Z indicate the possibility that the bond may in each case be a single covalent bond or a double covalent bond - in accordance with the atom (or group of atoms) present at each of the X E , X E , X G , X H and X J positions.
  • the skilled person understands that the standard valencies of carbon, nitrogen and oxygen are as mentioned above, and as such they can understand whether each dashed bond should be interpreted as a single bond or a double bond in any given Z group in the compound of Formula (I). The same applies to the X E2 , X E2 , X G2 , X H2 and X J2 positions in Z A .
  • X G and X H are adjacent each other, X H and X J are also adjacent each other, but X G is not adjacent X J .
  • 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.
  • heteroatom may represent an oxygen, nitrogen or sulfur atom unless explicitly further limited in a given context.
  • minimum length of [... ] atoms between ‘a’ and ‘b’ refers to the shortest chain of atoms in the chain between ‘a’ and ‘b’. Therefore, if the chain consisted of -CH2CH2CH2-, the number of atoms in the chain is 3 (the hydrogen atoms are regarded as not being in the chain). Alternatively if the chain consisted of 1,3-phenylene, where the shorter route around the phenyl ring contains 3 C atoms and the long route around the phenyl ring contains 5 C atoms, the minimum length of such a chain would be counted as 3 atoms.
  • rings or “heterocyclic groups” may include single rings, fused rings, spirocyclic rings and bridged rings.
  • the branching where present may be present on a chain (even a chain of 1 atom length) and/or on a ring.
  • the skilled person would generally interpret in this manner, but for the avoidance of doubt, it is to be understood that the “branching” that occurs inherently in order to form a ring is not considered “branching” in the context of the Linker embodiments described herein.
  • Linker #22 described hereinafter is an example where there is one branch (-Me) coming from a chain within the Linker.
  • branches refer to branches that branch off the main chain of atoms between ‘a’ and ‘b’, leading to a ‘dead end’ in the molecular structure.
  • point of attachment of a given group to some other group may be represented by a line meeting a bond substantially at right angles to said bond, for example as shown on the far right-hand side of Formula (la) herein, and for example at either end of Linkers 1 to 46 depicted hereinafter.
  • a reference to a secondary or tertiary amine is intended to have the normal meaning in the art and therefore a nitrogen atom that is part of an amide group or a sulphonamide group, for example, is not to be regarded as a secondary or tertiary amine.
  • a saturated heterocyclic group refers to at least one ring of atoms (including bridged rings, spiro rings, fused rings, and single rings) containing carbon atoms and at least one heteroatom, where the heteroatom(s) is/are each independently selected from N, O and S, and where each atom in the ring is linked to its adjacent atoms by single covalent bonds. Therefore, an example of a heterocyclic group is a spiro heterocyclic group having two rings and a total of one heteroatom such as 9-azasprio[5.5]undecane.
  • a saturated heterocyclic group will have at least two carbon atoms separating each of the heteroatom(s) present in said group to ensure a suitable level of chemical stability for use in a pharmaceutical context.
  • a “nitrogen-containing saturated (or partially unsaturated) heterocyclic group” this requires the presence of at least one nitrogen heteroatom but does not limit the possibility of one or more non-nitrogen heteroatoms (i.e. S, O) being present in addition.
  • a partially unsaturated heterocyclic group refers to at least one ring of atoms (including bridged rings, spiro rings, fused rings, and single rings) containing carbon atoms and at least one heteroatom, where the heteroatom(s) is/are each independently selected from N, O and S, and where at least two atoms within the heterocyclic group are connected to each other via a double covalent bond.
  • partially unsaturated does not include fully unsaturated heterocyclic groups - i.e. where the group contains the maximum possible number of double bonds for the atomic framework in question.
  • a cyclic group e.g. a heterocyclic group having a specified number of ring atoms
  • an alkylene group (for example a C .salkvlene ) is a saturated group consisting only of carbon and hydrogen atoms with two points of attachment to adjacent atoms/groups. They may include straight chain(s), branched chain(s) and/or ring(s). Accordingly Cialkylene represents -CH2-, a C2alkylene can represent -CH2CH2- or -CH(Me)-, C i.salkvlene includes for example -CI hfcvclobut- 1,3 -diyl)-.
  • a “straight chain C ui . ⁇ alkylene” corresponds to -(CH2) U - where u is an integer from ul to u2.
  • a hydrocarbyl group means any group consisting only of C and H atoms.
  • Ci-yhydrocarbyl includes methyl, phenyl and p-tolvl.
  • the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • the term “therapy” also includes “prophylaxis” or “prophylactic” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • prophylactic is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • variable groups are as follows. One, two or more of such values, may be used in any combination with any other definitions, claims, aspects or embodiments herein (unless the context doesn’t permit) to provide further embodiments/claims of the specification.
  • X 1 is C & 0, 1 or 2 of X 2 , X 3 & X 4 is N and are otherwise C.
  • X 1 is C & 0 or 1 of X 2
  • X 3 & X 4 is N and are otherwise C.
  • X 1 is C & 1 or 2 of X 2
  • X 3 & X 4 is/are N and are otherwise C.
  • X 1 is C & 1 of X 2
  • X 3 & X 4 is N and are otherwise C.
  • X 1 , X 2 , X 3 & X 4 are all C.
  • each R 1 is selected from Cl, F, C i.vilkvl (optionally substituted by one or more F) and Ci-salkoxy.
  • p is 1 and R 1 is selected from Cl, C _;,alkvl (optionally substituted by one or more F) and Ci-aalkoxy.
  • p is 1 and R 1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.
  • p is 1, X 1 is C attached to R 1 , where R 1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.
  • p is 1
  • X 1 is C attached to R 1
  • R 1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.
  • p is 1 and R 1 is C i-salkyl optionally substituted by one or more F.
  • p is 1 and R 1 is methyl, cyclopropyl, CF3 or CHF2.
  • p is 1 and R 1 is CF3 or CHF2.
  • p is 1 and R 1 is CHF2.
  • p is 1 and R 1 is CF3.
  • p is 1 and R 1 is methyl.
  • p is 1 and R 1 is cyclopropyl.
  • p is 1 and R 1 is methoxy.
  • p is 2, and one R 1 is CFs and the other R 1 is F or ethyl.
  • p is 2, and one R 1 is CFs and the other R 1 is F.
  • p is 2, and one R 1 is CT; and the other R 1 is ethyl.
  • p is 2
  • X 1 is C attached to a first R 1 and X 2 is C attached to a second R 1 .
  • p is 2
  • X 1 is C attached to a CT
  • X 2 is C attached to either F or ethyl.
  • p is 2, X 1 is C attached to a CT; and X 2 is C attached to F.
  • p is 2, X 1 is C attached to a CT; and X 2 is C attached to ethyl.
  • n 0.
  • n 1
  • n is 2.
  • m is 0.
  • n 1
  • n 0 and m is 1.
  • n 1 and m is 1.
  • n 0 and m is 0.
  • n 0, 1 or 2; and m is 1.
  • n is 1
  • m is 1
  • Q is CH.
  • n is 1
  • m is 1
  • Q is N.
  • n is 1
  • m is 1
  • Q is CH or N
  • R 2a is H
  • R 2b is H.
  • n is 1
  • m is 1
  • Q is CH
  • R 2a is H
  • R 2b is H.
  • n 0, m is 1 , Q is CH, R 2a is H and R 2b is H
  • n 1
  • m 1
  • R 2a is H and R 2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an ( T (-stereochemical configuration.
  • n 1
  • m 1
  • R 2a is H and R 2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an (S)- stereochemical configuration.
  • n 1
  • m 1
  • R 2a is H
  • R 2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an ( T (-stereochemical configuration.
  • n is 1
  • m is 1
  • R 2a is H
  • R 2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an (S)- stereochemical configuration.
  • n is 1
  • m is 1
  • Q is N
  • R 2a is H
  • R 2b is H.
  • Q is CH with an ( R)-stereochemical configuration at said C atom.
  • Q is CH with an (S)- stereochemical configuration at said C atom.
  • n is 2; m is 1 ; R 2a & R 2b are both H: and Q is CH.
  • n 2: m is 1 : R 2a & R 2b are both H: and Q is CH with an (R)- stereochemical configuration at said C atom.
  • n 2: m is 1 : R 2a & R 2b are both H: and Q is CH with an (.S')-stereochemical configuration at said C atom.
  • R 2a and R 2b are substituents on the same or different C atoms other than at Q, each independently selected from H and Chalky 1.
  • R 2a and R 2b are substituents on the same or different C atoms other than at Q, each independently selected from H and Me.
  • R 2a and R 2b are substituents on the same or different C atoms adjacent Q and are otherwise as defined herein.
  • R 2a and R 2b are substituents on the same or different C atoms adjacent Q, each independently selected from H and C .vilkvl (for example Me).
  • R 2a and R 2b are substituents on the same or different C atoms and are both H.
  • R 2a and R 2b are substituents on the same or different C atoms other than at Q, each independently selected from H, F and Ci-aalkyl.
  • R 2a and R 2b are substituents on the same or different C atoms other than at Q, each independently selected from H and Chalky 1, or R 2a & R 2b together form a -(CH2)r- group where r is 1, 2 or 3.
  • r is 1.
  • r is 2.
  • r is 3.
  • R 2a and R 2b are substituents on the same or different C atoms other than at Q, where R 2a is Me and R 2b is H.
  • R 2a and R 2b are substituents on the same C atom other than at Q, where R 2a and R 2b are both Me.
  • R 2a and R 2b are substituents on the same C atom adjacent Q, where R 2a and R 2b are both Me.
  • Y 1 , Y 2 , Y 3 & Y 4 are respectively selected from (C, C, C, C), (N, C, C, C), (C, N, C, C) and (N, C, N, C).
  • 0 or 1 of Y 1 , Y 2 , Y 3 & Y 4 is N and are otherwise C.
  • Y 1 , Y 2 , Y 3 & Y 4 is/are N and are otherwise C.
  • Y 1 , Y 2 , Y 3 & Y 4 are respectively selected from (N, C, C, C), (C, N, C, C) and (N, C, N, C).
  • Y 1 , Y 2 , Y 3 & Y 4 is N and are otherwise C.
  • Y 1 is N: and Y 2 , Y 3 & Y 4 are all C.
  • Y 2 is N; and Y 1 , Y 3 & Y 4 are all C.
  • Y 1 , Y 2 , Y 3 & Y 4 are N and are otherwise C.
  • Y 1 & Y 3 are N: and Y 2 and Y 4 are C. In one embodiment Y 1 , Y 2 , Y 3 & Y 4 are all C.
  • q is 0 or 1.
  • q is 0.
  • q is 1.
  • q is 2.
  • q is 0, 1 or 2 and R 3 (when present) is a substituent on any C atom at Y 1 , Y 2 , Y 3 & Y 4 selected from F, CN and Chalky 1.
  • q is 0, 1 or 2 and R 3 (when present) is a substituent on any C atom at Y 1 , Y 2 , Y 3 & Y 4 selected from F and Ci-aalkyl.
  • q is 0 or 1 and R 3 (when present) is a substituent on any C atom at Y 1 , Y 2 , Y 3 & Y 4 selected from F or Ci-aalkyl.
  • q is 0 or 1 and R 3 (when present) is a substituent on any C atom at Y 1 , Y 2 , Y 3 & Y 4 selected from F or Me.
  • R 3 (when present) is Ci-aalkyl.
  • R 3 (when present) is Me.
  • R 3 (when present) is F.
  • R 3 (when present) is CN.
  • q is 1 and R 3 is attached to C at Y 1 .
  • q is 1 and R 3 is attached to C at Y 1 , and R 3 is selected from F, CN and Me.
  • q is 2 and both R 3 groups are F.
  • q is 2 and the R 3 groups are attached to C at Y 1 and Y 3 .
  • each R 3 group is F, which are attached to C at Y 1 and Y 3 .
  • Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and a minimum length of from 6 to 26 atoms between ‘a’ and ‘b’; wherein said framework may include one or more straight and/or branched chains and/or rings and is optionally substituted on any available C atom(s) by one or more F.
  • the framework of the Linker is a saturated or partially unsaturated framework.
  • the framework of the Linker is a saturated framework.
  • the framework of the Linker comprises C and H atoms and at least two heteroatoms.
  • the framework of the Linker comprises C and H atoms and at least two heteroatoms selected from O and N.
  • the framework of the Linker comprises C and H atoms and at least one nitrogen heteroatom.
  • the framework of the Linker comprises C and H atoms and at least two heteroatoms including at least one nitrogen heteroatom.
  • 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.
  • 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 C and H atoms and at least two heteroatoms including at least one nitrogen heteroatom in the form of a secondary or tertiary amine.
  • the framework of the Linker comprises C and H atoms and at least two heteroatoms including at least one nitrogen heteroatom in the form of a tertiary amine.
  • the Linker has a minimum length of from 6 to 20 atoms between ‘a’ and ‘b’.
  • the Linker has a minimum length of from 6 to 15 atoms between ‘a’ and ‘b’ .
  • the Linker has a minimum length of from 7 to 14 atoms between ‘a’ and ‘b’.
  • the total number of C and hetero atoms in the Linker framework is from 6 to 26.
  • the total number of C and hetero atoms in the Linker framework is from 7 to 24.
  • the total number of C and hetero atoms in the Linker framework is from 8 to 22.
  • the total number of C and hetero atoms in the Linker framework is from 9 to 20.
  • the Linker is attached at any available C atom at X B or X c of Z.
  • the framework of the Linker may include one or more straight chains and/or rings and is optionally substituted on any available C atom(s) by one or more F.
  • the framework of the Linker consists of one or more straight chains and/or rings that are optionally substituted on any available C atom(s) by one or more F.
  • the framework of the Linker may include (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) that are optionally substituted on any available C atom(s) by one or more F.
  • the framework of the Linker may include (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) that are optionally substituted on any available C atom(s) by one or more F.
  • the framework of the Linker may include (or consist of) one or more straight and/or branched chains and/or rings (wherein the total number of branches is 0 or 1) that are optionally substituted on any available C atom(s) by one or more F.
  • the total number of branches is 0.
  • the total number of branches is 1.
  • the total number of branches is 2.
  • the total number of branches is 3.
  • any/each branch in the framework of a Linker has from 1 to 5 C and/or hetero atoms.
  • any/each branch in the framework of a Linker has 1 or 2 C and/or hetero atoms.
  • any/each branch in the framework of a Linker has 1 C and/or hetero atom.
  • any/each branch in the framework of a Linker has 1 C atom.
  • the total number of C and/or heteroatoms in the branch(es) (where present) of the framework of the Linker is from 1 to 5.
  • the total number of C and/or heteroatoms in the branch(es) (where present) of the framework of the Linker is from 1 to 3.
  • the total number of C and/or heteroatoms in the branch(es) (where present) of the framework of the Linker is 1.
  • any the framework of the Linker is either unbranched or has one branch that is Me.
  • the framework of the Linker is optionally substituted on any available C atom(s) by 1 or 2 F (for example by 2 F, for example where said 2 F are substituted on the same carbon atom).
  • the framework of the Linker is not substituted by any F.
  • the Linker is a saturated or a partially unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and: a minimum length of from 7 to 14 atoms between ‘a’ and ‘b’; wherein the total number of C and hetero atoms in the Linker framework is from 9 to 20: where said framework comprises one or more straight and/or branched chains and/or rings that are optionally substituted on any available C atom(s) by 1 or 2 F (for example by 2 F); wherein the total number of branches is 0 or 1 and when present said branch is Me.
  • the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A 2 unit where A 1 and A 2 are each independently selected from N and O.
  • the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A 2 unit where A 1 and A 2 are each independently selected from N and O.
  • the framework of the Linker includes a A'-CI F-CI F-A 2 unit where A 1 and A 2 are each independently selected from N and O.
  • the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N and the other of A 1 & A 2 is selected from N or O.
  • nitrogen-containing saturated or partially unsaturated heterocyclic group e.g. having from 4 to 12 ring atoms
  • A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N and the other of A 1 & A 2 is selected from N or O.
  • the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N and the other of A 1 & A 2 is selected from N or O.
  • nitrogen-containing saturated heterocyclic group e.g. having from 4 to 12 ring atoms
  • A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N and the other of A 1 & A 2 is selected from N or O.
  • the framework of the Linker includes a A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N and the other of A 1 & A 2 is selected from N or O.
  • the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N in the form of a secondary or tertiary amine, and the other of A 1 & A 2 is selected from N or O.
  • nitrogen-containing saturated or partially unsaturated heterocyclic group e.g. having from 4 to 12 ring atoms
  • A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N in the form of a secondary or tertiary amine, and the other of A 1 & A 2 is selected from N or O.
  • the framework of the Linker includes a A'-CI F-CI F-A 2 unit where one of A 1 & A 2 is N in the form of a secondary or tertiary amine, and the other of A 1 & A 2 is selected from N or O.
  • the framework of the Linker includes at least one saturated or partially unsaturated heterocyclic group.
  • the framework of the Linker includes at least one saturated heterocyclic group.
  • the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group.
  • the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group. In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group having from 4 to 12 ring atoms.
  • the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group having from 4 to 12 ring atoms.
  • A'-CHi-CHi-A 2 unit where one of A 1 & A 2 is N in the form of a secondary or tertiary amine, and the other of A 1 & A 2 is selected from N or O: and/or
  • the framework of the Linker includes 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, l,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole, 1,2,3,6- tetrahydropyridine and 9-azaspiro[5.5]undecane.
  • a 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-diazas
  • the framework of the Linker includes an O-CH2-CH2-N unit.
  • the framework of the Linker includes an O-CH2CH2-O-CH2CH2-N unit.
  • the framework of the Linker includes a piperazine group.
  • the framework of the Linker includes an azetidine group.
  • the framework of the Linker includes a piperidine group.
  • the framework of the Linker includes a 1 ,4-diazepane group.
  • the framework of the Linker includes a 12-oxa-3,9-diazaspiro[5.6]dodecane group.
  • the framework of the Linker includes a pyrrolidine group.
  • the framework of the Linker includes a 3,9-diazaspiro[5.5]undecane group.
  • the framework of the Linker includes a 2,5-diazabicyclo[2.2.1]heptane group.
  • the framework of the Linker includes a 1 ,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole group.
  • the framework of the Linker includes a 1 ,2,3,6-tetrahydropyridine group.
  • the framework of the Linker includes a 9-azaspiro[5.5]undecane group.
  • the framework of the Linker includes at least two nitrogen-containing saturated or partially unsaturated heterocyclic groups.
  • the framework of the Linker includes at least two nitrogen-containing saturated heterocyclic groups. In one embodiment the framework of the Linker includes a C, N or O atom at the ‘a’ point of attachment.
  • the framework of the Linker includes an N or O atom at the ‘a’ point of attachment.
  • the framework of the Linker includes an N or O atom at the ‘b’ point of attachment.
  • the framework of the Linker includes a C atom at the ‘a’ point of attachment.
  • the framework of the Linker includes an N atom at the ‘a’ point of attachment.
  • the framework of the Linker includes a C or N atom at the ‘b’ point of attachment.
  • the framework of the Linker includes an N atom at the ‘b’ point of attachment.
  • the framework of the Linker includes a C atom at the ‘b’ point of attachment.
  • the framework of the Linker includes an O atom at the ‘a’ point of attachment.
  • the framework of the Linker includes an O atom at the ‘b’ point of attachment.
  • the framework of the Linker includes an N or O atom at both the ‘a’ and ‘b’ points of attachment.
  • the framework of the Linker includes a C, N or O atom at the ‘a’ point of attachment and a C or N atom at the ‘b’ point of attachment.
  • the framework of the Linker includes at least one nitrogen-containing saturated or partially saturated heterocyclic group selected from piperazin- 1,4-diyl, azetidin-l,3-diyl, piperidin- 1,4- diyl, 1 ,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-l,3-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1, 3 ,3a, 4 ,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3.6-dihvdro-2//-pvridin- 1 .4-divl. and 9-azaspiro[5.5]unde
  • the framework of the Linker includes a piperazin- 1,4-diyl group.
  • the framework of the Linker includes an azetidin- 1 ,3-diyl group.
  • the framework of the Linker includes a piperidin- 1,4-diyl group.
  • the framework of the Linker includes a 1 ,4-diazepan-l ,4-diyl group.
  • the framework of the Linker includes a 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl group.
  • the framework of the Linker includes a pyrrolidin-l,3-diyl group.
  • the framework of the Linker includes a 3,9-diazaspiro[5.5]undecan-3,9-diyl group.
  • the framework of the Linker includes a 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl group.
  • the framework of the Linker includes a 1 ,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5- diyl group.
  • the framework of the Linker includes a 3.6-dihvdro-2//-pvridin- 1 .4-divl group. In one embodiment the framework of the Linker includes a 9-azaspiro[5.5]undecan-3,9-diyl group.
  • the Linker has the Formula: a -Q A -Q B -Q C - b wherein:
  • ‘a’ and ‘b’ represent the end points of attachment
  • Q A is -G-Q H - or -G-(Ci- 5 alkylene)-;
  • Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or C .vilkvlene optionally substituted by one or more F (for example 1 or 2 F, for example 2 F); where:
  • Q B1 & Q B3 each independently represent a direct bond or C ⁇ alkylene
  • Q B2 is Q H , -O-CH2CH2-O-, -O- or -N(R J )- where R J is H or Ci. 3 alkyl;
  • Q c is -Q H -G- or -(Ci. 5 alkylene)-G-; each G is independently a direct bond, -CH2-, -O-, or -N(R G )- where each R G is independently H or Ci. 3 alkyl; each Q H is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of Q A , Q B and Q c are selected so that the Linker does not contain any N-N or N-O bonds.
  • the Linker has the Formula: a -Q A -Q B -Q C - b wherein:
  • ‘a’ and ‘b’ represent the end points of attachment
  • Q A is -G-Q H - or -G-(Ci. 5 alkylene)-;
  • Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or C].
  • 3 alkylene optionally substituted by one or more F (e.g. 1 or 2); where:
  • Q B1 & Q B3 each independently represent a direct bond or Chalky lene
  • Q B2 is Q H , -O-CH2CH2-O- or -N(R J )- where R J is Ci. 3 alkyl;
  • Q c is -QH-G- or -(Ci. 5 alkylene)-G-; each G is independently a direct bond, -CH2-, -O-, or -N(R G )- where each R G is independently H or
  • each Q H is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of Q A , Q B and Q c are selected so that the Linker does not contain any N-N or N-O bonds.
  • the Linker has the Formula: a -Q A -Q B -Q C - b wherein:
  • ‘a’ and ‘b’ represent the end points of attachment
  • Q A is -G A -Q HA - or -G A -(Ci-5alkylene)-; where G A is a direct bond, -CH2-, -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 i-aalkylene optionally substituted by one or more F (e.g. 1 or 2); where:
  • Q B1 & Q B3 each independently represent a direct bond or Chalky lene
  • Q B2 is piperazin- 1,4-diyl, -O-CH2CH2-O- or -N(R J )- where R J is Ci-jalkyl;
  • Q c is -Q HC -G C - or -(C i-2alkvlene)-G c -: where 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; where the values of Q A , Q B and Q c are selected so that the Linker does not contain any N-N or N-O bonds.
  • Q A is -G A -Q HA - or -G A -(C].5alkylene)- where:
  • G A is selected from a direct bond, -CH2-, -O- or -N(R G )-; each R G is independently H or Chalky 1; and
  • Q HA is a 4 to 11 -membered nitrogen-containing saturated heterocyclic group.
  • Q A is -G A -Q HA - or -G A -(C].5alkylene)- where:
  • G A is selected from a direct bond, -CH2-, -O- or -N(R G )-; each R G is independently H or Chalky 1; and
  • Q HA is selected from azetidin-l,3-diyl, pyrro lidin- 1,3 -diyl, piperidin- 1,4-diyl, piperazin- 1,4-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl and 9-azaspiro[5.5]undecan-3,9-diyl.
  • Q A is -G A -Q HA - or -G A -(Ci-5alkylene)- where:
  • G A is selected from a direct bond, -CH2-, -O-or -NH- or -N(Me)-;
  • Q HA is selected from azetidin-l,3-diyl, pyrro lidin- 1,3 -diyl, piperidin- 1,4-diyl, piperazin- 1,4-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl and 9-azaspiro[5.5]undecan-3,9-diyl; and the C i.salkvlene within said -G A -(Ci-5alkylene)- is selected from -( C I F )i- where f is an integer from 1 to 5, cyclobut-l,3-diyl and -CH2(cyclobut-l,3-diyl)-.
  • Q A is selected from azetidin- 1,3 -diyl, pyrrolidin-l,3-diyl, piperidin- 1,4-diyl, -O(piperidin- 1 ,4-diyl)-, -C I F( piperidin- 1 ,4-diyl)-, piperazin- 1 ,4-diyl, 3 ,9-diazaspiro[5.5]undecan-3 ,9- diyl, -O(9-azaspiro[5.5]undecan-3,9-diyl)-, -O(cyclobut-l,3-diyl)-, -OCH2(cyclobut-l,3-diyl)-, -(CH2)f-, -O-(CH2)f-, -NH-(CH2)f- and -N(Me)-(CH2)r-, where f is an integer from 1 to 5.
  • Q A is azetidin-l,3-diyl.
  • Q A is pyrro lidin- 1 ,3-diyl.
  • Q A is piperidin- 1,4-diyl.
  • Q A is -O(piperidin-l,4-diyl)-.
  • Q A is -CI F( piperidin- 1,4-diyl)-.
  • Q A is piperazin- 1,4-diyl.
  • Q A is 3,9-diazaspiro[5.5]undecan-3,9-diyl.
  • Q A is -O(9-azaspiro[5.5]undecan-3,9-diyl)-.
  • Q A is -G-(Ci-5alkylene)-.
  • Q A is selected from -O(cyclobut-l,3-diyl)-, -OCH2(cyclobut-l,3-diyl)-, -(CI F ir-. -O(CH2)f-, -NH-(CH2)f- and -N(Me)-(CH2)r-, where f is an integer from 1 to 5.
  • Q A is -O(cyclobut-l,3-diyl)-. In one embodiment Q A is -OCH2(cyclobut-l,3-diyl)-.
  • Q A is -(CH2)f- where f is an integer from 1 to 4 (for example, f is 4)
  • Q A is -O-(CH2)r- where f is an integer from 1 to 5 (for example, f is 1 or 2).
  • Q A is -NH-(CH2)r- where f is an integer from 1 to 5.
  • Q A is -N(Me)-(CH2)r-, where f is an integer from 1 to 4.
  • Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or a straight chain Ci-salkylene optionally substituted by one or more F (for example 1 or 2 F, for example by 2 F).
  • Q B is a direct bond
  • Q B is -Q B1 -Q B2 -Q B3 -.
  • Q B is C .;,alkvlerie optionally substituted by one or more F.
  • Q B is C .;,alkvlerie optionally substituted by one or two F (for example by 2 F).
  • Q B is a straight chain C .;,alkvlerie optionally substituted by 1 or 2 F (for example by 2 F).
  • Q B is C i-salkylene
  • Q B is a straight chain C .;,alkvlerie.
  • Q B is -CF2-CH2-CH2- or -(CFb)TM- where w is 1 to 3.
  • Q B1 and Q B3 each independently represent a direct bond, -CH2- or -CH2CH2-.
  • Q B1 is a direct bond or -CH2-.
  • Q B1 is a direct bond.
  • Q B1 is -CH2-.
  • Q B3 is a direct bond, -CH2- or -CH2CH2-.
  • Q B3 is a direct bond.
  • Q B3 is -CH2-.
  • Q B3 is -CH2CH2-.
  • Q B2 is Q H , -O-CH2CH2-O- or -N(R J )- where R J is Ci- 3 alkyl.
  • Q B2 is Q H , -O-CH2CH2-O- or -N(Me)-.
  • Q B2 is piperazin- 1,4-diyl, azetidin- 1,3 -diyl, -O-CH2CH2-O- or -N(Me)-.
  • Q B2 is piperazin- 1,4-diyl, -O-CH2CH2-O- or -N(Me)-.
  • Q B2 is Q H .
  • Q B2 is piperazin- 1,4-diyl.
  • Q B2 is azetidin- 1 ,3-diyl.
  • Q B2 is -O-CH2CH2-O-.
  • Q B2 is -N(R J )- where R J is Ci-salkyl.
  • Q B2 is -N(Me)-.
  • Q c is -Q H -G- or -(Chalky lene)-G-.
  • Q c is -Q H -G- or -(Ci-3alkylene)-G-.
  • Q c is -Q H -G- or -(Chalky lene)-G-.
  • Q c is -Q HC -G C - or -(Ci-5alkylene)-G c - where:
  • 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.
  • Q c is -Q HC -G C - or -(Ci-2alkylene)-G c - where: G c is selected from a direct bond, -O- or -Ni l-: and
  • Q HC is a 6 to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.
  • Q c is -Q HC -G C - or -(Ci-2alkylene)-G c - where:
  • G c is selected from a direct bond, -O- or -Ni l-:
  • Q HC is selected from piperazin- 1,4-diyl, piperidin-l,4-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1,4- diazepan-l,4-diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl, 12-oxa-3,9-diazaspiro[5.6]-dodecan-3,9-diyl, l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl and 3.6-dihvdro-2/7-pvridin- l ,4-divl.
  • Q c is selected from piperazin- 1,4-diyl, piperidin- 1,4-diyl, -(piperidin-l,4-diyl)O-, 2,5- diazabicyclo[2.2.1]heptan-2,5-diyl, 1,4-diazepan- 1,4-diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl, 12-oxa-
  • Q c is piperazin- 1,4-diyl.
  • Q c is piperidin- 1,4-diyl.
  • Q c is -(piperidin- 1,4-diy 1)0-.
  • Q c is 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl.
  • Q c is 1,4-diazepan- 1,4-diyl.
  • Q c is 3,9-diazaspiro[5.5]undecan-3,9-diyl.
  • Q c is 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl.
  • Q c is l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl.
  • Q c is 3.6-dihvdro-2/7-pvridin- l ,4-divl.
  • Q c is -(Ci-5alkylene)-G- [for example, -(CH2)g-O- where g is an integer from 1 to 5],
  • Q c is -(Chalky lene)-G- [for example, -(CH2)g-O- where g is an integer from 1 to 4],
  • Q c is -(Ci-3alkylene)-G- [for example, -(CH2)g-O- where g is 1, 2 or 3],
  • Q c is -(Chalky lene)-G- [for example, -(CH2)g-O- where g is 1 or 2],
  • Q c is -(CH2)g-G c - where g is an integer from 1 to 5 and G c is -O- or -NH-.
  • Q c is -(CH2)g-G c - where g is 1 or 2 and G c is -O- or -NH-.
  • Q c is -CH2CH2NH-.
  • each Q H is independently selected from piperazin- 1,4-diyl, azetidin- 1,3 -diyl, piperidin- 1,4-diyl, 1,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-l,3-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1, 3 ,3a, 4 ,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3.6-dihvdro-2/7-pvridin- 1 .4-divl and 9-azaspiro[5.5]undecan-
  • each Q H is independently selected from piperazin- 1,4-diyl, azetidin- 1,3 -diyl, piperidin- 1,4-diyl, 1,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-l,3-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1, 3 ,3a, 4, 6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl and 9-azaspiro[5.5]undecan-3,9-diyl.
  • Q H is piperazin- 1,4-diyl.
  • Q H is azetidin- 1 ,3-diyl.
  • Q H is piperidin- 1,4-diyl.
  • Q H is 1,4-diazepan- 1,4-diyl. In one embodiment Q H is 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl.
  • Q H is pyrrolidin-l,3-diyl.
  • Q H is 3,9-diazaspiro[5.5]undecan-3,9-diyl.
  • Q H is 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl. In one embodiment Q H is l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl.
  • Q H is 3,6-dihydro-2H-pyridin- 1 ,4-diyl.
  • Q H is 9-azaspiro[5.5]undecan-3,9-diyl.
  • R J is Ci-aalkyl
  • R J is Me. In one embodiment R G is Ci-aalkyl.
  • R G is H or Me.
  • R G is Me.
  • R G is H.
  • the Linker (for example ‘a’ -Q A -Q B -Q C - ‘b’) is selected from any of Linkers 1 to 46 or 1 to 48 shown below:
  • W is an E3 ubiquitin ligase cereblon binder unit attached to the ‘b’ end of the Linker via an available C atom within said E3 ubiquitin ligase cereblon binder unit.
  • W is W1 which is: -Z-(R A )h where Z is: wherein: represents a single covalent bond or a double covalent bond;
  • 1 ofX G , X H & X J is C(O); 1 ofX G , X H & X J is N-(2,6-dioxopiperidin-3-yl) (Y); and 1 ofX G , X H & X J is selected from C(R T ) 2 , -CH 2 CH 2 -, C(O), N(Ci.
  • each R T is selected from H, F, Me or together with the carbon of C(R T ) 2 forms a cycloprop- 1,1 -diyl group;
  • X G , X H & X J are selected such that there are not two C(O) groups present at adjacent positions, and that the
  • N-(2,6-dioxopiperidin-3-yl) is not at an adjacent position to either N(Ci. 3 alkyl) or O; each R A is independently a substituent on any available C atom at X A , X B , X c or X D selected from F, Cl, Ci-salkyl, C i-salkoxy wherein said Ci-salkyl and C i-salkoxy is independently optionally substituted by one or more F ; h is 0, 1 or 2; and wherein the Linker is attached to any C atom at X A , X B , X c or X D .
  • 0 or 1 of X A , X B , X c , X D , X E & X F is N and are otherwise C.
  • 1 or 2 of X A , X B , X c , X D , X E & X E is/are N and are otherwise C.
  • X A , X B , X c , X D , X E & X E are all C.
  • X A , X B , X c , X D , X E & X E is N and are otherwise C.
  • X A , X B , X c , X D , X E & X E are N where X E & X E are not both N, and are otherwise C.
  • X B , X D & X E are all C, and 0, 1 or 2 of X A , X c & X E is/are N, and are otherwise C.
  • X B , X D & X E are all C, and 0, 1 or 2 of X A , X c & X E is/are N, and are otherwise C; where the Linker is attached to X B or to X A when X A is C.
  • X B , X D & X E are all C, and 0, 1 or 2 of X A , X c & X E is/are N, and are otherwise C; where the Linker is attached to X B .
  • X G -X H -X J is CH 2 -NY-C(O).
  • X G -X H -X J is CH 2 CH 2 -NY-C(O).
  • X G -X H -X J N-NY-C(O).
  • X G -X H -X J is C(O)-NY-C(O). In one embodiment X G -X H -X J is O-C(O)-NY.
  • X G -X H -X J is N(Ci-3alkyl)-C(O)-NY [for example N(Me)-C(O)-NY].
  • X G -X H -X J is C(O)-NY-CH2.
  • each R A is a substituent on any available C at X A , X B , X c or X D selected from F, Cl and C i-salkoxy optionally substituted by one or more F.
  • each R A is a substituent on any available C at X A , X B , X c or X D selected from F, Cl, OMe and -OCHF 2 .
  • h 0.
  • h is 1.
  • h is 2.
  • the Linker is attached to X c , where X c is C: and X A is C attached to R A where R A is OMe where said methyl is optionally substituted by one or more F (e.g. -OCHF2).
  • F e.g. -OCHF2
  • the Linker is attached to X c , where X c is C: and X A is C attached to R A where R A is OMe or -OCHF2.
  • -Z-(R A )h together represent any one of groups 1, 4, 16, 17 and 19 (referring to the specific -Z-(R A )h groups 1 to 21 whose structures are drawn out below).
  • h is 1 and R A is Ci-salkoxy [for example OMe],
  • h is 1 or 2
  • one R A is OMe and the other R A (when present, i.e. when h is 2) is Cl.
  • h is 1 or 2
  • one R A is Cl and the other R A (when present, i.e. when h is 2) is OMe.
  • h is 1 and R A is F.
  • h is 1 and R A is Cl.
  • h is 1 and R A is -OCHF2.
  • the Linker is attached to a C at X A or X B , and h is 0.
  • the Linker is attached to a C at X A or X B , h is 1 and R A is a substituent on X c where X c is C and R A is F.
  • the Linker is attached to a C at X A or X B , h is 1 and R A is a substituent on X D where X D is C and R A is OMe or -OCHF 2 .
  • the Linker is attached to a C at X B , h is 0, 1 or 2; the first R A (when present, i.e. when h is 1 or 2) is a substituent on an available C at X D and the second R A (when present, i.e. when h is 2) is on an available C at X A .
  • the Linker is attached to a C at X B , h is 0, 1 or 2; the first R A (when present, i.e. when h is 1 or 2) is a substituent on an available C at X D selected from Cl, OMe and -OCHF2; and the second R A (when present, i.e. when h is 2) is on an available C at X A and is selected from Cl and OMe.
  • -Z-(R A )h together represent any of the groups 1 to 21 shown below:
  • W is W2 which is
  • Z A is: wherein: represents a single covalent bond or a double covalent bond;
  • X* 2 , X B2 , X C2 & X D2 is C and covalently bound to Y ;
  • each R AA is a substituent on any available C or N atom of Z - in each case independently selected from R AAI optionally substituted by one or more R AA2 : where R AA is further selected from R AA2 when R AA is a substituent on an available C atom of Z A ; each R AAI is independently Ci.4alkyl, C2-3alkenyl, C2-3alkynyl,
  • each R AA2 is independently selected from F, Cl, Br, CN, NH2, Chalky 1,
  • Ci-salkyl O(C].3alkyl), NH(Ci-3alkyl) and N(Ci-3alkyl)2; wherein said Ci-salkyls are optionally substituted by one or more F; v is 0, 1 or 2;
  • Y is N-(2,6-dioxopiperidin-3-yl).
  • Z A is: wherein: represents a single covalent bond or a double covalent bond; 1 ol' X A2 & X B2 is C and covalently bound to Y and the other of X A2 & X B2 is C;
  • X C2 & X D2 is N and is/are otherwise C;
  • -Z A -Y together represent any one or more of the groups Al to A6 shown below, where in each case said Z A group is optionally substituted on available C and/or N atom(s) by -[ R AA ]v as further defined herein.
  • each R AA is a substituent on any available C or N atom of Z A - in each case independently selected from R AAI optionally substituted by one or more R AA2 : where R AA is further selected from R AA2 w
  • each R AA is a substituent on any available C or N atom of Z A - in each case independently selected from R AAI optionally substituted by one or more R AA2 : where R AA is further selected from R AA2 w
  • each R AA is a substituent on an available C atom of Z A , each independently selected from methyl, isopropyl, cyclopropyl, pyridin-2-yl, 1 -methylpyrazol-4-yl, -CH2CN, F, Cl, CN; and/or a methyl substituent on an available N atom of Z A .
  • v is 0.
  • v is 1.
  • v is 2.
  • v is 1 or 2.
  • v is 0 or 1.
  • v is 1 ;
  • X A1 is a C atom; and
  • R AA is a substituent on X A1 .
  • v is 1 ;
  • X A1 is a C atom; and
  • R AA is a Ci.4alkyl substituent on X A1 .
  • v is 1 ;
  • X C1 is a C atom; and
  • R AA is a substituent on X cl .
  • v is 1 ;
  • X D1 is a C atom; and
  • R AA is a substituent on X D1 .
  • v is 1 ;
  • X D1 is a C atom; and
  • R AA is a Ci.4alkyl (e.g. methyl) or F substituent on X D1 .
  • v is 1 ;
  • X G1 is a C atom; and
  • R AA is a substituent on X G1 .
  • v is 1 ;
  • X G1 is a C atom; and R AA is a substituent on X G1 ; where R AA is selected from R AAI optionally substituted by one or more R AA2 : or R AA is selected from R AA2 : wherein R AAI is Ci.4alkyl or a 4-6 membered heterocyclyl; and R AA2 is selected from F, Cl, CN and Ci-aalkyl.
  • v is 1 ;
  • X G1 is a C atom; and R AA is a substituent on X G1 ; where R AA is selected from methyl, isopropyl, cyclopropyl, pyridine- 2-yl, 1 -methylpyrazol-4-yl, -CH2CN, F, Cl and CN.
  • v is 1 or 2;
  • X G1 is a C atom; and one/the R AA is a substituent on X G1 ; where R AA is selected from R AAI optionally substituted by one or more R AA2 : or R AA is selected from R AA2 : wherein R AAI is C].4alkyl or a 4-6 membered heterocyclyl; and R AA2 is selected from F, Cl, CN and Ci-aalkyl; and when v is 2, the additional R AA is a fluoro substituted on an available C atom of Z A .
  • v is 1 ;
  • X G1 is a N atom; and
  • R AA is a substituent on X G1 .
  • v is 1 ;
  • X G1 is a N atom; and
  • R AA is a Ci.4alkyl (e.g. methyl) substituent on X G1 .
  • v is 1 ;
  • X H1 is a C atom; and
  • R AA is a substituent on X H1 .
  • v is 1 ;
  • X H1 is a C atom; and
  • R AA is a substituent on X H1 that is CN or Ci.4alkyl (e.g. methyl).
  • v is 1 or 2; X H1 and X G1 are both C atoms, one or both of which are substituted by R AA where each R AA is independently selected from CN or Ci.4alkyl (e.g. methyl).
  • the group: together represents one or more of the groups Al to A29, shown below:
  • X K and X L are either N-linker and CH or NMe and C-linker respectively;
  • X N may be N if X M is not C-F ; the remainder of X N , X M and X° are CH.
  • W represents any of the groups 22 to 26 shown below:
  • Formula (la) is selected from any one or more of the following groups
  • PROTAC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) or Formula (lb): where:
  • Q A is -G-Q H - or -G-(Ci. 5 alkylene)-;
  • R G is a direct bond, -CH2-, -O-, or -N(R G )- where each R G is independently H or Ci-aalkyl;
  • Q H is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; and 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 may take any of the values defined herein for each of these groups/variables respectively.
  • Q H is a 4-12-membered nitrogen-containing saturated heterocyclic group.
  • Formula (lb) indicates a point of connection via a single covalent bond to the remainder of the PROTAC compound.
  • PROTAC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of Formula (la) of Formula (lb), as defined herein.
  • Formula (lb) may be: where L x may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where Q A may take any value(s) disclosed herein for Q A .
  • PROTAC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) of Formula (Ic): where:
  • Q A is -G-Q H - or -G-(Ci. 5 alkylene)-;
  • G is a direct bond, -CH2-, -O-, or -N(R G )- where R G is H or Ci.jalkyl;
  • Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or Ci-aalkylene optionally substituted by one or more F (e.g. 1 or 2 ): where:
  • Q B1 & Q B3 each independently represent a direct bond or Chalky lene
  • Q B2 is Q H , -O-CH2CH2-O-, -O- or -N(R J )- where R J is H or Ci. 3 alkyl; and each Q H is indepdendently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of Q A and Q B are selected so that Formula (Ic) does not contain any N-N or N-O bonds; and 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 may otherwise take any of the values defined herein for each of these groups/variables respectively.
  • Q H is a 4-12-membered nitrogen-containing saturated heterocyclic group.
  • Formula (Ic) indicates a point of connection via a single covalent bond to the remainder of the PROF AC compound.
  • PROF AC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of Formula (la) of Formula (Ic), as defined herein.
  • Formula (lb) may be: where L x may be any of the groups (1) to (28) listed hereinabove in connection with Formula (la); and where Q A and Q B may take any value(s) disclosed herein for Q A and Q B .
  • R Z1 is H or F; is H or F;
  • R Z 3 is H or F; 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: where Y is N-(2,6-dioxopiperidin-3-yl).
  • R Z1 is H or F
  • L z is a linker selected from 1 and 3: and W z is selected from 1, 2 and 10: where Y is N-(2,6-dioxopiperidin-3-yl).
  • R Z1 isHorF
  • R Z2 isHorF
  • R Z3 is H or F; L z is a linker selected from 3, 45 and 47 : and W z is selected from 1, 3, 16, 22, 23, 24 and 26: where Y is N-(2,6-dioxopiperidin-3-yl).
  • a further embodiment provides any of the embodiments, claims or aspects defined herein with the proviso that one or more specific Examples (for instance one Example, or two or three specific Examples) selected from the group consisting of 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,
  • a further embodiment provides any of the embodiments, claims or aspects defined herein with the proviso that one or more specific Examples (for instance one Example, or two or three specific Examples) selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
  • the compounds of Formula (I) and PROTAC compounds containing binding units of Formula (la) may have one or more chiral centres and it will be recognised that such compounds may be prepared, isolated and/or supplied with or without the presence of one or more of the other possible enantiomeric and/or diastereomeric isomers of said compounds or that such isomers may be provided in any relative proportions.
  • enantioenriched/ enantiopure and/or diastereoenriched/ diastereopure compounds may be carried out by standard techniques of organic chemistry that are well known in the art, for example by synthesis from enantioenriched or enantiopure starting materials, and/or by use of an appropriately enantioenriched or enantiopure catalyst during synthesis, and/or by resolution of a racemic or partially enriched mixture of stereoisomers, for example via chiral chromatography.
  • composition comprising a compound of Formula (I) [or PROTAC compound containing a unit of Formula (la)] or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la)] or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la)] or pharmaceutically acceptable salt thereof is present within the composition with a diastereomeric excess (%de) of > 90%.
  • the %de in the above-mentioned composition is > 95%.
  • the %de in the above-mentioned composition is > 98%.
  • the %de in the above-mentioned composition is > 99%.
  • composition comprising a compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90%.
  • the %ee in the above-mentioned composition is > 95%.
  • the %ee in the above-mentioned composition is > 98%.
  • the %ee in the above-mentioned composition is > 99%.
  • composition comprising a compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.
  • %ee and %de may take any combination of values as listed below:
  • a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient.
  • a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] , or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90%.
  • the %ee in the above-mentioned composition is > 95%.
  • the %ee in the above-mentioned composition is > 98%.
  • the %ee in the above-mentioned composition is > 99%.
  • a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] , or pharmaceutically acceptable salt thereof is present within the composition with a diastereomeric excess (%de) of > 90%.
  • the %de in the above-mentioned composition is > 95%.
  • the %de in the above-mentioned composition is > 98%.
  • the %de in the above-mentioned composition is > 99%.
  • a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] , or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.
  • %ee and %de may take any combination of values as listed below:
  • the compounds of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], and pharmaceutically acceptable salts thereof may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or other stoichiometry of hydrate) and/or solvated forms. It is to be understood that the present specification encompasses any and all such solid forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], and pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) or PROTACs of Formula (la) may be prepared, for example, by the following methods.
  • a compound of Formula (I) [or salt thereof] or a PROTAC compound of Formula (la) [or a salt thereof] may be prepared from a compound of Formula (II): or a salt thereof, where:
  • Q A is -G-Q H - or -G-(Ci- 5 alkylene)-;
  • G is a direct bond, -CH2-, -O-, or -N(R G )- where R G is H or Ci-jalkyl;
  • 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, Q, R 2a , R 2b , Y 1 , Y 2 , Y 3 , Y 4 , R 3 and q may take any of the values disclosed herein for each of those groups/variables respectively.
  • Q H is a 4-12-membered nitrogen-containing saturated heterocyclic group.
  • such compound of Formula (II) as described above is an aldehyde which may be reacted with a suitable molecule containing an amine group (for example a secondary amine group) to form the compound of Formula (I) or PROTAC compound of Formula (la) - either directly, or after one or more additional reaction steps.
  • a suitable molecule containing an amine group for example a secondary amine group
  • Such reaction of said aldehyde with said amine can be carried out under reductive amination conditions, using for example NaBI [(OAcy or another reductive amination protocol known to the skilled person.
  • Such aldehyde may in turn be prepared from the corresponding acetal, for example a compound of Formula (II), or salt thereof, as defined above, except that: R L1 and R L2 are each independently C ...alkoxv (for example Ci-aalkoxy) or R L1 & R L2 together form -O-(CH2)k-O- where k is 2 or 3.
  • R L1 and R L2 are each independently C ...alkoxv (for example Ci-aalkoxy) or R L1 & R L2 together form -O-(CH2)k-O- where k is 2 or 3.
  • Such acetal may be converted to the corresponding aldehyde under acidic conditions, for example using formic acid under conditions well known to the skilled person.
  • the above-mentioned aldehyde may be prepared by oxidation of the corresponding primary alcohol, i.e. a compound of Formula (II), or salt thereof, as defined above except that R L1 is OH and R L2 is H.
  • oxidation may be carried out using mild oxidising conditions, for example Dess-Martin periodinane or some other mild oxidation protocol known to the skilled person.
  • a compound of Formula (I) [or salt thereof] or a PROTAC compound of Formula (la) [or a salt thereof] may 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 compound of Formula (II) is an electrophile that may be reacted with a molecule containing an amine group (for example a secondary amine group) via an alkylation reaction to form the compound of Formula (I) or PROTAC compound of Formula (la) - either directly, or after one or more additional reaction steps.
  • an electrophile that may be reacted with a molecule containing an amine group (for example a secondary amine group) via an alkylation reaction to form the compound of Formula (I) or PROTAC compound of Formula (la) - either directly, or after one or more additional reaction steps.
  • Suitable leaving groups for alkylation reactions are well known to the skilled person and include Cl, Br, I, trifluoromethanesulfonate, mesylate and tosylate.
  • Alkylation reaction conditions are well known to the skilled person and generally involve a non-nucleophilic base (e.g. DIPEA) and a polar aprotic solvent (e.g. MeCN).
  • a metal iodide salt may be used in the reaction mixture to form the corresponding iodide in-situ (i.e. where R L1 is I) to facilitate the overall alkylation process.
  • a compound of Formula (II) where R L1 is a bromo leaving group may be prepared from the corresponding primary alcohol (i.e. as already described above where R L1 is OH, and R L2 & R L3 are both H.
  • Such reduction may be carried out using strong reduction conditions, for example using DIBAL or other stronger reducing conditions which are well known to the skilled person.
  • the above-mentioned primary alcohol compound of Formula (II) may be convenient to form the above-mentioned primary alcohol compound of Formula (II) via deprotection of a protected form of the alcohol.
  • deprotection of a compound where there alcohol is protected by a silicon-based protecting group using a source of fluoride in order to achieve the deprotection, for example TBAF or other deprotection methods well-known to the skilled person.
  • Q A is -G-Q H - or -G-(Ci- 5 alkylene)-;
  • G is a direct bond, -CH2-, -O-, or -N(R G )- where R G is H or Ci-jalkyl;
  • Q H is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group
  • Q D is a direct bond or C ⁇ alkylene optionally substituted by one or more F (for example 1 or 2 F);
  • R L1 & R L2 are each independently Ci-salkoxy (for example OMe), and R L3 is H;
  • R L1 & R L2 together form -O-(CH2)k-O- where k is 2 or 3, and R L3 is H; or
  • R L1 is OH, OPG 1 (where PG 1 is a protecting group), or LG 1 (where LG 1 is a leaving group), and
  • R L2 & R L3 are both H; where when Q D is a direct bond and Q A is -G-Q H -, the value of Q H is selected so that Q D connects to a C atom of Q H ; and 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 take any of the values disclosed herein for each of those groups/variables respectively.
  • Q H is a 4-12-membered nitrogen-containing saturated heterocyclic group.
  • PG 1 is an alcohol protecting group.
  • PG 1 is a silicon-based alcohol protecting group.
  • PG 1 is Si( R Sl h where each R S
  • PG 1 is tert-butyldimethylsilyl or tert-butyldiphenylsilyl.
  • the LG 1 is selected from Cl, Br, I, trifluoromethanesulfonate and C i.yhydrocarbylsulfonate (for example mesylate or p-toliienesiill'onate).
  • LG 1 is Br or I.
  • LG 1 is Br.
  • LG 1 is Cl.
  • LG 1 is I.
  • LG 1 is trifluoromethanesulfonate.
  • LG 1 is C .-Iwdrocarbv I sulfonate.
  • LG 1 is mesylate. In one embodiment LG 1 is />-toluenesulfonate.
  • Q D is a direct bond, -CH2-, -CH2CH2- or -CF2CH2-.
  • Q D is a direct bond
  • Q D is CH2.
  • Q D is Ci.2alkylene optionally substituted by 1 or 2 F.
  • Q D is Ci.2alkylene.
  • Q D is -CH2CH2-.
  • Q D is -CF2CH2-.
  • Formula (II) may be Formula (Ila): where L x may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where Q A , Q D , R L1 , R L2 and R L3 may take any of the values disclosed herein for each of said groups respectively.
  • certain compounds of Formula (I) and certain PROTACS of Formula (la) and certain intermediate compounds of Formula (II) may be prepared using a compound of Formula (III): or a salt thereof, where G x is OH, where the oxygen atom of said OH is alkylated by a suitable molecule to form certain compounds of Formula (I) or PROTACs of Formula (la) - either directly, or after one or more further reaction steps (for example via Formula (II) as described hereinabove).
  • alkylation reactions may be carried out under conditions well known to the skilled person, for example using a primary alkyl bromide (or using some other leaving group in place of Br) using a non-nucleophilic base such as a metal carbonate (e.g. K2CO3) in a polar aprotic solvent such as MeCN, optionally in the presence of a metal iodide salt such as KI.
  • a non-nucleophilic base such as a metal carbonate (e.g. K2CO3)
  • a polar aprotic solvent such as MeCN
  • a metal iodide salt such as KI.
  • a compound of Formula (III) where G x is -NH(R G ) [where R G is H or C .vilkvl (for example Me)] may be used as an intermediate to prepare compounds of Formula (I) or PROTACs of Formula (la) via reductive amination chemistry with an appropriate aldehyde- containing compound.
  • a compound of Formula (III) where G x is bromo may be coupled with a secondary amine compound to give certain compounds of Formula (I) or PROTACs of Formula (la) - either directly, or after one or more further reaction steps (for example via Formula (II) as described hereinabove).
  • compounds of Formula (111) where G x is chloro or trifluoromethanesulfonate may also be used in a coupling reaction with the relevant secondary amine to give certain compounds of Formula (I) or PROTACs of Formula (la).
  • Such coupling may be carried out under palladium-based coupling conditions (e.g. using ‘Ruphos Pd G3’ and ‘Ruphos’) in the presence of a base and an anhydrous solvent such as 1,4-dioxane under an inert atmosphere, or by heating with Cui in the presence of a base such as K3PO4 in a polar solvent such as DMSO.
  • a compound of Formula (III) where G x is bromo may be coupled with a suitable alcohol to form certain compounds of Formula (I) or PROTACs of Formula (la) - either directly, or after one or more further reaction steps (for example via Formula (II) as described hereinabove).
  • Such coupling may be carried out using a palladium-based reagent such as ‘Rockphos Pd G3’ in the presence of a base such as CS2CO3 in a solvent such as toluene.
  • compounds of Formula (III), and salts thereof may be useful as intermediates in the synthesis of certain compounds of Formula (I) or PROP AC compounds of Formula (la) or compounds of Formula (II), and accordingly such intermediate compounds provide a further aspect of the specification.
  • G x is OH, Cl, Br, triflouoromethanesulfonate or -NH(R G ) where R G is H or Ci-salkyl; and 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 take any of the values disclosed herein for each of those groups/variables respectively.
  • G x is OH, Cl, Br, triflouoromethanesulfonate or -NH(R G ) where R G is C i-salkyl (for example Me).
  • G x is OH, Br, trifluoromethanesulfonate or -NH(R G ) where R G is C i-salkyl (for example Me).
  • G x is OH, Br or -NH(R G ) where R G is C i-salkyl (for example 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.
  • G x is trifluoromethanesulfonate.
  • G x is -NH(R G ) where R G is H or Ci-salkyl. In one embodiment G x is -NH(R G ) where R G is Ci-salkyl. In one embodiment G x is -NH(Me).
  • Formula (III) may be L x — G x wherein L x may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where G x may take any value(s) disclosed herein for G x .
  • certain compounds of Formula (I) and PROTACs of Formula (la) may be prepared using an intermediate compound of Formula (IV): or a salt thereof, as further defined below.
  • a compound of Formula (IV), or salt thereof, where J is H i.e. a secondary amine compound
  • a compound of Formula (IV), or salt thereof, where J is H may be coupled to a further chemical fragment, using chemistry well known to the skilled person and exemplified in the experimental section hereinafter, to provide a compound of Formula (I) or PROTAC of Formula (la), either directly, or after one or more further reaction steps.
  • such a compound of Formula (IV) where J is H may conveniently be prepared via deprotection of an TV-protected form of the aforementioned amine compound.
  • compounds of Formula (IV) where J is H may be conveniently be prepared using a compound of Formula (IV) where J is PG 2 where PG 2 is a nitrogen protecting group (for example a Ci-ealkoxy carbonyl group such as tertbutoxycarbonyl). Therefore, compounds of Formula (IV) where J is PG 2 are useful intermediates in the preparation of the compound of Formula (I) and PROTAC of Formula (la) and provide a further aspect of the specification.
  • J is H or PG 2 where PG 2 is a nitrogen protecting group (for example a tert-butoxycarbonyl group);
  • Q A is -G-Q H - or -G-(Ci. 5 alkylene)-;
  • G is a direct bond, -CH2-, -O-, or -N(R G )- where R G is H or Ci-aalkyl;
  • Q B is a direct bond, -Q B1 -Q B2 -Q B3 - or Ci.vilkvlene optionally substituted by one or more F (e.g. 1 or 2); where:
  • Q B1 & Q B3 each independently represent a direct bond or Chalky lene
  • Q B2 is Q H , -O-CH2CH2-O-, -O- or -N(R J )- where R J is H or Ci. 3 alkyl; and each Q H (including the “Q H Ring” attached to J) is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of Q A , Q B and Q H Ring are selected so that Formula (IV) does not contain any N-N or N-O bonds; and 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 may take any of the values defined herein for each of these groups/variables respectively.
  • each Q H (including the “Q H Ring” attached to J) is independently a 4-12-membered nitrogen-containing saturated heterocyclic group.
  • the Q H Ring is piperidin-l,4-diyl or piperazin- 1 ,4-diyl.
  • J is H.
  • J is PG 2 .
  • PG 2 is C i-ealkoxycarbonyl.
  • PG 2 is tert-butoxycarbonyl. In one embodiment where PG 2 is C i-ealkoxycarbonyl (e.g. tert-butoxycarbonyl) the ‘and salts thereof element of the claim is excluded.
  • the compound of Formula (IV) may take any combination of alternative values mentioned in relation to Q A Q B and Q H in any other context, embodiment, aspect or claim found herein.
  • Formula (IV) may be Formula (IVa): where L x may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where Q A , Q B , Q H and J may take any of the values disclosed herein for each of said groups respectively.
  • X x is N substituted by J where J is H;
  • G is a direct bond, -CH2-, -O-, or -N(R G )- where R G is H or Ci-aalkyl;
  • Q H Ring is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of G and Q H Ring are selected so that Formula (V) does not contain any N-N or N-O bonds; and 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 may take any of the values defined herein for each of these groups/variables respectively.
  • Such a compound of Formula (V) may be converted to a compound of Formula (I) or PROTAC of Formula (la) via reductive amination or alkylation or other coupling chemistry known to the skilled person - to provide the compound of Formula (I) or PROTAC of Formula (la) either directly, or after one or more additional steps.
  • such a compound of Formula (V), or a salt thereof may be conveniently prepared by deprotection of the corresponding TV-protected compound.
  • N- protected form may be a BOC-protected form (i.e. tert-butoxycarbonyl) or may use another A -protecting group known to the skilled person.
  • BOC-protected form i.e. tert-butoxycarbonyl
  • a -protecting group known to the skilled person.
  • TV-protected compounds are also useful intermediates in the preparation of the compounds of Formula (I) and PROTACs of Formula (la) and provide a further aspect of the specification.
  • one aspect of the specification provides a compound of Formula (V), or a salt thereof, as described above except that X x is N substituted by J where J is PG 3 and PG 3 is a protecting group.
  • PG 3 is Ci-ealkoxy carbonyl.
  • PG 3 is tert-butoxy carbonyl.
  • PG 3 is Ci-ealkoxycarbonyl (e.g. tert-butoxycarbonyl) the ‘and salts thereof element of the claim is excluded.
  • Such an intermediate may be converted to a compound of Formula (I) or PROTAC of Formula (la) by reductive amination chemistry using an appropriate amine- containing compound, using reductive amination conditions that well-known to the skilled person - either directly or via one or more additional synthetic steps.
  • ketal compound may be represented as a compound of Formula (V), or a salt thereof, as described above except that X x is C substituted by R U1 and R 1 2 : where R U1 and R U2 are each Ci-ealkoxy; or R U1 and R U2 together represent -O-(CH2)u-O- where u is 2 or 3.
  • G is a direct bond, -CH2-, -O-, or -N(R G )- where R G is H or Ci-aalkyl;
  • Q H Ring is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; and the values of G and Q H Ring are selected so that Formula (V) does not contain any N-N or N-O bonds; and 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 may take any of the values defined herein for each of these group s/variables respectively.
  • J is H.
  • J is PG 3 .
  • PG 3 is C i-ealkoxycarbonyl.
  • PG 3 is tert-butoxycarbonyl.
  • X x is C substituted by R U1 and R U2 ; where R U1 and R U2 are each C ...alkoxv.
  • G is a direct bond or -O-.
  • Q H Ring is a 4-12-membered nitrogen-containing saturated heterocyclic group.
  • the values of Q H Ring may take any of the values mentioned herein for Q H .
  • 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.
  • Formula (V) may be Formula (Va): where L x may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where G, Q H Ring and X x may take any of the values disclosed herein for each of said groups respectively.
  • the compounds of Formulae (I), (II), (III), (IV) & (V) and PROTAC compounds including Formula (la) may be prepared according to the general procedures and chemical transformations demonstrated in the experimental section hereinafter and using standard procedures and knowledge known to the skilled chemist.
  • a pharmaceutical composition which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, in association with a pharmaceutically acceptable excipient.
  • a pharmaceutical composition which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of cancer.
  • a pharmaceutical composition which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of a solid tumour.
  • a pharmaceutical composition which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of an AR-sensitive tumour type.
  • a pharmaceutical composition which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of tumour types that harbour one or more mutated forms of the androgen receptor.
  • a pharmaceutical composition which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of prostate cancer (for example CRPC, for example metastatic CRPC).
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of prostate cancer (for example CRPC, for example metastatic CRPC).
  • a pharmaceutical composition which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of AR-mutated cancer.
  • cancer any embodiment, aspect or claim herein that mentions “cancer” without further specificity, further embodiments, aspects or claims may be provided where said cancer is (or includes) AR+ breast cancer.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing).
  • the compositions may be obtained by conventional procedures using conventional pharmaceutical excipients that are well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host being treated and the particular route of administration.
  • the size of the dose for therapeutic or prophylactic purposes of compounds of the present specification 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, according to well-known principles of medicine.
  • the compounds of the present specification may be of value as anti-tumour agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of tumour growth and survival and to inhibition of metastatic tumour growth.
  • the compounds of the present specification may be of value as antiproliferative and anti- invasive agents in the containment and/or treatment of solid tumour disease.
  • the compounds of the present specification may be useful in the prevention or treatment of those tumours which are sensitive to degradation of the androgen receptor and that are involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the migratory ability and invasiveness of metastasising tumour cells. Further, the compounds of the present specification may be useful in the prevention or treatment of those tumours which are treatable by degradation of androgen receptors, i.e. the compounds may be used to produce an androgen receptor degradation effect in a warmblooded animal in need of such treatment.
  • a method for producing an antiproliferative effect in a warm-blooded animal, such as man, in need of such effect comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for producing an anti- invasive effect by the containment and/or treatment of solid tumour disease, in a warm-blooded animal, such as man, in need of such effect comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for the prevention or treatment of cancer in a warm-blooded animal, such as man, in need of such treatment comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for the prevention or treatment of solid tumour(s) in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for the prevention or treatment of those tumour types that are sensitive to degradation of androgen receptors in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • tumour types that are sensitive to degradation of androgen receptors include prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC).
  • prostate cancer for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC.
  • a method for providing a degrading effect on androgen receptors in a warm-blooded animal, such as man, in need of such effect comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for providing a selective degrading effect on androgen receptors in a warm-blooded animal, such as man, in need of such effect comprises administering an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for the prevention or treatment of those tumour types that harbour androgen receptor mutations in a warm-blooded animal, such as man, in need of such prevention or treatment which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • tumour types known to harbour androgen receptor mutations include prostate tumours and therefore prostate cancer, castrate-resistant prostate cancer (CRPC), and metastatic (CRPC).
  • CRPC castrate-resistant prostate cancer
  • CRPC metastatic
  • prostate cancer for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC).
  • prostate cancer for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC).
  • a method for treating prostate cancer for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC) in a warmblooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of Formula (I) [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
  • said cancer is prostate cancer.
  • said cancer is CRPC.
  • said cancer is metastatic CRPC.
  • SFC supercritical fluid chromatography
  • S Phos 2-dicyclohexylphosphino-2,6-di-methyloxy- 1,1 -biphenyl
  • XPhos 2-dicyclo- hexylphosphino-2',4',6'-triisopropylbiphenyl.
  • NMR NMR was carried out at 400 MHz in deuterated DMSO and at a temperature of 20-30°C unless otherwise stated.
  • Preparative reverse phase HPLC using decreasingly polar mixture of eluents (e.g. water and MeCN) may typically involve a gradient over 10-20 minutes, at 40-50mL per minute, from a 95:5 mixture of solvents a 5:95 mixture.
  • eluents e.g. water and MeCN
  • Salts Where certain compounds were obtained as an acid-addition salt, for example a monohydrochloride 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 have been determined experimentally e.g. by means of elemental analysis data.
  • Pd(OH)2 (10wt%, 0.73 g, 0.52 mmol) was added to benzyl 4-(dimethoxymethyl)piperidine-l -carboxylate (7.60 g, 25.9 mmol) in MeOH (60 mL) at RT under N2 in a steel pressured reactor. The resulting suspension was purged with N2 followed by H2 and was then stirred at RT at a pressure of 4 atmospheres of H2 for 2 days. The mixture was then filtered through celite and washed through with MeOH (500 mL).
  • 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 3h. The mixture was then cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was passed through a phase separator cartridge and concentrated.
  • Pd-PEPPSI-IHept cl (0.380 g, 0.39 mmol) was added to tert-butyl piperazine- 1 -carboxylate (2.183 g, 11.72 mmol), CS2CO3 (3.82 g, 11.72 mmol) and 3-(5-bromo-7-methoxy-l-oxo-l .3-dihvdro-2/7-isoindol-2-vl )- piperidine-2, 6-dione (1.38 g, 3.91 mmol) in degassed 1 ,4-dioxane (39 mL) at RT under N2. The resulting suspension was stirred at 100°C for 6h.
  • the mixture was then diluted with DCM (100 mL) and washed sequentially with 5% AcOH in water (100 mL), water (100 mL), sat. Nal ICO;, (100 mL) and sat. brine (100 mL).
  • the organic layer was dried (MgSO.4) and concentrated.
  • Example 1 4-f4-[4-(4-f4-[2-(2.6-DioxoDiDeridin-3-yl)-7-methoxy-l-oxo-2.3-dihvdro- isoindol-5-yl1- piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl) benzonitrile
  • CS2CO3 (57.40 g, 176 mmol) and Pd-PEPPSI-IPent (2.33 g, 2.94 mmol) were added in one portion to a degassed solution of tert-butyl piperazine- 1 -carboxylate (14.22 g, 76.36 mmol) and 3-(5-bromo-l-oxo-l,3- dihydro-2H-isoindol-2-yl)piperidine-2, 6-dione (19.0 g, 58.74 mmol) in 1,4-dioxane (590 mL) under N2. The resulting mixture was stirred at 90°C for 24h.
  • Example 2 4-!4-[4-(4-!4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-yl
  • 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 K3PO4 (5.57 g, 26.25 mmol) in toluene (20 mL) at RT under N2. The resulting mixture was stirred at 100°C for 3h. The mixture was then filtered through Celite and washed through with EtOAc (30 mL).
  • Ruphos Pd G3 (88 mg, 0.10 mmol) and Ruphos (46 mg, 0.10 mmol) were added to a mixture of CS2CO3 (1.025 g, 3.15 mmol), 4-(dimethoxymethyl)piperidine (334 mg, 2.10 mmol) and 4-(4-(4-bromophenyl)- piperidin-l-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1,4-dioxane (6 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h. After cooling, the solvent was removed under reduced pressure.
  • CS2CO3 (73.6 g, 225.95 mmol) was added portion-wise 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 RT.
  • the resulting cream suspension was stirred at RT for 18h and was then diluted slowly with water (600 mL).
  • the resulting cream suspension was stirred at RT for 0.5h, then filtered, washed with water (2 x 25 mL) and Et2O (50 mL).
  • the mixture was degassed by bubbling N2 through the mixture for 5 mins and was then stirred at 100°C for 2h.
  • the mixture was then cooled to RT and water (320 mL) was added.
  • a precipitate formed which was collected by filtration to give an orange solid.
  • the solid was slurried in MTBE (50 mL), heated at 45°C for 0.5h then allowed to cool to RT and filtered.
  • Example 4 4-(4-!4-
  • 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-l-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol) and CS2CO3 (2.79 g, 8.55 mmol) in toluene (20 mL) at RT under N2. The resulting mixture was stirred at 90°C for 18h. The mixture was then cooled to RT and diluted with EtOAc (50 mL) and water (15 mL).
  • Diisobutylaluminum hydride (IM in toluene, 1.048 mL, 1.05 mmol) was added dropwise to a stirred solution of ethyl 2-(3-(4-(l-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)cyclobutyl)acetate (340 mg, 0.70 mmol) in THF (10 mL) at 0°C under N2. The resulting mixture was stirred at 0°C for 10 mins. The reaction was then quenched by addition of Rochelle’s salt (15 mL). EtOAc (25 mL) was added and the mixture was stirred at RT for 18h.
  • IM in toluene 1.048 mL, 1.05 mmol
  • Example 5 4-14-14- !ltlr,3s)-3-t2- 14-12-12, 6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2, 3-d ihvdro- isoindol-5-yl1piperazin-l-yllethyl)cvclobutyl1oxylphenyl)piperidin-l-yl1-2-(trifluoromethyl)benzonitrile
  • Dess Martin periodinane (101 mg, 0.24 mmol) was added to 3-fluoro-4-(4-(4-(4-(hydroxymethyl)piperidin-l- yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.22 mmol) in DCM (3 mL) at 0°C. The resulting mixture was stirred at RT for Ih. The mixture was then diluted with DCM (15 mL) and poured into a mixture of sat. Nal ICOa (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 mins and the layers separated.
  • Example 6 4-(4-f4-[4-(f4-[2-(2.6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2.3-dihvdro-l/7-isoindol-5-yl1- piperazin-l-yllmethyl)piperidin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl)benzonitrile
  • NaBH(OAc)3 (0.092 g, 0.44 mmol) was added and the mixture stirred for Ih.
  • the mixture was diluted with DCM (20 mL), washed (sat. Nal ICOa (20 mL), water (20 mL) then sat. brine (20 mL)), dried ( NaiSO i ) and concentrated.
  • Example 7 4-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1- piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-3-fluoro-2-(trifluoromethyl) benzonitrile
  • NaBH(OAc)a (0.117 g, 0.55 mmol) was then added and the mixture stirred for Ih. The mixture was then diluted with DCM (20 mL) and washed (sat. Nal ICO;, (20 mL), water (20 mL) then sat. brine (20 mL)), dried (Na2SO4) and concentrated.
  • Pd(dppf)2C12-DCM complex (0.467 g, 0.571 mmol) was then added and the resulting mixture was heated to 100°C for 3h, then cooled to RT. 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 (TS ⁇ SCL) and concentrated.
  • CS2CO3 (711 mg, 2.182 mmol) and 1 ,4-dibromobutane (0.391 mL, 3.27 mmol) were added to a solution of 4- (4-(5-hydroxypyrimidin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (380 mg, 1.091 mmol) in DMF (5 mL) at RT. The mixture was stirred at RT for 2h, 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 (Na2SO4) and concentrated.
  • Example 8 4-[4-[5-[4-[4-[2-(2,6-Dioxo-3-piperidyl)-7-methoxy-l-oxo-isoindolin-5-yl1piperazin-l-yl1- butoxy1pyrimidin-2-yl1-l-piperidyl1-2-(trifluoromethyl)benzonitrile
  • the mixture was then heated to 80°C for 16h, cooled to RT 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), sat. Nal ICO;, (20 mL)then sat. brine (20 mL)), dried (Na2SO4) and concentrated.
  • the crude material was purified by preparative HPLC (Column B, Eluent C). Fractions containing the desired compound were combined, concentrated cold to a minimum amount of solvent and basified with sat. Nal ICO;, solution.
  • the phases were separated and the aqueous phase was extracted with DCM (4 x 30 mL).
  • Example 9 4-(4-(5-(4-(4-(2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazin-l- yl)butoxy)pyridin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
  • Example 10 4-(4-(4-(3-(2-(4-(2-(2.6-Dioxopiperidin-3-vD-7-methoxy-l-oxoisoindolin-5-vDpiperazin-l- yl)ethvDazetidin-l-vDphenvDpiperidin-l-vD-2-(trifluoromethvDbenzonitrile
  • Example 11 5-(4-(4-(4-(4-(4-(2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazin-l- yl)butoxy)phenvDpiperidin-l-vD-3-(trifluoromethvDpicolinonitrile
  • RockPhos Pd G3 (0.290 g, 0.34 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoro- methyl)benzonitrile (1.39 g, 3.40 mmol), 3,3-difluoropentane-l,5-diol (1.19 g, 8.49 mmol) and CS2CO3 (239 mg, 0.73 mmol) in 1,4-dioxane (50 mL) at RT. The resulting mixture was then stirred at 100°C for Ih. The mixture was then cooled to RT and concentrated.
  • Methane sulfonic anhydride (167 mg, 0.96 mmol) was added in one portion to 4-(4-(4-((3,3-difluoro-5- hydroxy-pentyl)oxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.38 mmol) and NEta (160 pL, 1.15 mmol) in DCM (2 mL) at RT and the mixture was stirred for 18h. The mixture was then diluted with DCM (25 mL) and washed sequentially with sat NH4CI (10 mL), sat Nal ICO;, (10 mL), water (20 mL) and sat.
  • RockPhos Pd G3 (88 mg, 0.10 mmol) was added to a mixture of butane- 1,4-diol (142 mg, 1.57 mmol), CS2CO3 (1.03 g, 3.15 mmol) and 4-(4-(4-bromophenyl)piperidin-l-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1 ,4-dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h and then concentrated.
  • DIPEA (57.8 Lil,. 0.33 mmol) was added to a mixture of KI (4 mg, 0.02 mmol), 4-(4-(4-(4-bromobutoxy)- phenyl)piperidin-l-yl)-2-cyclopropylbenzonitrile (50 mg, 0.11 mmol) and 3-[7-methoxy-l-oxo-5-(piperazin-l- vl 1 .3-dihvdro-2/7-isoindol-2-vl
  • piperidine-2.6-dione hydrochloride salt (43.5 mg, 0.12 mmol) in MeCN (2 mL) at RT.
  • Ph(OH)2 on carbon (0.54 g, 0.38 mmol) was added to benzyl 4-(2,2-dimethoxyethyl)piperidine-l- carboxylate (5.90 g, 19.2 mmol) in MeOH (60 mL) at RT under N2 in a steel pressure reactor. The resulting suspension was purged with N2 and then H2 and then stirred at RT at a pressure of 4 atmospheres for 3 days. The mixture was then filtered through celite and washed through with MeOH (250 mL).
  • RuPhos Pd G3 (0.205 g, 0.24 mmol) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), 4-(2,2-dimethoxyethyl)piperidine (0.64 g, 3.67 mmol), CS2CO3 (2.388 g, 7.33 mmol) and RuPhos (0.114 g, 0.24 mmol) in 1,4-dioxane (20 mL) at RT under N2. The resulting solution was stirred at 100°C for 1 Oh and then concentrated.
  • DIPEA (2.3 mL, 13.10 mmol) was added to 3-[l-oxo-5-(piperazin-l-yl)-l,3-dihydro-277-isoindol-2-yl]- piperidine-2, 6-dione hydrochloride salt (1.05 g, 2.88 mmol) in DMSO (20 mL) at RT. The mixture was sonicated until a hazy solution was obtained and was then stirred at RT for 0.5h.

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Abstract

Compounds of Formula (I) or a pharmaceutically acceptable salt thereof are PROTAC compounds useful in the treatment of prostate cancer.

Description

Compounds and Their Use in Treating Cancer
FIELD
This specification relates to certain Proteolysis Targeting Chimera (PROTAC) compounds and, as a minimum, their ability to degrade the Androgen Receptor (AR) and therefore their use for the treatment of diseases or disorders dependent on the androgen receptor in mammals. Degradation of androgen receptors may provide, for example, an anti-tumour effect and accordingly this specification relates in part to the use of such compounds for the treatment of cancer and to pharmaceutical compositions containing them. It also relates to intermediate compounds that may be useful in the preparation of such PROTACs.
BACKGROUND
Traditional small molecule drugs reversibly (or sometimes irreversibly) bind to a target protein as a means of modulating a given biological activity. In contrast, PROTACs bind to their target proteins, but then bring about the target protein’s degradation. Having achieved this effect, the PROTAC is in theory able to repeat this process with another target protein. Accordingly, unlike with “traditional small molecule” inhibitors, the PROT AC-driven degradation mechanism can in theory operate in a sub- stoichiometric manner - meaning that more modest exposures of a PROTAC compound could still achieve a desired level of efficacy in vivo. In practice this can mean that the degradation power (DC50 and Dmax) of a PROTAC can have an improved effect than that reflected only by its binding affinity.
At a simplistic level, PROTAC molecules are often described as having three parts - (1) a part that is capable of binding to the target protein to be degraded, (2) a second part that is capable of binding to an E3 ubiquitin ligase, and finally, a linker that connects (1) and (2) together.
In use, the PROTAC binds to both the target protein and E3 ubiquitin ligase simultaneously to form 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 labelling the target protein for degradation by the cell’ s proteasome machinery. A PROTAC can then dissociate from the target protein and initiate another cycle of this process in a catalytic manner. Meanwhile, the ubiquitinated target proteins are recognized and degraded by the cell’s proteasome machinery.
This PROTAC-mediated approach may be valuable as a method of treating certain diseases where the targeted degradation of specific bodily 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 which controls the expression of a range of genes involved in growth and survival of prostate cells. AR is composed of four distinct domains: the N-terminal domain (NTD), DNA binding domain (DBD), a hinge region which 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 dimerise and translocate from the cytoplasm into the nucleus. Within the nucleus receptor dimers bind to androgen response elements (AREs) in the promoters of androgen responsive genes such as PSA and FKBP5. The AR signalling pathway is critical for normal prostate development and male sexual differentiation fails to occur in the absence of androgens or without a functioning AR.
The relationship between androgens and prostate cancer was first discovered in a seminal study by Huggins and Hodges in 1941 and subsequent work has shown that androgen deprivation therapy is highly effective in the treatment of recurrent prostate cancer. However, despite good responses initially most tumour cells adapt to low androgen levels and patients relapse within a few years developing a disease state known as castrate resistant prostate cancer (CRPC). Several second generation antiandrogens have been approved by the US FDA for the treatment of CRPC. These include enzalutamide, apalutamide and darolutamide, which all compete with androgens for binding to the ligand binding domain. As well as antagonising the AR, preventing its activation, they also inhibit nuclear translocation and DNA binding thus effectively shutting down AR signalling. In contrast abiraterone acetate is an androgen biosynthesis inhibitor which targets cytochrome p450 enzyme 17R-hydroxlase-17,20-lyase (CYP17). Testosterone is processed in the testes and adrenal glands by CYP17 and therefore inhibition of this enzyme inhibits prostate tumour growth by decreasing circulating androgen levels.
Whilst the above-mentioned drugs significantly prolong survival of patients with late stage prostate cancer they are not curative and resistance inevitably occurs. However, it is clear that the AR remains central to the progression of CRPC meaning there is still a need to develop alternative AR inhibitors. Several resistance mechanisms have been identified including AR amplification, mutation or the generation of splice variants that lack the ligand binding domain. Mutations in the ligand binding domain, for example F877L or L702H, can convert antagonists into agonists or allow the receptor to utilise alternative steroid hormones such as glucocorticoids or progesterone. Agents that degrade AR, removing it from the cell could therefore help tackle these forms of resistance. As such, AR PROTACs, which bind the ligand binding domain of the androgen receptor and simultaneously recruit an E3 ligase such as cereblon leading to ubiquitination and degradation of AR via the proteasome, could offer therapeutic benefit to patients with prostate cancer, particularly metastatic CRPC. AR PROTACs may also be useful against AR+ breast cancer.
Given that the above-mentioned resistance mutations that can occur in the ligand binding domain and may limit the effectiveness of known CRPC treatments, it would be beneficial to develop AR degrading PROTACs that do not just target the “wild-type” AR, but which are also effective in degrading clinically relevant mutated forms of AR too.
Whichever target protein binding unit (1) is used at one end of a PROTAC’s linker unit, a fundamental element that must always be present at the other end of a PROTAC molecule is a unit (2) that helps to direct the tagging of the target protein for degradation, for example an E3 ubiquitin ligase cereblon binder unit. Scientific endeavours have already provided a number of such E3 ubiquitin ligase cereblon binder units and further examples are demonstrated hereinafter by the present researchers.
WO2018/071606 describes certain PROTAC compounds said to be AR degraders.
As with “traditional small molecule” binders and PROTACs alike, there is always the issue of “off- target” activity in vivo which can be important to avoid in the development of safe and effective drug treatments. In other words, a given binding unit may be very potent against the intended target, but if it is inadvertently potent against other unintended biological targets in the human body, it may cause unacceptable toxicities, side effects and so on.
It is therefore an ongoing challenge to develop potent molecules for pharmaceutical use that are also suitably selective - i.e. avoiding inhibition/binding/degradation of unintended biological targets in vivo.
For example, the present researchers have surprisingly found that certain compounds of this specification show beneficial selectivity that is expected to avoid or reduce the risk of mitotoxicity in vivo.
As part of developing current and future PROTAC drug treatments for medicinal use (e.g. cancer), there is still a need to develop androgen receptor PROTAC compounds that have a combination of beneficial/improved properties. As mentioned above, development of PROTACs that target both wild-type AR and one or more clinically relevant mutated forms of AR is an example of such a combination effect.
Furthermore, there is a need to develop androgen receptor binder units that can be incorporated into a PROTAC, regardless of which an E3 ubiquitin ligase cereblon binder unit is selected for use at the other end of the molecule.
Other properties of interest during pharmaceutical discovery and development of such PROTACs may relate to selectivity profile, absorption/bioavailability, distribution, metabolism, elimination, toxicity and side-effect profile, stability, manufacturability and so on.
SUMMARY
The compounds of this specification provide, as a minimum, potent AR binding units suitable for incorporation into PROTAC compounds, and to PROTAC compounds containing such AR binding units together with an E3 ubiquitin ligase cereblon binder unit at the other end of the PROTAC molecule. Certain AR binding units are advantageously configured to degrade not only the wild-type AR, but also one or more clinically relevant mutant forms of AR too, for example L702H. Certain PROTAC compounds of this specification also have a surprisingly beneficial combination of properties, e.g. relating to AR degradation and selectivity/safety profile in combination.
This specification relates to the above-mentioned AR-binding units and to PROTAC compounds (and pharmaceutically acceptable salts thereof) that incorporate such AR binding units together with an E3 ubiquitin ligase cereblon binder unit (the two units being linked by a linker).
This specification also relates to pharmaceutical compositions containing such PROTACs (and pharmaceutically acceptable salts thereof) and their use in methods of treatment in the human or animal body, for example in the treatment or prevention of cancer. This specification also relates to processes and intermediate compounds (and salts thereof) involved in the preparation of said PROTACs.
According to the first aspect of this specification there is provided a compound of Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein:
X1 is C & 0, 1 or 2 of X2, X3 & X4 is/are N, and are otherwise C: or
X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and with Xs attached to Xs, where 1 or 2 of X1, X2, Xs, X6, X7 & Xs is/are N, and are otherwise C: p is 1 or 2 and X1 is C attached to R1 when X3 & X4 are not substituted by
-X5=X6-X7=X8-: and otherwise p is 0. I or 2: where: each R1 is a substituent on any C atom at X1, X2, X3 & X4, (or at X1, X2, Xs, X6, X7
& Xs when X3 & X4 are substituted by -X5=X6-X7=X8-), and is/are independently selected from F, Cl, Ci-aalkyl and Ci-aalkoxy, wherein said Ci-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F; n is 0, 1 or 2; m is 0 or 1 ;
Q is CH or N when n & m are both other than 0 and otherwise Q is CH;
R2a and R2b are substituents on the same or different C atoms other than at Q, each independently selected from H, F and Ci-aalkyl, or R2a & R2b together form a -(CH2)r- group where r is 1 , 2 or 3 ;
0, 1 or 2 of Y1, Y2, Y3 & Y4 is/are N, and are otherwise C; each R3 is a substituent on any C atom at Y1, Y2, Y3 & Y4, and is/are independently selected from F, Cl, CN, C i-aalkyl and Ci-aalkoxy, wherein said C i-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F ; q is 0, 1 or 2;
Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and a minimum length of from 6 to 26 atoms between ‘a’ and ‘b’; wherein said framework may include one or more straight and/or branched chains and/or rings and is optionally substituted on any available C atom(s) by one or more F; and
W is an E3 ubiquitin ligase cereblon binder unit.
This specification also describes, in part, a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
This specification also describes, in part, a method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
As shown in the experimental section hereinafter, the present researchers have not just developed a range of beneficial AR binding units, but gained an understanding about where such binding units can incorporate a linker (leading to an E3 ubiquitin ligase cereblon binder unit) without it interfering with their AR binding capability. Accordingly the present researchers understand that when incorporating their AR binding units into a PROTAC, the linker of said PROTAC should not attach at the left or central rings in Formula (I) shown hereinabove, but may suitably attach at the specified position on the right-hand ring in the compound of Formula (I) as shown herein.
Therefore, in a further aspect of this specification there is provided a PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la):
Figure imgf000006_0001
where R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q may take any of the values defined herein for each of these integers respectively.
Figure imgf000006_0002
For avoidance of doubt in Formula (la) indicates a point of connection via a single covalent bond to the remainder of the PROTAC compound.
In one embodiment there is provided a PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of Formula (la) as described herein.
As described herein, the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 6 to 26 atoms, said atoms being linked by single covalent bonds and each selected from carbon or a heteroatom (i.e. O, N or S).
As described herein, the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 7 to 14 atoms, said atoms being linked by single covalent bonds and each selected from carbon or a heteroatom (i.e. O, N or S). In one embodiment, the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 6 to 26 atoms, said atoms being linked by single covalent bonds and each selected from C, N or O.
In one embodiment, the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length corresponding to the length of a linear chain of from 7 to 14 atoms, said atoms being linked by single covalent bonds and each selected from C, N or O.
It is to be understood that although a link length “corresponding to the length of [certain atoms in a chain]” it is not to be interpreted that this limits said link to said atoms, and for example sulfur atom(s) may also be present in the link even if S atoms are not included in the length descriptor.
As described herein, the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length of from 0.9 nm to 4 nm.
As described herein, the link between an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) as shown hereinabove preferably has a length of from 1.0 nm to 2.2 nm.
In a further aspect of the specification there is provided an androgen receptor binding unit of Formula (la), as described herein, for use in a PROTAC compound (or pharmaceutically acceptable salt thereof) that also contains an E3 ubiquitin ligase cereblon binder unit.
In a further aspect of the specification there is provided an androgen receptor binding unit of Formula (la), as described herein, for use in a PROTAC compound (or pharmaceutically acceptable salt thereof) that is linked to an E3 ubiquitin ligase cereblon binder unit.
Accordingly, there is provided an androgen receptor binding unit of Formula (la), as described herein, for use in a PROTAC compound (or pharmaceutically acceptable salt thereof) where said PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit.
Accordingly, there is provided an androgen receptor binding unit of Formula (la), as described herein, for use in a PROTAC compound (or pharmaceutically acceptable salt thereof) where said PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit that is linked to said androgen receptor binding unit.
Accordingly, there is provided an androgen receptor binding unit of Formula (la), as described herein, for incorporation into a PROTAC compound (or pharmaceutically acceptable salt thereof) where said PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit.
Accordingly, there is provided an androgen receptor binding unit of Formula (la), as described herein, for incorporation into a PROTAC compound (or pharmaceutically acceptable salt thereof) where said PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit that is linked to said androgen receptor binding unit.
Therefore, there is provided an androgen receptor binding unit of Formula (la), as described herein, contained within a PROTAC compound (or a pharmaceutically acceptable salt thereof) where said PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit.
Therefore, there is provided an androgen receptor binding unit of Formula (la), as described herein, contained within a PROTAC compound (or a pharmaceutically acceptable salt thereof) where said PROTAC compound also contains an E3 ubiquitin ligase cereblon binder unit that is linked to said androgen receptor binding unit.
In one embodiment the link between androgen receptor binding unit of Formula (la) [as described above] and an E3 ubiquitin ligase cereblon binder unit is a Linker as defined according to any embodiment or claim herein, where the point of attachment shown in Formula (la) above connects to the ‘a’ point of connection on any Linker as defined herein.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
Many embodiments of this disclosure are detailed throughout the specification and will be apparent to a reader skilled in the art.
A pharmaceutically acceptable salt of a compound of Formula (I) or PROTAC compound described herein may be, for example, an acid-addition salt when said compound contains a basic functional group, such as an amine. An acid-addition salt may be formed using an inorganic acid or an organic acid. A pharmaceutically acceptable salt of said compound may be, for example, a base-addition salt when said compound contains an acidic functional group, such as a carboxylic acid. An acid-addition salt may be formed using an inorganic base or an organic base. “Pharmaceutically acceptable salt” is used to specify that the salt is suitable for use in the human or animal body. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. A pharmaceutically acceptable salt of a compound of Formula (I) or PROTAC compound includes such salts that may be formed within the human or animal body after administration of said compound to said human or animal body.
As used herein the term “alkyl” includes straight chain, branched chain and cyclic alkyl groups and combinations thereof having the specified number of carbon atoms. Therefore, C i.vilkvl includes methyl, ethyl, w-propyl, isopropyl and cyclopropyl; and Ci.galkyl 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. Therefore, Ci-aalkoxy includes methoxy, ethoxy, w-propoxy, isopropoxy and cyclopropoxy.
In this specification chemical abbreviations familiar to the skilled person may be used including for example “Me” = methyl, “Ef ’ = ethyl, “Pr” = propyl, “Bu” = butyl and “Ph” = phenyl.
Where the term “optionally” is used, it is intended that the subsequent feature may occur or may not occur. As such, 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 by one or more F” includes -CI L. -CH2F, -CHF2 and -CF3.
The term “substituted” means that one or more hydrogens on the designated atom or group is replaced by the indicated substituent(s) provided that any atom(s) bearing such substituent(s) maintains its permitted valency where the skilled person understands that the standard valencies of carbon, nitrogen and oxygen are 4, 3 and 2 respectively. Therefore, “substituted on any available C atom(s)” is to be understood to mean that the substituent(s) is/are limited in their positioning (and/or potentially in their number) according to whether there are any hydrogen atoms remaining on the designated atom or group which could be replaced by said substituent(s).
The dashed bonds included in Z , " ", indicate the possibility that the bond may in each case be a single covalent bond or a double covalent bond - in accordance with the atom (or group of atoms) present at each of the XE, XE, XG, XH and XJ positions. The skilled person understands that the standard valencies of carbon, nitrogen and oxygen are as mentioned above, and as such they can understand whether each dashed bond should be interpreted as a single bond or a double bond in any given Z group in the compound of Formula (I). The same applies to the XE2, XE2, XG2, XH2 and XJ2 positions in ZA.
The term “adjacent” or “adjacent position” - for example in reference to XG, XH and XJ of Z refers to the next closest position in the molecular chain/ring system. Accordingly, in the context of Z: XG and XH are adjacent each other, XH and XJ are also adjacent each other, but XG is not adjacent XJ.
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 fragments that may be present within a partly or fully unsaturated group or framework are C=C, C=N, C=O, N=N, C=C or C=N in cases where nitrogen and oxygen heteroatoms are permitted/present, and may also include S=O in cases where sulfur heteroatoms are also permitted/present.
It is to be understood that “heteroatom” may represent an oxygen, nitrogen or sulfur atom unless explicitly further limited in a given context.
The term “minimum length of [... ] atoms between ‘a’ and ‘b’” refers to the shortest chain of atoms in the chain between ‘a’ and ‘b’. Therefore, if the chain consisted of -CH2CH2CH2-, the number of atoms in the chain is 3 (the hydrogen atoms are regarded as not being in the chain). Alternatively if the chain consisted of 1,3-phenylene, where the shorter route around the phenyl ring contains 3 C atoms and the long route around the phenyl ring contains 5 C atoms, the minimum length of such a chain would be counted as 3 atoms.
It is to be understood that the points of attachment ‘a’ and ‘b’ each represent single covalent bonds to the relevant adjacent groups/atoms.
It is to be understood that in this specification “rings” or “heterocyclic groups” may include single rings, fused rings, spirocyclic rings and bridged rings.
In reference to the Linker, as described herein, it is to be understood that the branching, where present may be present on a chain (even a chain of 1 atom length) and/or on a ring. The skilled person would generally interpret in this manner, but for the avoidance of doubt, it is to be understood that the “branching” that occurs inherently in order to form a ring is not considered “branching” in the context of the Linker embodiments described herein. It is to be understood that said branches may occur on the same or different atoms of the Linker framework. For example it is possible to have two “=O” branches on a sulfur heteroatom in order to form a SO2 group within the Linker framework. Linker #22 described hereinafter is an example where there is one branch (-Me) coming from a chain within the Linker.
It is further to be understood that ‘branches’ (and definitions for branches provided herein) refer to branches that branch off the main chain of atoms between ‘a’ and ‘b’, leading to a ‘dead end’ in the molecular structure. In this specification it is to be understood that the point of attachment of a given group to some other group (via a single covalent bond) may be represented by a line meeting a bond substantially at right angles to said bond, for example as shown on the far right-hand side of Formula (la) herein, and for example at either end of Linkers 1 to 46 depicted hereinafter.
In this specification when “0, 1 or 2 of XA, XB, Xc, XD, XE & XF is/are N where XE & XE are not both N, and are otherwise C” - certain of the C atoms are to be understood to implicitly possess a hydrogen atom where necessary in order to satisfy the standard valency (4) for carbon atoms. The skilled person will understand that such H atom cannot be present on a C at XE or XE or on a C at XA, XB, Xc or XD when a substituent or Linker is attached to said carbon. The same principle applies in respect of X1, X2, X3, X4 (and with Xs, X6, X7 & Xs where present), and also with Y1, Y2, Y3 & Y4. The same applies to XA2, XB2, XC2, XD2, XE2, XE2, XG2, XH2 & X32.
In this specification a reference to a secondary or tertiary amine is intended to have the normal meaning in the art and therefore a nitrogen atom that is part of an amide group or a sulphonamide group, for example, is not to be regarded as a secondary or tertiary amine.
In this specification a saturated heterocyclic group refers to at least one ring of atoms (including bridged rings, spiro rings, fused rings, and single rings) containing carbon atoms and at least one heteroatom, where the heteroatom(s) is/are each independently selected from N, O and S, and where each atom in the ring is linked to its adjacent atoms by single covalent bonds. Therefore, an example of a heterocyclic group is a spiro heterocyclic group having two rings and a total of one heteroatom such as 9-azasprio[5.5]undecane. Typically, a saturated heterocyclic group will have at least two carbon atoms separating each of the heteroatom(s) present in said group to ensure a suitable level of chemical stability for use in a pharmaceutical context. Where reference is made to a “nitrogen-containing saturated (or partially unsaturated) heterocyclic group” this requires the presence of at least one nitrogen heteroatom but does not limit the possibility of one or more non-nitrogen heteroatoms (i.e. S, O) being present in addition. In this specification a partially unsaturated heterocyclic group refers to at least one ring of atoms (including bridged rings, spiro rings, fused rings, and single rings) containing carbon atoms and at least one heteroatom, where the heteroatom(s) is/are each independently selected from N, O and S, and where at least two atoms within the heterocyclic group are connected to each other via a double covalent bond. As the skilled person would understand, partially unsaturated does not include fully unsaturated heterocyclic groups - i.e. where the group contains the maximum possible number of double bonds for the atomic framework in question.
Where reference is made to a cyclic group (e.g. a heterocyclic group) having a specified number of ring atoms, this includes the atoms making up the ring (including atoms involved in the bridge of a bridged ring, and all atoms of a fused or spiro ring) but does not include any hydrogen atoms or other substituent atoms attached to the ring atoms. Therefore, for example, a cyclic group which is l,4-piperazin-l,4-diyl has 6 ring atoms (4C and 2N).
In this specification an alkylene group (for example a C .salkvlene ) is a saturated group consisting only of carbon and hydrogen atoms with two points of attachment to adjacent atoms/groups. They may include straight chain(s), branched chain(s) and/or ring(s). Accordingly Cialkylene represents -CH2-, a C2alkylene can represent -CH2CH2- or -CH(Me)-, C i.salkvlene includes for example -CI hfcvclobut- 1,3 -diyl)-. A “straight chain Cui .^alkylene” corresponds to -(CH2)U- where u is an integer from ul to u2. In this specification a hydrocarbyl group means any group consisting only of C and H atoms. For example, Ci-yhydrocarbyl includes methyl, phenyl and p-tolvl.
The term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" or “prophylactic” unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.
The term “prophylactic” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
The term “treatment” is used synonymously with “therapy”. Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.
Some values of variable groups are as follows. One, two or more of such values, may be used in any combination with any other definitions, claims, aspects or embodiments herein (unless the context doesn’t permit) to provide further embodiments/claims of the specification.
In one embodiment X1 is C & 0 or 1 of X2, X3 & X4 is N and are otherwise C; or X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and Xs attached to Xs, where 1 of X1, X2, Xs, X6, X7 & Xs is N, and are otherwise C.
In one embodiment X1 is C & 0, 1 or 2 of X2, X3 & X4 is N and are otherwise C.
In one embodiment X1 is C & 0 or 1 of X2, X3 & X4 is N and are otherwise C.
In one embodiment X1 is C & 1 or 2 of X2, X3 & X4 is/are N and are otherwise C.
In one embodiment X1 is C & 1 of X2, X3 & X4 is N and are otherwise C.
In one embodiment X1, X2, X3 & X4 are all C.
In one embodiment X1 & X2 are C and X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and Xs attached to Xs, where 1 of Xs, X6, X7 & Xs is N, and are otherwise C.
In one embodiment X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and Xs attached to Xs; X6 & X7 are all C and Xs is N.
In one embodiment each R1 is a substituent on X1, and when p is 2, on any other C atom at X2, X3 & X4, (or each R1 is a substituent at X1, X2, Xs, X6, X7 or Xs when X3 & X4 are substituted by -X5=X6-X7=X8-), and in each case is independently selected from F, Cl, Me, cyclopropyl, CHF2, CF3 and OMe.
In one embodiment each R1 is a substituent on X1, and when p is 2, on any other C atom at X2, X3 & X4 when X3 & X4 are not substituted by -X5=X6-X7=X8-, and the values of R1 is/are otherwise as defined herein.
In one embodiment each R1 is selected from Cl, F, C i.vilkvl (optionally substituted by one or more F) and Ci-salkoxy.
In one embodiment p is 1 or 2 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-, and otherwise p is 1 or 2.
In one embodiment p is 1 or 2 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-, and otherwise p is 0 or 1. In one embodiment p is 1 or 2 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-, and otherwise p is 0.
In one embodiment p is 1 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-, and otherwise p is 0, 1 or 2.
In one embodiment p is 2 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-, and otherwise p is 0, 1 or 2.
In one embodiment p is 2 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-, and otherwise p is 0.
In one embodiment p is 0 and X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and Xs attached to Xs.
In one embodiment p is 1 or 2 and X3 & X4 are not substituted by -X5=X6-X7=X8-.
In one embodiment p is 1 or 2; X3 & X4 are not substituted by -X5=X6-X7=X8-, and X1 is C attached to R1 where-R1 is CFs.
In one embodiment p is 1 ; X3 & X4 are not substituted by -X5=X6-X7=X8-, and X1 is C attached to R1.
In one embodiment p is 1 ; X3 & X4 are not substituted by -X5=X6-X7=X8-, and X1 is C attached to R1 where R1 is CF3.
In one embodiment p is 1 and R1 is selected from Cl, C _;,alkvl (optionally substituted by one or more F) and Ci-aalkoxy.
In one embodiment p is 1 and R1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.
In one embodiment p is 1, X1 is C attached to R1, where R1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.
In one embodiment p is 1 , X1 is C attached to R1, X3 & X4 are not substituted by -X5=X6-X7=X8-, and R1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe.
In one embodiment p is 1 or 2; X3 & X4 are not substituted by -X5=X6-X7=X8-; X1 is C attached to an R1 where said R1 is selected from Cl, Ci-salkyl (optionally substituted by one or more F) and C i-salkoxy, and if present (i.e. when p is 2) the other R1 is F.
In one embodiment p is 1 or 2; X3 & X4 are not substituted by -X5=X6-X7=X8-; X1 is C attached to an R1 where said R1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe, and if present (i.e. when p is 2) the other R1 is F.
In one embodiment p is 1 or 2; X3 & X4 are not substituted by -X5=X6-X7=X8-; X1 is C attached to R1 where R1 is selected from Cl, Me, cyclopropyl, CHF2, CF3 and OMe, and if present (i.e. when p is 2) the additional R1 substituent is F attached to X2 where X2 is C.
In one embodiment p is 1 and R1 is C i-salkyl optionally substituted by one or more F.
In one embodiment p is 1 and R1 is methyl, cyclopropyl, CF3 or CHF2.
In one embodiment p is 1 and R1 is CF3 or CHF2.
In one embodiment p is 1 and R1 is CHF2.
In one embodiment p is 1 and R1 is CF3.
In one embodiment p is 1 and R1 is methyl.
In one embodiment p is 1 and R1 is cyclopropyl.
In one embodiment p is 1 and R1 is methoxy. The above 8 embodiments may for example be in the context where X3 & X4 are not substituted by -X5=X6- X7=XS- X1 is C and the above-mentioned R1 is a substituent on said C at X1.
In one embodiment p is 2: X1 & X2 are both C; X3 & X4 are not substituted by -X5=X6-X7=X8- and the values of R1 are such that X1 is substituted by CFs and X2 is substituted by F.
In one embodiment p is 1 ; X3 & X4 are not substituted by -X5=X6-X7=X8- X1, X2, X3 & X4 are all C and R1 is a substituent on X1 as defined herein.
In one embodiment p is 1 ; X3 & X4 are not substituted by -X5=X6-X7=X8- X1, X2, X3 & X4 are all C and R1 is a substituent on X1 and is CFs.
In one embodiment p is 2, and one R1 is CFs and the other R1 is F or ethyl.
In one embodiment p is 2, and one R1 is CFs and the other R1 is F.
In one embodiment p is 2, and one R1 is CT; and the other R1 is ethyl.
In one embodiment p is 2, X1 is C attached to a first R1 and X2 is C attached to a second R1.
In one embodiment p is 2, X1 is C attached to a CT; and X2 is C attached to either F or ethyl.
In one embodiment p is 2, X1 is C attached to a CT; and X2 is C attached to F.
In one embodiment p is 2, X1 is C attached to a CT; and X2 is C attached to ethyl.
The above 7 embodiments may for example be in the context where X3 & X4 are not substituted by -X5=X6- X7=X8-.
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, R2a is H and R2b is H.
In one embodiment n is 1 , m is 1 , Q is CH, R2a is H and R2b is H.
In one embodiment n is 0, m is 1 , Q is CH, R2a is H and R2b is H
In one embodiment n is 1 , m is 0, R2a is H and R2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an ( T (-stereochemical configuration.
In one embodiment n is 1 , m is 0, R2a is H and R2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an (S)- stereochemical configuration.
In one embodiment n is 1 , m is 1 , R2a is H and R2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an ( T (-stereochemical configuration.
In one embodiment n is 1 , m is 1 , R2a is H and R2b is C i.;alkyl attached to a C atom other than at Q, where said C atom has an (S)- stereochemical configuration.
In one embodiment n is 1 , m is 1 , Q is N, R2a is H and R2b is H. In one embodiment Q is CH with an ( R)-stereochemical configuration at said C atom.
In one embodiment Q is CH with an (S)- stereochemical configuration at said C atom.
In one embodiment n is 2; m is 1 ; R2a & R2b are both H: and Q is CH.
In one embodiment n is 2: m is 1 : R2a & R2b are both H: and Q is CH with an (R)- stereochemical configuration at said C atom.
In one embodiment n is 2: m is 1 : R2a & R2b are both H: and Q is CH with an (.S')-stereochemical configuration at said C atom.
In one embodiment R2a and R2b are substituents on the same or different C atoms other than at Q, each independently selected from H and Chalky 1.
In one embodiment R2a and R2b are substituents on the same or different C atoms other than at Q, each independently selected from H and Me.
In one embodiment R2a and R2b are substituents on the same or different C atoms adjacent Q and are otherwise as defined herein.
In one embodiment R2a and R2b are substituents on the same or different C atoms adjacent Q, each independently selected from H and C .vilkvl (for example Me).
In one embodiment R2a and R2b are substituents on the same or different C atoms and are both H.
In one embodiment R2a and R2b are substituents on the same or different C atoms other than at Q, each independently selected from H, F and Ci-aalkyl.
In one embodiment R2a and R2b are substituents on the same or different C atoms other than at Q, each independently selected from H and Chalky 1, or R2a & R2b together form a -(CH2)r- group where 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 R2a and R2b are substituents on the same or different C atoms other than at Q, where R2a is Me and R2b is H.
In one embodiment R2a and R2b are substituents on the same C atom other than at Q, where R2a and R2b are both Me.
In one embodiment R2a and R2b are substituents on the same C atom adjacent Q, where R2a and R2b are both Me.
In one embodiment Y1, Y2, Y3 & Y4 are respectively selected from (C, C, C, C), (N, C, C, C), (C, N, C, C) and (N, C, N, C).
In one embodiment 0 or 1 of Y1, Y2, Y3 & Y4 is N and are otherwise C.
In one embodiment 1 or 2 of Y1, Y2, Y3 & Y4 is/are N and are otherwise C.
In one embodiment Y1, Y2, Y3 & Y4 are respectively selected from (N, C, C, C), (C, N, C, C) and (N, C, N, C).
In one embodiment 1 of Y1, Y2, Y3 & Y4 is N and are otherwise C.
In one embodiment Y1 is N: and Y2, Y3 & Y4 are all C.
In one embodiment Y2 is N; and Y1, Y3 & Y4 are all C.
In one embodiment 2 of Y1, Y2, Y3 & Y4 are N and are otherwise C.
In one embodiment Y1 & Y3 are N: and Y2 and Y4 are C. In one embodiment Y1, Y2, Y3 & Y4 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 R3 (when present) is a substituent on any C atom at Y1, Y2, Y3 & Y4 selected from F, CN and Chalky 1.
In one embodiment q is 0, 1 or 2 and R3 (when present) is a substituent on any C atom at Y1, Y2, Y3 & Y4 selected from F and Ci-aalkyl.
In one embodiment q is 0 or 1 and R3 (when present) is a substituent on any C atom at Y1, Y2, Y3 & Y4 selected from F or Ci-aalkyl.
In one embodiment q is 0 or 1 and R3 (when present) is a substituent on any C atom at Y1, Y2, Y3 & Y4 selected from F or Me.
In one embodiment R3 (when present) is Ci-aalkyl.
In one embodiment R3 (when present) is Me.
In one embodiment R3 (when present) is F.
In one embodiment R3 (when present) is CN.
In one embodiment q is 1 and R3 is attached to C at Y1.
In one embodiment q is 1 and R3 is attached to C at Y1, and R3 is selected from F, CN and Me.
In one embodiment q is 2 and both R3 groups are F.
In one embodiment q is 2 and the R3 groups are attached to C at Y1 and Y3.
In one embodiment q is 2 and each R3 group is F, which are attached to C at Y1 and Y3.
In one embodiment Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and a minimum length of from 6 to 26 atoms between ‘a’ and ‘b’; wherein said framework may include one or more straight and/or branched chains and/or rings and is optionally substituted on any available C atom(s) by one or more F.
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 C and H atoms and at least two heteroatoms including 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 C and H atoms and at least two heteroatoms including 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 two heteroatoms including at least one nitrogen heteroatom in the form of a tertiary amine.
In one embodiment the Linker has a minimum length of from 6 to 20 atoms between ‘a’ and ‘b’.
In one embodiment the Linker has a minimum length of from 6 to 15 atoms between ‘a’ and ‘b’ .
In one embodiment the Linker has a minimum length of from 7 to 14 atoms between ‘a’ and ‘b’.
In one embodiment the total number of C and hetero atoms in the Linker framework is from 6 to 26.
In one embodiment the total number of C and hetero atoms in the Linker framework is from 7 to 24.
In one embodiment the total number of C and hetero atoms in the Linker framework is from 8 to 22.
In one embodiment the total number of C and hetero atoms in the Linker framework is from 9 to 20.
In one embodiment when W is -Z-RA, the Linker is attached at any available C atom at XB or Xc of Z.
In one embodiment the framework of the Linker may include one or more straight chains and/or rings and is optionally substituted on any available C atom(s) by one or more F.
In one embodiment the framework of the Linker consists of one or more straight chains and/or rings that are optionally substituted on any available C atom(s) by one or more F.
In one embodiment the framework of the Linker may include (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) that are optionally substituted on any available C atom(s) by one or more F.
In one embodiment the framework of the Linker may include (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) that are optionally substituted on any available C atom(s) by one or more F.
In one embodiment the framework of the Linker may include (or consist of) one or more straight and/or branched chains and/or rings (wherein the total number of branches is 0 or 1) that are optionally substituted on any available C atom(s) by one or more F.
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 2.
In one embodiment the total number of branches is 3.
In one embodiment any/each branch in the framework of a Linker has from 1 to 5 C and/or hetero atoms.
In one embodiment any/each branch in the framework of a Linker has 1 or 2 C and/or hetero atoms.
In one embodiment any/each branch in the framework of a Linker has 1 C and/or hetero atom.
In one embodiment any/each branch in the framework of a Linker has 1 C atom.
In one embodiment the total number of C and/or heteroatoms in the branch(es) (where present) of the framework of the Linker is from 1 to 5.
In one embodiment the total number of C and/or heteroatoms in the branch(es) (where present) of the framework of the Linker is from 1 to 3.
In one embodiment the total number of C and/or heteroatoms in the branch(es) (where present) of the framework of the Linker is 1.
In one embodiment any the framework of the Linker is either unbranched or has one branch that is Me. In one embodiment the framework of the Linker is optionally substituted on any available C atom(s) by 1 or 2 F (for example by 2 F, for example where said 2 F are substituted on the same carbon atom).
In one embodiment the framework of the Linker is not substituted by any F.
In one embodiment the Linker is a saturated or a partially unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and: a minimum length of from 7 to 14 atoms between ‘a’ and ‘b’; wherein the total number of C and hetero atoms in the Linker framework is from 9 to 20: where said framework comprises one or more straight and/or branched chains and/or rings that are optionally substituted on any available C atom(s) by 1 or 2 F (for example by 2 F); wherein the total number of branches is 0 or 1 and when present said branch is Me.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A2 unit where A1 and A2 are each independently selected from N and O.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A2 unit where A1 and A2 are each independently selected from N and O.
In one embodiment the framework of the Linker includes a A'-CI F-CI F-A2 unit where A1 and A2 are each independently selected from N and O.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A2 unit where one of A1 & A2 is N and the other of A1 & A2 is selected from N or O.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A2 unit where one of A1 & A2 is N and the other of A1 & A2 is selected from N or O.
In one embodiment the framework of the Linker includes a A'-CI F-CI F-A2 unit where one of A1 & A2 is N and the other of A1 & A2 is selected from N or O.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group (e.g. having from 4 to 12 ring atoms) or a A'-CI F-CI F-A2 unit where one of A1 & A2 is N in the form of a secondary or tertiary amine, and the other of A1 & A2 is selected from N or O.
In one embodiment the framework of the Linker includes a A'-CI F-CI F-A2 unit where one of A1 & A2 is N in the form of a secondary or tertiary amine, and the other of A1 & A2 is selected from N or O.
In one embodiment the framework of the Linker includes at least one saturated or partially unsaturated heterocyclic group.
In one embodiment the framework of the Linker includes at least one saturated heterocyclic group.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group. In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group having from 4 to 12 ring atoms.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated heterocyclic group having from 4 to 12 ring atoms.
In one embodiment the framework of the Linker includes:
(1) a A'-CI I2-CI 12- A2 unit where A1 and A2 are each independently selected from N and C): 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 includes:
(1) a A'-CHi-CHi-A2 unit where one of A1 & A2 is N in the form of a secondary or tertiary amine, and the other of A1 & A2 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, l,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 includes 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, l,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 includes an O-CH2-CH2-N unit.
In one embodiment the framework of the Linker includes an O-CH2CH2-O-CH2CH2-N unit.
In one embodiment the framework of the Linker includes a piperazine group.
In one embodiment the framework of the Linker includes an azetidine group.
In one embodiment the framework of the Linker includes a piperidine group.
In one embodiment the framework of the Linker includes a 1 ,4-diazepane group.
In one embodiment the framework of the Linker includes a 12-oxa-3,9-diazaspiro[5.6]dodecane group.
In one embodiment the framework of the Linker includes a pyrrolidine group.
In one embodiment the framework of the Linker includes a 3,9-diazaspiro[5.5]undecane group.
In one embodiment the framework of the Linker includes a 2,5-diazabicyclo[2.2.1]heptane group.
In one embodiment the framework of the Linker includes a 1 ,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole group.
In one embodiment the framework of the Linker includes a 1 ,2,3,6-tetrahydropyridine group.
In one embodiment the framework of the Linker includes a 9-azaspiro[5.5]undecane group.
In one embodiment the framework of the Linker includes at least two nitrogen-containing saturated or partially unsaturated heterocyclic groups.
In one embodiment the framework of the Linker includes at least two nitrogen-containing saturated heterocyclic groups. In one embodiment the framework of the Linker includes a C, N or O atom at the ‘a’ point of attachment.
In one embodiment the framework of the Linker includes an N or O atom at the ‘a’ point of attachment.
In one embodiment the framework of the Linker includes an N or O atom at the ‘b’ point of attachment.
In one embodiment the framework of the Linker includes a C atom at the ‘a’ point of attachment.
In one embodiment the framework of the Linker includes an N atom at the ‘a’ point of attachment.
In one embodiment the framework of the Linker includes a C or N atom at the ‘b’ point of attachment.
In one embodiment the framework of the Linker includes an N atom at the ‘b’ point of attachment.
In one embodiment the framework of the Linker includes a C atom at the ‘b’ point of attachment.
In one embodiment the framework of the Linker includes an O atom at the ‘a’ point of attachment.
In one embodiment the framework of the Linker includes an O atom at the ‘b’ point of attachment.
In one embodiment the framework of the Linker includes an N or O atom at both the ‘a’ and ‘b’ points of attachment.
In one embodiment the framework of the Linker includes a C, N or O atom at the ‘a’ point of attachment and a C or N atom at the ‘b’ point of attachment.
In one embodiment the framework of the Linker includes:
(1) a A1-CH2-CH2-A2 unit where one of A1 & A2 is N in the form of a secondary or tertiary amine, and the other of A1 & A2 is selected from N or C): and/or
(2) at least one nitrogen-containing saturated or partially saturated heterocyclic group selected from piperazin- 1,4-diyl, azetidin- 1,3 -diyl, piperidin-l,4-diyl, l,4-diazepan-l,4-diyl, 12-oxa-3,9- diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin- 1,3 -diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl, 2,5- diazabicyclo[2.2.1]heptan-2,5-diyl, l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3,6-dihydro- 2//-pvridin- 1,4-diyl, and 9-azaspiro[5.5]undecan-3,9-diyl.
In one embodiment the framework of the Linker includes at least one nitrogen-containing saturated or partially saturated heterocyclic group selected from piperazin- 1,4-diyl, azetidin-l,3-diyl, piperidin- 1,4- diyl, 1 ,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-l,3-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1, 3 ,3a, 4 ,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3.6-dihvdro-2//-pvridin- 1 .4-divl. and 9-azaspiro[5.5]undecan- 3,9-diyl.
In one embodiment the framework of the Linker includes a piperazin- 1,4-diyl group.
In one embodiment the framework of the Linker includes an azetidin- 1 ,3-diyl group.
In one embodiment the framework of the Linker includes a piperidin- 1,4-diyl group.
In one embodiment the framework of the Linker includes a 1 ,4-diazepan-l ,4-diyl group.
In one embodiment the framework of the Linker includes a 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl group.
In one embodiment the framework of the Linker includes a pyrrolidin-l,3-diyl group.
In one embodiment the framework of the Linker includes a 3,9-diazaspiro[5.5]undecan-3,9-diyl group.
In one embodiment the framework of the Linker includes a 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl group.
In one embodiment the framework of the Linker includes a 1 ,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5- diyl group.
In one embodiment the framework of the Linker includes a 3.6-dihvdro-2//-pvridin- 1 .4-divl group. In one embodiment the framework of the Linker includes a 9-azaspiro[5.5]undecan-3,9-diyl group.
In one embodiment the Linker has the Formula: a -QA-QB-QC- b wherein:
‘a’ and ‘b’ represent the end points of attachment;
QA is -G-QH- or -G-(Ci-5alkylene)-;
QB is a direct bond, -QB1-QB2-QB3- or C .vilkvlene optionally substituted by one or more F (for example 1 or 2 F, for example 2 F); where:
QB1 & QB3 each independently represent a direct bond or C ^alkylene;
QB2 is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJ is H or Ci.3alkyl;
Qc is -QH-G- or -(Ci.5alkylene)-G-; each G is independently a direct bond, -CH2-, -O-, or -N(RG)- where each RG is independently H or Ci.3alkyl; each QH is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA, QB and Qc are selected so that the Linker does not contain any N-N or N-O bonds.
In one embodiment the Linker has the Formula: a -QA-QB-QC- b wherein:
‘a’ and ‘b’ represent the end points of attachment;
QA is -G-QH- or -G-(Ci.5alkylene)-;
QB is a direct bond, -QB1-QB2-QB3- or C].3alkylene optionally substituted by one or more F (e.g. 1 or 2); where:
QB1 & QB3 each independently represent a direct bond or Chalky lene;
QB2 is QH, -O-CH2CH2-O- or -N(RJ)- where RJ is Ci.3alkyl;
Qc is -QH-G- or -(Ci.5alkylene)-G-; each G is independently a direct bond, -CH2-, -O-, or -N(RG)- where each RG is independently H or
Ci-3alkyl; each QH is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA, QB and Qc are selected so that the Linker does not contain any N-N or N-O bonds.
In one embodiment the Linker has the Formula: a -QA-QB-QC- b wherein:
‘a’ and ‘b’ represent the end points of attachment;
QA is -GA-QHA- or -GA-(Ci-5alkylene)-; where GA is a direct bond, -CH2-, -O-, -NH- or -N(Me)-;
QHA is a 4 to 11 -membered nitrogen-containing saturated heterocyclic group; QB is a direct bond, -QB1-QB2-QB3- or C i-aalkylene optionally substituted by one or more F (e.g. 1 or 2); where:
QB1 & QB3 each independently represent a direct bond or Chalky lene;
QB2 is piperazin- 1,4-diyl, -O-CH2CH2-O- or -N(RJ)- where RJ is Ci-jalkyl;
Qc is -QHC-GC- or -(C i-2alkvlene)-Gc-: where Gc is a direct bond, -O- or -NH-;
QHC is a 6 to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA, QB and Qc are selected so that the Linker does not contain any N-N or N-O bonds.
In one embodiment QA is -GA-QHA- or -GA-(C].5alkylene)- where:
GA is selected from a direct bond, -CH2-, -O- or -N(RG)-; each RG is independently H or Chalky 1; and
QHA is a 4 to 11 -membered nitrogen-containing saturated heterocyclic group.
In one embodiment QA is -GA-QHA- or -GA-(C].5alkylene)- where:
GA is selected from a direct bond, -CH2-, -O- or -N(RG)-; each RG is independently H or Chalky 1; and
QHA is selected from azetidin-l,3-diyl, pyrro lidin- 1,3 -diyl, piperidin- 1,4-diyl, piperazin- 1,4-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl and 9-azaspiro[5.5]undecan-3,9-diyl.
In one embodiment QA is -GA-QHA- or -GA-(Ci-5alkylene)- where:
GA is selected from a direct bond, -CH2-, -O-or -NH- or -N(Me)-;
QHA is selected from azetidin-l,3-diyl, pyrro lidin- 1,3 -diyl, piperidin- 1,4-diyl, piperazin- 1,4-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl and 9-azaspiro[5.5]undecan-3,9-diyl; and the C i.salkvlene within said -GA-(Ci-5alkylene)- is selected from -( C I F )i- where f is an integer from 1 to 5, cyclobut-l,3-diyl and -CH2(cyclobut-l,3-diyl)-.
In one embodiment QA is selected from azetidin- 1,3 -diyl, pyrrolidin-l,3-diyl, piperidin- 1,4-diyl, -O(piperidin- 1 ,4-diyl)-, -C I F( piperidin- 1 ,4-diyl)-, piperazin- 1 ,4-diyl, 3 ,9-diazaspiro[5.5]undecan-3 ,9- diyl, -O(9-azaspiro[5.5]undecan-3,9-diyl)-, -O(cyclobut-l,3-diyl)-, -OCH2(cyclobut-l,3-diyl)-, -(CH2)f-, -O-(CH2)f-, -NH-(CH2)f- and -N(Me)-(CH2)r-, where f is an integer from 1 to 5.
In one embodiment QA is azetidin-l,3-diyl.
In one embodiment QA is pyrro lidin- 1 ,3-diyl.
In one embodiment QA is piperidin- 1,4-diyl.
In one embodiment QA is -O(piperidin-l,4-diyl)-.
In one embodiment QA is -CI F( piperidin- 1,4-diyl)-.
In one embodiment QA is piperazin- 1,4-diyl.
In one embodiment QA is 3,9-diazaspiro[5.5]undecan-3,9-diyl.
In one embodiment QA is -O(9-azaspiro[5.5]undecan-3,9-diyl)-.
In one embodiment QA is -G-(Ci-5alkylene)-.
In one embodiment QA is selected from -O(cyclobut-l,3-diyl)-, -OCH2(cyclobut-l,3-diyl)-, -(CI F ir-. -O(CH2)f-, -NH-(CH2)f- and -N(Me)-(CH2)r-, where f is an integer from 1 to 5.
In one embodiment QA is -O(cyclobut-l,3-diyl)-. In one embodiment QA is -OCH2(cyclobut-l,3-diyl)-.
In one embodiment QA is -(CH2)f- where f is an integer from 1 to 4 (for example, f is 4)
In one embodiment QA is -O-(CH2)r- where f is an integer from 1 to 5 (for example, f is 1 or 2).
In one embodiment QA is -NH-(CH2)r- where f is an integer from 1 to 5.
In one embodiment QA is -N(Me)-(CH2)r-, where f is an integer from 1 to 4.
In one embodiment QB is a direct bond, -QB1-QB2-QB3- or a straight chain Ci-salkylene optionally substituted by one or more F (for example 1 or 2 F, for example by 2 F).
In one embodiment QB is a direct bond.
In one embodiment QB is -QB1-QB2-QB3-.
In one embodiment QB is C .;,alkvlerie optionally substituted by one or more F.
In one embodiment QB is C .;,alkvlerie optionally substituted by one or two F (for example by 2 F).
In one embodiment QB is a straight chain C .;,alkvlerie optionally substituted by 1 or 2 F (for example by 2 F).
In one embodiment QB is C i-salkylene.
In one embodiment QB is a straight chain C .;,alkvlerie.
In one embodiment QB is -CF2-CH2-CH2- or -(CFb)™- where w is 1 to 3.
In one embodiment QB1 and QB3 each independently represent a direct bond, -CH2- or -CH2CH2-.
In one embodiment QB1 is a direct bond or -CH2-.
In one embodiment QB1 is a direct bond.
In one embodiment QB1 is -CH2-.
In one embodiment QB3 is a direct bond, -CH2- or -CH2CH2-.
In one embodiment QB3 is a direct bond.
In one embodiment QB3 is -CH2-.
In one embodiment QB3 is -CH2CH2-.
In one embodiment QB2 is QH, -O-CH2CH2-O- or -N(RJ)- where RJ is Ci-3alkyl.
In one embodiment QB2 is QH, -O-CH2CH2-O- or -N(Me)-.
In one embodiment QB2 is piperazin- 1,4-diyl, azetidin- 1,3 -diyl, -O-CH2CH2-O- or -N(Me)-.
In one embodiment QB2 is piperazin- 1,4-diyl, -O-CH2CH2-O- or -N(Me)-.
In one embodiment QB2 is QH.
In one embodiment QB2 is piperazin- 1,4-diyl.
In one embodiment QB2 is azetidin- 1 ,3-diyl.
In one embodiment QB2 is -O-CH2CH2-O-.
In one embodiment QB2 is -N(RJ)- where RJ is Ci-salkyl.
In one embodiment QB2 is -N(Me)-.
In one embodiment Qc is -QH-G- or -(Chalky lene)-G-.
In one embodiment Qc is -QH-G- or -(Ci-3alkylene)-G-.
In one embodiment Qc is -QH-G- or -(Chalky lene)-G-.
In one embodiment Qc is -QHC-GC- or -(Ci-5alkylene)-Gc- where:
Gc is selected from a direct bond, -O- or -NH-; and
QHC is a 6 to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.
In one embodiment Qc is -QHC-GC- or -(Ci-2alkylene)-Gc- where: Gc is selected from a direct bond, -O- or -Ni l-: and
QHC is a 6 to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.
In one embodiment Qc is -QHC-GC- or -(Ci-2alkylene)-Gc- where:
Gc is selected from a direct bond, -O- or -Ni l-: and
QHC is selected from piperazin- 1,4-diyl, piperidin-l,4-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1,4- diazepan-l,4-diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl, 12-oxa-3,9-diazaspiro[5.6]-dodecan-3,9-diyl, l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl and 3.6-dihvdro-2/7-pvridin- l ,4-divl.
In one embodiment Qc is selected from piperazin- 1,4-diyl, piperidin- 1,4-diyl, -(piperidin-l,4-diyl)O-, 2,5- diazabicyclo[2.2.1]heptan-2,5-diyl, 1,4-diazepan- 1,4-diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl, 12-oxa-
3.9-diazaspiro[5.6]-dodecan-3,9-diyl, l ,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3.6-dihvdro-2/7-pvridin- 1 ,4-divl. and -CH2CH2-NH- and -(CH2)g-O- where g is an integer from 1 to 4.
In one embodiment Qc is piperazin- 1,4-diyl.
In one embodiment Qc is piperidin- 1,4-diyl.
In one embodiment Qc is -(piperidin- 1,4-diy 1)0-.
In one embodiment Qc is 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl.
In one embodiment Qc is 1,4-diazepan- 1,4-diyl.
In one embodiment Qc is 3,9-diazaspiro[5.5]undecan-3,9-diyl.
In one embodiment Qc is 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl.
In one embodiment Qc is l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl.
In one embodiment Qc is 3.6-dihvdro-2/7-pvridin- l ,4-divl.
In one embodiment Qc is -(Ci-5alkylene)-G- [for example, -(CH2)g-O- where g is an integer from 1 to 5],
In one embodiment Qc is -(Chalky lene)-G- [for example, -(CH2)g-O- where g is an integer from 1 to 4],
In one embodiment Qc is -(Ci-3alkylene)-G- [for example, -(CH2)g-O- where g is 1, 2 or 3],
In one embodiment Qc is -(Chalky lene)-G- [for example, -(CH2)g-O- where g is 1 or 2],
In one embodiment Qc is -(CH2)g-Gc- where g is an integer from 1 to 5 and Gc is -O- or -NH-.
In one embodiment Qc is -(CH2)g-Gc- where g is 1 or 2 and Gc is -O- or -NH-.
In one embodiment Qc is -CH2CH2NH-.
In one embodiment each QH is independently selected from piperazin- 1,4-diyl, azetidin- 1,3 -diyl, piperidin- 1,4-diyl, 1,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-l,3-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1, 3 ,3a, 4 ,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3.6-dihvdro-2/7-pvridin- 1 .4-divl and 9-azaspiro[5.5]undecan-
3.9-diyl.
In one embodiment each QH is independently selected from piperazin- 1,4-diyl, azetidin- 1,3 -diyl, piperidin- 1,4-diyl, 1,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-l,3-diyl, 3,9- diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl, 1, 3 ,3a, 4, 6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl and 9-azaspiro[5.5]undecan-3,9-diyl.
In one embodiment QH is piperazin- 1,4-diyl.
In one embodiment QH is azetidin- 1 ,3-diyl.
In one embodiment QH is piperidin- 1,4-diyl.
In one embodiment QH is 1,4-diazepan- 1,4-diyl. In one embodiment QH is 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl.
In one embodiment QH is pyrrolidin-l,3-diyl.
In one embodiment QH is 3,9-diazaspiro[5.5]undecan-3,9-diyl.
In one embodiment QH is 2,5-diazabicyclo[2.2.1]heptan-2,5-diyl. In one embodiment QH is l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl.
In one embodiment QH is 3,6-dihydro-2H-pyridin- 1 ,4-diyl.
In one embodiment QH is 9-azaspiro[5.5]undecan-3,9-diyl.
In one embodiment RJ is Ci-aalkyl.
In one embodiment RJ is Me. In one embodiment RG is Ci-aalkyl.
In one embodiment RG is H or Me.
In one embodiment RG is Me.
In one embodiment RG is H.
In one embodiment the Linker (for example ‘a’ -QA-QB-QC- ‘b’) is selected from any of Linkers 1 to 46 or 1 to 48 shown below:
Figure imgf000025_0001
16 17 18
Figure imgf000026_0001
Figure imgf000027_0001
In one embodiment W is an E3 ubiquitin ligase cereblon binder unit attached to the ‘b’ end of the Linker via an available C atom within said E3 ubiquitin ligase cereblon binder unit.
In one embodiment W is W1 which is: -Z-(RA)h where Z is:
Figure imgf000027_0002
wherein: represents a single covalent bond or a double covalent bond;
0, 1 or 2 of XA, XB, Xc, XD, XE & XF is/are N, where XE & XE are not both N, and are otherwise C;
1 ofXG, XH & XJ is C(O); 1 ofXG, XH & XJ is N-(2,6-dioxopiperidin-3-yl) (Y); and 1 ofXG, XH & XJ is selected from C(RT)2, -CH2CH2-, C(O), N(Ci.3alkyl), -O- and -N=, wherein each RT is selected from H, F, Me or together with the carbon of C(RT)2 forms a cycloprop- 1,1 -diyl group; where XG, XH & XJ are selected such that there are not two C(O) groups present at adjacent positions, and that the
N-(2,6-dioxopiperidin-3-yl) is not at an adjacent position to either N(Ci.3alkyl) or O; each RA is independently a substituent on any available C atom at XA, XB, Xc or XD selected from F, Cl, Ci-salkyl, C i-salkoxy wherein said Ci-salkyl and C i-salkoxy is independently optionally substituted by one or more F ; h is 0, 1 or 2; and wherein the Linker is attached to any C atom at XA, XB, Xc or XD.
In one embodiment 0 or 1 of XA, XB, Xc, XD, XE & XF is N and are otherwise C.
In one embodiment 1 or 2 of XA, XB, Xc, XD, XE & XE is/are N and are otherwise C.
In one embodiment XA, XB, Xc, XD, XE & XE are all C.
In one embodiment 1 of XA, XB, Xc, XD, XE & XE is N and are otherwise C.
In one embodiment 2 of XA, XB, Xc, XD, XE & XE are N where XE & XE are not both N, and are otherwise C.
In one embodiment XB, XD & XE are all C, and 0, 1 or 2 of XA, Xc & XE is/are N, and are otherwise C.
In one embodiment XB, XD & XE are all C, and 0, 1 or 2 of XA, Xc & XE is/are N, and are otherwise C; where the Linker is attached to XB or to XA when XA is C.
In one embodiment XB, XD & XE are all C, and 0, 1 or 2 of XA, Xc & XE is/are N, and are otherwise C; where the Linker is attached to XB.
In one embodiment XG-XH-XJ is:
(i) XG-NY-C(O) where XG is -CH2-, -CH2CH2-, =N- or C(O);
(ii) XG-C(O)-NY where XG is -O- or N(Ci-3alkyl) [for example N(Me)]; or
(iii) C(O)-NY-CH2.
In one embodiment the Linker is attached to a C atom at XA or XB and XG-XH-XJ is:
(i) XG-NY-C(O) where XG is -CH2-, -CH2CH2-, =N- or C(O);
(ii) XG-C(O)-NY where XG is -O- or N(Ci-3alkyl) [for example N(Me)]; or
(iii) C(O)-NY-CH2.
In one embodiment the Linker is attached to a C atom at XB and XG-XH-XJ is:
(i) XG-NY-C(O) where XG is -CH2-, -CH2CH2-, =N- or C(O);
(ii) XG-C(O)-NY where XG is -O- or N(Ci-3alkyl) [for example N(Me)]; or
(iii) C(O)-NY-CH2.
In one embodiment XG-XH-XJ is CH2-NY-C(O).
In one embodiment XG-XH-XJ is CH2CH2-NY-C(O).
In one embodiment XG-XH-XJ is =N-NY-C(O).
In one embodiment XG-XH-XJ is C(O)-NY-C(O). In one embodiment XG-XH-XJ is O-C(O)-NY.
In one embodiment XG-XH-XJ is N(Ci-3alkyl)-C(O)-NY [for example N(Me)-C(O)-NY].
In one embodiment XG-XH-XJ is C(O)-NY-CH2.
In one embodiment each RA is a substituent on any available C at XA, XB, Xc or XD selected from F, Cl and C i-salkoxy optionally substituted by one or more F.
In one embodiment each RA is a substituent on any available C at XA, XB, Xc or XD selected from F, Cl, OMe and -OCHF2.
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 Xc, where Xc is C: and XA is C attached to RA where RA is OMe where said methyl is optionally substituted by one or more F (e.g. -OCHF2).
In one embodiment the Linker is attached to Xc, where Xc is C: and XA is C attached to RA where RA is OMe or -OCHF2.
In one embodiment -Z-(RA)h together represent any one of groups 1, 4, 16, 17 and 19 (referring to the specific -Z-(RA)h groups 1 to 21 whose structures are drawn out below).
In one embodiment h is 1 and RA is Ci-salkoxy [for example OMe],
In one embodiment h is 1 or 2, one RA is OMe and the other RA (when present, i.e. when h is 2) is Cl.
In one embodiment h is 1 or 2, one RA is Cl and the other RA (when present, i.e. when h is 2) is OMe.
In one embodiment h is 1 and RA is F.
In one embodiment h is 1 and RA is Cl.
In one embodiment h is 1 and RA is -OCHF2.
In one embodiment the Linker is attached to a C at XA or XB, and h is 0.
In one embodiment the Linker is attached to a C at XA or XB, h is 1 and RA is a substituent on Xc where Xc is C and RA is F.
In one embodiment the Linker is attached to a C at XA or XB, h is 1 and RA is a substituent on XD where XD is C and RA is OMe or -OCHF2.
In one embodiment the Linker is attached to a C at XB, h is 0, 1 or 2; the first RA (when present, i.e. when h is 1 or 2) is a substituent on an available C at XD and the second RA (when present, i.e. when h is 2) is on an available C at XA.
In one embodiment the Linker is attached to a C at XB, h is 0, 1 or 2; the first RA (when present, i.e. when h is 1 or 2) is a substituent on an available C at XD selected from Cl, OMe and -OCHF2; and the second RA (when present, i.e. when h is 2) is on an available C at XA and is selected from Cl and OMe.
In one embodiment -Z-(RA)h together represent any of the groups 1 to 21 shown below:
Figure imgf000030_0001
Figure imgf000031_0001
In one embodiment W is W2 which is
ZA is:
Figure imgf000031_0002
wherein: represents a single covalent bond or a double covalent bond;
1 of X*2, XB2, XC2 & XD2 is C and covalently bound to Y ;
0, 1 or 2 of XA2, XB2, XC2, XD2, XE2 & XF2 is/are N (where XE2 & XE2 are not both N) and are otherwise C;
1 or 2 of XG2, XH2 & XJ2 is/are N; and are otherwise C; each RAA is a substituent on any available C or N atom of Z - in each case independently selected from RAAI optionally substituted by one or more RAA2: where RAA is further selected from RAA2 when RAA is a substituent on an available C atom of ZA; each RAAI is independently Ci.4alkyl, C2-3alkenyl, C2-3alkynyl,
Ci-salkoxyCi-salkyl, carboxyCi-salkyl, Cj-ycarbocyclyl or a 4-6 membered heterocyclyl; each RAA2 is independently selected from F, Cl, Br, CN, NH2, Chalky 1,
O(C].3alkyl), NH(Ci-3alkyl) and N(Ci-3alkyl)2; wherein said Ci-salkyls are optionally substituted by one or more F; v is 0, 1 or 2;
Y is N-(2,6-dioxopiperidin-3-yl).
In one embodiment ZA is:
Figure imgf000031_0003
wherein: represents a single covalent bond or a double covalent bond; 1 ol' XA2 & XB2 is C and covalently bound to Y and the other of XA2 & XB2 is C;
0 or 1 of XC2 & XD2 is N and is/are otherwise C;
1 ofXG2 & XJ2 is N and the other of XG2 & XJ2 is C; and
XH2 xE2 & XF2 are all C.
In one embodiment -ZA-Y together represent any one or more of the groups Al to A6 shown below, where in each case said ZA group is optionally substituted on available C and/or N atom(s) by -[ RAA ]v as further defined herein.
Figure imgf000032_0001
In one embodiment each RAA is a substituent on any available C or N atom of ZA - in each case independently selected from RAAI optionally substituted by one or more RAA2: where RAA is further selected from RAA2 w|len RAA js a substituent on an available C atom of Z; wherein each RAAI is independently Ci. 4alkyl or a 4-6 membered heterocyclyl; and each RAA2 is independently selected from F, Cl, CN and Ci. aalkyl.
In one embodiment each RAA is a substituent on any available C or N atom of ZA - in each case independently selected from RAAI optionally substituted by one or more RAA2: where RAA is further selected from RAA2 w|len RAA js a substituent on an available C atom of ZA; wherein each RAAI is independently methyl, isopropyl, cyclopropyl, pyridinyl or pvrazolvk and each RAA2 is independently F, Cl, CN or methyl.
In one embodiment each RAA is a substituent on an available C atom of ZA, each independently selected from methyl, isopropyl, cyclopropyl, pyridin-2-yl, 1 -methylpyrazol-4-yl, -CH2CN, F, Cl, CN; and/or a methyl substituent on an available N atom of ZA.
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 0 or 1.
In one embodiment v is 1 ; XA1 is a C atom; and RAA is a substituent on XA1.
In one embodiment v is 1 ; XA1 is a C atom; and RAA is a Ci.4alkyl substituent on XA1.
In one embodiment v is 1 ; XB1 is a C atom; and RAA is a substituent on XB1. In one embodiment v is 1 ; XB1 is a C atom; and RAA is a Cj_ ialkvl (e.g. methyl) substituent on XB1.
In one embodiment v is 1 ; XC1 is a C atom; and RAA is a substituent on Xcl.
In one embodiment v is 1; XC1 is a C atom; and RAA is a Ci- ialkvl (e.g. methyl) substituent on Xcl.
In one embodiment v is 1 ; XD1 is a C atom; and RAA is a substituent on XD1.
In one embodiment v is 1 ; XD1 is a C atom; and RAA is a Ci.4alkyl (e.g. methyl) or F substituent on XD1.
In one embodiment v is 1 ; XG1 is a C atom; and RAA is a substituent on XG1.
In one embodiment v is 1 ; XG1 is a C atom; and RAA is a substituent on XG1; where RAA is selected from RAAI optionally substituted by one or more RAA2: or RAA is selected from RAA2: wherein RAAI is Ci.4alkyl or a 4-6 membered heterocyclyl; and RAA2 is selected from F, Cl, CN and Ci-aalkyl.
In one embodiment v is 1 ; XG1 is a C atom; and RAA is a substituent on XG1; where RAA is selected from methyl, isopropyl, cyclopropyl, pyridine- 2-yl, 1 -methylpyrazol-4-yl, -CH2CN, F, Cl and CN.
In one embodiment v is 1 or 2; XG1 is a C atom; and one/the RAA is a substituent on XG1; where RAA is selected from RAAI optionally substituted by one or more RAA2: or RAA is selected from RAA2: wherein RAAI is C].4alkyl or a 4-6 membered heterocyclyl; and RAA2 is selected from F, Cl, CN and Ci-aalkyl; and when v is 2, the additional RAA is a fluoro substituted on an available C atom of ZA.
In one embodiment v is 1 ; XG1 is a N atom; and RAA is a substituent on XG1.
In one embodiment v is 1 ; XG1 is a N atom; and RAA is a Ci.4alkyl (e.g. methyl) substituent on XG1.
In one embodiment v is 1 ; XH1 is a C atom; and RAA is a substituent on XH1.
In one embodiment v is 1 ; XH1 is a C atom; and RAA is a substituent on XH1 that is CN or Ci.4alkyl (e.g. methyl).
In one embodiment v is 1 or 2; XH1 and XG1 are both C atoms, one or both of which are substituted by R AA where each RAA is independently selected from CN or Ci.4alkyl (e.g. methyl).
In one embodiment the group:
Figure imgf000033_0001
together represents one or more of the groups Al to A29, shown below:
Figure imgf000034_0001
Figure imgf000035_0001
wherein:
XK and XL are either N-linker and CH or NMe and C-linker respectively;
1 ofXM and X° is N-(2,6-dioxopiperidin-3-yl) (Y);
0 or 1 of XM and XN is C-F;
XN may be N if XM is not C-F ; the remainder of XN, XM and X° are CH.
In one embodiment W represents any of the groups 22 to 26 shown below:
Figure imgf000035_0002
In a further aspect of the specification Formula (la) is selected from any one or more of the following groups
(1) to (28) or (1) to (39):
( 1 ) 4- [ 1 - [4-cy ano-3 -(trifluoromethyl)pheny 1] -4-piperidy l]phenyl,
(2) 4-[l-(4-cyano-3-cyclopropyl-phenyl)-4-piperidyl]phenyl,
(3) 4-[l-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl,
(4) 2-[l-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyrimidin-5-yl,
(5) 6-[l-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]pyridin-3-yl,
(6) 4-[l-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-4-piperidyl]phenyl,
(7) 4-[l-(3-chloro-4-cyano-phenyl)-4-piperidyl]phenyl,
(8) 4-[l-(4-cyano-3-methoxy-phenyl)-4-piperidyl]phenyl,
(9) 4-[l-(5-cyano-6-methyl-2-pyridyl)-4-piperidyl]phenyl,
(10) 4-[l-(5-cyano-8-quinolyl)-4-piperidyl]phenyl,
(11) 4- [(4S)- 1 -[4-cyano-3-(trifluoromethyl)phenyl] -3 ,3-dimethyl-4-piperidyl]phenyl
(12) 4-[(4R)-l-[4-cyano-3-(trifluoromethyl)phenyl]-3,3-dimethyl-4-piperidyl]phenyl
(13) 4-[l - [4-cy ano-3 -(trifluoromethyl)pheny 1] -3 ,3 -dimethy 1-4-piperidy 1] phenyl,
(14) 4-[l-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-2-fluorophenyl,
(15) 4-[l-[4-cyano-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-fluorophenyl,
(16) 4- [ 1 - [4-cy ano-3 -(trifluoromethyl)pheny 1] -4-piperidy 1]- 3-methy Iphenyl,
(17) 4-[(2>S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-l-yl]phenyl,
(18) 4- [(2R)-4- [4-cyano-3 -(trifluoromethyl)pheny 1] -2-methy 1-piperazin- 1 -yl] phenyl,
(19) 4-[4-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-piperazin-l-yl]phenyl,
(20) 5- [ 1 - [4-cy ano-3 -(trifluoromethyl)pheny 1] -4-piperidy l]pyridin-2-y 1,
(21) 4- [4- [4-cy ano-3 -(trifluoromethyl)pheny l]piperazin- 1 -y l]pheny 1,
(22) 4-[(3R)-l-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl,
(23) 4-[(3S)-l-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl,
(24) 4-[l-[4-cyano-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl]phenyl,
(25) 4-[l-[4-cyano-3-(difluoromethyl)phenyl]-4-piperidyl]phenyl,
(26) 4-[(4R)-l-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl,
(27) 4- [(4R)- 1 - [4-cyano-3 -(trifluoromethyl)pheny 1] azepan-4-y l]pheny 1,
(28) 4-[l-[4-cyano-3-(trifluoromethyl)phenyl]azepan-4-yl]phenyl,
(29) 4-[l-[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-l-yl]phenyl,
(31) 4-[(3R)-4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methyl-piperazin-l-yl]phenyl,
(32) 4-[(3S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methyl-piperazin-l-yl]phenyl,
(33) (3S,4R)-l-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-4-piperidyl,
(34) (3R,4S)-l-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-4-piperidyl,
(35) 4-[l-[4-cyano-2-ethyl-3-(trifluoromethyl)phenyl]-4-piperidyl]phenyl,
(36) 4-[l-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3,5-difluoro-phenyl,
(37) 4-[l-[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-[l-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-4-piperidyl]-3-methyl-phenyl.
In a further aspect of the specification there is provided a PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) or Formula (lb):
Figure imgf000037_0001
where:
QA is -G-QH- or -G-(Ci.5alkylene)-;
G is a direct bond, -CH2-, -O-, or -N(RG)- where each RG is independently H or Ci-aalkyl;
QH is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; and where R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q may take any of the values defined herein for each of these groups/variables respectively.
In one embodiment QH is a 4-12-membered nitrogen-containing saturated heterocyclic group.
Figure imgf000037_0002
For avoidance of doubt in Formula (lb) indicates a point of connection via a single covalent bond to the remainder of the PROTAC compound.
In a further aspect of the specification there is provided a PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of Formula (la) of Formula (lb), as defined herein.
In further embodiments of this specification Formula (lb) may be:
Figure imgf000037_0003
where Lx may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where QA may take any value(s) disclosed herein for QA.
In a further aspect of the specification there is provided a PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) of Formula (Ic):
Figure imgf000038_0001
where:
QA is -G-QH- or -G-(Ci.5alkylene)-;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci.jalkyl;
QB is a direct bond, -QB1-QB2-QB3- or Ci-aalkylene optionally substituted by one or more F (e.g. 1 or 2 ): where:
QB1 & QB3 each independently represent a direct bond or Chalky lene;
QB2 is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJ is H or Ci.3alkyl; and each QH is indepdendently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA and QB are selected so that Formula (Ic) does not contain any N-N or N-O bonds; and where R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q may otherwise take any of the values defined herein for each of these groups/variables respectively.
In one embodiment QH is a 4-12-membered nitrogen-containing saturated heterocyclic group. For avoidance of doubt in Formula (Ic) indicates a point of connection via a single covalent bond to the remainder of the PROF AC compound.
In a further aspect of the specification there is provided a PROF AC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit linked to an AR binding unit of Formula (la) of Formula (Ic), as defined herein.
In further embodiments of this specification Formula (lb) may be:
Figure imgf000038_0002
where Lx may be any of the groups (1) to (28) listed hereinabove in connection with Formula (la); and where QA and QB may take any value(s) disclosed herein for QA and QB.
In further embodiments there is/are provided compound(s) or pharmaceutically acceptable salt thereof wherein said compound(s) is/are selected from one or more of the “Examples” listed hereinafter. Phus, these embodiments include one or more specific Examples (for instance one Example, or two or three specific Examples) selected from the group consisting of Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,
73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101,
102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 153, 164, 165, 166 and 167.
It is to be understood that the compound of an Example listed hereinafter relates to the title compound name, and is not limited in any way by the method of preparation nor whether a given compound was isolated in the form of a salt rather than as a neutral molecule.
In some embodiments there is provided a compound of Formula (VI):
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof, wherein:
RZ1 is H or F; is H or F;
RZ3 is H or F; is a linker selected from 1, 3, 45 and 47:
Figure imgf000039_0002
Figure imgf000040_0001
and Wz is selected from 1, 2, 3, 10, 16, 22, 23, 24 and 26:
Figure imgf000040_0002
Figure imgf000041_0002
where Y is N-(2,6-dioxopiperidin-3-yl).
In some embodiments there is provided a compound of Formula (VI-1):
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof, wherein:
RZ1 is H or F;
Lz is a linker selected from 1 and 3:
Figure imgf000041_0003
Figure imgf000042_0003
and Wz is selected from 1, 2 and 10:
Figure imgf000042_0002
where Y is N-(2,6-dioxopiperidin-3-yl).
In some embodiments there is provided a compound of Formula (VI-2):
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof, wherein:
RZ1 isHorF;
RZ2 isHorF;
RZ3 is H or F; Lz is a linker selected from 3, 45 and 47 :
Figure imgf000043_0001
and Wz is selected from 1, 3, 16, 22, 23, 24 and 26:
Figure imgf000043_0002
Figure imgf000044_0001
where Y is N-(2,6-dioxopiperidin-3-yl).
A further embodiment provides any of the embodiments, claims or aspects defined herein with the proviso that one or more specific Examples (for instance one Example, or two or three specific Examples) selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,
78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104,
105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 and 136 is individually disclaimed. A further embodiment provides any of the embodiments, claims or aspects defined herein with the proviso that one or more specific Examples (for instance one Example, or two or three specific Examples) selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104,
105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126,
127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,
149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 153, 164, 165, 166 and 167 is individually disclaimed. The compounds of Formula (I) and PROTAC compounds containing binding units of Formula (la) may have one or more chiral centres and it will be recognised that such compounds may be prepared, isolated and/or supplied with or without the presence of one or more of the other possible enantiomeric and/or diastereomeric isomers of said compounds or that such isomers may be provided in any relative proportions. The preparation of enantioenriched/ enantiopure and/or diastereoenriched/ diastereopure compounds may be carried out by standard techniques of organic chemistry that are well known in the art, for example by synthesis from enantioenriched or enantiopure starting materials, and/or by use of an appropriately enantioenriched or enantiopure catalyst during synthesis, and/or by resolution of a racemic or partially enriched mixture of stereoisomers, for example via chiral chromatography.
For use in a pharmaceutical context it may be preferable to provide such compounds (or a pharmaceutically acceptable salt thereof) without large amounts of the other stereoisomeric forms being present.
Accordingly, in one embodiment there is provided a composition comprising a compound of Formula (I) [or PROTAC compound containing a unit of Formula (la)] or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la)] or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la)] or pharmaceutically acceptable salt thereof is present within the composition with a diastereomeric excess (%de) of > 90%.
In a further embodiment the %de in the above-mentioned composition is > 95%.
In a further embodiment the %de in the above-mentioned composition is > 98%.
In a further embodiment the %de in the above-mentioned composition is > 99%.
In a further embodiment there is provided a composition comprising a compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90%.
In a further embodiment the %ee in the above-mentioned composition is > 95%.
In a further embodiment the %ee in the above-mentioned composition is > 98%.
In a further embodiment the %ee in the above-mentioned composition is > 99%.
In a further embodiment there is provided a composition comprising a compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.
In further embodiments of the above-mentioned composition the %ee and %de may take any combination of values as listed below:
• The %ee is <5% and the %de is > 80%.
• The %ee is <5% and the %de is > 90%.
• The %ee is <5% and the %de is > 95%.
• The %ee is <5% and the %de is > 98%.
• The %ee is > 95% and the %de is > 95%.
• The %ee is > 98% and the %de is > 98%.
• The %ee is > 99% and the %de is > 99%.
In a further embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient.
In one embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] , or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90%.
In a further embodiment the %ee in the above-mentioned composition is > 95%.
In a further embodiment the %ee in the above-mentioned composition is > 98%.
In a further embodiment the %ee in the above-mentioned composition is > 99%.
In one embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] , or pharmaceutically acceptable salt thereof is present within the composition with a diastereomeric excess (%de) of > 90%.
In a further embodiment the %de in the above-mentioned composition is > 95%.
In a further embodiment the %de in the above-mentioned composition is > 98%.
In a further embodiment the %de in the above-mentioned composition is > 99%.
In one embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] , or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.
In further embodiments of the above-mentioned pharmaceutical composition the %ee and %de may take any combination of values as listed below:
• The %ee is > 95% and the %de is > 95%.
• The %ee is > 98% and the %de is > 98%.
• The %ee is > 99% and the %de is > 99%.
The compounds of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], and pharmaceutically acceptable salts thereof may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], or pharmaceutically acceptable salt thereof may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or other stoichiometry of hydrate) and/or solvated forms. It is to be understood that the present specification encompasses any and all such solid forms of the compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein], and pharmaceutically acceptable salts thereof.
In further embodiments there is provided a compound of Formula (I) [or PROTAC compound containing a unit of Formula (la) as defined herein] which is obtainable by the methods described in the ‘Examples’ section hereinafter.
Intermediate Compounds
As demonstrated in the experimental section hereinafter, the compounds of Formula (I) or PROTACs of Formula (la) may be prepared, for example, by the following methods.
A compound of Formula (I) [or salt thereof] or a PROTAC compound of Formula (la) [or a salt thereof] may be prepared from a compound of Formula (II):
Figure imgf000047_0001
or a salt thereof, where:
QA is -G-QH- or -G-(Ci-5alkylene)-;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-jalkyl;
QH is a 4 to 12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;
QD is a direct bond or Ci.2alkylene optionally substituted by one or more F; RL1 and RL2 together form “=O”, RL3 is H: where when QD is a direct bond and QA is -G-QH-; the value of QH is selected so that QD connects to a C atom of Q": and
R1, p, X1, X2, X3, X4, n, m, Q, R2a, R2b, Y1, Y2, Y3, Y4, R3 and q may take any of the values disclosed herein for each of those groups/variables respectively.
In one embodiment QH is a 4-12-membered nitrogen-containing saturated heterocyclic group.
Accordingly such compound of Formula (II) as described above is an aldehyde which may be reacted with a suitable molecule containing an amine group (for example a secondary amine group) to form the compound of Formula (I) or PROTAC compound of Formula (la) - either directly, or after one or more additional reaction steps. Such reaction of said aldehyde with said amine can be carried out under reductive amination conditions, using for example NaBI [(OAcy or another reductive amination protocol known to the skilled person.
Such aldehyde may in turn be prepared from the corresponding acetal, for example a compound of Formula (II), or salt thereof, as defined above, except that: RL1 and RL2 are each independently C ...alkoxv (for example Ci-aalkoxy) or RL1 & RL2 together form -O-(CH2)k-O- where k is 2 or 3. Such acetal may be converted to the corresponding aldehyde under acidic conditions, for example using formic acid under conditions well known to the skilled person.
Alternatively, as shown in the experimental section hereinafter, the above-mentioned aldehyde may be prepared by oxidation of the corresponding primary alcohol, i.e. a compound of Formula (II), or salt thereof, as defined above except that RL1 is OH and RL2 is H. Such oxidation may be carried out using mild oxidising conditions, for example Dess-Martin periodinane or some other mild oxidation protocol known to the skilled person.
As shown in the experimental section hereinafter, a compound of Formula (I) [or salt thereof] or a PROTAC compound of Formula (la) [or a salt thereof] may be prepared from a compound of Formula (II) or a salt thereof, as described above except that RL1 is a leaving group and RL2 is H. Accordingly, such compound of Formula (II) is an electrophile that may be reacted with a molecule containing an amine group (for example a secondary amine group) via an alkylation reaction to form the compound of Formula (I) or PROTAC compound of Formula (la) - either directly, or after one or more additional reaction steps. Suitable leaving groups for alkylation reactions are well known to the skilled person and include Cl, Br, I, trifluoromethanesulfonate, mesylate and tosylate. Alkylation reaction conditions are well known to the skilled person and generally involve a non-nucleophilic base (e.g. DIPEA) and a polar aprotic solvent (e.g. MeCN). As demonstrated in the experimental section hereinafter, in cases where the leaving group is not I, a metal iodide salt may be used in the reaction mixture to form the corresponding iodide in-situ (i.e. where RL1 is I) to facilitate the overall alkylation process. As shown in the experimental section hereinafter, a compound of Formula (II) where RL1 is a bromo leaving group may be prepared from the corresponding primary alcohol (i.e. as already described above where RL1 is OH, and RL2 & RL3 are both H.
In turn, the above-mentioned primary alcohol compound of Formula (II) may be prepared by the reduction of the corresponding ester compound, i.e. a compound of Formula (II), or salt thereof, as defined above, except that: RL1 and RL2 together form “=O” and RL3 is C ...alkoxv (for example C .vilkoxv ;. Such reduction may be carried out using strong reduction conditions, for example using DIBAL or other stronger reducing conditions which are well known to the skilled person.
Alternatively, as demonstrated in the experimental section hereinafter, it may be convenient to form the above-mentioned primary alcohol compound of Formula (II) via deprotection of a protected form of the alcohol. For example, deprotection of a compound where there alcohol is protected by a silicon-based protecting group, using a source of fluoride in order to achieve the deprotection, for example TBAF or other deprotection methods well-known to the skilled person.
Therefore, as described above, various compounds of Formula (II), and salts thereof, may be useful as intermediates in the synthesis of the compounds of Formula (I) or PROTAC compounds of Formula (la), and accordingly such intermediate compounds provide a further aspect of the specification.
Therefore, in a further aspect there is provided a compound of Formula (II), as shown above, or a salt thereof, wherein:
QA is -G-QH- or -G-(Ci-5alkylene)-;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-jalkyl;
QH is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;
QD is a direct bond or C ^alkylene optionally substituted by one or more F (for example 1 or 2 F); and
(i) RL1 & RL2 together form “=O” and RL3 is H or Ci-ealkoxy (for example OMe);
(ii) RL1 & RL2 are each independently Ci-salkoxy (for example OMe), and RL3 is H;
(iii) RL1 & RL2 together form -O-(CH2)k-O- where k is 2 or 3, and RL3 is H; or
(iv) RL1 is OH, OPG1 (where PG1 is a protecting group), or LG1 (where LG1 is a leaving group), and
RL2 & RL3 are both H; where when QD is a direct bond and QA is -G-QH-, the value of QH is selected so that QD connects to a C atom of QH; and R1, p, X1, X2, X3, X4, n, m, Q, R2a, R2b, Y1, Y2, Y3, Y4, R3 and q may take any of the values disclosed herein for each of those groups/variables respectively.
In one embodiment QH is a 4-12-membered nitrogen-containing saturated heterocyclic group.
The skilled person is aware of suitable protecting groups for alcohol groups and therefore is aware of suitable values of PG1. For example PG1 is an alcohol protecting group.
In one embodiment PG1 is a silicon-based alcohol protecting group.
In one embodiment PG1 is Si( RSlh where each RS| is independently a C i-ehydrocarbyl group.
In one embodiment PG1 is tert-butyldimethylsilyl or tert-butyldiphenylsilyl.
In one embodiment the LG1 is selected from Cl, Br, I, trifluoromethanesulfonate and C i.yhydrocarbylsulfonate (for example mesylate or p-toliienesiill'onate).
In one embodiment LG1 is Br or I.
In one embodiment LG1 is Br.
In one embodiment LG1 is Cl.
In one embodiment LG1 is I.
In one embodiment LG1 is trifluoromethanesulfonate.
In one embodiment LG1 is C .-Iwdrocarbv I sulfonate.
In one embodiment LG1 is mesylate. In one embodiment LG1 is />-toluenesulfonate.
In one embodiment QD is a direct bond, -CH2-, -CH2CH2- or -CF2CH2-.
In one embodiment QD is a direct bond.
In one embodiment QD is CH2.
In one embodiment QD is Ci.2alkylene optionally substituted by 1 or 2 F.
In one embodiment QD is Ci.2alkylene.
In one embodiment QD is -CH2CH2-.
In one embodiment QD is -CF2CH2-.
In further embodiments of this specification Formula (II) may be Formula (Ila):
Figure imgf000050_0001
where Lx may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where QA, QD, RL1, RL2 and RL3 may take any of the values disclosed herein for each of said groups respectively.
As demonstrated in the experimental section hereinafter, certain compounds of Formula (I) and certain PROTACS of Formula (la) and certain intermediate compounds of Formula (II) may be prepared using a compound of Formula (III):
Figure imgf000050_0002
or a salt thereof, where Gx is OH, where the oxygen atom of said OH is alkylated by a suitable molecule to form certain compounds of Formula (I) or PROTACs of Formula (la) - either directly, or after one or more further reaction steps (for example via Formula (II) as described hereinabove). Such alkylation reactions may be carried out under conditions well known to the skilled person, for example using a primary alkyl bromide (or using some other leaving group in place of Br) using a non-nucleophilic base such as a metal carbonate (e.g. K2CO3) in a polar aprotic solvent such as MeCN, optionally in the presence of a metal iodide salt such as KI.
Alternatively, as shown in the experimental section hereinafter, a compound of Formula (III) where Gx is -NH(RG) [where RG is H or C .vilkvl (for example Me)] may be used as an intermediate to prepare compounds of Formula (I) or PROTACs of Formula (la) via reductive amination chemistry with an appropriate aldehyde- containing compound. Alternatively, as shown in the experimental section hereinafter, a compound of Formula (III) where Gx is bromo may be coupled with a secondary amine compound to give certain compounds of Formula (I) or PROTACs of Formula (la) - either directly, or after one or more further reaction steps (for example via Formula (II) as described hereinabove). Similarly, compounds of Formula (111) where Gx is chloro or trifluoromethanesulfonate may also be used in a coupling reaction with the relevant secondary amine to give certain compounds of Formula (I) or PROTACs of Formula (la). Such coupling may be carried out under palladium-based coupling conditions (e.g. using ‘Ruphos Pd G3’ and ‘Ruphos’) in the presence of a base and an anhydrous solvent such as 1,4-dioxane under an inert atmosphere, or by heating with Cui in the presence of a base such as K3PO4 in a polar solvent such as DMSO. Alternatively, also as shown in the experimental section herein, a compound of Formula (III) where Gx is bromo may be coupled with a suitable alcohol to form certain compounds of Formula (I) or PROTACs of Formula (la) - either directly, or after one or more further reaction steps (for example via Formula (II) as described hereinabove). Such coupling may be carried out using a palladium-based reagent such as ‘Rockphos Pd G3’ in the presence of a base such as CS2CO3 in a solvent such as toluene.
Accordingly, compounds of Formula (III), and salts thereof, may be useful as intermediates in the synthesis of certain compounds of Formula (I) or PROP AC compounds of Formula (la) or compounds of Formula (II), and accordingly such intermediate compounds provide a further aspect of the specification.
Therefore, in a further aspect there is provided a compound of Formula (III), as shown above, or a salt thereof, wherein:
Gx is OH, Cl, Br, triflouoromethanesulfonate or -NH(RG) where RG is H or Ci-salkyl; and R1, p, X1, X2, X3, X4, n, m, Q, R2a, R2b, Y1, Y2, Y3, Y4, R3 and q may take any of the values disclosed herein for each of those groups/variables respectively.
Gx is OH, Cl, Br, triflouoromethanesulfonate or -NH(RG) where RG is C i-salkyl (for example Me). In one embodiment Gx is OH, Br, trifluoromethanesulfonate or -NH(RG) where RG is C i-salkyl (for example Me).
In one embodiment Gx is OH, Br or -NH(RG) where RG is C i-salkyl (for example Me). In one embodiment Gx is OH or Br. In one embodiment Gx is OH. In one embodiment Gx is Br. In one embodiment Gx is Cl.
In one embodiment Gx is trifluoromethanesulfonate.
In one embodiment Gx is -NH(RG) where RG is H or Ci-salkyl. In one embodiment Gx is -NH(RG) where RG is Ci-salkyl. In one embodiment Gx is -NH(Me).
In further embodiments of this specification, Formula (III) may be Lx — Gx wherein Lx may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where Gx may take any value(s) disclosed herein for Gx.
As demonstrated in the experimental section hereinafter, certain compounds of Formula (I) and PROTACs of Formula (la) may be prepared using an intermediate compound of Formula (IV):
Figure imgf000052_0001
or a salt thereof, as further defined below. For example, a compound of Formula (IV), or salt thereof, where J is H (i.e. a secondary amine compound) may be coupled to a further chemical fragment, using chemistry well known to the skilled person and exemplified in the experimental section hereinafter, to provide a compound of Formula (I) or PROTAC of Formula (la), either directly, or after one or more further reaction steps.
In turn, such a compound of Formula (IV) where J is H may conveniently be prepared via deprotection of an TV-protected form of the aforementioned amine compound. Accordingly compounds of Formula (IV) where J is H may be conveniently be prepared using a compound of Formula (IV) where J is PG2 where PG2 is a nitrogen protecting group (for example a Ci-ealkoxy carbonyl group such as tertbutoxycarbonyl). Therefore, compounds of Formula (IV) where J is PG2 are useful intermediates in the preparation of the compound of Formula (I) and PROTAC of Formula (la) and provide a further aspect of the specification.
Therefore in a further aspect of the specification there is provided a compound of Formula (IV) as depicted above, or a salt thereof, wherein:
J is H or PG2 where PG2 is a nitrogen protecting group (for example a tert-butoxycarbonyl group);
QA is -G-QH- or -G-(Ci.5alkylene)-;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-aalkyl;
QB is a direct bond, -QB1-QB2-QB3- or Ci.vilkvlene optionally substituted by one or more F (e.g. 1 or 2); where:
QB1 & QB3 each independently represent a direct bond or Chalky lene;
QB2 is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJ is H or Ci.3alkyl; and each QH (including the “QH Ring” attached to J) is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA, QB and QH Ring are selected so that Formula (IV) does not contain any N-N or N-O bonds; and where R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q may take any of the values defined herein for each of these groups/variables respectively.
In one embodiment each QH (including the “QH Ring” attached to J) is independently a 4-12-membered nitrogen-containing saturated heterocyclic group.
In one embodiment the QH Ring is piperidin-l,4-diyl or piperazin- 1 ,4-diyl.
In one embodiment J is H.
In one embodiment J is PG2.
In one embodiment PG2 is C i-ealkoxycarbonyl.
In one embodiment PG2 is tert-butoxycarbonyl. In one embodiment where PG2 is C i-ealkoxycarbonyl (e.g. tert-butoxycarbonyl) the ‘and salts thereof element of the claim is excluded.
In further embodiments the compound of Formula (IV) may take any combination of alternative values mentioned in relation to QA QB and QH in any other context, embodiment, aspect or claim found herein.
In further embodiments of this specification Formula (IV) may be Formula (IVa):
Figure imgf000053_0001
where Lx may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where QA, QB, QH and J may take any of the values disclosed herein for each of said groups respectively.
As also demonstrated in the experimental section hereinafter, certain compounds of Formula (I) and PROTACs of Formula (la) may be prepared using an intermediate compound of Formula (V):
Figure imgf000053_0002
or a salt thereof, wherein:
Xx is N substituted by J where J is H;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-aalkyl;
QH Ring is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of G and QH Ring are selected so that Formula (V) does not contain any N-N or N-O bonds; and where R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q may take any of the values defined herein for each of these groups/variables respectively.
Such a compound of Formula (V) may be converted to a compound of Formula (I) or PROTAC of Formula (la) via reductive amination or alkylation or other coupling chemistry known to the skilled person - to provide the compound of Formula (I) or PROTAC of Formula (la) either directly, or after one or more additional steps.
In turn, as shown in the experimental section hereinafter, such a compound of Formula (V), or a salt thereof, may be conveniently prepared by deprotection of the corresponding TV-protected compound. Such N- protected form may be a BOC-protected form (i.e. tert-butoxycarbonyl) or may use another A -protecting group known to the skilled person. Accordingly, such TV-protected compounds are also useful intermediates in the preparation of the compounds of Formula (I) and PROTACs of Formula (la) and provide a further aspect of the specification. Accordingly one aspect of the specification provides a compound of Formula (V), or a salt thereof, as described above except that Xx is N substituted by J where J is PG3 and PG3 is a protecting group. In one embodiment PG3 is Ci-ealkoxy carbonyl. In one embodiment PG3 is tert-butoxy carbonyl. In one embodiment where PG3 is Ci-ealkoxycarbonyl (e.g. tert-butoxycarbonyl) the ‘and salts thereof element of the claim is excluded.
Other compounds of Formula (I) and PROTACs of Formula (la) - and salts thereof - may be prepared from an intermediate compound of Formula (V), or a salt thereof, as described above except that Xx is C=O. Such an intermediate may be converted to a compound of Formula (I) or PROTAC of Formula (la) by reductive amination chemistry using an appropriate amine- containing compound, using reductive amination conditions that well-known to the skilled person - either directly or via one or more additional synthetic steps.
In turn, as demonstrated in the experimental section hereinafter, such compounds of Formula (V) where Xx is C=O may be conveniently prepared from the corresponding compound where the ketone is protected/masked as a ketal. Accordingly such ketal compounds, and salts thereof are useful intermediates in the preparation of a compound of Formula (I) or a PROTAC of Formula (la) and provide a further aspect of the specification.
Accordingly such ketal compound may be represented as a compound of Formula (V), or a salt thereof, as described above except that Xx is C substituted by RU1 and R1 2: where RU1 and RU2 are each Ci-ealkoxy; or RU1 and RU2 together represent -O-(CH2)u-O- where u is 2 or 3.
Therefore, in a further aspect of the specification there is provided compound of Formula (V), as depicted above, or a salt thereof, wherein: Xx is selected from:
(i) N substituted by J where J is H or PG3 where PG3 is a protecting group; and
(ii) C substituted by oxo, or by RU1 and RU2; where RU1 and RU2 are each Ci-ealkoxy; or RU1 and RU2 together represent -O-(CH2)u-O- where u is 2 or 3 ;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-aalkyl;
QH Ring is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; and the values of G and QH Ring are selected so that Formula (V) does not contain any N-N or N-O bonds; and where R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q may take any of the values defined herein for each of these group s/variables respectively.
In one embodiment J is H.
In one embodiment J is PG3.
In one embodiment PG3 is C i-ealkoxycarbonyl.
In one embodiment PG3 is tert-butoxycarbonyl.
In one embodiment Xx is C=O.
In one embodiment Xx is C substituted by RU1 and RU2; where RU1 and RU2 are each C ...alkoxv.
In one embodiment Xx is C substituted by RU1 and RU2; where RU1 and RU2 together represent -O-(CH2)u-O- where u is 2 or 3 (for example u = 2).
In one embodiment G is a direct bond or -O-.
In one embodiment QH Ring is a 4-12-membered nitrogen-containing saturated heterocyclic group. The values of QH Ring may take any of the values mentioned herein for QH.
In one embodiment QH 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 further embodiments of this specification Formula (V) may be Formula (Va):
Figure imgf000055_0001
where Lx may be any of the groups (1) to (28) or (1) to (39) listed hereinabove in connection with Formula (la); and where G, QH Ring and Xx may take any of the values disclosed herein for each of said groups respectively.
In addition to the methods described above, the compounds of Formulae (I), (II), (III), (IV) & (V) and PROTAC compounds including Formula (la) may be prepared according to the general procedures and chemical transformations demonstrated in the experimental section hereinafter and using standard procedures and knowledge known to the skilled chemist.
In further embodiments of this specification there is/are provided compound(s), or a salt thereof, wherein said compound(s) is/are selected from one or more of the “Intermediates” listed hereinafter in the experimental section.
It is to be understood that the compound of an Intermediate listed hereinafter relates to the title chemical name listed in the experimental section, and is not limited in any way by the method of preparation nor 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 specification there is provided a pharmaceutical composition, which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, in association with a pharmaceutically acceptable excipient.
According to a further aspect of the specification there is provided a pharmaceutical composition, which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of cancer.
According to a further aspect of the specification there is provided a pharmaceutical composition, which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of a solid tumour.
According to a further aspect of the specification there is provided a pharmaceutical composition, which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of an AR-sensitive tumour type. According to a further aspect of the specification there is provided a pharmaceutical composition, which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of tumour types that harbour one or more mutated forms of the androgen receptor.
According to a further aspect of the specification there is provided a pharmaceutical composition, which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of prostate cancer (for example CRPC, for example metastatic CRPC).
According to a further aspect of the specification there is provided a pharmaceutical composition, which comprises a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of AR-mutated cancer.
In any embodiment, aspect or claim herein that mentions “cancer” without further specificity, further embodiments, aspects or claims may be provided where said cancer is (or includes) AR+ breast cancer.
The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing). The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients that are well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
For further information on formulations the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host being treated and the particular route of administration.
The size of the dose for therapeutic or prophylactic purposes of compounds of the present specification 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, according to well-known principles of medicine.
As explained hereinabove, the compounds of the present specification may be of value as anti-tumour agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of tumour growth and survival and to inhibition of metastatic tumour growth. Particularly, the compounds of the present specification may be of value as antiproliferative and anti- invasive agents in the containment and/or treatment of solid tumour disease.
Accordingly, the compounds of the present specification may be useful in the prevention or treatment of those tumours which are sensitive to degradation of the androgen receptor and that are involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the migratory ability and invasiveness of metastasising tumour cells. Further, the compounds of the present specification may be useful in the prevention or treatment of those tumours which are treatable by degradation of androgen receptors, i.e. the compounds may be used to produce an androgen receptor degradation effect in a warmblooded animal in need of such treatment.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use as a medicament.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in therapy.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in a method of treatment of the human or animal body by therapy.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an anti-proliferative effect (for example, in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the production of an anti-proliferative effect (for example, in a warmblooded animal such as man).
According to a further aspect of the specification, there is provided a method for producing an antiproliferative effect in a warm-blooded animal, such as man, in need of such effect, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use as an anti- invasive agent in the containment and/or treatment of solid tumour disease (for example: in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease (for example: in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided a method for producing an anti- invasive effect by the containment and/or treatment of solid tumour disease, in a warm-blooded animal, such as man, in need of such effect, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the prevention or treatment of cancer (for example: in a warm-blooded animal such as man).
According to a further aspect of the specification there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the prevention or treatment of cancer (for example: in a warm-blooded animal such as man).
According to a further aspect of the specification there is provided a method for the prevention or treatment of cancer in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the prevention or treatment of solid tumour(s) (for example, in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the prevention or treatment of solid tumour(s) (for example, in a warmblooded animal such as man).
According to a further aspect of the specification, there is provided a method for the prevention or treatment of solid tumour(s) in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the prevention or treatment of tumour types that are sensitive to degradation of androgen receptors.
According to a further aspect of the specification, there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the prevention or treatment of those tumour types that are sensitive to degradation of androgen receptors. According to a further aspect of the specification, there is provided a method for the prevention or treatment of those tumour types that are sensitive to degradation of androgen receptors in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
As explained hereinabove, tumour types that are sensitive to degradation of androgen receptors include prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC).
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in providing a degrading effect on androgen receptors (for example in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for providing a degrading effect on androgen receptors (for example in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided a method for providing a degrading effect on androgen receptors in a warm-blooded animal, such as man, in need of such effect, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in providing a selective degrading effect on androgen receptors (for example in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for providing a selective degrading effect on androgen receptors (for example in a warm-blooded animal such as man).
According to a further aspect of the specification, there is provided a method for providing a selective degrading effect on androgen receptors in a warm-blooded animal, such as man, in need of such effect, which comprises administering an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of tumour types that harbour androgen receptor mutations. According to a further aspect of the specification, there is provided the use of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the prevention or treatment of those tumour types that harbour androgen receptor mutations.
According to a further aspect of the specification, there is provided a method for the prevention or treatment of those tumour types that harbour androgen receptor mutations in a warm-blooded animal, such as man, in need of such prevention or treatment, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
As mentioned above, tumour types known to harbour androgen receptor mutations include prostate tumours and therefore prostate cancer, castrate-resistant prostate cancer (CRPC), and metastatic (CRPC).
According to a further aspect of the specification, there is provided a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC).
According to a further aspect of the specification, there is provided the use of a compound of the Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the treatment of prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC).
According to a further aspect of the specification, there is provided a method for treating prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC) in a warmblooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I), [or a PROTAC compound containing an E3 ubiquitin ligase cereblon binder unit and (e.g. linked to) an AR binding unit of Formula (la)] or a pharmaceutically acceptable salt thereof, as defined herein.
In one embodiment where cancer is mentioned herein, said cancer is prostate cancer.
In one embodiment where cancer is mentioned herein, said cancer is CRPC.
In one embodiment where cancer is mentioned herein, said cancer is metastatic CRPC.
General Experimental Conditions and Abbreviations
The following abbreviations are used: AcOH = acetic acid; AIBN = 2,2'-azobis(2-methylpropionitrile); aq. = aqueous; Boc = butoxy carbonyl; Brettphos = 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl- l,l '-biphenyl; Brettphos Pd G3 = [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1,1 '- biphenyl)-2-(2'-amino-l,l ' -biphenyl)]palladium(II) methanesulfonate; CDI = l,l'-Carbonyldiimidazole; Dave-phos-Pd G3 = Methane sulfonato 2-dicyclohexylphosphino-2-(A,A-dimethylamino)biphenyl(2'-amino- l,l '-bipheny 1-2-yl) palladium(II); DCM = dichloromethane; DIAD = Diisopropyl azodicarboxylate; DIPEA = A,A-diisopropylethylamine; Cbz = carboxybenzyl; Dess-Martin periodinane = 3-Oxo-115- benzo[</|[l,2]iodaoxole-l,l,l(3//)-triyl triacetate; DMF = \\ \’-diineth\ llbnnainide: DMSO = dimethylsulfoxide; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOEI = ethanol; FSC = flash silica chromatography; h = hour(s); EIPLC = high-performance liquid chromatography; IPA = isopropyl alcohol; MeCN = acetonitrile; MeOH = methanol; mins. = minutes; m/z = mass to charge ratio observed for major mass spectrometry peak(s); MTBE = methyl-tert-butyl-ether; NBS = A-bromosuccinimide; NMP = A-methyL 2-pyrrolidone; NMR = nuclear magnetic resonance; Pd;dba;, = tris(dibenzylideneacetone)dipalladium; Pd- PEPPSI-IEIeptcl = dichloro[l,3-bis(2,6-di-4-heptylphenyl)imidazol-2-yldiene(3-chloropyridyl)palladium(II); Pd-PEPPSI-IPent = dichloro[l,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II), Pd(dppf)2C12-DCM = l,l'-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 (~17-25°C); RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G3 = methanesulfonato(2-dicyclohexylphosphino-2',6'-di-iso-propoxy- 1 ,l'-bipheny l)(2'-amino- 1 , l'-bipheny 1-2- 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.
NMR was carried out at 400 MHz in deuterated DMSO and at a temperature of 20-30°C unless otherwise stated. The following standard abbreviations are used for NMR data: s = singlet, d = doublet, m = multiplet, br = broad, dd = doublet of doublets, q = quartet, dt = doublet of triplets, etc.
Preparative reverse phase HPLC (RP HPLC) using decreasingly polar mixture of eluents (e.g. water and MeCN) may typically involve a gradient over 10-20 minutes, at 40-50mL per minute, from a 95:5 mixture of solvents a 5:95 mixture. The following Column and Eluent conditions are used herein:
Column A: Waters XSelect CSH Cl 8 ODB column, 5|im silica, 30 mm diameter, 100 mm length Column B: Waters XSelect CSH Cl 8 ODB column, 5 pm silica, 19 mm diameter, 150 mm length Eluent A: Decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN Eluent B: Decreasingly polar mixtures of water (containing 0.3% formic acid aq) and MeCN Eluent C: Decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN Eluent D: Decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN After HPLC (which often involves the presence of formic acid or trifluoroacetic acid in the eluent), the fractions containing desired product were in some cases treated with a suitable base as part of a further work-up step in order to ensure delivery of the title compound as a neutral molecule rather than a salt. Accordingly where “Basic Work-Up A” is mentioned: fractions containing the desired compound were concentrated to remove MeCN. The resulting, mainly-aqueous fractions were basified with Nal ICO;, solution (e.g. 50 mL) and extracted into DCM (e.g. 3 * 100 mL). The combined organic solutions were washed with brine (e.g. 100 mL), dried (e.g. with Na2SO4 or MgSO i ) and concentrated to give the title compound.
Concentration: where solutions or mixtures are described as being concentrated, this is generally performed on a rotary evaporator under reduced pressure using a warm or hot water bath.
Salts: Where certain compounds were obtained as an acid-addition salt, for example a monohydrochloride 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 have been determined experimentally e.g. by means of elemental analysis data.
Chemical naming: In general Examples and Intermediate compounds were named using ACD Name, “Structure to Name” part of ChemDraw Ultra (Cambridge Soft) or Biovia Draw 2016.
Intermediate la: Benzyl 4-(dimethoxymethyl)piperidine-l-carboxylate
Figure imgf000062_0001
4-Formyl-A/-Cbz-piperidine (5.00 g, 20.22 mmol) was dissolved in MeOH (11 mL) at 0°C under N2. A solution of TiCl4 (0.11 mL, 1.01 mmol) in DCM (1.1 mL) was then added, followed after 15 mins by NEta (0.338 mL, 2.43 mmol) and the resulting solution was stirred at RT for 0.5h. The mixture was then diluted with DCM (50 mL) and water (20 mL) and stirred at RT for 0.5h. The layers were then separated, the organic portion was dried over 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 colourless oil; *H NMR: (CDCh) 1.14-1.33 (2H, m), 1.63-1.82 (3H, m), 2.63-2.84 (2H, m), 3.35 (6H, s), 4.02 (1H, d), 4.13-4.3 (2H, m), 5.12 (2H, s), 7.3-7.44 (5H, m).
Intermediate lb: 4-(DimethoxymethvDpiperidine
Figure imgf000062_0002
Pd(OH)2 (10wt%, 0.73 g, 0.52 mmol) was added to benzyl 4-(dimethoxymethyl)piperidine-l -carboxylate (7.60 g, 25.9 mmol) in MeOH (60 mL) at RT under N2 in a steel pressured reactor. The resulting suspension was purged with N2 followed by H2 and was then stirred at RT at a pressure of 4 atmospheres of H2 for 2 days. The mixture was then filtered through celite and washed through with MeOH (500 mL). The filtrate was concentrated to give the title compound (4.00 g, 97%) as a colourless oil; *H NMR: (CDCh) 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
Figure imgf000062_0003
A25% methanolic solution ofNaOMe (512 Lil,. 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 RT under N2. The resulting mixture was stirred at RT for 18h (reaction complete within Ih). The mixture was then cooled to 0°C and quenched with EtOAc (20 mL) and IN HC1 (10 mL). The phases were separated and the aqueous portion was extracted with EtOAc (2 x 30 mL). The combined organic solutions were dried (MgSOy) and concentrated. Purification by FSC (gradient 0-25% EtOAc in heptane) gave the title compound (0.410 g, 74%) as a colourless oil which solidified on standing; *H NMR: (CDCL) 2.25 (3H, s), 3.81 (3H, s), 3.90 (3H, s), 6.91 (IH, d), 6.98 (IH, dd).
Intermediate Id: 3-(5-Bromo-7-methoxy-l-oxo-l,3-dihvdro-2/7-isoindol-2-yl)piperidine-2,6-dione
Figure imgf000063_0001
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 3h. The mixture was then cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was passed through a phase separator 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, that was 70% pure. DIPEA (1.654 mL, 9.29 mmol) was added in one portion to a stirred solution of methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate (1.495 g, 3.10 mmol) and 3-aminopiperidine-2,6- dione hydrochloride (0.510 g, 3.10 mmol) in MeCN (20 mL) at RT under air. The resulting solution was stirred at 80°C for 16h. The mixture was then cooled to 0°C and a solid was collected by filtration. The solid was washed with MeCN (50 mL) and Et2O (50 mL) and dried under vacuum to give the title compound (0.761 g, 39% over 2 steps) as a mauve solid; >H NMR: 1.97 (1H, dtd), 2.34 (1H, qd), 2.54-2.63 (1H, m), 2.90 (1H, ddd), 3.90 (3H, s), 4.25 (1H, d), 4.38 (1H, d), 5.02 (1H, dd), 7.26 (1H, d), 7.39 (1H, d), 10.94 (1H, s); m/z\ ES+ [M+H]+ = 355.0.
Intermediate le: tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro-l/7-isoindol-5- yllpiperazine-l-carboxylate
Figure imgf000063_0002
Pd-PEPPSI-IHeptcl (0.380 g, 0.39 mmol) was added to tert-butyl piperazine- 1 -carboxylate (2.183 g, 11.72 mmol), CS2CO3 (3.82 g, 11.72 mmol) and 3-(5-bromo-7-methoxy-l-oxo-l .3-dihvdro-2/7-isoindol-2-vl )- piperidine-2, 6-dione (1.38 g, 3.91 mmol) in degassed 1 ,4-dioxane (39 mL) at RT under N2. The resulting suspension was stirred at 100°C for 6h. The mixture was then diluted with DCM (100 mL) and washed sequentially with 5% AcOH in water (100 mL), water (100 mL), sat. Nal ICO;, (100 mL) and sat. brine (100 mL). The organic layer was dried (MgSO.4) and concentrated. Trituration with EtOAc (40 mL) and washing with Et2O (50 mL) gave a solid which was collected by filtration and dried under vacuum to give the title compound (1.154 g, 64%) as a dark grey powder; ‘H NMR: 1.43 (9H, s), 1.79-1.97 (1H, m), 2.28 (1H, dd), 2.53-2.62 (1H, m), 2.76-2.94 (1H, m), 3.32 (4H, s), 3.41-3.54 (4H, m), 3.85 (3H, s), 4.12 (1H, d), 4.24 (1H, d), 4.95 (1H, dd), 6.51 (1H, d), 6.62 (1H, s), 10.87 (1H, s); m/z\ ES+ [M+H]+ = 459.2.
Intermediate If: 3-[7-Methoxy-l-oxo-5-(piperazin-l-yl)-l,3-dihvdro-2/T-isoindol-2-yllpiperidine-2,6- dione
Figure imgf000064_0001
4M HCI 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-l-oxo-2,3-dihydro-l/f-isoindol-5-yl]piperazine-l-carboxylate (107 mg, 0.19 mmol) at RT under air. The resulting mixture was stirred at RT for 1 day, then diluted with Et2O (20 mL). The resulting mixture was filtered and the solid was washed with Et2O (20 mL) to give the title compound as a hydrochloride salt (0.080 g, 100%) as a white solid; >H NMR: 1.93 (1H, dd), 2.25-2.4 (1H, m), 2.57 (1H, d), 2.89 (1H, s), 3.19 (4H, s), 3.59 (4H, s), 3.86 (3H, s), 4.14 (1H, d), 4.26 (1H, d), 4.97 (1H, dd), 6.49-6.6 (1H, m), 6.68 (1H, s), 9.55 (2H, s), 10.89 (1H, s); m/z\ ES+ [M+H]+ = 359.2.
Figure imgf000064_0002
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 18h. The mixture was then cooled to RT, diluted with water (150 mL) and then stirred for 18h. A resulting solid was collected by filtration, washed with Et2O (50 mL) and dried under vacuum to give the title compound (5.65 g, 62%) as a yellow solid; ‘H NMR: (CDC13) 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 Ih: 4-1
Figure imgf000064_0003
,3-Dioxolan-2-’
Figure imgf000064_0004
i-l-vl)-2-i
Figure imgf000064_0005
rom
Figure imgf000064_0006
benzonitrile
Figure imgf000064_0007
2-(3-Chloropropyl)-l,3-dioxolane (2.57 mL, 19.49 mmol) was added in one portion to 4-(4-(4-hydroxy- phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (3.75 g, 10.83 mmol), K2CO3 (3.74 g, 27.07 mmol) and KI (4.49 g, 27.07 mmol) in MeCN (100 mL) at RT under air. The resulting suspension was stirred at 90°C for 2 days. The mixture was then cooled to RT, 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 sat. brine (100 mL), dried (MgSCL) and concentrated. Purification by FSC (gradient 0-5% MeOH in DCM) gave the title compound (3.10 g, 62%) as a yellow solid; >H NMR: (CDCI3) 1.56-1.67 (2H, m), 1.71 (2H, ddd), 1.74-1.82 (2H, m), 1.85 (2H, d), 2.77 (IH, ddd), 3-3.1 (2H, m), 3.75-3.82 (2H, m), 3.85- 3.92 (2H, m), 3.95 (2H, q), 4.17 (2H, d), 4.85 (IH, t), 6.79-6.9 (2H, m), 7.15 (2H, d), 7.23-7.38 (2H, m), 7.81 (IH, d); m/z\ ES+ [M+H]+ = 461.3.
Example 1: 4-f4-[4-(4-f4-[2-(2.6-DioxoDiDeridin-3-yl)-7-methoxy-l-oxo-2.3-dihvdro- isoindol-5-yl1-
Figure imgf000065_0001
piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl) benzonitrile
Figure imgf000065_0002
4-(4-(4-(3-(l,3-Dioxolan-2-yl)propoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (178 mg, 0.39 mmol) and tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl )-7-methoxy- l-oxo-2,3-dihydro- 1 //-isoindol-5- yl]piperazine-l -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 18h. The mixture was then concentrated and the residue was re-dissolved in IPA (2 mL) and DCM (2 mL) at RT under air. NaBJ 1(0 Ac);, (164 mg, 0.77 mmol) was added in one portion after 10 mins. The resulting dark suspension was stirred at RT for Ih and then concentrated. Purification by preparative HPLC (Column A, Eluent A) gave the title compound in the form of a formate salt (70 mg, 23%) as a dry film; *H NMR: (CDClj) 1.54-1.68 (4H, m), 1.74 (2H, q), 1.84 (2H, d), 1.92 (IH, dd), 2.28 (IH, dd), 2.39 (2H, t), 2.54- 2.62 (2H, m), 2.76 (IH, td), 2.89 (IH, ddd), 3.04 (2H, t), 3.2-3.38 (6H, m), 3.47 (IH, s), 3.84 (3H, s), 3.97 (2H, t), 4.07-4.29 (4H, m), 4.96 (IH, dd), 6.48 (IH, d), 6.60 (IH, s), 6.81-6.94 (2H, m), 7.16 (2H, d), 7.27 (IH, dd), 7.32 (IH, d), 7.81 (IH, d), 8.16 (2H, s), 10.88 (IH, s); m/z\ ES+ [M+H]+ = 759.4.
Intermediate 2a: 3-(5-Bromo-l-oxo-l,3-dihvdro-2/7-isoindol-2-yl)piperidine-2,6-dione
Figure imgf000065_0003
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 N2. The resulting suspension was stirred at 80°C for 4h. The mixture was cooled to RT and filtered. The resulting solid was washed with MeCN (60 mL), MeCN:Et2O (50 mL [2:3]) and Et2O (2 x 50 mL) to give the title compound (13.10 g, 85%) as a dark blue solid; ‘HNMR: 1.95-2.08 (IH, m), 2.34-2.46 (IH, m), 2.57-2.65 (IH, m), 2.91 (IH, ddd), 4.35 (IH, d), 4.48 (IH, d), 5.11 (IH, dd), 7.67 (IH, d), 7.72 (IH, dd), 7.83-7.96 (IH, m), 10.98 (IH, s).Wz: ES+ [M+H]+ = 323.0. Intermediate 2b: tert- Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-
Figure imgf000066_0001
yl1piperazine-l-carboxylate
Figure imgf000066_0002
CS2CO3 (57.40 g, 176 mmol) and Pd-PEPPSI-IPent (2.33 g, 2.94 mmol) were added in one portion to a degassed solution of tert-butyl piperazine- 1 -carboxylate (14.22 g, 76.36 mmol) and 3-(5-bromo-l-oxo-l,3- dihydro-2H-isoindol-2-yl)piperidine-2, 6-dione (19.0 g, 58.74 mmol) in 1,4-dioxane (590 mL) under N2. The resulting mixture was stirred at 90°C for 24h. The mixture was then cooled to RT, diluted with DCM (IL) and washed sequentially with 5% AcOH in water (500 mL) and brine (500 mL). The organic solution was then dried (MgSCL) and concentrated. Trituration with EtOAc (250 mL) gave a solid that was collected by filtration, washed with Et2O (100 mL) and dried under vacuum to give the title compound (22.10 g, 88%) as a grey solid; ‘H NMR: 1.43 (9H, s), 1.96 (1H, d), 2.31-2.41 (1H, m), 2.59 (1H, d), 2.87 (1H, s), 3.29 (4H, d), 3.47 (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-[l-Oxo-5-(Piperazin-l-yl)-l,3-dihvdro-2/T-isoindol-2-yl1piperidine-2,6-dione
Figure imgf000066_0003
A solution of 4M HC1 in dioxane (8.75 mL, 35.0 mmol) was added to tert-butyl 4-[2-(2,6-dioxopiperidin-3- vl )- 1 -oxo-2.3-dihvdro- 1 /7-isoindol-5-vl Ipiperazine- 1 -carboxvlate (1.50 g, 3.50 mmol) in 1,4-dioxane (2 mL) at RT and the mixture was stirred for Ih. EtOAc (5 mL) was then added and the mixture was stirred for 10 mins. The resulting precipitate was collected by filtration, washed with EtOAc (2 x 5 mL) and dried under vacuum to give the title compound in the form of a hydrochloride salt (1.08 g, 85%) as a dark grey solid; *H NMR: 1.97 (IH, dd), 2.36-2.44 (IH, m), 2.60 (IH, d), 2.84-2.99 (IH, m), 3.23 (4H, s), 3.5-3.57 (4H, m), 4.27 (IH, s), 4.34 (IH, s), 5.06 (IH, dd), 7.11-7.18 (2H, m), 7.59 (IH, d), 9.17 (2H, s), 10.93 (IH, s); m/z\ ES+ [M+H]+ 329.0.
Intermediate 2d: 4-(4-(4-(4-Oxobutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000067_0001
4-(4-(4-(3-(l,3-Dioxolan-2-yl)propoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (example Ih) (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 18h. The solvent was then removed under reduced pressure to give the title compound as a yellow oil (used directly in next step, assumed 100% yield); m/z\ ES+ [M+H]+ = 417.0.
Example 2: 4-!4-[4-(4-!4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-yl|piperazin-l-
Figure imgf000067_0002
yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000067_0003
4-(4-(4-(4-Oxobutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (4.17 g, 8.71 mmol), 3-[l-oxo-5- (piperazin-l-yl)-l,3-dihydro-2/f-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 RT. The resulting suspension was stirred for Ih at RT then NaBH(OAc)3 (3.69 g, 17.42 mmol) was added and the mixture was stirred for 0.5h. The mixture was then diluted with DCM (200 mL) and washed sat. Nal ICO;, (2 x 200 mL) then sat. brine (200 mL). The organic solution was then dried (MgSO.4) and concentrated. Purification by preparative HPLC (Column A, Eluent B, Basic Work-Up A) gave the title compound (820 mg, 13%); *H NMR: 1.52-1.69 (4H, m), 1.74 (2H, p), 1.84 (2H, d), 1.91-2.03 (IH, m), 2.34-2.42 (3H, m), 2.52-2.54 (4H, m), 2.59 (IH, d), 2.76 (IH, td), 2.83-2.96 (IH, 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 (IH, d), 5.05 (IH, dd), 6.78-6.9 (2H, m), 7.05 (2H, d), 7.15 (2H, d), 7.23-7.36 (2H, m), 7.52 (IH, d), 7.81 (IH, d), 10.92 (IH, s); m/z\ ES+ [M+H]+ = 729.5.
Intermediate 3a: 2-Cvclopropyl-4-fluorobenzonitrile
Figure imgf000067_0004
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 K3PO4 (5.57 g, 26.25 mmol) in toluene (20 mL) at RT under N2. The resulting mixture was stirred at 100°C for 3h. The mixture was then filtered through Celite and washed through with EtOAc (30 mL). The filtrate was concentrated and purification by FSC (gradient: 0-5% EtOAc in petroleum ether) gave the title compound (0.950 g, 79%) as a green solid; ‘HNMR: 0.85-0.94 (2H, m), 1.07-1.21 (2H, m), 2.13-2.25 (IH, m), 6.95-7.03 (IH, m), 7.15-7.25 (IH, m), 7.81-7.89 (IH, m).
Figure imgf000068_0001
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 CS2CO3 (6.06 g, 18.61 mmol) in DMSO (1.5 mL) at 80°C. The resulting mixture was stirred at 80°C for 16h, then cooled to RT and diluted with water. The mixture was then filtered, diluted with EtOAc (1 L), and washed with water (500 mL) then sat. brine (500 mL). The organic layer was dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (1.70 g, 72%) as a yellow solid; ‘HNMR: 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.
Figure imgf000068_0002
Ruphos Pd G3 (88 mg, 0.10 mmol) and Ruphos (46 mg, 0.10 mmol) were added to a mixture of CS2CO3 (1.025 g, 3.15 mmol), 4-(dimethoxymethyl)piperidine (334 mg, 2.10 mmol) and 4-(4-(4-bromophenyl)- piperidin-l-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1,4-dioxane (6 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h. 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; ‘H NMR: 0.79-0.90 (2H, m), 0.97-1.10 (2H, m), 1.20-1.41 (2H, m), 1.50-1.74 (5H, m), 1.80 (2H, d), 1.97-2.15 (lH, 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.
Figure imgf000068_0003
2-Cyclopropyl-4-(4-(4-(4-(dimethoxymethyl)piperidin-l-yl)phenyl)piperidin-l-yl)benzonitrile (150 mg, 0.33 mmol) and 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l,3-dihydro-2/f-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 dissolved in IPA (2 mL) and DCM (2 mL) at RT under air. NaBH(OAc)3 (138 mg, 0.65 mmol) was then added in one portion after 10 mins and the resulting dark suspension was stirred at RT for Ih. The mixture was then concentrated, dissolved in DMF (3 mL) and filtered. Purification by preparative HPLC (Column A, Eluent A) gave the title compound as a formate salt (59 mg, 24%) as a white solid; >H 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 (IH, d), 1.79-1.83 (4H, m), 1.88-1.96 (IH, m), 2.09 (IH, s), 2.23 (2H, d), 2.28-2.37 (IH, 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 (IH, d), 4.24 (IH, d), 4.96 (IH, dd), 6.44-6.52 (2H, m), 6.61 (IH, s), 6.86 (3H, td), 7.07 (2H, d), 7.47 (IH, d), 8.15 (2H, s), 10.88 (IH, s); m/z\ ES+ [M+H]+ = 756.7.
Intermediate 4a: 4-(4-(4-Bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000069_0001
CS2CO3 (73.6 g, 225.95 mmol) was added portion-wise 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 RT. The resulting cream suspension was stirred at RT for 18h and was then diluted slowly with water (600 mL). The resulting cream suspension was stirred at RT for 0.5h, then filtered, washed with water (2 x 25 mL) and Et2O (50 mL). The solid was dried under vacuum to give the title compound (35.0 g, 95%) as a cream solid; ‘HNMR: 1.65 (2H, qd), 1.87 (2H, d), 2.85 (1H, tt), 3.06 (2H, td), 4.19 (2H, d), 7.22-7.26 (2H, m), 7.28 (1H, dd), 7.33 (1H, d), 7.43-7.59 (2H, m), 7.74-7.88 (1H, m).
Intermediate 4b: 4-(4-(4-(4-(l,3-Dioxolan-2-yl)piperidin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000069_0002
Anhydrous 1,4-dioxane (160 mL) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoro- methyl)benzonitrile (10.00 g, 24.43 mmol), 4-(l,3-dioxolan-2-yl)piperidine (4.17 g, 26.51 mmol), RuPhos Pd G3 (1.533 g, 1.83 mmol), RuPhos (0.855 g, 1 .83 mmol) and sodium 2-methylpropan-2-olate (7.04 g, 73.30 mmol). The mixture was degassed by bubbling N2 through the mixture for 5 mins and was then stirred at 100°C for 2h. The mixture was then cooled to RT and water (320 mL) was added. A precipitate formed which was collected by filtration to give an orange solid. The solid was slurried in MTBE (50 mL), heated at 45°C for 0.5h then allowed to cool to RT 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; 'H NMR: 1.39 (2H, qd), 1.54-1.68 (3H, m), 1.72 (2H, d), 1.84 (2H, d), 2.58 (2H, td), 2.65-2.79 (IH, m), 2.99-3.12 (2H, m), 3.66 (2H, d), 3.76-3.83 (2H, m), 3.83-3.91 (2H, m), 4.17 (2H, d), 4.61 (IH, d), 6.86 (2H, d), 7.08 (2H, d), 7.27 (IH, dd), 7.32 (IH, d), 7.81 (IH, d); m/z\ ES+ [M+H]+ = 486.3.
Intermediate 4c: 4-(4-(4-(4-Formylpiperidin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000070_0001
4-(4-(4-(4-(l,3-Dioxolan-2-yl)piperidin-l-yl)phenyl)piperidin-l-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 Ih. The mixture was then cooled to RT, diluted with EtOAc (50 mL) and water (50 mL). The layers were separated. The organic solution was washed with water (50 mL), sat. Nal ICO;, (50 mL) and brine (50 mL), then dried (MgSO.4) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (4.60 g, 51%) as a white solid; >H NMR: 1.53-1.68 (4H, m), 1.84 (2H, d), 1.92 (2H, dd), 2.45 (IH, dd), 2.73 (IH, 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 (IH, d), 9.59-9.72 (IH, m); m/z\ ES+ [M+H]+ 442.3.
Example 4: 4-(4-!4-|4-(!4-|2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro- isoindol-5-yl|-
Figure imgf000070_0002
piperazin-l-yllmethyl)piperidin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000070_0003
A mixture of 4-(4-(4-(4-formylpiperidin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (4.60 g, 10.42 mmol) and 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l,3-dihydro-2/f-isoindol-2-yl]piperidine-2, 6-dione hydrochloride salt (4.11 g, 10.42 mmol) and NaOAc (1.71 g, 20.84 mmol) was stirred in IPA(2 mL) and DCM (250 mL) at RT under air. NaBJ 1(0 Ac);, (4.42 g, 20.84 mmol) was added portion-wise after Ih. The resulting dark suspension was stirred at RT for Ih. The mixture was then diluted with DCM (2 x 250 mL), washed (sat. Nal ICO; (250 mL), water (250 mL) then sat. brine (250 mL)), dried (Na2SO4) 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 RT and collected by filtration to give the title compound (2.05 g, 31%) as a white solid; *H NMR: 1.18-1.31 (2H, m), 1.55-1.74 (3H, m), 1.80-1.86 (4H, m), 1.88-1.97 (IH, 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-(l-(4-cvano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-
Figure imgf000071_0001
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-l-yl)-2-(trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol) and CS2CO3 (2.79 g, 8.55 mmol) in toluene (20 mL) at RT under N2. The resulting mixture was stirred at 90°C for 18h. The mixture was then cooled to RT and diluted with EtOAc (50 mL) and water (15 mL). The organic layer was separated and washed with sat. brine (20 mL), dried (MgSC>4) and concentrated. Purification by FSC (gradient: 0-60% EtOAc in heptane) gave the title compound (0.34 g, 29%) as a white solid; ‘H NMR: (CDCh) 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.
Intermediate 5b and 5c: 4-(4-(4-((lr,3s)-3-(2-Hvdroxyethyl)cvclobutoxy)phenyl)piperidin-l-yl)-2-
(trifluoromethvDbenzonitrile and 4-(4-(4-((ls,3r)-3-(2-hvdroxyethyl)cvclobutoxy)phenyl)piperidin-l-yl)-
2-(trifluoromethyl)benzonitrile
Figure imgf000071_0002
Diisobutylaluminum hydride (IM in toluene, 1.048 mL, 1.05 mmol) was added dropwise to a stirred solution of ethyl 2-(3-(4-(l-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)cyclobutyl)acetate (340 mg, 0.70 mmol) in THF (10 mL) at 0°C under N2. The resulting mixture was stirred at 0°C for 10 mins. The reaction was then quenched by addition of Rochelle’s salt (15 mL). EtOAc (25 mL) was added and the mixture was stirred at RT for 18h. The phases were then separated and the aqueous portion was extracted with EtOAc (3 x 50 mL). The combined organic solutions were washed with brine (50 mL), dried (MgSCM) and concentrated. Purification by FSC (gradient: 0- 100% EtOAc in heptane) gave a ~2 : 1 mixture of cis/trans isomers (0.280 g, 90%). A sample was purified on Sepiatec SFC system (Column: YMC Chiral Art Cellulose- SJ, 20 x 250 mm, 5|im, Eluent: 70% CO2, 30% MeOI 1+0. 1 %NH;,) to give the title compounds: Intermediate 5b {cis, 0.142 g, 53%) and Intermediate 5c {trans, 0.054 g, 20%); Intermediate 5b (cis): ‘H NMR: 1.52-1.69 (6H, m), 1.85 (2H, d), 1.98 (IH, ddd), 2.53-2.61 (2H, m), 2.7-2.83 (IH, m), 2.97-3.1 (2H, m), 3.36 (2H, td), 4.17 (2H, d), 4.31 (IH, t), 4.49 (IH, p), 6.65-6.83 (2H, m), 7.06-7.19 (2H, m), 7.27 (IH, dd), 7.32 (IH, d), 7.81 (lH, d); Intermediate 5c (trans): ‘H NMR: 1.55-1.72 (4H, m), 1.85 (2H, d), 2.14-2.16 (4H, m), 2.34-2.4 (IH, m), 2.7-2.82 (IH, m), 2.96-3.13 (2H, m), 3.34-3.44 (2H, m), 4.17 (2H, d), 4.33 (IH, t), 4.76 (IH, p), 6.64-6.78 (2H, m), 7.14 (2H, d), 7.27 (IH, dd), 7.32 (IH, d), 7.81 (IH, d).
Intermediate 5d: 4-(4-(4-((ls,3s)-3-(2-Bromoethyl)cvclobutoxy)phenyl)piperidin-l-yl)-2-(trifluoro-
Figure imgf000072_0001
A solution of PPh3 (142 mg, 0.54 mmol) in THF (2 mL) was added dropwise to a stirred mixture of 4-(4-(4- ((lr,3s)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (120 mg, 0.27 mmol) and CBr i (179 mg, 0.54 mmol) in THF (2 mL) at 0°C. The resulting mixture was stirred at RT for Ih and then filtered. The solid was then washed with EtOAc (20 mL) and the filtrate concentrated under reduced pressure. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (0.140 g, 100%) as a colourless oil; ‘HNMR: (500 MHz, CDCh) 1.21-1.26 (IH, m), 1.63-1.78 (4H, m), 1.90 (2H, d), 1.95 (IH, d), 2.01-2.15 (IH, m), 2.49-2.73 (3H, m), 2.98 (2H, td), 3.28 (2H, t), 3.9-3.98 (2H, m), 4.44 (IH, p), 6.68-6.75 (2H, m), 6.92 (IH, dd), 6.98-7.07 (2H, m), 7.09 (IH, d), 7.55 (IH, s); m/z: ES+ [M+H]+ = 507.1.
Example 5: 4-14-14- !ltlr,3s)-3-t2- 14-12-12, 6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2, 3-d ihvdro-
Figure imgf000072_0002
isoindol-5-yl1piperazin-l-yllethyl)cvclobutyl1oxylphenyl)piperidin-l-yl1-2-(trifluoromethyl)benzonitrile
Figure imgf000072_0003
4-(4-(4-((ls,3s)-3-(2-Bromoethyl)cyclobutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (65.0 mg, 0.13 mmol), 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l,3-dihydro-2/f-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 Lil,. 0.64 mmol) were dissolved in MeCN (2.5 mL) and stirred at 70°C for 18h. The mixture was then diluted with DCM (20 mL), washed (5% AcOH in water (20 mL), water (20 mL) then sat. Nal ICO;, (20 mL)), dried (Na2SO4) and concentrated. Purification by preparative HPLC (Column A, Eluent A, Basic Work-Up A) gave the title compound (8 mg, 8%) as a white solid; ‘H NMR: 1.66-1.75 (3H, m), 1.75-1.84 (3H, m), 1.92-1.99 (3H, m), 2.15 (1H, dtd), 2.28 (1H, td), 2.32-2.4 (2H, m), 2.54-2.61 (4H, m), 2.61-2.69 (2H, m), 2.69-2.78 (1H, m), 2.78- 2.85 (1H, m), 2.85-2.91 (1H, m), 3.05 (2H, td), 3.27-3.36 (4H, m), 3.94 (3H, s), 4.02 (2H, d), 4.19 (1H, d), 4.35 (1H, d), 4.49 (1H, p), 5.12 (1H, dd), 6.36 (1H, 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 (1H, d), 7.96 (1H, s); m/z\ ES+ [M+H]+ = 785.4.
Intermediate 6a: 3,4-Difluoro-2-(trifluoromethyl)benzonitrile
Figure imgf000073_0001
l-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 3h. The mixture was then cooled to RT, diluted with Et2O (100 mL), washed with sat. brine (3 * 100 mL) then dilute Ni l;, solution (50 mL), dried (MgSCL) and concentrated to give the title compound (4.27 g) which was used in the next step without further purification; ‘HNMR: (500 MHz, CDC13) 7.46 (1H, q), 7.59 (1H, dddd).
Intermediate 6b: 4-(4-(4-Bromophenyl)piperidin-l-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile
Figure imgf000073_0002
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 0.5h, then cooled to RT and diluted with Et2O (100 mL). The mixture was washed with brine (2 x 100 mL), 2M aqueous HC1 (50 mL) then sat. Nal ICO; (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 pale brown solid which was used without further purification; ‘H NMR: (500 MHz, CDCh) 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-(hvdroxymethyl)piperidin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoro-
Figure imgf000073_0003
Cui (44.6 mg, 0.23 mmol) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-l-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 K3PO4 (497 mg, 2.34 mmol) in DMSO (5 mL) under Na. The mixture was stirred at 110°C for 18h. The mixture was then cooled to RT and poured into water (50 mL) then extracted with EtOAc (3 x 50 mL). The combined organic solutions were washed with Nal ICO3 (50 mL) and brine (50 mL), dried (MgSCL) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.10 g, 19%) as a white solid; 'H NMR: (CDCI3) 1.28 (IH, d), 1.41 (2H, qd), 1.53 (IH, s), 1.57-1.71 (IH, 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 (IH, d); m/z\ ES+ [M+H]+ = 462.2.
Intermediate 6d: 3-Fluoro-4-(4-(4-(4-formylpiperidin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)-
Figure imgf000074_0001
Dess Martin periodinane (101 mg, 0.24 mmol) was added to 3-fluoro-4-(4-(4-(4-(hydroxymethyl)piperidin-l- yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.22 mmol) in DCM (3 mL) at 0°C. The resulting mixture was stirred at RT for Ih. The mixture was then diluted with DCM (15 mL) and poured into a mixture of sat. Nal ICOa (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 mins and the layers separated. The organic layer was dried (NaaSCL) and concentrated to give the title compound as a yellow dry film, which was used in the next step without further purification (assumed 100% yield); m/z\ ES+ [M+H]+ = 460.3.
Example 6: 4-(4-f4-[4-(f4-[2-(2.6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2.3-dihvdro-l/7-isoindol-5-yl1- piperazin-l-yllmethyl)piperidin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000074_0002
3-Fluoro-4-(4-(4-(4-formylpiperidin- 1 -yl)phenyl)piperidin- 1 -yl)-2-(trifhioromethyl)benzonitrile (0.100 g, 0.22 mmol), 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l,3-dihydro-2K-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 RT and stirred for 10 mins. NaBH(OAc)3 (0.092 g, 0.44 mmol) was added and the mixture stirred for Ih. The mixture was diluted with DCM (20 mL), washed (sat. Nal ICOa (20 mL), water (20 mL) then sat. brine (20 mL)), dried ( NaiSO i ) and concentrated. Purification by preparative HPLC (Column A, Eluent A) gave the title compound as a formate salt (42 mg, 24%) as a white solid; *H NMR: 1.23 (2H, q), 1.62-1.78 (3H, m), 1.82- 1.84 (4H, m), 1.89-1.97 (1H, m), 2.23 (2H, d), 2.26-2.38 (2H, m), 2.52-2.54 (4H, m), 2.56-2.67 (3H, m), 2.83- 2.96 (1H, m), 3.04 (2H, t), 3.31 (4H, s), 3.68 (4H, dd), 3.84 (3H, s), 4.12 (1H, d), 4.24 (1H, d), 4.96 (1H, dd), 6.49 (1H, 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-hvdroxybutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000075_0001
4-(4-(4-Bromophenyl)piperidin-l-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (0.500 g, 1.17 mmol), CS2CO3 (1.335 g, 4.10 mmol) and butane- 1,4-diol (0.501 mL, 5.85 mmol) were dissolved in toluene (15 mL) and degassed with Ni. Rockphos Pd G3 (0.049 g, 0.06 mmol) was added and the mixture was heated at 90°C for 18h. The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL) then sat. brine (100 mL), dried (TS^SCL) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (0.363 g, 71%) as a pale yellow solid; ‘H NMR: (CDCI3) 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-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000075_0002
3-( )xo- l l5-ben/o| J|| 1 .2|iodaoxole- l .1 . l(3/7)-trivl triacetate (192 mg, 0.45 mmol) was added to 3-fluoro-4-(4- (4-(4-hydroxybutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.41 mmol) in DCM (2 mL) at 0°C and warmed to RT for Ih. The mixture was then diluted with DCM (15 mL) and poured into mixture of sat. Nal ICC);, (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 mins then the phases were separated. The organic solution was dried (Na2SO4) 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-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1- piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-3-fluoro-2-(trifluoromethyl) benzonitrile
Figure imgf000076_0001
3-Fluoro-4-(4-(4-(4-oxobutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (0.120 g, 0.28 mmol), 3- [7-m ethoxy- 1 -oxo-5-(piperazin- 1 -yl)- 1 , 3-dihvdro-2/7-iso indo l-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) at RT and stirred for 10 mins. NaBH(OAc)a (0.117 g, 0.55 mmol) was then added and the mixture stirred for Ih. The mixture was then diluted with DCM (20 mL) and washed (sat. Nal ICO;, (20 mL), water (20 mL) then sat. brine (20 mL)), dried (Na2SO4) and concentrated. Purification by preparative HPLC (Column A, Eluent A) gave the title compound (0.084 g, 39%) as a white solid; ‘H NMR: 1.61 (2H, p), 1.75-1.76 (4H, m), 1.86 (2H, d), 1.89-1.98 (IH, m), 2.28 (IH, dd), 2.39 (2H, t), 2.52-2.53 (4H, m), 2.54-2.62 (IH, m), 2.67-2.78 (IH, m), 2.89 (IH, 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 (IH, m), 4.24 (IH, d), 4.96 (IH, dd), 6.48 (IH, d), 6.60 (IH, s), 6.8-6.92 (2H, m), 7.18 (2H, d), 7.46 (IH, t), 7.80 (IH, d), 10.88 (IH, s); m/z\ ES+ [M+H]+ = 777.3.
Intermediate 8a: tert- Butyl 4-(5-hvdroxypyrimidin-2-yl)-3,6-dihvdropyridine-l carboxylate
Figure imgf000076_0002
Figure imgf000076_0003
Na;CO;, (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-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2//)-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; for 15 mins. Pd(dppf)2C12-DCM complex (0.467 g, 0.571 mmol) was then added and the resulting mixture was heated to 100°C for 3h, then cooled to RT. 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 (TS^SCL) and concentrated. Purification by FSC (gradient: 0-40% EtOAc in heptane) gave the title compound (1.10 g, 65%) as a pale brown sticky liquid; ‘HNMR: 1.43 (9H, s), 2.56 (2H, d), 3.51 (2H, t), 4.04 (2H, s), 6.91 (IH, s), 8.34 (2H, s), 10.42 (IH, br s); m/z\ ES+ [M-56]+ = 222.2.
Intermediate 8b: tert-Butyl 4-(5-hvdroxypyrimidin-2-yl)piperidine-l-carboxylate
Figure imgf000076_0004
tert-Butyl 4-(5-hydroxypyrimidin-2-yl)-3,6-dihydropyridine-l(2//)-carboxylate (1.10 g, 3.97 mmol) was dissolved in EtOH (30 mL) and the solution bubbled with N 2 for a period of 15 mins. Pd-on-C (0.55 g, 0.517 mmol) (10% w/w) was added under N2 and the mixture was then stirred under an atmosphere of H2 at RT for 5h. The mixture was then filtered through celite and the filter cake washed with MeOH (250 mL). The filtrate was concentrated to give the title compound (1.05 g, 70%) as a pale brown sticky liquid which was used in the next step without further purification; ‘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- [M-H]’ = 278.3.
Intermediate 8c: 2-(Piperidin-4-yl)pyrimidin-5-ol
Figure imgf000077_0001
4N HC1 in 1,4-dioxane (5 mL, 20.00 mmol) was added to a solution of tert-butyl 4-(5-hydroxypyrimidin-2- yl)-piperidine-l -carboxylate (500 mg, 1.79 mmol) in DCM (10 mL) at 0°C. The mixture was stirred at 0°C to RT for 2h and then concentrated. The resulting solid was triturated with hexanes (10 mL) gave the title compound as a hydrochloride salt (460 mg, 99%) as an off-white solid; *H NMR: 1.90-2.00 (2H, m), 2.03-2.15 (2H, m), 2.95-3.11 (3H, m), 3.29 (2H, d), 8.36 (2H, s), 8.89 (1H, br s), 9.14 (1H, br s), 10.60 (1H, br s); m/z\ ES+ [M+H]+ = 180.2.
Figure imgf000077_0002
DIPEA (0.831 mL, 4.76 mmol) was added to a solution of 4-fhioro-2-(trifhioromethyl)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) at RT under air. The mixture was heated at 50°C for 6h, then cooled to RT, 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 (Na2SC>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; >H NMR: (CDCI3) 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-yl1-l-piperidyl1-2-(trifluoromethyl)benzonitrile
Figure imgf000077_0003
CS2CO3 (711 mg, 2.182 mmol) and 1 ,4-dibromobutane (0.391 mL, 3.27 mmol) were added to a solution of 4- (4-(5-hydroxypyrimidin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (380 mg, 1.091 mmol) in DMF (5 mL) at RT. The mixture was stirred at RT for 2h, 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 (Na2SO4) and concentrated. Purification by FSC (gradient: 0-40% EtOAc in heptane) gave the title compound (390 mg, 71%) as an off-white solid; >H NMR: (CDCh) 1.96-2.21 (8H, m), 3.12-3.22 (3H, m), 3.51 (2H, t), 4.02 (2H, d), 4.11 (2H, t), 7.01 (1H, dd), 7.17 (1H, d), 7.62 (1H, d), 8.39 (2H, s); m/z\ ES+ [M+H]+ = 483.1.
Example 8: 4-[4-[5-[4-[4-[2-(2,6-Dioxo-3-piperidyl)-7-methoxy-l-oxo-isoindolin-5-yl1piperazin-l-yl1- butoxy1pyrimidin-2-yl1-l-piperidyl1-2-(trifluoromethyl)benzonitrile
Figure imgf000078_0001
Amixture of DIPEA (0.216 mL, 1.241 mmol), 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l .3-dihvdro-2/7- isoindol-2-yl]piperidine-2, 6-dione hydrochloride salt (137 mg, 0.348 mmol), 4-(4-(5-(4- bromobutoxy)pyrimidin-2-yl)-piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (120 mg, 0.248 mmol) and KI (124 mg, 0.745 mmol) were stirred in DMSO (4 mL) at RT under N2. The mixture was then heated to 80°C for 16h, cooled to RT 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), sat. Nal ICO;, (20 mL)then sat. brine (20 mL)), dried (Na2SO4) and concentrated. The crude material was purified by preparative HPLC (Column B, Eluent C). Fractions containing the desired compound were combined, concentrated cold to a minimum amount of solvent and basified with sat. Nal ICO;, solution. The phases were separated and the aqueous phase was extracted with DCM (4 x 30 mL). The combined organic solutions were washed with water (20 mL), dried over a phase separator and lyophilized to give the title compound (55 mg, 29%) as an off white solid; *H NMR: 1.57-1.67 (2H, m), 1.69-1.83 (4H, m), 1.92-2.04 (3H, m), 2.34-2.42 (3H, m), 2.59 (1H, d), 2.85-2.97 (1H, m), 3.06-3.20 (3H, m), 3.26 (4H, s), 4.08-4.25 (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), 8.49 (2H, s), 10.95 (1H, s); m/z\ ES+ [M+H]+= 761.2.
Intermediate 9a: tert-Butyl 5-hvdroxy-3’.6’-dihvdro-[2.4’-bipyridine1-l’ carboxylate
Figure imgf000078_0002
Figure imgf000078_0003
Na;CO; (1.218 g, 11.49 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- pvndine- l(2/7)-carboxvlate (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 RT. The mixture was degassed withN2 for 15 min, then Pd(dppf)C12-DCM (0.079 g, 0.575 mmol) was then added and the mixture was heated to 100°C for 3h. The mixture was then cooled to RT, diluted with water (120 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2 x 150 mL) and the combined organic solutions were washed with brine (100 mL), dried (Na2SO4) 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; *H NMR: (CDCh) 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-hvdroxypyridin-2-yl)piperidine-l-carboxylate
Figure imgf000079_0001
10% Pd-on-C (125 mg, 1.175 mmol) was added to a solution of tert-butyl 5-hydroxy-3',6'-dihydro-[2,4'-bi- pvridine|- 1'( 2'/7)-carboxvlate (500 mg, 1 .809 mmol) in MeOH (10 mL) under N2. The resulting suspension was purged with H2 and stirred at RT for 2h under an atmosphere of 112. The mixture was then filtered through celite and washed through with MeOH (150 mL). Concentration of the filtrate gave the title compound (410 mg, 81%) as an off-white solid; >H NMR: 1.41 (9H, s), 1.46-1.59 (2H, m), 1.76 (2H, d), 2.67-2.83 (3H, m), 4.03 (2H, d), 7.08 (2H, d), 8.05 (1H, s), 9.63 (1H, br s); m/z\ ES+ [M+H]+ = 279.4.
Intermediate 9c: 6-(piperidin-4-yl)pyridine-3-ol. TFA salt
Figure imgf000079_0002
TFA (0.886 mL, 11.50 mmol) was added to a solution of tert-butyl 4-(5-hydroxypyridin-2-yl)piperidine-l- carboxylate (400 mg, 1.437 mmol) in DCM (8.0 mL) at 0°C. The mixture was then warmed to RT over 2h and then concentrated. Trituration with MTBE (50 mL) gave the title compound as a trifluoroacetate salt (430 mg, 99%) as an off white solid; ‘H NMR: 1.77-1.91 (2H, m), 1.94-2.03 (2H, m), 2.91-3.08 (3H, m), 3.37 (2H, d), 7.19-7.34 (2H, m), 8.13 (1H, d), 8.40 (1H, br s), 8.69 (1H, br s), 10.26 (1H, br s); m/z\ ES+ [M+H]+ = 179.1.
Figure imgf000079_0003
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 RT. The mixture was then heated to 50°C for 5h, then cooled to RT and diluted with water (80 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 * 120 mL). The combined organic solutions were dried (TS^SCL) and concentrated. Trituration with hexanes (100 mL) gave the title compound (530 mg, 96%) as an off-white solid; >H NMR: 1.69 (2H, qd), 1.88 (2H, d), 2.86-2.99 (1H, m), 3.09 (2H, t), 4.16 (2H, d), 7.08-7.12 (2H, m), 7.27 (1H, dd), 7.32 (1H, s), 7.81 (1H, d), 8.04 (1H, d), 9.66 (1H, s); m/z\ ES+ [M+H]+ = 348.1.
Intermediate 9e: 4-(4-(5-(4-Bromobutoxy)pyridin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000080_0001
K2CO3 (80 mg, 0.576 mmol) and 1 ,4-dibromobutane (186 mg, 0.864 mmol) were added to a stirred solution of 4-(4-(5-hydroxypyridin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.288 mmol) in acetone (3.0 mL) at RT. The mixture was then heated to 60°C for 4h, then cooled to RT 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 sat. brine (50 mL), dried (Na2SO4) and concentrated to give crude compound (170 mg). The same method was repeated with CS2CO3 (188 mg, 0.576 mmol) instead of K2CO3 and the mixture was stirred at RT for 2h. After the same workup as previously described, 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; 'H NMR: (CDCI3) 1.84-2.03 (4H, m), 2.05-2.14 (4H, m), 2.93-3.02 (1H, m), 3.13 (2H, td), 3.51 (2H, t), 4.02-4.10 (4H, m), 7.01 (1H, dd), 7.12 (1H, d), 7.17 (2H, dd), 7.63 (1H, d), 8.25 (1H, d); m/z\ ES+ [M+H]+ = 482.1.
Example 9: 4-(4-(5-(4-(4-(2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazin-l- yl)butoxy)pyridin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000080_0002
DIPEA (0.221 mL, 1.266 mmol), 4-(4-(5-(4-bromobutoxy)pyridin-2-yl)piperidin-l-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-l- oxo-5-(piperazin-l-yl)-l,3-dihydro-2/f-isoindol-2-yl]piperidine-2, 6-dione hydrochloride salt (100 mg, 0.253 mmol) in DMSO (3.0 mL) RT under N2. The mixture was then heated to 80°C for 12h, then cooled to RT and diluted with DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), sat.
Nal ICO, (20 mL) then sat. brine (20 mL)), dried (TS^SCL) and concentrated. The crude material was purified by preparative HPLC (Column C, Eluent C). Fractions containing the desired compound were combined, concentrated cold to a minimum amount of solvent and basified with sat. Nal ICO;, 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 over a phase separator and lyophilized to give the title compound (28 mg, 14%) as an off white solid; ‘HNMR: 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-l-carboxylate
Figure imgf000081_0001
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-l -carboxylate (1.00 g, 4.97 mmol) in DCM (8 mL) at 0°C. The mixture was stirred at RT for 2h and then partitioned between water (2 mL) and DCM (10 mL). The organic phase was dried (IS^SCL) and concentrated to give the title compound (1.10 g, 90%) which was used in the next step without further purification; *H NMR: 0.99 (9H, s), 1.21 (9H, s), 1.74-1.86 (2H, m), 2.61-2.79 (1H, m), 3.42-3.54 (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
Figure imgf000081_0002
TFA (1.92 mL, 25.0 mmol) was carefully added to a solution of tert-butyl 3-(2-((tert-butyldiphenylsilyl)oxy)- ethyl)azetidine-l -carboxylate (1.10 g, 2.502 mmol) in DCM (8 mL) at 0°C. The mixture was then stirred at 0°C for 2h then further diluted with DCM (5 mL) and washed with sat Nal ICO;, (20 mL). The organic solution was dried (Na2SO4) and concentrated to give the title compound (810 mg, 91%) as thick liquid that was used in the next step without further purification; m/z\ ES+ [M+H]+ = 340.4.
Intermediate 10c: 4-(4-(4-(3-(2-((tert-ButyldiphenylsilvDoxy)ethvDazetidin-l-vDphenvDpiperidin-l-vD-2-
(trifluoromethvDbenzonitrile
Figure imgf000081_0003
3-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)azetidine (809 mg, 2.382 mmol) and CS2CO3 (1.04 g, 3.18 mmol) were added to a solution of 4-(4-(4-bromophenyl)piperidin-l-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;dba; (145 mg, 0.159 mmol) and SPhos (85 mg, 0.318 mmol) were added. The mixture was then stirred at 120°C for 3h, cooled to RT 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 (Na2SC>4) and concentrated to give the title compound (1.20 g, 43%) as a grey solid that was used in the next step without further purification; m/z\ ES+ [M+H]+ = 668.2.
Intermediate IQd: 4-(4-(4-(3-(2-Hvdroxyethyl)azetidin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000082_0001
Tetra w-butylammonium fluoride (IN solution in THF, 0.843 mL, 0.843 mmol) was added to a solution of 4- (4-(4-(3-(2-((tert-butyl-diphenylsilyl)oxy)ethy l)azetidin- 1 -yl)phenyl)piperidin- 1 -yl)-2-(trifluorom ethylbenzonitrile (512 mg, 0.767 mmol) in THF (4 mL) at 0°C and the resulting mixture was stirred for 3h. The mixture was then concentrated and dissolved into DCM (25 mL). The resulting solution was washed with sat. Nal ICO;, solution (25 mL), dried (Na2SO4) and concentrated to give the title compound (360 mg, 67%) as a thick liquid; m/z\ ES+ [M+H]+ = 430.2.
Intermediate IQe: 4-(4-(4-(3-(2-Bromoethyl)azetidin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000082_0002
PPhs (286 mg, 1.090 mmol) was added to a solution of 4-(4-(4-(3-(2-hydroxyethyl)azetidin-l-yl)phenyl)- piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (360 mg, 0.838 mmol) in DCM (5 mL) and the mixture was stirred for 5 min at RT. CBrj (361 mg, 1.090 mmol) was then added and the mixture was stirred at RT for 2h. The solvent was reduced to half quantity (2 mL) after concentration then the product was triturated with pentane to give the title compound that 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-vD-7-methoxy-l-oxoisoindolin-5-vDpiperazin-l- yl)ethvDazetidin-l-vDphenvDpiperidin-l-vD-2-(trifluoromethvDbenzonitrile
Figure imgf000083_0001
Amixture ofDIPEA (0.25 mL, 1.422 mmol), 4-(4-(4-(3-(2-bromoethyl)azetidin-l-yl)phenyl)piperidin-l-yl)-2- (trifluoro-methyl)benzonitrile (140 mg, 0.284 mmol), 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l .3-dihvdro-2/7- 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 RT. The mixture was then heated to 80°C for 12h, then concentrated and slowly poured into ice- water. The resulting solids were collected by filtration, washed with water (10 mL) and dried under vacuum. Purification by preparative HPLC (Column B, Eluent C, Basic Work-Up A) gave the title compound (34 mg, 15%) as an off white solid; ‘H NMR: 1.50-1.66 (2H, m), 1.66-1.77 (1H, m), 1.77-1.87 (2H, m), 1.87-1.99 (1H, m), 2.09-2.18 (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), 6.39-6.51 (3H, m), 6.57-6.68 (1H, m), 6.96-7.11 (2H, m), 7.23-7.37 (2H, m), 7.81 (1H, d), 11.0 (1H, br s); m/z\ ES+ [M+H]+ = 770.2.
Intermediate Ila: 5-(4-(4-Hvdroxyphenyl)piperidin-l-yl)-3-(trifluoromethyl)picolinonitrile
Figure imgf000083_0002
K2CO3 (826 mg, 5.98 mmol) was added to a solution of 5-bromo-3-(trifluoromethyl)picolinonitrile (500 mg, 1.992 mmol), 4-(piperidin-4-yl)phenol hydrobromide (771 mg, 2.99 mmol) and A0,A5-dimethylethane-l,2- diamine (35.1 mg, 0.398 mmol) in 1,4-dioxane (8 mL). The mixture was degassed with N2 for 15 mins and then Cui (37.9 mg, 0.199 mmol) was added. The mixture was heated to 120°C for 16h, then cooled to RT, diluted with water (100 mL) and extracted with EtOAc (2 * 150 mL). The combined organic solutions were washed with brine (80 mL), dried (TS^SCL) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (310 mg, 43%) as a pale yellow solid; '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-l-yl)-3-(trifluoromethyl)picolinonitrile
Figure imgf000083_0003
K2CO3 (119 mg, 0.864 mmol) was added to a solution of 5-(4-(4-hydroxyphenyl)piperidin-l-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 RT. The mixture was heated to 70°C for 6h, then cooled to RT, diluted with water (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic solutions were washed with sat. brine (30 mL), dried (NaaSCL) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (145 mg, 65%) as an off-white semi-solid; ‘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-l-oxoisoindolin-5-yl)piperazin-l- yl)butoxy)phenvDpiperidin-l-vD-3-(trifluoromethvDpicolinonitrile
Figure imgf000084_0001
DIPEA (0.332 mL, 1.899 mmol) was added to a solution of 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l,3- dihvdro-2//-isoindol-2-vl |piperidine-2.6-dione hydrochloride salt (150 mg, 0.380 mmol), 5-(4-(4-(4- bromobutoxy)-phenyl)piperidin-l-yl)-3-(trifluoromethyl)picolinonitrile (220 mg, 0.456 mmol) and KI (189 mg, 1.140 mmol) in DMSO (4 mL) at RT under N2. The mixture was stirred at 80°C for 16h, then cooled to RT and diluted with DCM (20 mL). This solution was washed (5% AcOH in water (20 mL), water (20 mL), sat. Nal ICO3 (20 mL) then sat. brine (20 mL)), dried ( Na^SO i ) and concentrated. Purification by preparative HPLC (Column B, Eluent C, Basic Work-Up A) and trituration with pentane (10 mL) gave the title compound (52 mg, 18 %) as an off white solid; ‘HNMR: 1.58-1.78 (6H, m), 1.81-2.01 (3H, m), 2.27-2.38 (3H, m), 2.60- 2.78 (2H, m), 2.80-2.98 (2H, m), 3.11 (3H, t), 3.83 (3H, s), 3.97 (2H, 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-hvdroxypentvDoxy)phenvDpiperidin-l-vD-2-(trifluoro-
Figure imgf000084_0002
RockPhos Pd G3 (0.290 g, 0.34 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoro- methyl)benzonitrile (1.39 g, 3.40 mmol), 3,3-difluoropentane-l,5-diol (1.19 g, 8.49 mmol) and CS2CO3 (239 mg, 0.73 mmol) in 1,4-dioxane (50 mL) at RT. The resulting mixture was then stirred at 100°C for Ih. The mixture was then cooled to RT and concentrated. The resulting residue was dissolved into 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 solutions were dried (MgSCL) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (0.60 g, 38%) as a yellow gum; *H NMR: (CDCh) 1.62 (IH, 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 (IH, 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 (IH, dd), 7.09-7.21 (3H, m), 7.61 (IH, d).
Intermediate 12b: 5-(4-(l-(4-Cvano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3- difluoropentyl methanesulfonate
Figure imgf000085_0001
Methane sulfonic anhydride (167 mg, 0.96 mmol) was added in one portion to 4-(4-(4-((3,3-difluoro-5- hydroxy-pentyl)oxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.38 mmol) and NEta (160 pL, 1.15 mmol) in DCM (2 mL) at RT and the mixture was stirred for 18h. The mixture was then diluted with DCM (25 mL) and washed sequentially with sat NH4CI (10 mL), sat Nal ICO;, (10 mL), water (20 mL) and sat. brine (10 mL). The solution was then dried with a phase separating 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. Dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazin-l-yl)-
Figure imgf000085_0002
idin-l-yl)-2-(trifluorom
Figure imgf000085_0003
Figure imgf000085_0004
KI (200 mg, 1.21 mmol), 5-(4-(l-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)-3,3-difluoro- pentyl methane sulfonate (220 mg, 0.40 mmol), 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l,3-dihydro-2/7- 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 18h. The mixture was then cooled to RT, concentrated. The resulting residue was dissolved with DCM (20 mL), washed with water (20 mL), separated through a phase separator and concentrated. Purification by preparative HPLC (Column A, Eluent A, Basic Work-Up A) gave the title compound (10.2 mg, 3%) as a yellow dry film; *H NMR: ( CDCh ) 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' [M-H]’ 807.5.
Intermediate 13a: 4-(4-(4-(3-Hvdroxypropoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000086_0001
Prepared from 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoro-methyl)benzonitrile according to the procedure described in Example 12 but using propane- 1,3-diol.
Intermediate 13b: 4-(4-(4-(3-
Figure imgf000086_0002
in-l-vl)-2-i
Figure imgf000086_0003
Figure imgf000086_0004
A solution of PPh3 (419 mg, 1.60 mmol) in TEIF (10 mL) was added dropwise to a stirred mixture of 4-(4-(4- (3-hydroxypropoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (323 mg, 0.80 mmol) and CBr i (530 mg, 1.60 mmol) in THF (10 mL) at 0°C. The resulting mixture was stirred at RT for Ih, then filtered and washed with EtOAc (20 mL). The combined filtrate was concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (346 mg, 93%) as a pale yellow solid; *H NMR: (CDCla) 1.76 (2H, qd), 1.98 (2H, dd), 2.31 (2H, p), 2.74 (IH, tt), 3.06 (2H, td), 3.60 (2H, t), 4.02 (2H, dd), 4.09 (2H, t), 6.83-6.91 (2H, m), 6.99 (IH, dd), 7.09-7.19 (3H, m), 7.58-7.64 (IH, m).
,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazin-l-
Figure imgf000086_0005
l-vl)-2-i
Figure imgf000086_0006
Figure imgf000086_0007
A mixture of 3-[7-methoxy-l-oxo-5-(piperazin-l-yl)-l,3-dihydro-2/f-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-l-yl)-2-(trifluoromethyl)benzonitrile (142 mg, 0.304 mmol) and KI (126 mg, 0.760 mmol) was stirred in DMSO (4 mL) at RT under N2. The mixture was then heated at 80°C for 12h, then cooled to RT and diluted DCM (20 mL). The solution was washed (5% AcOH in water (20 mL), water (20 mL), sat. Nal ICO;, (20 mL) then sat. brine (20 mL)), dried (Na2SO4) and concentrated. Purification by preparative HPLC (Column B, Eluent C, Basic Work-Up A) with lyophilizing and washing with hexanes gave the title compound (26 mg, 13%) as brown solid; ‘H NMR: 1.55-1.72 (2H, m), 1.80-1.97 (5H, m), 2.22-2.31 (1H, m), 2.58 (2H, br s), 2.75-2.82 (1H, m), 2.85-2.96 (1H, m), 3.05 (2H, br t), 3.44-3.59 (4H, m), 3.83 (3H, s), 4.00 (2H, br t), 4.07- 4.29 (5H, m), 4.96 (1H, br dd), 6.49 (1H, s), 6.61 (1H, s), 6.87 (2H, br d), 7.16 (2H, br d), 7.27 (1H, br d), 7.33 (1H, br s), 7.81 (1H, br d), 10.90 (1H, br s); m/z\ ES+ [M+H]+ 745.4.
Intermediate 14a: 2-Cvclopropyl-4-(4-(4-(4-hvdroxybutoxy)phenyl)piperidin-l-yl)benzonitrile
Figure imgf000087_0001
RockPhos Pd G3 (88 mg, 0.10 mmol) was added to a mixture of butane- 1,4-diol (142 mg, 1.57 mmol), CS2CO3 (1.03 g, 3.15 mmol) and 4-(4-(4-bromophenyl)piperidin-l-yl)-2-cyclopropylbenzonitrile (400 mg, 1.05 mmol) in 1 ,4-dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h 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; >H 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-l-yl)-2-cvclopropylbenzonitrile
Figure imgf000087_0002
CBt' i (153 mg, 0.46 mmol) was added to a mixture of PPh;, (121 mg, 0.46 mmol) and 2-cyclopropyl-4-(4-(4- (4-hy droxy butoxy )phenyl)piperidin-l-yl)benzonitrile (90 mg, 0.23 mmol) in DCM (1 mL) at RT and the mixture was stirred for 2h then concentrated. Purification by FSC (gradient: 0-23% EtOAc in petroleum ether) gave the title compound (81 mg, 78%) as a white solid; *H 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-CvcloDroDyl-4-(4-(4-(4-(4-(2-(2.6-dioxoDiDeridin-3-yl)-7-methoxy-l-oxoisoindolin-5- yllpiperazin-l-vDbutoxylphenvDpiperidin-l-yr) benzonitrile
Figure imgf000088_0001
DIPEA (57.8 Lil,. 0.33 mmol) was added to a mixture of KI (4 mg, 0.02 mmol), 4-(4-(4-(4-bromobutoxy)- phenyl)piperidin-l-yl)-2-cyclopropylbenzonitrile (50 mg, 0.11 mmol) and 3-[7-methoxy-l-oxo-5-(piperazin-l- vl 1 .3-dihvdro-2/7-isoindol-2-vl |piperidine-2.6-dione hydrochloride salt (43.5 mg, 0.12 mmol) in MeCN (2 mL) at RT. The resulting mixture was stirred at 80°C for 16h and then concentrated. Purification by preparative TLC (DCM/MeOH = 20/1) gave the title compound (13 mg, 16%) as a white solid; *H 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.
I
Figure imgf000088_0002
To a solution of 2-(piperidin-4-yl)ethan-l-ol (5.00 g, 38.7 mmol) in DCM (100 mL) was added NaiCO, (18.46 g, 174.1 mmol) in water (100 mL) at 0°C, and then benzyl carbonochloridate (6.08 mL, 42.6 mmol) was added drop wise. The mixture was stirred for 6h at RT, then diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic solutions were washed with sat. brine (100 mL), dried (NaaSO^ and concentrated. Purification by FSC (gradient: 0-70% EtOAc in heptane) gave the title compound (8.34 g, 82%) as a pale yellow oil; ‘H NMR: (CDCh) 1.15 (2H, qd), 1.43 (lH, t), 1.52 (2H, q), 1.62 (1H, dddd), 1.69 (2H, t), 2.78 (2H, t), 3.69 (2H, q), 4.14 (2H, dd), 5.12 (2H, s), 7.28-7.45 (5H, m); m/z\ ES+ [M+H]+ 264.3.
Figure imgf000088_0003
To a solution of benzyl 4-(2-hydroxyethyl)piperidine-l -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 RT for 3h, then quenched by the addition of sat. NaHCOa solution (50 mL) and filtered to remove solid residue. The solid residue was washed with DCM (50 mL). The phases were separated and the organic solution was washed with sat. brine (20 mL x 2), dried (TS^SCL) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (5.20 g, 63%) as a colourless oil; 'H NMR: (CDCI3) 1.20 (2H, q), 1.71 (2H, d), 2.07 (IH, 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 (IH, t); m/z\ ES+ [M+H]+ 262.2.
Intermediate 15c: Benzyl 4-(2,2-dimethoxyethyl)piperidine-l-carboxylate
Figure imgf000089_0001
To a solution of benzyl 4-(2-oxoethyl)piperidine-l -carboxylate (5.20 g, 19.9 mmol) in MeOH (60 mL) was added trimethoxymethane (10.9 mL, 99.5 mmol) and 4-methylbenzenesulfonic acid (0.17 g, 0.99 mmol) at 15°C. The mixture was stirred at this temperature for Ih. The reaction was then quenched by addition of water (50 mL) and diluted with DCM (100 mL). The phases were separated and the organic solution was washed with sat. brine (3 x 20 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (5.90 g, 96%) as a colourless oil; >H NMR: (CDCh) 1.04-1.25 (2H, m), 1.5-1.57 (2H, m), 1.57-1.63 (IH, m), 1.68 (2H, t), 2.78 (2H, t), 3.31 (6H, s), 4.15 (2H, d), 4.46 (IH, t), 5.12 (2H, s), 7.27-7.37 (5H, m).
Intermediate 15d: 4-(2,2-Dimethoxyethyl)piperidine
Figure imgf000089_0002
10% Ph(OH)2 on carbon (0.54 g, 0.38 mmol) was added to benzyl 4-(2,2-dimethoxyethyl)piperidine-l- carboxylate (5.90 g, 19.2 mmol) in MeOH (60 mL) at RT under N2 in a steel pressure reactor. The resulting suspension was purged with N2 and then H2 and then stirred at RT at a pressure of 4 atmospheres for 3 days. The mixture was then filtered through celite and washed through with MeOH (250 mL). The filtrate was concentrated to give the title compound (3.14 g, 94%) as a colourless oil; *H NMR: (CDCI3) 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 (IH, t).
Intermediate 15e: 4-(4-(4-(4-(2.2-DimethoxyethvDpiperidin-l-vDphenvDpiperidin-l-vD-2-(trifluoro- methvDbenzonitrile
Figure imgf000089_0003
RuPhos Pd G3 (0.205 g, 0.24 mmol) was added to a mixture of 4-(4-(4-bromophenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (1.00 g, 2.44 mmol), 4-(2,2-dimethoxyethyl)piperidine (0.64 g, 3.67 mmol), CS2CO3 (2.388 g, 7.33 mmol) and RuPhos (0.114 g, 0.24 mmol) in 1,4-dioxane (20 mL) at RT under N2. The resulting solution was stirred at 100°C for 1 Oh and then concentrated. Purification by flash C 18-flash chromatography (gradient: 0-100% MeCN in water) gave the title compound (1.20 g, 98%) as a yellow solid; ‘HNMR: 1.21-1.31 (2H, m), 1 .39-1.51 (3H, m), 1 .52-1.67 (2H, m), 1.70-1.77 (2H, m), 1.79-1.87 (2H, m), 2.51-2.61 (2H, m), 2.71 (1H, t), 2.98-3.08 (2H, m), 3.22 (6H, s), 3.58 (2H, d), 4.16 (2H, d), 4.43-4.50 (1H, m), 6.84 (2H, d), 7.07 (2H, d), 7.26 (1H, d), 7.32 (1H, s), 7.80 (1H, d); m/z ES+ [M+H]+ = 502.2.
Intermediate 15f: 4-(4-(4-(4-(2-*
Figure imgf000090_0001
idin-1 -yl)phenyl)piperidin- 1 -yl)-2 - 1
Figure imgf000090_0002
benzonitrile
Figure imgf000090_0003
A solution of 4-(4-(4-(4-(2,2-dimethoxyethyl)piperidin- 1 -yl)phenyl)piperidin- 1 -yl)-2-(trifluorom ethylbenzonitrile (200 mg, 0.40 mmol) in formic acid (2 mL) was stirred at RT for 5h. The mixture was then concentrated to give the title compound (0.17 g, 94%) which was used in the next step without further purification; ‘HNMR: 1.23-1.33 (2H, m), 1.54-1.67 (2H, m), 1.67-1.76 (2H, m), 1.79-1.87 (2H, m), 1.95 (1H, s), 2.36-2.43 (2H, m), 2.57-2.69 (2H, m), 2.69-2.76 (1H, m), 3.03 (2H, t), 3.58 (2H, d), 4.16 (2H, d), 6.85 (2H, d), 7.07 (2H, d), 7.22-7.29 (1H, m), 7.31 (1H, s), 7.80 (1H, d), 9.70 (1H, d); m/z ES+ [M+H]+ = 456.1. Dioxopiperidin-3-vl)-7-methoxv-l-oxoisoindolin-5-vl)piperazin-l-
Figure imgf000090_0004
in-l-yD-2-i
Figure imgf000090_0005
Figure imgf000090_0006
tert-Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazine-l -carboxylate (50 mg, 0.11 mmol) was added to a solution of 4-(4-(4-(4-(2-oxoethyl)piperidin-l-yl)phenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (50 mg, 0.11 mmol) in formic acid (2 mL) at RT. The resulting solution was stirred at 40°C for Ih, then cooled to RT and concentrated. The resulting residue was dissolved in DCM (2 mL) and then NaBH(OAc)3 (47 mg, 0.22 mmol) was added. This mixture was stirred at RT for Ih. The mixture was then diluted with DCM, washed (AcOH (5%, aq), water (20 mL) then sat. brine (20 mL)), dried (Na2SC>4) and concentrated. Purification by preparative SFC (Column: Torus 2-PIC; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.5% 2M NI L-MeOH ): Flow rate: 50 mL/min; isocratic gradient: 30% B) gave the title compound (6.1 mg, 7%) as a pale yellow solid; ‘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 (4H, m), 3.10-3.50 (8H, m), 3.61 (2H, d), 3.84 (3H, s), 4.04-4.29 (4H, m), 4.97 (IH, dd), 6.49 (IH, s), 6.61 (IH, s), 6.86 (2H, d), 7.08 (2H, d), 7.19-7.39 (2H, m), 7.82 (IH, d), 10.91 (IH, s); m/z ES+ [M+H]+ = 798.4. idin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-
Figure imgf000090_0007
Figure imgf000091_0001
4-(Piperidin-4-yl)phenol hydrobromide salt (5.14 g, 19.91 mmol) and di-tert-butyl dicarbonate (4.56 g, 20.91 mmol) was slurried in DCM (60 mL) at RT. NEta (5.53 mL, 39.82 mmol) was then added in one portion and the mixture was stirred for 45 mins. The mixture was then diluted with DCM (200 mL), washed with water (3 x 100 mL), dried over a phase separator and concentrated to give the title compound (5.70 g, 100%) as a white solid; ‘HNMR: 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- [M-H]' = 276.3.
Intermediate 16b: tert-Butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l- yllbutoxylphenvDpiperidine-l-carboxylate
Figure imgf000091_0002
tert-Butyl 4-(4-hydroxyphenyl)piperidine-l -carboxylate (2.20 g, 7.93 mmol), K2CO3 (1.32 g, 9.52 mmol) and 1,4-dibromobutane (2.37 mL, 19.83 mmol) were dissolved in anhydrous MeCN (80 mL) under N 2. The mixture was stirred at 80°C for 3h then cooled to RT. The mixture was then filtered and washed through 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; *H NMR: (CDCI3) 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-/Bu| 356.0.
Intermediate 16c: tert- Butyl 4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l- yl)butoxy)phenyl)piperidine-l -carboxylate
Figure imgf000091_0003
DIPEA (2.3 mL, 13.10 mmol) was added to 3-[l-oxo-5-(piperazin-l-yl)-l,3-dihydro-277-isoindol-2-yl]- piperidine-2, 6-dione hydrochloride salt (1.05 g, 2.88 mmol) in DMSO (20 mL) at RT. The mixture was sonicated until a hazy solution was obtained and was then stirred at RT for 0.5h. KI (1.30 g, 7.86 mmol) then a solution of tert-butyl 4-(4-(4-bromobutoxy)phenyl)piperidine-l -carboxylate (1.08 g, 2.62 mmol) in DMSO (7 mL) were then added and the mixture was stirred at 70°C for 18h. After cooling the mixture was diluted with EtOAc (200 mL), washed with water (3 * 100 mL) then brine (2 x 100 mL), dried (MgSOy) and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (1.08 g, 63%) as a pale yellow gum; ‘H NMR: 1.48 (9H, s), 1.53-1.89 (9H, m), 2.14-2.25 (1H, m), 2.32 (lH, 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-(l-Oxo-5-(4-(4-(4-(piperidin-4-yl)phenoxy)butyl)piperazin-l-yl)isoindolin-2-
Figure imgf000092_0001
4M HC1 in dioxane (2 mL, 8.00 mmol) was added in one portion to tert-butyl 4-(4-(4-(4-(2-(2,6- dioxopiperidin-3 -y 1)- 1 -oxoisoindolin- 5-y l)piperazin- 1 -y l)butoxy)phenyl)piperidine- 1 -carboxylate ( 1.07 g, 1.62 mmol) in DCM (5 mL) at RT under air and the mixture was stirred for 2h. The mixture was then concentrated, slurried in Et2O (30 mL) and filtered to give the title compound as a hydrochloride salt as a beige solid that was used in the next step without further purification; m/z\ ES+ [M+H]+ 560.3.
Example 16: 2-Chloro-4-f4-[4-(4-f4-[2-(2,6-dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1- piperazin-l-yl!butoxy)phenyl|piperidin-l-yl!benzonitrile
Figure imgf000092_0002
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 K2CO3 (58.0 mg, 0.42 mmol) was suspended in DMSO (1 mL) and stirred at 90°C for 1 ,5h. Purification by preparative HPLC (Column A, Eluent A) gave the title compound (65 mg, 56%) as a white solid; *H NMR: 1.55-1.65 (4H, m), 1.68-1.77 (2H, m), 1.81 (2H, d), 1.89-2.02 (1H, m), 2.34-2.43 (3H, m), 2.52-2.64 (1H, m), 2.7-2.94 (2H, m), 2.99 (2H, t), 3.21-3.4 (8H, m), 3.97 (2H, t), 4.09 (2H, d), 4.21 (1H, d), 4.33 (1H, d), 5.04 (1H, dd), 6.85 (2H, d), 7.00 (1H, dd), 7.05 (2H, d), 7.11-7.18 (3H, m), 7.51 (1H, d), 7.62 (1H, d), 10.91 (1H, s); Wz: ES+ [M+H]+ 695.5.
Example 17: 4-!4-[4-(4-!4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-yl|piperazin-l-
Figure imgf000092_0003
yllbutoxy)phenyl1piperidin-l-yll-2-methoxybenzonitrile
Figure imgf000092_0004
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 K2CO3 (58.0 mg, 0.42 mmol) was suspended in DMSO (1 mL) and stirred at 90°C for 2.5h. After cooling to RT, purification by preparative HPLC (Column A, Eluent A) gave the title compound (40 mg, 35%) as a white solid; ‘HNMR: 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), 3.11-3.49 (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. dihydro-lZT-isoindol-5-yllpiperazin-l-
Figure imgf000093_0003
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-fhioro-2-methylnicotinonitrile (16.3 mg, 0.12 mmol) and K2CO3 (39.4 mg, 0.29 mmol) was suspended in DMSO (1.5 mL) and then stirred at 120°C for Ih in a microwave. Purification by preparative HPLC (Column A, Eluent A) gave the title compound (0.018 g, 23%) as a beige solid; ‘H NMR: (CDCI3) 1.62-1.77 (4H, m), 1.79-1.88 (2H, m), 1.93 (2H, d), 2.20 (IH, ddq), 2.32 (IH, 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 (IH, d), 4.41 (IH, d), 4.60 (2H, d), 5.19 (IH, dd), 6.47 (IH, d), 6.81-6.9 (3H, m), 6.99 (IH, dd), 7.07-7.16 (2H, m), 7.54 (IH, d), 7.73 (IH, d), 7.91 (IH, s); m/z\ ES+ [M+H]+ = 676.6.
Intermediate 19a: 8-Fluoroquinoline-5-carbonitrile
Figure imgf000093_0001
KO Ac (0.104 g, 1.062 mmol) and potassium hexacyanoferrate(II) trihydrate (1.869 g, 4.42 mmol) were added to 5-bromo-8-fluoroquinoline (2.00 g, 8.85 mmol) in 1,4-dioxane (30 mL) and water (30 mL). The mixture was degassed under N2 for 5 min at RT followed by the addition of XPhos (0.422 g, 0.885 mmol) and Xphos Pd G3 (0.374 g, 0.442 mmol). The mixture was then stirred at 100°C for 3h and then cooled to RT. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic solutions were washed with sat. brine (100 mL), dried (T^SCh) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (0.4 g, 26%) as off white solid; ‘H NMR: 7.82 (IH, dd), 7.91 (IH, dd), 8.35 (IH, dd), 8.56 (IH, dt), 9.15 (IH, dd); m/z\ ES+ [M+H]+ = 173.0.
Intermediate 19b: 8-(4-(4-Hydroxyphenyl)piperidin-l-yl)quinoline-5-carbo nitrile
Figure imgf000093_0002
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 RT. The mixture was stirred at 50°C for 6h, then cooled to RT and concentrated. The mixture was slowly poured into ice- water. A solid was collected by filtration, washed with water (20 mL) and dried under vacuum to give the title compound (0.700 g, 89%) as yellow solid; ‘HNMR: 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- [M-H]’ = 328.0.
Intermediate 19c: 8-(4-(4-(4-Bromobutoxy)phenyl)piperidin-l-yl)quinoline-5-carbonitrile
Figure imgf000094_0001
1 ,4-Dibromobutane (0.262 g, 1.214 mmol) and K2CO3 (0.252 g, 1.821 mmol) were added to 8-(4-(4-hydroxy- phenyl)piperidin-l-yl)quinoline-5-carbonitrile (0.200 g, 0.607 mmol) in MeCN (5 mL) atRT. The mixture was then stirred at 60°C for 6h. Water (40 mL) was then added and the mixture was extracted with EtOAc (2 x 70 mL). The combined organic solutions were washed with sat. brine (50 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (0.200 g, 68%) as yellow solid; ‘HNMR: 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), 7.74 (1H, dd), 8.05 (1H, d), 8.40 (1H, dd), 8.98 (1H, dd).
Example 19: 8-f4-[4-(4-f4-[2-(2.6-Dioxopiperidin-3-yl)-l-oxo-2.3-dihvdro-l/T-isoindol-5-yl1piperazin-l- yllbutoxy)phenyl1piperidin-l-yllquinoline-5-carbonitrile
Figure imgf000094_0002
KI (0.205 g, 1.233 mmol) and DIPEA (0.359 mL, 2.056 mmol) were added to a mixture of 3-[l-oxo-5- (piperazin-l-yl)-l,3-dihydro-2/f-isoindol-2-yl]piperidine-2, 6-dione hydrochloride salt (0.150 g, 0.411 mmol) and 8-(4-(4-(4-bromobutoxy)phenyl)piperidin-l-yl)quinoline-5-carbonitrile (0.115 g, 0.247 mmol) in DMSO (5 mL) at RT. The mixture was then stirred at 80°C for 16h, then cooled to RT and concentrated. The residue was slowly poured into ice-water. Solids were collected by filtration, washed with water (10 mL) and dried under vacuum. Preparative HPLC (Column C, Eluent C, Basic Work-Up A) gave the title compound (0.090 g, 30%) as off white solid; ‘H NMR: 1.57-1.67 (2H, m), 1.70-1.80 (2H, m), 1.84-2.00 (5H, m), 2.27-2.43 (3H, m), 2.51-2.64 (5H, m)2.69-2.82 (1H, m), 2.84-2.97 (1H, m), 3.00-3.11 (2H, m), 3.24-3.31 (4H, m), 3.99 (2H, t), 4.17-4.25 (1H, m), 4.27-4.42 (3H, m), 5.05 (1H, dd), 6.89 (2H, d), 7.01-7.10 (2H, m), 7.22 (3H, dd), 7.52 (1H, d), 7.71-7.77 (1H, m), 8.05 (1H, d), 8.40 (1H, dd), 8.97 (1H, dd), 10.94 (1H, s); m/z\ ES+ [M+H]+ = 712.4. Intermediate 20a: 2-(2,6-Dii
Figure imgf000095_0001
idin-3-yl)-5,6-difluoroisoindoline-l, 3-dione
Figure imgf000095_0002
Potassium acetate (5.04 g, 51.37 mmol) was added in one portion to 3-aminopiperidine-2, 6-dione hydrochloride salt (3 g, 18.23 mmol) and 4,5-difhiorophthalic acid (3.35 g, 16.57 mmol) inAcOH (30 mL) at RT. The resulting solution was stirred at 90°C for 18h. The mixture was then cooled to RT and a solid formed. Water (30 mL) was added. The solid was collected by filtration, washed with water (2 x5 mL) and dried at 45°C under vacuum overnight to give the title compound (3.43 g, 70%) as a dark grey/purple solid; *H NMR: 2.01-2.12 (1H, m), 2.53-2.7 (2H, m), 2.83-2.95 (1H, m), 5.17 (1H, dd), 8.15 (2H, t), 11.13 (1H, s); m/z\ ES- [M-H]- 293.
Intermediate 20b: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperazine-
Figure imgf000095_0003
DMSO (0.5 mL) and then DIPEA (118 Lil,. 0.68 mmol) were 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). This mixture was then heated at 100°C for 2h. Sat. NH4CI solution (0.5mL) and water (1.5 mL) were then added. A brown precipitate was collected by filtration, washed with water and dried in a vacuum oven to give the title compounds (86 mg, 55%) as dark brown/black solid; *H 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- [M-H]’ 459.
Intermediates 20c and 20d: 3-(5-Fluoro-l-oxo-6-(piperazin-l-yl)isoindolin-2-yl)piperidine-2,6-dione and
3-(6-Fluoro-l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2.6-dione
Figure imgf000095_0004
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-l,3-dioxoisoindolin-5-yl)piperazine-l-carboxylate (170 mg, 0.37 mmol) inAcOH (3.4 mL) at RT. The resulting suspension was stirred at 60°C for 48h. Further Zn powder (72.4 mg, 1.11 mmol) was added and the mixture was stirred at 60°C for 24h. 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 RT and triethylsilane (587 Lil ,. 3.68 mmol) was added in one portion. The resulting orange solution was stirred at RT for Ih. The mixture was then concentrated. Trituration with Et2O and collection of a solid by filtration gave the title compounds (in the form of trifluoroacetate salts) as a mixture of isomers (170 mg, 57%) as beige solids that were used in the next step without further purification; m/z\ ES+ [M+H]+ = 347.
Example 20: 4-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-3-oxo-2,3-dihvdro-l/f-isoindol-5-yl1- piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl) benzonitrile
Figure imgf000096_0001
Intermediate 2d was reacted with Intermediates 20c and 20d using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A). *H NMR: (500 MHz, CDClj) 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 (OH, 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), 6.81-6.88 (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-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-l-oxo-2,3-dihvdro-l/f-isoindol-5-yl1- in-l-vll-2-i
Figure imgf000096_0002
Intermediate 2d was reached with Intermediate 20c and 20d using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column A, Eluent A); *H NMR: (500 MHz, CDClj) 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 (OH, s), 6.82-6.88 (2H, m), 6.99 (1H, dd), 7.09-7.18 (4H, m), 7.48 (1H, d), 7.55 (OH, dd), 7.61 (1H, d), 7.98 (1H, s), 8.16 (2H, s); m/z ES+ [M+H]+ = 747.4.
Example 22: 4-f4-[5-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/f-isoindol-5-yl1piperazin-l- yllbutoxy)pyrimidin-2-yl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000096_0003
Intermediate 8e was reacted with Intermediate 2c using the general synthetic method illustrated by Example 8 to give the title compound after purification by HPLC (Column: Zorbax Eclipse Plus C18 50 x 2.1mm, 1.8 pm, Eluent C, Basic Work-Up A); ‘H 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 (IH, m), 3.05-3.2 (3H, m), 3.23-3.3 (4H, m), 4.05-4.26 (5H, m), 4.33 (IH, d), 5.05 (IH, dd), 6.99-7.12 (2H, m), 7.27 (IH, d), 7.32 (IH, s), 7.52 (IH, d), 7.82 (IH, d), 8.49 (2H, s), 10.95 (IH, s); m/z ES+ [M+H]+ = 731.2.
Example 23: 4-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-vD-6-fhioro-l,3-dioxo-2,3-dihvdro-l/Z-isoindol-5-yl1- piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl) benzonitrile
Figure imgf000097_0001
Intermediate Ih was reacted with Intermediate 20b using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H NMR: (CDClj) 1.65-1.87 (6H, m), 1.92-2 (2H, m), 2.07-2.2 (1H, m), 2.41-2.53 (2H, m), 2.56-2.67 (4H, m), 2.67-2.96 (4H, m), 3.06 (2H, td), 3.22-3.35 (4H, m), 3.92-4.1 (4H, m), 4.93 (1H, dd), 6.78-6.92 (2H, m), 6.99 (1H, dd), 7.07-7.21 (3H, m), 7.37 (1H, d), 7.47 (1H, d), 7.61 (1H, d), 7.97 (1H, s); m/z ES+ [M+H]+ = 761.5.
Intermediate 24a: tert-Butyl 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihvdropyridine-l(2//)- carboxylate
Figure imgf000097_0002
Lithium bid(trimethylsilyl)amide (60.7 mL, 60.71 mmol) was added slowly to tert-butyl 3,3-dimethyl-4- oxopiperidine-1 -carboxylate (9.2 g, 40.47 mmol) in THF (80 mL) at -78°C over 20 min under N2. The resulting mixture was stirred at -78°C for 0.5h. A-(5-Chloropyridin-2-yl)-l ,1 , l-trifluoro-A-((trifluoromethyl)- sulfonyl)methanesulfonamide (23.84 g, 60.71 mmol) was then added and the resulting mixture was stirred at RT for 16h. The reaction was then quenched with sat. NH4CI solution. The mixture was diluted with EtOAc, washed with water then sat. brine, dried (Na2SC>4) and concentrated Purification by FSC (gradient: 0-5% EtOAc in petroleum ether) gave the title compound (11.00 g, 76 %) as a yellow liquid; *H NMR (300 MHz) 5.82 (s, IH), 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-dihvdropyridine-
Figure imgf000097_0003
carboxylate
Figure imgf000098_0001
Pd(dppf)2C12-DCM (0.818 g, 1.00 mmol) was added to tert-butyl 3,3-dimethyl-4-(((trifhioromethyl)sulfonyl)- oxy)-3,6-dihydropyridine-l(2H)-carboxylate (3.600 g, 10.02 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetra- methyl-l,3,2-dioxaborolane (4.66 g, 15.03 mmol) and K2CO3 (4.15 g, 30.05 mmol) in 1,4-dioxane (40 mL) and water (10 mL) at RT under N2. The resulting mixture was stirred at 100°C for 3h. The mixture was then diluted with EtOAc, washed with water then sat. brine, dried QS^SCL) and concentrated. Purification by CIS- flash chromatography (gradient: 5- 90% MeCN in water (0.1 % NH4HCO3)) gave the title compound (1.980 g, 50%) as a pale yellow solid; >H NMR: 7.47-7.43 (m, 2H), 7.42-7.37 (m, 2H), 7.36-7.30 (m, IH), 7.12-7.05 (m, 2H), 6.99-6.93 (m, 2H), 5.40 (s, IH), 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-hvdroxyphenyl)-3.3-dimethyl-piperidine-l-carboxylate
Figure imgf000098_0002
A mixture of tert-butyl 4-(4-(benzyloxy)phenyl)-3,3-dimethyl-3,6-dihydropyridine-l(2//)-carboxylate (1.00 g, 2.54 mmol) and Pd-on-C (0.27 g, 0.25 mmol) in MeOH (10 mL) was stirred under an atmosphere of H2 at 20 atm and 80°C for Ih. Concentration of the mixture then gave the title compound (0.844 g, 109 %) which was used in the next step without further purification; *H NMR (300 MHz) 0.68 (s, 6H), 1.41 (s, 9H), 1.80-2.10 (m, IH), 2.33-2.43 (m, IH), 2.73 - 2.75 (m, IH), 3.32 (s, 2H), 3.66-3.69 (m, IH), 4.10-4.12 (m, IH), 6.67 (d, 2H), 6.93 (d, 2H), 9.21 (s, IH); m/z ES+ [M-tBu]+ = 250.
Intermediates 24d: 4-(3,3-Dimethylpiperidin-4-yl)phenol
Figure imgf000098_0003
4M HC1 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 RT and the mixture was stirred for 16h. Concentration of the mixture then gave the title compound as a hydrochloride salt (0.750 g, 116 %) which was used in the next step without further purification; *H 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: (.S,)-4-(4-(4-Hvdroxyphenyl)-3,3-dimethylpiperidin-l-yl)-2-
Figure imgf000099_0001
(trifluoromethvDbenzonitrile (isomer 1) and )-4-(4-(4-Hvdroxyphenyl)-3,3-dimethylpiperidin-l-
Figure imgf000099_0002
yl)-2-(trifluoromethyl)benzonitrile (isomer 2)
Figure imgf000099_0003
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 Lil,. 10.67 mmol) in DMSO (10 mL) at RT. The resulting mixture was stirred at 60°C for 16h. The mixture was then diluted with EtOAc, washed with water then sat. brine, dried (TS^SCL) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave material that was further purified by preparative chiral-HPLC (Column: CHIRALPAK AD-3, 3.0mm*100mm, 3Lim: Mobile Phase A, Mobile Phase B:MeOH(0.1% diethylamine); Flow rate:2 mL/min; Gradient:10% B; 220 nm) to give the title compounds as pale yellow solids: Intermediate 24e (0.320 g, 24 %); Intermediate 24f (0.289 g, 22%). Intermediate 24e (eluting first): ‘HNMR: 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 ES+ [M+H]+ = 375. Intermediate 24f: >H NMR: 0.69 (3H, s), 0.78 (3H, s), 1.53 (1H, d), 2.12 (1H, m), 2.55 (1H, d), 2.82 (1H, d), 2.91-3.03 (1H, m), 3.85-3.93 (1H, m), 4.14-4.25 (1H, m), 6.56-6.78 (2H, m), 6.81-7.06 (2H, m), 7.16-7.35 (2H, m), 7.77 (1H, d), 9.21 (1H, s); m/z ES+ [M+H]+ = 375. 3-dimethylpiperidin-l-yl)-2-
Figure imgf000099_0004
rel-(S)-4-(4-(4-Hy droxyphenyl)- 3 ,3 -dimethylpiperidin- 1 -yl)-2-(trifluoromethy l)benzonitrile (Intermediate 24e, Isomer 1, 100 mg, 0.27 mmol), K2CO3 (44.3 mg, 0.32 mmol) and 1 ,4-dibromobutane (80 Lil,. 0.67 mmol) were dissolved in anhydrous MeCN (2.59 mL) under N2. The mixture was stirred at 60°C for 5h then at 40°C for 2 days. The mixture was then cooled to RT, filtered and washed through with DCM (20 mL). The filtrate was then concentrated to give the title compound as a colourless oil which was used in the next step without further purification.
Example 24: /•<?/-(.S,)-4-!4-[4-(4-!4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l //-isoindo 1-5- yl1piperazin-l-yllbutoxy)phenyl1-3,3-dimethylpiperidin-l-yll-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet confirmed)
Figure imgf000100_0001
Intermediate 2c was reacted with Intermediate 24g using the general synthetic method illustrated by Example 5 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). *H NMR: (CDCI3) 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), 3.46 (4H, q), 3.63 (1H, dd), 3.93-4.14 (3H, m), 4.26 (1H, d), 4.42 (1H, d), 5.19 (1H, dd),
6.8-6.86 (2H, m), 6.89 (1H, d), 6.98 (2H, ddd), 7.02-7.08 (2H, m), 7.12 (1H, d), 7.58 (1H, d), 7.75 (1H, d), 8.07 (1H, s), 8.23 (1H, s); m/z ES+ [M+H]+ = 757.4.
Intermediate 25a: reZ-(R)-4-(4-(4-(4-Bromobutoxy)phenyl)-3,3-dimethylpiperidin-l-yl)-2-(trifluoro-
Figure imgf000100_0002
rel-( R)-4-(4-( 4-1 lydroxyphenyl )-3,3-dimethylpiperidin- 1 -yl )-2-( trilliioromethvl )benzonitrile (intermediate 24f, isomer 2, 250 mg, 0.67 mmol), K2CO3 (346 mg, 0.80 mmol) and 1 ,4-dibromobutane (0.199 mL, 1.67 mmol) were dissolved in anhydrous MeCN (4 mL) under N2. The mixture was stirred at 70°C for 2h then cooled to RT. The mixture was filtered and washed through with DCM (20 mL). The filtrate was concentrated to give the title compound as a colourless oil that was use in the next step without further purification.
Example 25: reZ-tf?)-4-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5- yl1piperazin-l-yllbutoxy)phenyl1-3,3-dimethylpiperidin-l-yll-2-(trifluoromethyl)benzonitrile (absolute stereochemistry not yet confirmed)
Figure imgf000100_0003
Intermediate 2c was reacted with Intermediate 25a using the general synthetic method illustrated by Example 5 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A); *H NMR: (CDCI3) 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-dihvdrobenzo[</loxazol-6-yl)piperazine-l-carboxylate
Figure imgf000101_0001
6-Bromobenzo| J|oxazol-2( 3/7)-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 stir bar. The vial was sealed by a rubber septum and then degassed by N2. THF (3 mL), lithium bis(trimethylsilyl)amide (3.30 mL, 3.30 mmol) and tert-butyl piperazine- 1-carboxylate (0.335 g, 1.80 mmol) were then added. The reaction was degassed by N2 again. The resulting solution was stirred at 70°C for 16h. AcOH was then added and the mixture was concentrated. Purification by FSC (gradient: 0-80% EtOAc in hexanes) gave the title compound (0.250 g, 52 %) as a grey solid; ‘HNMR (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-) [M-H]' = 318.2.
Intermediate 26b: tert-Butyl-4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihvdrobenzo[</loxazol-6- vf)piperazine-l-carboxylate
Figure imgf000101_0002
tert-Butyl 4-( 2-oxo-2.3-dihvdrobenzo| J|oxazol-6-vl )piperazine- 1 -carboxylate (0.048 g, 0.15 mmol), 3- bromopiperidine-2, 6-dione (1.1 eq) and CS2CO3 (0.147 g, 0.45 mmol) were added to an oven-dried microwave vial with stir bar. The vial was then purged with N2. DMF (1 mL) was then added. The resulting slurry was stirred at 90°C for 16h and then concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.027 g, 41.8 %) as a white solid; >H NMR (500 MHz, CDCI3) 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), 3.55-3.81 (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); Wz ES+ [M+H]+ = 431.
Intermediate 26c: 3-(2-Oxo-6-(piperazin-l-yl)benzo[d1oxazol-3(2/D-yl)piperidine-2,6-dione
Figure imgf000102_0001
4M HC1 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[<7]oxazol-6-yl)piperazine-l-carboxylate (0.20 g, 0.46 mmol) in 1,4-dioxane (2.3 mL) at RT and the mixture was stirred at 40°C for 3h. Concentration of this mixture then gave the title compound as a hydrochloride salt (0.170 g, 100 %) as an off-white solid which was used without further purification; *H 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); Wz ES+ [M+H]+ = 331.
Example 26: 4- (4-[4-(4-f4-[3-(2,6-Dioxopiperidin-3-yl )-2-oxo-2,3-dihvdro-l,3-benzoxazol-6-yl 1 piperazinl-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000102_0002
Intermediate 2d was reacted with Intermediate 26c using the general synthetic method illustrated by Example 2 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). *H NMR: 1.56-1.69 (4H, m), 1.74 (2H, p), 1.85 (2H, d), 2.13 (1H, dt), 2.38 (2H, t), 2.53 (4H, d), 2.59-2.71 (2H, m), 2.71-2.83 (1H, m), 2.83-2.94 (1H, m), 2.99-3.06 (2H, m), 3.09 (4H, d), 3.31 (1H, s), 3.97 (2H, t), 4.17 (2H, d), 5.29 (1H, dd), 6.77 (1H, dd), 6.82-6.89 (2H, m), 7.03-7.12 (2H, m), 7.16 (2H, d), 7.27 (1H, dd), 7.32 (1H, d), 7.81 (1H, d), 8.18 (1H, s), 11.15 (1H, s); m/z ES+ [M+H]+ = 731.6. intermediate 27a: tert-butyl 4-((l-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-l-carboxylate
Figure imgf000102_0003
NaBH(C)Ac h (6.80 g, 32.08 mmol) was added in one portion to 1-Boc-piperazine (4.00 g, 21.48 mmol), 4- formyl-A-Cbz-piperidine (6.40 g, 25.88 mmol) and AcOH (1.50 mL, 26.23 mmol) in DCM (50 mL) at RT under air and the mixture was stirred at RT for 2h. The mixture was then diluted with sat. NaHCOa solution (60 mL) and the phases were separated. The aqueous layer was extracted with DCM (3 x 40 mL). The combined organic solutions were dried (MgSCL) and concentrated. Purification by FSC (gradient: 50-70% EtOAc in heptane) gave the title compound (8.83 g, 98 %) as a colourless oil; *H NMR: 0.91-1.05 (2H, m), 1.40 (9H, s), 1.6-1.77 (3H, m), 2.12 (2H, d), 2.22-2.32 (4H, m), 2.79 (2H, s), 3.26-3.33 (4H, m), 3.99 (2H, d), 5.07 (2H, s), 7.28-7.44 (5H, m); m/z\ ES+ [M+H]+ 418.3.
Intermediate 27b: tert-Butyl 4-tpiperidin-4-ylmethyl)piperazine-l-carboxylate
Figure imgf000103_0001
A mixture of tert-butyl 4-((l-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-l -carboxy late (9.50 g, 22.75 mmol) and 10% Pd(OH)2 on activated charcoal (3.20 g, 2.28 mmol) in EtOH (40 mL) was stirred under an atmosphere of H2 at 1 atm and RT for 18h. The mixture was then filtered through celite washing through with EtOH. The filtrate was concentrated. The residue was dissolved in EtOH (40 mL) and 10% Pd(OH)2 on activated charcoal (3.20 g, 2.28 mmol) was added. The suspension was stirred under H2 at 1 atm and RT for 3 days. The mixture was then filtered through celite and washed through with EtOH (100 mL). The filtrate was concentrated to dryness to give crude product (5.61 g, 87 %) as a grey solid. A portion of the crude product (2.32 g) was purified by ion exchange chromatography (SCX column, eluting with IM NI L/MeOH ) to give the title compound (1.84 g, 79 %) as a grey oil; >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-((l-(4-(l-(4-cvano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)- piperidin-4-vDmethvDpiperazine-l-carboxylate
Figure imgf000103_0002
A mixture of 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (350 mg, 0.86 mmol), tertbutyl 4-(piperidin-4-ylmethyl)piperazine-l -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 filled with N2, and the mixture stirred at 100°C for Ih. 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 solutions were dried (tSfeSOy) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.360 g, 69 %) as a pale yellow solid; *H NMR: 1.20 (2H, tt), 1.40 (9H, s), 1.53-1.67 (3H, m), 1.77 (2H, d), 1.84 (2H, d), 2.16 (2H, d), 2.26-2.31 (4H, m), 2.54-2.64 (2H, m), 2.68-2.77 (IH, 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 (IH, dd), 7.32 (IH, d), 7.81 (IH, d); m/z ES+ [M+H]+ = 611.9.
Intermediate 27d: Benzyl 4-(dibutoxymethyl)piperidine-l-carboxylate
Figure imgf000104_0001
4-Methylbenzenesulfonic acid hydrate (0.100 g, 0.53 mmol) was added to 4-formyl-A-Cbz-piperidine (20.0 g, 80.88 mmol) in w-butanol (40 mL) at RT under air. The resulting solution was stirred at 50°C for Ih. (Reaction incomplete). MgSCL (10.6 g, 88.07 mmol) was added and the suspension was stirred at 50°C for a further Ih. The reaction was incomplete so the temperature was increased to 70°C and the mixture was stirred for a further 1 day. The mixture was then filtered, washing through with EtOAc (200 mL), where the filtrate was collected in a vessel containing 2M aq. K2CO3 (40 mL). The phases were separated. The organic solution was washed (2M aq. K2CO3 (2 x 40 mL) then sat. brine (2 x 20 mL)), dried (MgSCL) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (20.5 g, 67 %) as a colourless liquid; ‘HNMR: 0.88 (6H, t), 1.11 (2H, qd), 1.27-1.4 (4H, m), 1.47 (4H, dq), 1.65 (2H, d), 1.73 (IH, dtt), 2.75 (2H, s), 3.37 (2H, dt), 3.54 (2H, dt), 3.95-4.06 (2H, m), 4.16 (IH, d), 5.07 (2H, s), 7.25-7.44 (5H, m).
Intermediate 27e: 4-(Dibutoxymethyl)piperidine
Figure imgf000104_0002
A mixture of benzyl 4-(dibutoxymethyl)piperidine-l -carboxylate (20.5 g, 54.30 mmol) and 10% Pd(OH)2 on activated charcoal (3.8 g, 2.71 mmol) in EtOH (120 mL) was stirred under EE (1 atm) at RT for 3 days. The mixture was then filtered through celite and washed though with EtOEI (200 mL). The filtrate was concentrated to dryness to give the title compound (13.10 g, 99 %) as a colourless oil; *H 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 (lH, 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-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000104_0003
Pd-PEPPSI-IHeptCl (0.23 g, 0.24 mmol) was added to a degassed mixture of 3-(5-bromo-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (1.5 g, 4.64 mmol), 4-(dibutoxymethyl)piperidine (1.5 g, 6.16 mmol) and CS2CO3 (4.54 g, 13.93 mmol) in 1,4-dioxane (45 mL) at RT under N2. The resulting mixture was vacuum degassed, backfilling with N2 and then stirred at 100°C for 3h. After cooling, the mixture was diluted with DCM (75 mL) and 10% aq. AcOH (50 mL) and the phases were separated. The aqueous portion was extracted with DCM (75 mL). The combined organic layers were washed with sat. Nal ICO3 (50 mL), dried (MgSCL) 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. Trituration with EtOAc (15 mL) gave a solid which was collected by filtration, washed sequentially with EtOAc (2 x 5 mL), EtOAc:Et2O (1 :1; 5 mL), and Et2O (5 mL) then dried under vacuum to give the title compound (1.659 g, 74 %) as a white solid; ‘HNMR: 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-f4-[4-(4-f[4-(n-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-
Figure imgf000105_0001
yl1piperidin-4-yllmethyl)piperazin-l-yl1methyllpiperidin-l-yl)phenyl1piperidin-l-yll-2- (trifluoromethyl)benzonitrile
Figure imgf000105_0002
Intermediate 27c was reacted with Intermediate 27f using the general synthetic method illustrated by Example 1 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). *H NMR: 1.09-1.27 (4H, m), 1.53-1.69 (3H, m), 1.77 (5H, d), 1.84 (2H, d), 1.92-2.01 (1H, m), 2.15 (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.
Figure imgf000105_0003
difluoropentyl 4-methylbenzenesulfonate
Figure imgf000105_0004
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-l-yl)-2-(trifluoromethyl)benzonitrile (190 mg, 0.41 mmol) and IAN (113 pL, 0.81 mmol) in DCM (2 mL) at RT and the solution was stirred for 2h. The reaction was incomplete and further 4-methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) and IAN (113 pl, 0.81 mmol) were added in one portion and the solution was stirred at RT for a further 18h. The reaction was incomplete and further 4- methylbenzenesulfonyl chloride (131 mg, 0.69 mmol) and IAN (113 Lil,. 0.81 mmol) were added in one portion and the solution was stirred at RT for a further 3h. The mixture was then diluted with DCM (25 mL), washed (sat. NH4CI (10 mL), sat. Nal ICO;, (10 mL), water (20 mL) then sat. brine (10 mL)), dried with a phase separating cartridge and concentrated. Purification by FSC (gradient: 0-60% EtOAc in heptane) gave the title compound (0.147 g, 58%) as a yellow gum; m/z: ES+ [M+H]+ 623.3 -
Figure imgf000106_0002
4-Bromo-l-fluoro-2-nitrobenzene (11.69 mL, 93.91 mmol) was added to a stirred milky suspension of di- tertbutyl L-glutamate hydrochloride salt (50.00 g, 169.03 mmol) and EtaN (52.4 mL, 375.62 mmol) in THF (500 mL) at RT. The mixture was then stirred at 70°C for 72h. Water (500 mL) was then added and this mixture was extracted with EtOAc (2 x 500 mL). The combined organic solutions were then washed with brine (500 mL), passed through phase separating cartridge and concentrated. Purification by FSC (gradient: 0-20% EtOAc in heptane) gave the title compound (49.50 g, 115 %) as a yellow gum; *H NMR (CDCL) 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: di-tert-Butyl (2-amino-4-bromophenyl)-L-glutamate
Figure imgf000106_0001
Iron powder (26.20 g, 469.15 mmol) was added in one portion to di- tert-butyl (4-bromo-2-nitrophenyl)-L- glutamate (43.10 g, 93.83 mmol) and NH4CI (25.09 g, 469.15 mmol) in IPA (400 mL) and water (80 mL) at RT. The resulting mixture was stirred at 80 °C for 16h. After cooling the mixture was filtered through celite and washed through with EtOAc (500 mL). The dark red filtrate was washed with water (250 mL), sat. 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; >H NMR (CDC13) 1.44 (9H, s), 1.44 (9H, s), 1.89-2.17 (2H, m), 2.27-2.53 (2H, m), 3.53 (2H, s), 3.68-3.97 (2H, m), 6.48 (1H, d), 6.71-6.95 (2H, m); m/z\ ES+ [M+H]+ 429.
Intermediate 29c: di-tert-Butyl (S)-2-(5-bromo-2-oxo-2,3-dihvdro-lH-benzo[d1imidazol-l-
Figure imgf000107_0001
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 RT. The resulting dark red solution was stirred at 60°C for 2h. The mixture was cooled to RT and concentrated. The residue was dissolved in EtOAc (500 mL). This solution was washed with water (500 mL) and brine (200 mL), dried (MgSCL) and concentrated to give the title compound (41.0 g, 107 %) as a beige solid; 'H NMR ^DClj) 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)
Figure imgf000107_0002
di-tert-Butyl (.S')-2-(5-bromo-2-oxo-2.3-dihvdro- l /7-benzo| J|imidazol- 1 -yl)pentanedioate (38.0 g, 83.45 mmol) was dissolved in DMFDMA(333 mL) and the solution was stirred at 100°C for 16h then concentrated. Purification by FSC (gradient: 0-25% EtOAc in heptane) gave the title compound (35.0 g, 89 %) as a pale yellow gum that solidified on standing; >H NMR (CDC13) 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-dihvdro-lH-benzo[d1imidazol-l-yl)pentanedioic
Figure imgf000107_0003
TFA (200 mL) was added to a stirred solution of di-tert-butyl (>S)-2-(5-bromo-3-methyl-2-oxo-2,3-dihydro-l/f- benzo| J|imidazol- 1 -vljpentanedioate (35.0 g, 74.57 mmol) in DCM (200 mL) at 0°C. This mixture was stirred for 15 mins then warned to RT and stirred for a further 3h. The mixture was then concentrated and the residue was azeotroped twice with toluene to give a yellow solid. This was then triturated in 3:1 heptaneMTBE overnight. A solid was collected by filtration and dried to give the title compound (25.2 g, 95 %) as a pale yellow solid; >H NMR: 2-2.44 (4H, m), 3.33 (3H, s), 5.04 (IH, dd), 7.05 (IH, d), 7.21 (IH, dd), 7.44 (IH, d), 12.16 (IH, s), 13.07 (IH, s);
Intermediate 29f: 3-(5-Bromo-3-methyl-2-oxo-2,3-dihvdro-l //-benzo|</|imidazol-l-yl)piperidine-2,6- dione
Figure imgf000108_0001
(N)-2-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-l/f-benzo[<7|imidazol-l-yl)pentanedioic acid (1.0 g, 2.48 mmol) was dissolved in DCM (30 mL). DIPEA (2.163 mL, 12.42 mmol) and l-(bis(dimethylamino)methylene)-l/7- [1.2.3 |triazolo|4.5-A |pvridine- 1 -ium 3-oxide hexafluorophosphate(V) (1.889 g, 4.97 mmol) was then added and the mixture was stirred for 10 mins at RT. 2,2,2-Trifluoroacetamide (0.281 g, 2.48 mmol) was then added and the mixture stirred for Ih. The mixture was then poured into 5% AcOH in water (200 mL). This mixture was extracted with DCM (2 x 150 mL) and the combined organic solutions were washed with sat. Nal ICO;, solution (200 mL) then passed through a phase separating cartridge and concentrated in vacuo to almost dryness (~75 mL). Purification by FSC (gradient: 0-80% EtOAc in heptane) gave crude product. The crude solid (0.8 g) was suspended in 1 :1 MTBE:heptane (10 mL) and triturated overnight. The resulting solid was collected by filtration and dried to give the title compound (0.70 g, 83 %) as a white solid; *H NMR (CDCI3) 2.11-2.33 (IH, m), 2.6-3.03 (3H, m), 3.42 (3H, s), 5.18 (IH, dd), 6.68 (IH, d), 7.1-7.24 (2H, m), 8.05 (IH, s); m/z: ES+ [M+H]+ 338. Material has racemized in this step.
Intermediate 29g: tert-Butyl-4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihvdro-l/7-
Figure imgf000108_0002
(DiMeIHeptcl)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-l/f-benzo[<7]imidazol-l-yl)piperidine-2,6- dione (0.100 g, 0.30 mmol), CS2CO3 (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 RT under N2. The resulting suspension was stirred at 100°C for 6h. The mixture was then diluted with DCM (25 mL), washed (5% AcOH in water (20 mL), water (20 mL), sat. NaHCOa solution (20 mL) then sat. brine (20 mL)), dried (MgSCL) and concentrated. Trituration with EtOAc gave a solid which was collected by filtration, washed with Et3O and dried under vacuum to give the title compound (0.107 g, 82 %) as a cream solid; ‘H NMR: 1.43 (9H, s), 1.91-1.99 (IH, m), 2.54-2.65 (2H, m), 2.74-2.88 (IH, m), 3-3.07 (4H, m), 3.31 (3H, s), 3.45-3.51 (4H, m), 5.11-5.26 (IH, m), 6.65 (IH, dd), 6.87 (IH, d), 6.92 (IH, d); m/z: ES+ [M+H]+ 444.2.
Example 29: 4-i4-[4-(4-i4-[l-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihvdro- henzimidazol-5-
Figure imgf000109_0001
yl1piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000109_0002
Intermediate Ih was reacted with Intermediate 29g using the general synthetic method illustrated by Example 1 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A); *H NMR: 1.56-1.68 (4H, m), 1.69-1.79 (2H, m), 1.85 (2H, d), 1.94-2.04 (IH, m), 2.39 (2H, t), 2.52-2.54 (4H, m), 2.58- 2.65 (IH, m), 2.67-2.71 (IH, m), 2.72-2.82 (IH, m), 2.85-2.96 (IH, m), 3.00-3.12 (6H, m), 3.31 (5H, br), 3.97 (2H, t), 4.17 (2H, d), 5.29 (IH, dd), 6.62 (IH, dd), 6.81-6.91 (3H, m), 6.94 (IH, d), 7.16 (2H, d), 7.27 (IH, dd), 7.32 (IH, d), 7.81 (IH, d), 8.17 (IH, s), 11.04 (IH, s); rn z HS [M+H]+ = 743.9.
Intermediate 30a: 4-(4-(4-((lr,3r)-3-(2-Bromoethyl)cvclobutoxy)phenyl)piperidin-l-yl)-2-
Figure imgf000109_0003
(trifluoro-methvDbenzonitrile
Figure imgf000109_0004
A solution of PPh3 (63.7 mg, 0.24 mmol) in THF (1 mL) was added dropwise to a stirred mixture of Irans-/- (4-(4-((ls,3r)-3-(2-hydroxyethyl)cyclobutoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 5c) (54.0 mg, 0.12 mmol) and CBr i (81.0 mg, 0.24 mmol) in THF (1.0 mL) at 0°C. The resulting mixture was stirred at RT for 1 week. The mixture was then filtered, washed through with EtOAc (20 mL) and the filtrate was concentrated. Purification by FSC (gradient: 0-30% EtOAc in heptane) gave the title compound (0.034 g, 55%) as a colourless oil; >H NMR (CDC13) 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), 3.36 (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: tr«M5-4-[4-(4-f[(ls,3r)-3-(2-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol- 5-' in-1-'
Figure imgf000110_0001
in-l-yll-2-i
Figure imgf000110_0002
Figure imgf000110_0003
Intermediate 2c was reacted with Intermediate 30a using the general synthetic method illustrated by Example 5 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). *H NMR: 1.56-1.69 (2H, m), 1.76 (2H, s), 1.85 (2H, d), 1.91-2.03 (1H, m), 2.16-2.20 (4H, m), 2.29 (1H, d), 2.36-2.44 (2H, m), 2.51-2.53 (4H, m), 2.60 (2H, d), 2.78 (1H, d), 2.86-2.96 (1H, m), 3.04 (2H, t), 4.20 (3H, dd), 4.34 (1H, d), 4.79 (1H, q), 5.05 (1H, dd), 6.75 (2H, d), 7.09 (2H, d), 7.15 (2H, d), 7.22-7.37 (2H, m), 7.54 (1H, d), 7.81 (1H, d), 10.92 (1H, s); 4H under solvent peak; m/z ES+ [M+H]+ = 755.4.
Intermediate 31a: tert-Butyl 4-(4-hvdroxybutyl)piperidine-l-carboxylate
Figure imgf000110_0004
Di-tert-butyl carbonate (8.86 mL, 38.15 mmol) was added to 4-(piperidin-4-yl)butan-l-ol (4.00 g, 25.44 mmol) in THF (50 mL) and sat. NaiCO;, solution (50 mL) at RT and the mixture was stirred for 16h. The mixture was then diluted with EtOAc (300 mL), washed with sat. brine (200 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-50% petroleum ether in EtOAc) gave the title compound (5.30 g, 81 %) as a white liquid; ‘H NMR: 0.86-1.00 (2H, m), 1 .13-1.22 (2H, m), 1.25-1.33 (2H, m), 1.35-1.40 (12H, m), 1.57-1.65 (2H, m), 2.65 (2H, s), 3.34-3.42 (2H, m), 3.91 (2H, d), 4.31 (1H, t); m z\ ES+ [M-tBu]+ = 202.
Intermediate 31b: tert-Butvl 4-(4-(4-(l-(4-i
Figure imgf000110_0005
lin-4-’
Figure imgf000110_0006
Figure imgf000110_0007
RockPhos Pd G3 (0.488 g, 0.58 mmol) was added to tert-butyl 4-(4-hydroxybutyl)piperidine-l -carboxylate (1.50 g, 5.83 mmol), 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (3.58 g, 8.74 mmol) and CS2CO3 (5.70 g, 17.48 mmol) in 1,4-dioxane (30 mL) at RT over 10 mins under Ni. The resulting mixture was stirred at 100°C for 16h. The mixture was then diluted with EtOAc (200 mL), washed with sat. brine (100 mL), dried (Na2SO4) and concentrated Purification by FSC (gradient: 0-15% EtOAc in petroleum ether) gave the title compound (1.50 g, 44 %) as a yellow liquid; >H NMR: 0.88-0.99 (2H, m), 1.22-1.28 (2H, m), 1.33- 1.45 (14H, m), 1.55-1.69 (6H, m), 1.79-1.88 (2H, m), 2.72-2.80 (1H, m), 2.98-3.08 (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-(PiDeridin-4-yl)butoxy)Dhenyl)Diperidin-l-yl)-2-
(trifluoromethvDbenzonitrile
Figure imgf000111_0001
tert-Butyl 4-(4-(4-(l-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)butyl)piperidine-l- carboxylate (500 mg, 0.85 mmol) was added to DCM (2 mL) and HC1 in dioxane (7 mL) at RT and the mixture was stirred for 16h. Concentration under reduced pressure then gave the title compound which was used in the next step without further purification; *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-f4-[4-(4-n-[2-(2.6-DioxoDiDeridin-3-yl)-l-oxo-2.3-dihvdro- isoindol-5-yllDiperidin-4-
Figure imgf000111_0002
yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000111_0003
Pd-PEPPSI-IPent (40.8 mg, 0.05 mmol) was added to 4-(4-(4-(4-(piperidin-4-yl)butoxy)phenyl)piperidin-l- yl)-2-(trifhioromethyl)benzonitrile (250 mg, 0.51 mmol), 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2,6- dione (166 mg, 0.51 mmol) and CS2CO3 (503 mg, 1.54 mmol) in 1,4-dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h. The mixture was then diluted with DCM, washed (5% AcOH (aq), water, then sat. brine), dried (Na2SO4) and concentrated. Purification by flash C18-flash chromatography (gradient: 5-85% MeCN in water (0.1 % NH4HCO3)) gave material that was further purified by preparative SFC (Column: Viridis BEH 2-Ethylpyridine Prep OBD, 30* 150mm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.5% 2M NH3-MeOH)-HPLC; Flow rate:50 mL/min; Gradient:28% B; 254 nm; RT1 :4.25; Injection Volumn: 1 mL; Number Of Runs:5) to give the title compound (7 mg, 2 %) as a white solid; 'H NMR: 1.13-1.33 (5H, m), 1.40-1.55 (3H, m), 1.55-1.77 (6H, m), 1.81-1.91 (2H, m), 1.92-2.04 (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-f[(lr,3s)-3-(2-f4-[2-(2,6-Dioxopiperidin-3-vD-l-oxo-2,3-dihvdro-l.H-isoindol-5-yl]-
Figure imgf000112_0001
Intermediate 2c was reacted with Intermediate 5d using the general synthetic method illustrated by Example 5 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A); *H NMR: 1.55-1.7 (6H, m), 1.85 (2H, d), 1.9-2.02 (2H, m), 2.25-2.31 (2H, m), 2.39 (2H, dd), 2.56-2.64 (3H, m), 2.75 (1H, d), 2.82-2.95 (1H, m), 3.04 (2H, t), 3.29 (8H, br), 4.11-4.27 (3H, m), 4.33 (1H, d), 4.51 (1H, p), 5.04 (1H, dd), 6.77 (2H, d), 7.06 (2H, d), 7.14 (2H, d), 7.27 (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)-l-oxoisoindolin-5-yl)-7-oxa-3.10-
Figure imgf000112_0002
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), CS2CO3 (1.66 g, 5.11 mmol) and 3-(5-bromo-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (0.550 g, 1.70 mmol) in 1,4-dioxane (12 mL) at RT under N2. The resulting suspension was stirred at 100°C for 20h. The mixture was then diluted with DCM (25 mL), washed (5% AcOH in water (10 mL), water (10 mL), and then sat. brine (10 mL)), dried (MgSCL) and concentrated. Purification by FSC (gradient 0-5% MeOH in DCM) gave the title compound (0.490 g, 56 %) as a yellow solid. *H NMR: 1.41 (9H, s), 1.49-1.6 (2H, m), 1.7-1.85 (4H, m), 1.91-2.02 (1H, m), 2.33-2.44 (1H, m), 2.55-2.64 (1H, m), 2.84- 2.96 (1H, m), 3.09-3.17 (2H, m), 3.38-3.47 (4H, m), 3.49-3.61 (2H, m), 3.62-3.69 (2H, m), 4.20 (1H, d), 4.32 (1H, d), 5.04 (1H, dd), 7-7.11 (2H, m), 7.50 (1H, d), 10.91 (1H, s); m/z ES+ [M+H]+ = 513.3.
Example 33: 4-f4-[4-(4-f3-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1-7-oxa-3,10- diazaspiro[5.61dodecan-10-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000112_0003
Intermediate Ih was reacted with Intermediate 33a using the general synthetic method illustrated by Example
1 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). *H NMR: 1.43-1.53 (2H, m), 1.53-1.67 (4H, m), 1.67-1.81 (6H, m), 1.85 (2H, d), 1.91-2 (1H, m), 2.35-2.4 (1H, m), 2.41-2.47 (2H, m), 2.54-2.63 (4H, m), 2.77 (1H, t), 2.85-2.95 (1H, m), 3.05 (2H, t), 3.16 (2H, t), 3.30 (2H, s), 3.54 (2H, d), 3.62 (2H, d), 3.95 (2H, t), 4.18 (3H, dd), 4.32 (1H, d), 5.04 (1H, dd), 6.85 (2H, d), 7.04 (2H, d), 7.15 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.50 (1H, d), 7.81 (1H, d), 8.16 (1H, s), 10.91 (1H, s); m/z ES+ [M+H]+ = 813.4.
Intermediate 34a: tert-Butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate
Figure imgf000113_0001
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 RT for 2h before being diluted with DCM (125 mL). This solution was washed with water (75 mL), citric acid solution (50 mL), brine (50 mL), then dried (MgSCL) and concentrated to give the title compound (4.69 g, 113 %) as a brown solid; *H NMR (CDCI3) 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
Figure imgf000113_0002
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 N2. The resulting mixture was stirred at 80°C for 3h. The mixture was then poured into water (100 mL). This mixture was then extracted with EtOAc (3 x 50 mL). The combined organic solutions were washed with brine (50 mL), dried (MgSCL) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (6.90 g, 67%) as a colourless liquid; ‘H NMR (CDCh) 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). i-l-oxoisoindolin-2-'
Figure imgf000113_0003
>2, 6-dione
Figure imgf000113_0004
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 RT under N2 and the mixture was stirred for 25h. The mixture was then diluted with water (50 mL). This mixture was then extracted with EtOAc (25 mL x 3) and the combined organic solutions were dried (MgSOy) and concentrated to give the title compound (2.00 g, 28 %); *H NMR (CDClj) 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-Hvdroxy-l-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000114_0001
A stirred solution of 3-(5-((tert-butyldimethylsilyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (1.50 g, 4.01 mmol) in 1,4-dioxane (10 mL) was treated with 4M HC1 (5.56 mL, 160.21 mmol) under N2. The resulting slurry was stirred at RT for 18h. The mixture was then concentrated under reduced. The residue was then dissolved with hot MeCN before being allowed to cool to RT, then to 0°C. A solid was collected by filtration and washed with cold MeCN and dried in a vacuum desiccator for 18h to give the title compound (1.16 g, 111 %) as a black solid; m/z (ES-) [M-H]' = 259.
Intermediate 34e: terZ-Butyl-4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)piperidine-l-
Figure imgf000114_0002
K2CO3 (0.320 g, 2.31 mmol) was added in one portion to a stirred solution of tert-butyl 4-((methylsulfonyl)- oxy)piperidine-l -carboxylate (0.644 g, 2.31 mmol) and 3-(5-hydroxy-l-oxoisoindolin-2-yl)piperidine-2,6- dione (0.500 g, 1.92 mmol) in DMF (10 mL) at RT under N2. The resulting solution was stirred for 18h at 100°C. The mixture was then diluted with water (50 mL). This mixture was then extracted with EtOAc (3 x 30mL) and the combined organic solutions were washed with brine (75 mL), dried (MgSOy) and concentrated. The residue (500mg) was dissolved into 4.5 mL 7:2 DMSOMeOH (111 mg/mL), then purified by preparative HPLC (Column A, Eluent A) to give the title compound (0.461 g, 54%) as a white solid; 'HNMR: 1.42 (9H, s), 1.56 (2H, d), 1.91-2.02 (3H, m), 2.40 (1H, td), 2.55-2.65 (1H, m), 2.8-2.98 (1H, m), 3.20 (2H, t), 3.68 (2H, dt), 4.27 (1H, d), 4.39 (1H, d), 4.70 (1H, dt), 5.07 (1H, dd), 7.09 (1H, dd), 7.22 (1H, d), 7.63 (1H, d), 10.94 (1H, s); m/z (ES-) [M-H]' = 442.2.
Example 34: 4-(4-f4-[4-(4-f[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/f-isoindol-5- yl1oxylpiperidin-l-vDbutoxy1phenyl|piperidin-l-vD-2-(trifluoromethvDbenzonitrile
Figure imgf000115_0001
Intermediate Ih was reacted with Intermediate 34e using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A). 'H NMR: 1.54-1.75 (8H, m), 1.85 (2H, d), 1.92-2.05 (3H, m), 2.21-2.32 (2H, m), 2.35-2.41 (3H, m), 2.56-2.65 (IH, m), 2.7-2.82 (3H, m), 2.84-2.95 (IH, m), 3.05 (3H, t), 3.96 (2H, t), 4.17 (2H, d), 4.26 (IH, d), 4.38 (IH, d), 4.51 (IH, dt), 5.07 (IH, dd), 6.81-6.91 (2H, m), 7.06 (IH, dd), 7.13-7.22 (3H, m), 7.27 (IH, dd), 7.32 (IH, d), 7.61 (IH, d), 7.81 (IH, d), 8.15 (IH, s), 10.94 (IH, s); Wz ES+ [M+H]+ = 744.4.
Intermediate 35a: Benzyl 4-(3-fluoro-4-hvdroxyphenyl)-3,6-dihvdropyridine-l(2/D-carboxylate
Figure imgf000115_0002
Pd(dppf)2Ch-DCM (0.824 g, 1.01 mmol) was added to 2-fluoro-4-iodophenol (2.40 g, 10.08 mmol), benzyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2//)-carboxylate (5.19 g, 15.13 mmol) and K2CO3 (4.18 g, 30.25 mmol) in 1 ,4-dioxane (1.6 mL) and water (0.4 mL) at RT under N2. The resulting mixture was stirred at 80°C for 16h. The mixture was then diluted with EtOAc, washed with water then sat. brine, dried (Na2SC>4) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (2.20 g, 67%) as a yellow solid; >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-hvdroxyphenyl)piperidine-l-carboxylate
Figure imgf000115_0003
10% Pd-on-C (1.365 g, 1.28 mmol) was added to di-tert-butyl carbonate (1.520 g, 7.06 mmol) and benzyl 4- (3-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-l(2/f)-carboxylate (2.100 g, 6.42 mmol) in MeOH (10 mL) at RT under H2. The resulting mixture was stirred at 80°C for 16h. 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; ‘HNMR: 1.35-1.48 (HH, m), 1.70 (2H, d), 2.57 (IH, tt), 2.76 (2H, s), 3.99-4.10 (2H, m), 6.83-6.86 (2H, m), 6.97-7.02 (IH, m), 9.56 (IH, s); m/z ES+ [MH-tBu]+ = 240.1.
Intermediate 35c: 2-Fluoro-4-(piperidin-4-yl)phenol
Figure imgf000116_0001
tert-Butyl 4-(3-fluoro-4-hydroxyphenyl)piperidine-l -carboxylate (500 mg, 1.69 mmol) was added to 4M HC1 in 1 ,4-dioxane (8 mL, 32.00 mmol) at RT and the mixture was stirred for 2h. Concentration under reduced pressure then gave the title compound as a hydrochloride salt (0.430 g, 130 %) as a white solid; *H 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 (OH, s), 9.72 (1H, s); m/z ES+ [M+H]+ = 196.0.
Figure imgf000116_0002
DIPEA (1.923 mL, 11.01 mmol) was added to 2-fluoro-4-(piperidin-4-yl)phenol (430 mg, 2.20 mmol) and 4- fhioro-2-(trifhioromethyl)benzonitrile (417 mg, 2.20 mmol) in DMSO (2 mL) at RT. The resulting solution was stirred at 60°C for 2h. The mixture was then poured into water (20 mL). This mixture was then extracted with EtOAc (3 x 250 mL) and the combined organic solutions were dried (Na2SO4) and concentrated.
Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (0.507 g, 63%) as a white solid; ‘H NMR: 1.59 (2H, qd), 1.78-1.87 (2H, m), 2.73 (1H, tt), 3.02 (2H, td), 4.16 (2H, dt), 6.84-6.89 (2H, m), 7.02 (1H, dd), 7.26 (1H, dd), 7.31 (1H, d), 7.80 (1H, d), 9.58 (1H, s); m/z ES+ [M+H]+ = 365.
Intermediate 35e: 4-(4-(4-(4-Bromobutoxy)-3-fluorophenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000116_0003
K2CO3 (228 mg, 1.65 mmol) was added to 4-(4-(3-fluoro-4-hydroxyphenyl)piperidin-l-yl)-2-(trifluoro- methyl)benzonitrile (200 mg, 0.55 mmol) and 1 ,4-dibromobutane (593 mg, 2.74 mmol) inDMF (2 mL) at RT under air and the mixture was stirred for 2h. The mixture was then poured into water (20 mL). This mixture was extracted with EtOAc (3 x 20 mL) and the combined organic solutions were dried (TS^SCL) and concentrated. Purification by flash Cl 8-flash chromatography (gradient: 0-100% MeCN in water) gave the title compound (0.210 g, 77 %) as a white solid; >H 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. lZT-isoindol-5-yllpiperazin-l-
Figure imgf000117_0001
Intermediate 2c was reacted with Intermediate 35e using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH;10:l); *H NMR: (300 MHz) 1.23-1.28 (2H, m), 1.54-1.89 (8H, m), 1.89-2.02 (lH, 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); Wz ES+ [M+H]+ = 747.4. in-4-'
Figure imgf000117_0002
Figure imgf000117_0003
RockPhos Pd G3 (291 mg, 0.35 mmol) was added to methyl 3 -(hydroxymethyl)cyclobutane-l -carboxylate (500 mg, 3.47 mmol), CS2CO3 (3.39 g, 10.40 mmol) and 4-(4-(4-bromophenyl)piperidin-l-yl)-2- (trifluoromethyl)-benzonitrile (1.42 g, 3.47 mmol) in 1,4-dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h 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; *H 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: 4-1
Figure imgf000117_0004
Figure imgf000117_0005
Figure imgf000118_0001
Methyl 3-((4-(l-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxy)methyl)cyclobutane-l- carboxylate (1.10 g, 2.33 mmol) was added to NaBH.4 (0.264 g, 6.98 mmol) in MeOH (10 mL) at RT and the mixture was stirred for 16h. After concentration under reduced pressure the mixture was poured into water (100 mL). This mixture was extracted with EtOAc (250 mL x 3), dried (NaiSO i) and concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) gave the title compounds (700 mg) as a mixture of cisltrans isomers. Further purification by preparative Prep-SFC (Column: CHIRAL ART Amylose- SA S, 3*25cm, 5pm; Mobile Phase A:CO2, Mobile Phase BMeOH (0.5% 2MNH3-MeOH)-HPLC; Flow rate:6.1 mL/min; Gradient:40% B; 220 nm; 36b RTE9.47; 36c RT2:10.97; Injection Volumn:1.5 mL; Number Of Runs:33) gave 36b (0.123 g, 12 %) and 36c (0.154 g, 15 %) as pale yellow solids.
Intermediate 36b: ‘H NMR (CDCI3, 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: 'H NMR ^DCh, 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); Wz ES+, [M+H]+ = 445.2
Intermediate 36d: 4-(4-(4-(((lr,3r)-3-(Bromomethyl)cvclobutyl)methoxy)phenyl)piperidin-l-yl)-2-
(trifluoromethvDbenzonitrile
Figure imgf000118_0002
CBr i (74.6 mg, 0.22 mmol) was added to PPh3 (59.0 mg, 0.22 mmol) and 4-(4-(4-(((lr,3r)-3-(hydroxymethyl)- cyclobutyl)methoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.11 mmol) in DCM (1 mL) at RT and the mixture was stirred for 2h. After concentration under reduced pressure, purification by preparative TLC (eluent: petroleum ether: EtOAc = 5:1) gave the title compound (0.050 g, 88 %) as a colourless gum; >H 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-f[(lr,3r)-3-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1- piperazin-l-yllmethyl)cvclobutyl1methoxylphenyl)piperidin-l-yl1-2-(trifluoromethyl)benzonitrile
Figure imgf000119_0001
Intermediate 2c was reacted with Intermediate 36d using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCMMeOH, 20:1); '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), 3.99 (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-l-yl)phenyl)piperidin-l-yl)-2-(trifluoro- methvDbenzonitrile
Figure imgf000119_0002
4-(4-(4-Bromophenyl)piperidin-l-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 a flask. The mixture was degassed, the flask filled with Ni. The mixture was then stirred at 100°C overnight, then concentrated after cooling to RT. Water (10 mL) was added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried (T^SCh) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.393 g, 33%) as a pale yellow solid; *H NMR (CDClj) 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-f4-[(4-f[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1oxyl- piperidin-l-yl)methyl1piperidin-l-yllphenyl)piperidin-l-yl1-2-(trifluoromethyl)benzonitrile
Figure imgf000120_0001
Intermediate 34e was reacted with Intermediate 37a using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A); *H NMR: (CDCI3) 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.
Figure imgf000120_0002
PdChCdppf) (118 mg, 0.16 mmol) was added to tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dilwdropvridine- 1 ( 2/7)-carboxvlate (500 mg, 1.62 mmol), 4-bromo-2-fluorophenol (340 mg, 1.78 mmol) and K2CO3 (670 mg, 4.85 mmol) in 1 ,4-dioxane (8 mL) and water (2 mL) at RT under N2. The resulting solution was stirred at 80°C for 4h. The mixture was then filtered through celite and the filtrate was concentrated. Purification by FCC (gradient: 0-10% EtOAc in petroleum ether) gave the title compound (0.40 g, 84 %) as a colourless oil; *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-hvdroxyphenyl)piperidine-l-carboxylate
Figure imgf000120_0003
10% Pd-on-C (1.451 g, 1.36 mmol) was added to tert-butyl 4-(2-fluoro-4-hydroxyphenyl)-3,6- dihydropyridine- 1 (277)-carboxylate (2.00 g, 6.82 mmol) in MeOH (10 mL) at RT under H2. The resulting mixture was stirred at 80°C for 16h. The mixture was then filtered through celite and the filtrate was concentrated. Purification by flash Cl 8-flash chromatography (gradient: 0-70% MeCN in water(0.1% formic acid)) gave the title compound (1.20 g, 60 %) as a white solid; 'H NMR: 1.42 (9H, s), 1.40-1.55 (2H, m), 1.63- 1.72 (2H, m), 2.71-2.92 (3H, m), 3.99-4.13 (2H, m), 6.51 (1H, dd), 6.56 (1H, dd), 7.08 (1H, t), 9.65 (1H, s); m/z\ ES+ [M-tBu]+ 240. Intermediate 38c: 3-Fluoro-4-(piperidin-4-'
Figure imgf000121_0001
A mixture of HC1 in 1,4-dioxane (18.8 mL, 8.00 mmol) and tert-butyl 4-(2-fluoro-4-hydroxyphenyl)- piperidine-1 -carboxylate (600 mg, 2.05 mmol) was stirred at RT for 2h. Concentration under reduced pressure then gave the title compound as a hydrochloride salt (0.580 g, 145 %) as a white solid; *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-t2-fluoro-4-hvdroxyphenyl)piperidin-l-yll-2-ttritluoromethyl)benzonitrile
Figure imgf000121_0002
DIPEA (3.81 mL, 21.80 mmol) was added to 3-fluoro-4-(piperidin-4-yl)phenol hydrochloride salt (1.01 g, 4.36 mmol) and 4-fluoro-2-(trifhioromethyl)benzonitrile (0.989 g, 5.23 mmol) in DMSO (10 mL) at RT under air and the mixture was stirred for 18h then poured into water (20 mL). This mixture was stirred at RT for 0.5h and then filtered. The collected solid was washed with water (20 mL) and 5% AcOH/water (20 mL) and dried under vacuum to give the title compound (1.51 g, 95 %) as a yellow solid; *H NMR: 1.67 (2H, qd), 1.80 (2H, d), 2.94-3.01 (1H, m), 3.03-3.18 (2H, m), 4.17 (2H, d), 6.45-6.63 (2H, m), 7.08 (1H, t), 7.19-7.38 (2H, m), 7.81 (1H, d), 9.65 (1H, s); m/z\ ES+ [M+H]+ 365.2.
Intermediate 38e: 4-(4-(4-(3-(l,3-Dioxolan-2-yl)propoxy)-2-fluorophenyl)piperidin-l-yl)-2-(trifluoro-
Figure imgf000121_0003
2-(3-Bromopropyl)-l,3-dioxolane (0.613 mL, 4.53 mmol) was added in one portion to 4-(4-(2-fluoro-4- hydroxyphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (1.50 g, 4.12 mmol) and K2CO3 (1.707 g, 12.35 mmol) in MeCN (10 mL) at RT under N2. The resulting suspension was stirred at 80°C for 5h. After cooling the mixture was filtered and water (150 mL) was added to the filtrate. A white precipitate was then collected by filtration to give the title compound (1.85 g, 94 %) as a yellow solid; 'H 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-f4-[4-(4-f4-[2-(2.6-Dioxopiperidin-3-yl)-l-oxo-2.3-dihvdro-lEI-isoindol-5-yllpiperazin-l- yllbutoxy)-2-fluorophenyl1piperidin-l-yll-2-(trifluoromethyl) benzonitrile
Figure imgf000122_0001
Intermediate 2b was reacted with Intermediate 38e using the general synthetic method illustrated by Example 1 to give the title compound after purification by EIPLC (Column A, Eluent A, Basic Work-Up A); 'El 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-(((lr,3r)-3-(Bromomethyl)cvclobutyl)methoxy)phenyl)piperidin-l-yl)-2-
(trifluoromethvDbenzonitrile
Figure imgf000122_0002
CBr i (74.6 mg, 0.22 mmol) was added to PPha (59.0 mg, 0.22 mmol) and 4-(4-(4-(((ls,3s)-3-(hydroxyl- methyl)cyclobutyl)methoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.11 mmol) in DCM (1 mL) at RT and the mixture was stirred for 2h then concentrated. Purification by preparative TLC (eluent EtOAc: petroleum ether = 1 :5) gave the title (0.050 g, 88 %) as a colourless gum; 'H NMR: 1.51-1.70 (4H, m), 1.85 (2H, d), 2.13-2.24 (2H, m), 2.53-2.64 (2H, m), 2.71-2.83 (1H, m), 3.05 (2H, dd), 3.56 (2H, d), 3.88 (2H, d), 4.18 (2H, d), 6.85 (2H, d), 7.15 (2H, d), 7.27 (1H, dd), 7.33 (1H, d), 7.82 (1H, d); m/z ES+, [M+H]+ = 507.
Example 39: 4-[4-(4-n(ls,3s)-3-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-yl1-
Figure imgf000122_0003
piperazin-l-yllmethyl)cvclobutyllmethoxylphenyl)piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000123_0001
Intermediate 2c was reacted with Intermediate 39a using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 20:1); 'H 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-(l-(4-cvano-3-(tritluoromethyl)rihenyl)riirieridin-4-yl)rihenoxy)-
Figure imgf000123_0002
DIAD (337 Lil 1.73 mmol) was added to 4-(4-(4-hydroxyphenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile (Example 1g) (300 mg, 0.87 mmol), tert-butyl 4-hydroxypiperidine- 1 -carboxylate (209 mg, 1.04 mmol) and PPha (454 mg, 1.73 mmol) in DCM (1 mL) at 0°C. The resulting mixture was stirred at RT for 16h then concentrated. Purification by 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; *H NMR: 1.40 (9H, s), 1.50 (2H, ddt), 1.62 (2H, qd), 1.78-1.93 (4H, m), 2.76 (lH, 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)DiDeridin-l-yl)-l-oxoisoindolin-2-yl)Diperidine-2.6-dione
Figure imgf000123_0003
Pd-PEPPSI-IPent (0.355 g, 0.45 mmol) was added to 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (1.45 g, 4.49 mmol), 4-(dimethoxymethyl)piperidine (1.00 g, 6.28 mmol) and CS2CO3 (4.38 g, 13.46 mmol) in 1,4-dioxane (45 mL) at RT under N2. The resulting suspension was vacuum degassed, backfilling with N2 and stirred at 90°C for 4.5h. The mixture was then allowed to stand at RT for 16h. The mixture was then diluted with DCM (75 mL) and 10% aq. AcOH (150 mL) and the layers were separated. The aqueous layer was extracted with DCM (75 mL x 2). The combined organic solutions were washed with sat. brine (60 mL), dried (MgSCh) and concentrated. Purification by FSC (gradient: 0-8% EtOH in EtOAc) gave the title compound (0.800 g, 44 %) as an off-white solid; ‘H 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. dol-5-yllpiperidin-4-
Figure imgf000124_0001
Intermediate 40a was reacted with Intermediate 40b using the general synthetic method illustrated by Example 1 to give the title compound after purification by preparative SFC (Column: DAICEL DCpak P4VP, 20mm*250mm, 5|im; Mobile Phase A:CC>2, Mobile Phase BMeOH— HPLC; Flow rate:50 mL/min;
Gradient:45% B; 254 nm; RT1 :5.67; Injection Volumn: 1 mL; Number Of Runs:5); *H 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. i-3,6-di
Figure imgf000124_0002
Figure imgf000124_0003
PdC12(dppf) (7.39 g, 10.10 mmol) was added to 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-l -carboxylic acid benzyl ester (3.47 g, 10.10 mmol), 4-bromo-l-iodo-2-methylbenzene (3.00 g, 10.10 mmol) and K2CO3 (4.19 g, 30.31 mmol) in 1,4-dioxane (20 mL) and water (5 mL) at RT under N2. The resulting solution was stirred at 80°C for 4h. The mixture was then diluted with EtOAc (50 mL). This solution was washed with water (20 mL x 3) then sat. brine (20 mL x 2), dried (Na2SO4) 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; ‘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. i-2-methylphenyl)-3,6-
Figure imgf000124_0004
Figure imgf000125_0001
Rockphos Pd G3 (0.217 g, 0.26 mmol) was added to benzyl 4-(4-bromo-2-methylphenyl)-3,6-dihydro- pyridine-l(277)-carboxylate (1.00 g, 2.59 mmol), 4-((tert-butyldimethylsilyl)oxy)butan-l-ol (0.794 g, 3.88 mmol) and CS2CO3 (2.53 g, 7.77 mmol) in 1,4-dioxane (1 mL) at RT under N2. The resulting solution was stirred at 100°C for 12h and then concentrated. Purification by flash C18-flash chromatography (gradient: 0- 100% MeCN in water) gave the title compound (0.700 g, 53 %) as a yellow solid; *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.
Figure imgf000125_0002
A mixture of benzyl 4-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)-3,6-dihydropyridine- l(277)-carboxylate (600 mg, 1.18 mmol) and platinum (IV) oxide hydrate (60 mg, 0.24 mmol) in EtOAc (10 mL) was stirred under H2 (20 atm) at 80°C for 1 Oh. The mixture was then filtered through celite pad and the filtrate was concentrated to give the title compound (460 mg, 103%); m/z ES+ [M+H]+ = 378. idin-l-vl)-2-
Figure imgf000125_0003
CS2CO3 (518 mg, 1.59 mmol) was added to 4-(4-(4-(( tert- butyldimethylsilyl )oxy)butoxy)-2-methylphenyl )- piperidine (200 mg, 0.53 mmol) and 4-fhioro-2-(trifhioromethyl)benzonitrile (150 mg, 0.79 mmol) in DMSO
(5 mL) at RT under air. The resulting solution was stirred at 60°C for 2h and then concentrated. Purification by flash C18-flash chromatography (gradient: 10-100% MeCN in water) gave the title compound (0.125 g, 43%) as a white solid; >H NMR (CD3OD, 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 (2H, t), 4.71 (2H, t), 4.98 (2H, d), 7.47 (1H, dd), 7.51 (1H, d), 7.84 (1H, d), 8.06 (1H, dd), 8.12 (1H, d), 8.61 (1H, d); Wz ES+ [M+H]+ = 547.
Intermediate 41e: 4-(4-(4-(4-
Figure imgf000125_0004
in-l-yD-2-i
Figure imgf000125_0005
benzonitrile
Figure imgf000126_0001
4-(4-(4-(4-((tert-Butyldimethylsilyl)oxy)butoxy)-2-methylphenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (90 mg, 0.16 mmol) was added to tetra-w-butylammonium fluoride (86 mg, 0.33 mmol) in THF (2 mL) at RT and the mixture was stirred for 16h, then concentrated. The residue was diluted with DCM (250 mL). This solution was washed with water (30 mL) then sat. brine (50 mL), dried (Na2SO4) and concentrated to give the title compound (0.085 g, 119 %); 'H NMR: 1.51-1.58 (2H, m), 1.61 (2H, dd), 1.71 (2H, dd), 1.77 (2H, d), 2.31 (3H, s), 2.95 (1H, ddd), 3.08 (2H, t), 3.40-3.50 (2H, m), 3.91 (2H, 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-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000126_0002
4-(4-(4-(4-Hydroxybutoxy)-2-methylphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (80.0 mg, 0.18 mmol) was added to ITh;, (97.0 mg, 0.37 mmol) and CBr i (123 mg, 0.37 mmol) in DCM (2 mL) at RT and the mixture was stirred for 3h, then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (0.075 g, 82 %) as a colourless gum; *H 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); rn z HS [M+H]+ = 495.2. ZT-isoindol-5-yllpiperazin-l-
Figure imgf000126_0003
Intermediate 2c was reacted with Intermediate 41 f using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCMMeOH, 10:1); *H 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. isoindol-5-
Figure imgf000127_0001
Intermediate 2b was reacted with Intermediate 3 c using the general synthetic method illustrated by Example 1 to give the title compound after purification by preparative SFC (Column: Triart Diol-NP, 20*250mm, 5|im; Mobile Phase A:CC>2, Mobile Phase B:IPA (0.2% Et2NH); Flow rate:50 mL/min; Gradient:40% B); *H 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-Cvclopropyl-4-f4-[4-(4-f4-[2-(2,6-dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5- in-1-'
Figure imgf000127_0002
Intermediate 2c was reacted with Intermediate 14b using the general synthetic method illustrated by Example 5 to give the title compound after purification by flash Cl 8-flash chromatography (gradient 0-37% MeCN in water) and further purification by preparative Prep-SFC (Column: GreenSep Basic; Mobile Phase A:CO2, Mobile Phase BMeOH (8mmol/L NI E.MeOH )— EIPLC; Flow rate:50 mL/min; Gradient:50% B); *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 (2H, 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), 6.83-6.90 (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-Hvdrazineyl-4-iodopyridine
Figure imgf000128_0001
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) at RT under air and the mixture was stirred for 2 days. Water was then added and a solid collected by filtration to give the title compound (4.30 g, 74 %) as a pale yellow solid; *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-[l,2,41triazolo[4,3-a1pyridin-3(2/D-one
Figure imgf000128_0002
CDI (4.45 g, 27.44 mmol) was added to 2-hydrazineyl-4-iodopyridine (4.30 g, 18.30 mmol) in MeCN (40 mL) at RT under air. The resulting solution was stirred at 60°C for 17h. The mixture was then filtered (with suction) and the solid was washed with MeCN to give the title compound (4.40 g, 92 %) as a pale yellow solid; *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-dihvdro-[l,2,41triazolo[4,3-a1pyridin-7-yl)piperazine-l- carboxylate
Figure imgf000128_0003
RuPhos Pd G3 (0.481 g, 0.57 mmol) was added to 7-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2//)-one (1.5g, 5.75 mmol), tert-butyl piperazine- 1 -carboxylate (2.14 g, 11.49 mmol) and sodium 2-methylpropan-2-olate (1.66 g, 17.24 mmol) in /BuOH (10 mL) at RT under N2. The resulting solution was stirred at 100°C for 3h then concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (1.50 g, 82 %) as a yellow solid; >H 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-dih vdro-[l, 2, 4ltriazolo [4,3- al pyridin-7-yl)piperazine-l -carboxylate
Figure imgf000128_0004
NaH (0.095 g, 3.95 mmol)(60%) was added to tert-butyl 4-(3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridin-7- yl)piperazine-l -carboxylate (1.05 g, 3.29 mmol) in DMF (10 mL) at RT under N2. The resulting solution was stirred at 60°C for 0.5h. 3-Bromopiperidine-2, 6-dione (0.631 g, 3.29 mmol) was then added and the solution was stirred at 60°C for lOh and then concentrated. Purification by flash C-18 chromatography (gradient: 10- 80% MeCN in water) gave the title compound (0.600 g, 42 %) as a green solid; *H 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); Wz ES+ [M+H]+ = 431.
Intermediate 44e: 3-(3-Oxo-7-(piperazin-l-yl)-|l,2,4|triazolo|4,3-a|pyridin-2(3//)-yl)piperidine-2,6- dione
Figure imgf000129_0001
tert-Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-l- carboxylate (151 mg, 0.35 mmol) was added to HC1 in 1 ,4-dioxane (3 mL, 12.00 mmol) at RT and the mixture was stirred for 2h. Concentration under reduced pressure then gave the title compound (0.120 g, 104 %) as a white solid; ‘H 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-f4-[4-(3-f4-[2-(2,6-Dioxopiperidin-3-yl)-3-oxo-2,3-dihvdro[l,2,41triazolo[4,3-«1pyridin-7- yl1piperazin-l-yllpropoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000129_0002
Intermediate 13a was reacted with Intermediate 44e using the general synthetic method illustrated by Example 12 to give the title compound after purification by preparative TLC (eluent: DCMMeOH, 10:1); *H 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); Wz ES+ [M+H]+ = 717.4.
Example 45: 4-(4-f4-[4-(2-f4-[2-(2.6-Dioxopiperidin-3-yl)-l-oxo-2.3-dihvdro-l/T-isoindol-5-yl1piperazin- l-yllethyl)piperidin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl) benzonitrile
Figure imgf000130_0001
Intermediate 2c was reacted with Intermediate 15f using the general synthetic method illustrated by Example 2 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 10: 1 ): 'H 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), 2.91 (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-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-lE7-isoindol-5-yl1piperazin-l-
Figure imgf000130_0002
Intermediate 2c was reacted with Intermediate 6d using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H 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-f4-[(4-f2-[-2,6-Dioxopiperidin-3-yl1-3-oxo-2,3-dihvdro[l,2,41triazolo[4,3-«1-pyridin-
7-yllpiperazin-l-yl)methyl1piperidin-l-yllphenyl)piperidin-l-yl1-2-(trifluoromethyl)benzonitrile
Figure imgf000130_0003
Intermediate 4c was reacted with Intermediate 44e using the general synthetic method illustrated by Example 2 to give the title compound after purification by flash Cl 8-flash chromatography (gradient: 0-40% MeCN in water (0.1% formic acid)) to give white solid which was further purified by preparative TLC (eluent: DCM:MeOH, 10:1); ‘HNMR: 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-(((/?.S,)-tetrahvdro-2//-py ran-2-yl)oxy)phenyl)piperazine- 1-carboxylate
Figure imgf000131_0001
2-(4-Bromophenoxy)tetrahydro-2/f-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 bubbling N2. The mixture was then heated to 90°C for 2h. After cooling the mixture was partitioned between EtOAc and water. The organic solution was dried (TS^SCL) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (1.10 g, 75 %) as a colourless oil; *H NMR (CDC13) 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: -4-(2-Methylpiperazin-l-vDphenol
Figure imgf000131_0002
Figure imgf000131_0003
4M EIC1 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- 2H-pyran-2-yl )oxy)phenyl )piperazine- 1 -carboxy late (1.10 g, 2.92 mmol) in DCM (20 mL) and the mixture was stirred overnight at RT. Et3O (100 mL) was added and a precipitate was collected by filtration under vacuum to give the title compound as a hydrochloride salt (0.696 g, 104 %) as a yellow solid; m/z ES+ [M+H]+ = 193.1.
Intermediate 48c: (>S)-4-(4-(4-Hvdroxyphenyl)-3-methylpiperazin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000132_0001
DIPEA (1.27 mL, 7.30 mmol), 4-fhioro-2-(trifhioromethyl)benzonitrile (0.552 g, 2.92 mmol) and (S)-4-(2- methylpiperazin-l-yl)phenol hydrochloride salt (0.668 g, 2.92 mmol) were dissolved in DMSO (5 mL) and the mixture was stirred at RT 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; *H NMR (CDCh) 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-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000132_0002
(S)-4-(4-(4-Hydroxyphenyl)-3-methylpiperazin-l-yl)-2-(trifluoromethyl)benzonitrile (0.244 g, 0.68 mmol), K2CO3 (0.112 g, 0.81 mmol) and 1 ,4-dibromobutane (0.161 mL, 1.35 mmol) were dissolved in anhydrous DMF (7 mL) under N2. The mixture was stirred at 50°C for 16h. After cooling the mixture was diluted with EtOAc (50 mL), washed with sat. Nal ICCL, (50 mL) then sat. brine (50 mL), dried (MgSCh) and concentrated. Purification by FSC (gradient: 0-40% EtOAc in heptane) gave the title compound (0.215 g, 64 %) as a yellow oil; ‘H NMR (CDCh) 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>y)-4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-
Figure imgf000132_0003
yl1piperazin-l-yllbutoxy)phenyl1-3-methylpiperazin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000132_0004
Intermediate 2c was reacted with Intermediate 48d using the general synthetic method illustrated by Example 5 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H 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.
Figure imgf000133_0001
CS2CO3 (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 RT. The resulting solution was stirred at 60°C for lOh. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic solutions were dried (Na2SC>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; *H 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. idin-l-yl)-3-
Figure imgf000133_0002
RockPhos Pd G3 (112 mg, 0.13 mmol) was added to pentane- 1,5-diol (209 mg, 2.01 mmol), CS2CO3 (1310 mg, 4.02 mmol) and 5-(4-(4-bromophenyl)piperidin-l-yl)-3-(trifluoromethyl)picolinonitrile (550 mg, 1 .34 mmol) in 1,4-dioxane (7 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h 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; ‘HNMR: 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.
Figure imgf000133_0003
CBt' i (153 mg, 0.46 mmol) was added to 1’1’113 (121 mg, 0.46 mmol) and 5-(4-(4-((5-hydroxypentyl)oxy)- phenyl)piperidin-l-yl)-3-(trifluoromethyl)picolinonitrile (100 mg, 0.23 mmol) in DCM (1 mL) at RT and the mixture was stirred for 2h 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-f4-[(5-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5-yl1piperazin-l- idin-l-yl)-3-i >2-carbonitrile
Figure imgf000134_0001
Intermediate 2c was reacted with Intermediate 49c using the general synthetic method illustrated by Example 5 to give the title compound after purification by FSC (gradient: 0-10% MeOH in DCM); 'HNMR: 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)phenyl1-l-piperidyl1-2-(trifluoromethyl)benzonitrile
Figure imgf000134_0002
4-(4-(4-Hydroxyphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (1.95 g, 5.63 mmol), K2CO3 (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 6h, starting material remained so further portions of K2CO3 (500 mg) and 1 ,4-dibromobutane (1 mL) were added and the mixture was stirred at 70°C overnight. A small amount of starting material remained so further portions of K2CO3 (500 mg) and 1 ,4-dibromobutane (1 mL) were added and the mixture was stirred at 70°C for 4h. The mixture was then cooled to RT and filtered (washing 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 on standing; *H NMR (CDCI3) 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), 6.82-6.89 (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-vDpiperazine-l -carboxylate
Figure imgf000135_0001
NEta (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 RT and the mixture was stirred for 2h. The mixture was then diluted with EtOAc, washed (water then sat. brine), dried ( Na^SO i ) 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; *H 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-hvdrazineylpyrimidin-4-yl)piperazine-l-carboxylate
Figure imgf000135_0002
Hydrazine (1.641 mL, 33.47 mmol) was added to tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-l- carboxylate (2.00 g, 6.69 mmol) in EtOH (15 mL) and water (3 mL) at RT. The resulting mixture was stirred at 80°C for 16h and then concentrated. Trituration with water to give a solid which was collected by filtration and dried under vacuum 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-dihvdro-[l,2,4]triazolo[4,3-«]pyrimidin-7-vDpiperazine-l- carboxylate
Figure imgf000135_0003
CDI (1.32 g, 8.15 mmol) was added to tert-butyl 4-(2-hydrazineylpyrimidin-4-yl)piperazine- 1 -carboxylate (2.00 g, 6.79 mmol) in THF (20 mL) at RT and the mixture was stirred for 1 ,5h, then concentrated. Trituration with MeCN and Et2O gave a solid which was collected by filtration and dried under vacuum to give the title compound (1.93 g, 89 %) as a pale yellow solid; ‘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); Wz ES+ [M+H]+ = 321.
Intermediate 50e: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-vD-3-oxo-2,3-dihvdro-[l,2,4]triazolo[4,3-
«]pyrimidin-7-vDpiperazine-l-carboxylate
Figure imgf000136_0001
NaH (0.233 g, 5.84 mmol) was added to tert-Butyl 4-(3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyrimidin-7- yl)piperazine-l -carboxylate (1.70 g, 5.31 mmol) in DMF (1 mL) at 0°C. The mixture was stirred at 0°C for 20 mins and warmed up to RT for further 20 mins. 3-Bromopiperidine-2, 6-dione (1.223 g, 6.37 mmol) was then added and the mixture stirred at 60°C for 2h. After cooling, the mixture was diluted with DCM. This solution was washed (5% AcOH, water and then sat. brine), dried (Na2SC>4) and concentrated. Purification by flash Cl 8-flash chromatography (gradient: 0-30% MeCN in water (0.1% formic acid)) gave the title compound (0.586 g, 26 %) as a white solid; ‘HNMR: 1.42 (9H, s), 2.04-2.16 (IH, m), 2.35-2.48 (IH, m), 2.57-2.73 (IH, m), 2.87 (IH, ddd), 3.38-3.44 (4H, m), 3.65-3.80 (4H, m), 5.19 (IH, dd), 6.65 (IH, d), 8.06 (IH, d), 11.01 (IH, s); m/z ES+ [M+H]+ = 432.
Intermediate 50f: 3-(3-Oxo-7-piperazin-l-yl-[l,2,41triazolo[4,3-«1pyrimidin-2-yl)piperidine-2,6-dione
Figure imgf000136_0002
HC1 in 1,4-dioxane (1 mL, 4.00 mmol) was added to tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-l-carboxylate (200 mg, 0.46 mmol) in DCM (1 mL) at RT and the mixture was stirred for Ih then concentrated. Trituration with Et2O to give a solid which was collected by filtration and dried under vacuum to the title compound (0.180 g, 96 %) as a pale yellow solid; *H NMR: 2.06-2.17 (IH, m), 2.37-2.48 (IH, m), 2.57-2.70 (IH, m), 2.83-2.95 (IH, m), 3.14-3.22 (4H, m), 3.91- 4.04 (4H, m), 5.21 (IH, dd), 6.70 (IH, d), 8.15 (IH, d), 9.22 (IH, br), 11.03 (IH, s).
Example 50: 4-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-3-oxo-2,3-dihvdro[l,2,41triazolo[4,3-«1pyrimidin-
7-vHpiperazin-l-yllbutoxy)phenvHpiperidin-l-yll-2-(trifluoromethyr) benzonitrile
Figure imgf000136_0003
Intermediate 50a was reacted with Intermediate 50f using the general synthetic method illustrated by Example 5 to give the title compound (as a formate salt) after purification by flash Cl 8-flash chromatography (gradient: 0-40% MeCN in water (0.1 % formic acid)); >H NMR: (300 MHz) 1.53-1.66 (4H, m), 1.65-1.79 (2H, m), 1.85 (2H, d), 2.04-2.17 (IH, m), 2.33-2.48 (7H, m), 2.54-2.66 (IH, 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 (IH, dd), 6.67 (IH, d), 6.86 (2H, t), 7.16 (2H, t), 7.24-7.36 (2H, m), 7.82 (IH, d), 8.03 (IH, d), 11.03 (IH, s); m/z ES+ [M+H]+ = 732.3. Intermediate 51a: 4-1
Figure imgf000137_0001
,3-Dioxolan-2-'
Figure imgf000137_0002
in-l-vD-2-i
Figure imgf000137_0003
nitrile
Figure imgf000137_0004
K2CO3 (1.197 g, 8.66 mmol) was added to 4-(4-(4-hydroxyphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzo- nitrile (1.00 g, 2.89 mmol) and 2-(4-bromobutyl)-l,3-dioxolane (0.604 g, 2.89 mmol) in DMF (2 mL) at RT under air. The resulting solution was stirred at 80°C for lOh. 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.
Figure imgf000137_0005
4-(4-(4-(4-(l ,3-Dioxolan-2-yl)butoxy)phenyl)piperidin-l -yl)-2-(trifhioromethyl)benzonitrile (1.00 g, 2.11 mmol) was added to formic acid (10 mL) at RT and the mixture was stirred for 4h and then concentrated.
Purification by FSC (gradient: 30-100% MeCN in water) gave the title compound (0.500 g, 55 %) as a purple oil; Wz ES+ [M+H]+ = 431. peridin-3-vl)-3-oxo-2,3-dihvdro[l,2,41triazolo[4,3-alpvridin-7-
Figure imgf000137_0006
lin-l-vl)-2-i
Figure imgf000137_0007
Figure imgf000137_0008
Intermediate 44e was reacted with Intermediate 51b using the general synthetic method illustrated by Example
2 to give the title compound after purification by preparative SFC (Column: Triart Diol-NP, 20*250mm, 5|im;
Mobile Phase A:CC>2, Mobile Phase B:IPA(8mmol/L NI L.MeOH )-HPI ,C: Flow rate:50 mL/min;
Gradient:27% B; 254 nm; RT1 :4.03; Injection Vo lumn: 1.5 mL; Number Of Runs: 10;); ‘HNMR: (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- 7.33 (2H, m), 7.72 (1H, d), 7.82 (1H, d), 11.04 (1H, s); m/z ES+ [M+H]+ = 745.4. ,6-Dioxopiperidin-3-vl)-l-oxo-2,3-dihvdro-l//-isoindol-5-vl|piperazin-l-
Figure imgf000138_0001
vl ! -3-i
Figure imgf000138_0002
-2-carbonitrile
Figure imgf000138_0003
Intermediate 2c was reacted with Intermediate 11b using the general synthetic method illustrated by Example 5 to give the title compound after purification by preparative TLC (eluent: DCM:MeOH, 10:1); 'H 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-Hvdroxyethyl)pyrrolidin-l-yl1phenyl1-l-piperidyl1-2-(trifluoromethyl)- benzonitrile
Figure imgf000138_0004
Cui (46.5 mg, 0.24 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (500 mg, 1.22 mmol), 2-(pyrrolidin-3-yl)ethan-l-ol (211 mg, 1.83 mmol), 2-((2,6-dimethylphenyl)amino)-2- oxoacetic acid (47.2 mg, 0.24 mmol) and K3PO4 (519 mg, 2.44 mmol) in DMSO (7 mL) under N2. The resulting mixture was stirred at 115°C for 18h. The mixture was then cooled to RT and poured into water (50 mL) then extracted with EtOAc (3 x 50 mL). The combined organic solutions were washed with brine (50 mL), dried (MgSCL) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (0.347 g, 64 %) as a white solid; >H NMR (CDCh) 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-l-yl1phenyl1-l-piperidyl1-2-(trifluoromethyl)- benzonitrile
Figure imgf000139_0001
Dess- Martin periodinane (184 mg, 0.43 mmol) was added to 4-[4-[4-[3-(2-hydroxyethyl)pyrrolidin-l- yl]phenyl]-l-piperidyl]-2-(trifluoromethyl)benzonitrile (175 mg, 0.39 mmol) in DCM (5 mL) at 0°C. The resulting mixture was stirred at RT for Ih. The mixture was then diluted with DCM (15 mL) and poured into mixture of sat. Nal ICO;, ( 15 mL) and sodium thiosulfate solution (15 mL). The resulting suspension was stirred vigorously for 10 mins then the layers were separated. The organic solution was dried (Na2SO4) 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-f4-[3-(2-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5-yl1piperazin- idin-l-yllphenyl}piperidin-l-yl)-2-i
Figure imgf000139_0002
Intermediate 2c was reacted with Intermediate 53b using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H NMR: (CDClj) 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-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5-yl1piperazin-l- yllbutoxy)phenyl1piperidin-l-yll-3-fluoro-2-(trifluoromethyl)benzonitrile
Figure imgf000139_0003
Intermediate 2c was reacted with Intermediate 7b using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H 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), 2.83-2.96 (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 (2H, 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 (/?)-3-methyl-4-(4-(((/?.S,)-tetrahvdro-2//-pyran-2-yl)oxy)phenyl)piperazine- 1-carboxylate
Figure imgf000140_0001
2-(4-Bromophenoxy)tetrahydro-2/f-pyran (1.0 g, 3.89 mmol), tert-butyl (R)-3-methylpiperazine- 1 -carboxy late (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 bubbling N2. The mixture was then heated to 80 °C for 2h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic solution was dried and concentrated. Purification by FSC (gradient: 0-50% EtOAc in heptane) gave the title compound (0.859 g, 59%) as a colourless oil; *H NMR (CDCh) 0.91 (3H, d), 1.48 (9H, s), 1.66 (3H, dddd), 1.85 (2H, dq), 1.92-2.11 (lH, 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: -4-(2-IVIcthylpipcrazin-l-yl)phcnol
Figure imgf000140_0002
Figure imgf000140_0003
4M HC1 in dioxane (5.7 mL, 22.82 mmol) was added dropwise to a solution of tert-butyl (R)-3-methyl-4-(4- (((/bSb-tetrahvdro-2//-pvran-2-vl (oxv)phenvl (piperazine- 1-carboxvlate (859 mg, 2.28 mmol) in DCM (20 mL) and the mixture was stirred overnight at RT. Et2O (100 mL) was added and the resulting precipitate was collected by filtration under vacuum to give the title compound as a hydrochloride salt (0.600 g, 115 %) as a yellow solid; m/z ES+ [M+H]+ = 193.1.
Intermediate 55c: (R)-4-(4-(4-Hvdroxyphenyl)-3-methylpiperazin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000140_0004
DIPEA (0.993 mL, 5.70 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (0.431 g, 2.28 mmol) and (R)-4-(2- methylpiperazin-l-yl)phenol hydrochloride salt (0.521 g, 2.28 mmol) were dissolved in DMSO (5 mL) and the mixture was stirred at RT 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; *H NMR (CDCI3) 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)phenvD-3-methylpiperazin-l-vD-2-(trifluoromethvD- benzonitrile
Figure imgf000141_0001
(R)-4-(4-(4-Hydroxyphenyl)-3-methylpiperazin-l-yl)-2-(trifluoromethyl)benzonitrile (0.184 g, 0.51 mmol), K2CO3 (0.084 g, 0.61 mmol) and 1 ,4-dibromobutane (0.122 mL, 1.02 mmol) were dissolved in anhydrous DMF (7 mL) under N2. This mixture was stirred at 50°C for 16h. The mixture was then diluted with EtOAc (50 mL), washed with sat. Nal ICO;, (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; *H NMR (CDCI3) 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-!t3/?)-4-l4-t4-!4-l2-t2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l //-isoindol-5-
-3-methylpiper az in-1 -vl I -2-1
Figure imgf000141_0002
Intermediate 2c was reacted with Intermediate 55d using the general synthetic method illustrated by Example 5 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H 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’-dihvdro-[3.4’-bipyridine1-l’(2’H)-carboxylate
Figure imgf000142_0001
tert-Butyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2/f-pyridine-l-carboxylate (50.0 g, 161 mmol), 5-bromo-2-chloro-pyridine (62.2 g, 323 mmol), K2CO3 (112 g, 808 mmol) and Pd(dppf)Ch (5.92 g, 8.09 mmol) were added to 1,4-dioxane (350 mL) and H2O (35.0 mL). The mixture was degassed and purged with N2 three times. The mixture was then stirred at 95°C for Ih. H2O (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 (Na2SO4) and concentrated. Purification by FSC (gradient: petroleum ether/EtOAc = 10/1 to 2/1) gave the title compound (34.2 g, 65%) as light yellow solid; *H NMR (CDCh) 1.49 (9H, s), 2.50 (IH, s), 3.65 (2H, t), 4.10 (2H, s), 6.09 (IH, s), 7.26 (IH, d), 7.62 (IH, dd), 8.40 (IH, s).
Figure imgf000142_0002
MeOH (400.0 mL) was added to tert-butyl 6-chloro-3',6'-dihydro-[3,4'-bipyridine]-r(2'H)-carboxylate (27.8 g, 94.3 mmol) and PtCh (4.29 g, 18.9 mmol). The resulting suspension was degassed and purged with H2 three times. The mixture was then stirred at 15°C for 4.5h under H2 (30 psi). The mixture was then filtered and the filtrate was concentrated. Purification by FSC (gradient: petroleum ether/EtOAc = 10/1 to 2/1) gave the title compound (13.09 g, 42%) as light yellow oil; *H NMR (CDCI3) 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 (IH, d), 7.49 (IH, dd), 8.26 (IH, s);
Figure imgf000142_0003
4N HC1 in MeOH (130 mL) was added to tert-butyl 4-(6-chloro-3-pyridyl)piperidine-l -carboxylate (12.9 g,
43.4 mmol) and the mixture stirred at RT for 20 mins. Concentration of the mixture then gave the title compound as a hydrochloride salt (11.6 g, 43.0 mmol, 99%) as light yellow solid; *H NMR (CD3OD) 1.96 (2H, m), 2.04- 8.47 (IH, s), 2.14-2.11 (2H, m), 3.21-3.07 (3H, m), 3.54 (2H, d), 7.66 (IH, d), 8.03 (IH, dd).
Figure imgf000142_0004
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 5.5h. The solution was then cooled to 0°C and hydrochloric acid (1 M, 50.0 mL) was added to the solution, (pH = 2). Sat Nal ICO; (200.0 mL) solution was then added to the mixture to pH = 8. A solid was collected by filtration and dried under vacuum . The solid was purified by recrystallization (petroleum ether/ EtO Ac = 10/1) to give the title compound (5.50 g, 37% yield) as light yellow solid; *H NMR (CDCla) 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-Hvdroxybutoxy)-3-pyridyl1-l-piperidyl1-2-(trifluoromethyl)benzonitrile
Figure imgf000143_0001
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 brought to RT. 4-(4-(6-Chloropyridin-3-yl)piperidin-l- yl)-2-(trifhioromethyl)benzonitrile (0.500 g, 1.37 mmol) was added in one portion and the mixture was heated to 85°C for 16h. 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 16h. After cooling the mixture was diluted with EtO Ac (50 mL). This solution was washed with water (50 mL), sat. Nal ICO;, (50 mL), and then sat. brine (50 mL). The solution was dried (MgSOy) and concentrated. Purification by FSC (gradient 0-100% EtOAc in heptane) gave the title compound (0.413 g, 72 %) as a colourless oil; >H NMR (CDC13) 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 IIS [M+H]+ = 420.0.
Intermediate 56f: 4-[4-[6-(4-Oxobutoxy)-3-pyridyl 1-1 -piperidyl 1-2-(trifluoromethvDbenzonitrile
Figure imgf000143_0002
Dess- Martin periodinane (228 mg, 0.54 mmol) was added to 4-(4-(6-(4-hydroxybutoxy)pyridin-3-yl)piperidin- l-yl)-2-(trifluoromethyl)benzonitrile (205 mg, 0.49 mmol) in DCM (5 mL) at RT and the mixture was stirred for Ih. The mixture was then diluted with DCM (15 mL) and poured into mixture of sat. Nal ICO;, (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 mins and the layers were separated. The organic portion was dried ( Na;SO i ) 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
Figure imgf000144_0001
POCh (61.7 mL, 662.28 mmol) was added to ethyl 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (24 g, 132.46 mmol) at RT. The resulting solution was stirred at 100°C for Ih then concentrated. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (23.00 g, 87 %) as a white solid; *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
Figure imgf000144_0002
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 CCI4 (300 mL). The resulting mixture was stirred at 80°C for 16h and then concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) gave the title compound (28.0 g, 96 %) as a yellow oil; IH 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 (IH, d); m/z ES+ [M+H]+ = 278.
Intermediate 56i: 3-(2-Chloro-5-oxo-5,7-dihvdro- pyrrolo[3,4-/>|pyridin-6-yl)piperidine-2,6-dione
Figure imgf000144_0003
Figure imgf000144_0004
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 2h and then at 100°C for 16h before concentration under reduced pressure. Purification by FSC (gradient: 0-100% EtOAc in petroleum ether) gave material that was further purified by crystallisation from EtOAc to give the title compound (10.00 g, 40 %) as a purple solid; *H NMR: 1.96-2.08 (IH, m), 2.35- 2.47 (IH, m), 2.56-2.66 (IH, m), 2.85-2.99 (IH, m), 4.39 (IH, d), 4.55 (IH, d), 5.17 (IH, dd), 7.67 (IH, d), 8.19 (IH, d), 11.02 (IH, s); rn z HS [M+H]+ = 280.1.
Intermediate 56j: tert-Butyl-4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihvdro-5//-pyrrolo|3,4-/>|pyridin-
2-vDDiperazine-l-carboxylate
Figure imgf000144_0005
DIPEA (1.40 mL, 7.79 mmol) was added to 3-(2-chloro-5-oxo-5,7-dihydro-677-pyrrolo[3,4-Z>]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 at 120°C for 3.5h in a microwave reactor. The mixture was then poured into ice water. A precipitate was collected by filtration and dried under vacuum for 2 days to give the title compound (0.950 g, 57 %) as a beige solid; >H 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.
Figure imgf000145_0001
4M HC1 in dioxane (8.7 mL, 34.93 mmol) was added in one portion to tert-butyl-4-(6-(2,6-dioxopiperidin-3- vl )-5-oxo-6.7-dilwdro-5//-pvrrolo| 3.4-b|pvridin-2-vl (piperazine- 1 -carbox vlate (150 mg, 0.35 mmol) at RT and the mixture was stirred for 4h. The mixture was then concentrated to give the title compound as a bishydrochloride salt as a yellow solid that was used in the next step without further purification; *H 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.
Figure imgf000145_0002
Intermediate 56f was reacted with Intermediate 56k using the general synthetic method illustrated by Example
2 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H 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); Wz ES+ [M+H]+ = 731.4.
Figure imgf000145_0003
Figure imgf000146_0001
Intermediate 9e was reacted with Intermediate 56k using the general synthetic method illustrated 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)); ‘H 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), 8.20 (1H, d), 10.94 (1H, s); Wz ES+ [M+H]+ = 731.4.
Example 58: 4-f4-[5-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1piperazin-l- yllbutoxy)pyridin-2-yl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000146_0002
Intermediate 2c was reacted with Intermediate 9e using the general synthetic method illustrated 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)); ‘HNMR: (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 (1H, s); m/z ES+ [M+H]+ = 730.4.
Intermediate 59a: tert-Butyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-l-carboxylate
Figure imgf000146_0003
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 RT. The resulting mixture was stirred at 120°C for 3h. The mixture was then poured into sat. brine (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic solutions were dried (Na2SC>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 (K)-4-(3-(2-ethoxyvinyl)-4-(methoxycarbonyl)phenyl)piperazine-l- carboxylate
Figure imgf000147_0001
RuPhos Pd G3 (1.678 g, 2.00 mmol) was added to tert-butyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)- piperazine-l-carboxylate (8.00 g, 20.04 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (7.94 g, 40.07 mmol) and CS2CO3 (6.53 g, 20.04 mmol) in 1,4-dioxane (50 mLO and H2O (50 mL) at RT under N2. The resulting mixture was stirred at 80°C for 2h. The mixture was poured into sat. brine (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 10-40% EtOAc in petroleum ether) gave the title compound (7.68 g, 98 %) as a yellow oil; ‘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-l-carboxylate
Figure imgf000147_0002
tert-Butyl (E)-4-(3-(2-ethoxyvinyl)-4-(methoxycarbonyl)phenyl)piperazine- 1 -carboxy late (1.00 g, 2.56 mmol) was added to hydrochloric acid (1.5 mL, 1 .50 mmol) in THF (10 mL) at RT. The resulting mixture was stirred at 40°C for 16h. The mixture was then poured into sat. Nal ICO;, solution (50 mL) and this mixture was extracted with EtOAc (2 x 100 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 20-50% EtOAc in petroleum ether) gave the title compound (0.47 g, 51%) as a pale yellow oil; >H 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-vD-l-oxo-1.2.3.4-tetrahvdroisoquinolin-6- yl)piperazine-l-carboxylate
Figure imgf000147_0003
tert-Butyl 4-(4-(methoxycarbonyl)-3-(2-oxoethyl)phenyl)piperazine-l-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 Q 5 mL) and DCM (15 mL) at RT and the mixture was stirred for Ih. NaBH(OAc)a (2.92 g, 13.80 mmol) was then added and the mixture was stirred at 40°C for 16h then concentrated. Purification by FSC (gradient: 10-50% EtOAc in petroleum ether) gave the title compound (0.50 g, 16%) as a white solid; *H NMR: 1.42 (9H, s), 1.83-1.94 (IH, m), 2.37 (IH, ddd), 2.54 (IH, d), 2.86 (3H, dtd), 3.26-3.28 (4H, m), 3.34-3.52 (6H, m), 5.16 (IH, s), 6.78 (IH, s), 6.89 (IH, d), 7.70 (IH, d), 10.85 (IH, s); m/z ES+ [M+H]+ = 443.
Intermediate 59e: 3-(l-oxo-6-(piperazin-l-yl)-3,4-dihvdroisoquinolin-2(lH)-yl)piperidine-2,6-dione
Figure imgf000148_0001
/w/-Butvl-4-(2-(2.6-dioxopiperidin-3-yl)-l -oxo- 1,2, 3, 4-tetrahydroisoquinolin-6-yl)piperazine-l -carboxylate (100 mg, 0.23 mmol) was added to HC1 in 1,4-dioxane (3 mL, 12.00 mmol) at RT and the mixture was stirred for Ih. The crude mixture was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to give the title compound (0.088 g, 114 %) as a white solid; 1H NMR (300 MHz) 1.82-1.95 (IH, m), 2.30-2.44 (IH, m), 2.57 (IH, d), 2.71-3.02 (3H, m), 3.19-3.20 (4H, m), 3.36-3.61 (6H, m), 5.07-5.29 (IH, m), 6.86 (IH, d), 6.95 (IH, dd), 7.74 (IH, d), 9.21 (IH, br, s), 10.87 (IH, s) m/z ES+ [M+H]+ = 343.
Example 59: 4-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-l,2,3,4-tetrahvdroisoquinolin-6- yl1piperazin-l-yllbutoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000148_0002
Intermediate 50a was reacted with Intermediate 59e using the general synthetic method illustrated 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)); ‘HNMR: 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 (IH, s), 6.78 (IH, s), 6.87 (3H, t), 7.15 (2H, d), 7.26 (IH, d), 7.32 (IH, s), 7.69 (IH, d), 7.81 (IH, d), 10.84 (IH, s); m/z ES+ [M+H]+ = 743.3. pyrrolo[3.4-fe1Pyridin-2-
Figure imgf000148_0003
Intermediate 50a was reacted with Intermediate 56k using the general synthetic method illustrated 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)); ‘H 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
Figure imgf000149_0001
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 CCI4 (5 mL) at RT. The resulting mixture was stirred at 80°C for 4h then concentrated. Purification by 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-dihvdro-2/T-Dyrrolo[3.4-clDyridin-2-yl)Diperidine-2.6-dione
Figure imgf000149_0002
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) at RT under air. The resulting solution was stirred at 80°C for 15h then the mixture was then poured into water (20 mL). This mixture was extracted with EtOAc (3 x 20 mL), and the combined organic solutions were dried (Na2SC>4) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in petroleum ether) gave the title compound as a colourless solid which was used in the next step without further purification.
Figure imgf000149_0003
Pd-PEPPSI-zPent (93 mg, 0.12 mmol) was added to 3-(6-chloro-3-oxo-l,3-dihydro-277-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 CS2CO3 (1153 mg, 3.54 mmol) in 1,4-dioxane (3 mL) at RT under N2. The resulting solution was stirred at 100°C for 3h. 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-l-yl)-l,3-dihvdro-2//-pyrrolo|3,4-t|pyridin-2-yl)piperidine-
2,6-dione
Figure imgf000150_0001
tert-Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-l/f-pyrrolo[3,4-c]pyridin-6-yl)piperazine-l- carboxylate (118 mg, 0.27 mmol) was added to 4M HC1 in 1,4-dioxane (2 mL) at RT under air and the mixture was stirred for 2h. The was then concentrated to give the title compound (0.110 g, 122 %) which was used in the next step without further purification; ‘H 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-f4-[4-(f4-[2-(2.6-DioxoDiDeridin-3-yl)-3-oxo-2.3-dihvdro-l/7-Dyrrolo[3.4-c1pyridin-6- yl1-piperazin-l-yllmethyl)piperidin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl) benzonitrile
Figure imgf000150_0002
Intermediate 4c was reacted with Intermediate 61 d using the general synthetic method illustrated by Example 2 to give the title compound after purification by preparative chiral-HPLC (Column: Viridis BEH 2- Ethylpyridine Prep OBD, 30*150mm, Sum: Mobile Phase A: CO2, Mobile Phase B: MeOH (8mmol/L NI E.MeOH): Flowrate:50 ml, /min: Gradient:28% B; 254 nm; RT1 :6.18; Injection Volume:l mL; Number Of Runs: 10); ‘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-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-3-oxo-2,3-dihvdro[l,2,41triazolo[4,3-«1pyridin-7- yl1-piperazin-l-yllbutoxy)DhenyllDiDeridin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000150_0003
Intermediate 44e was reacted with Intermediate 50a using the general synthetic method illustrated by Example 12 to give the title compound after purification by HPLC (Column: DAICEL DCpak P4VP, 20mm*250mm, Sum: Mobile Phase A:CC>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; ‘HNMR: (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-Hvdroxyphenyl)piperazin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000151_0001
DIPEA (1.47 mL, 8.42 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (1.06 g, 5.61 mmol) and 4-(piperazin- l-yl)phenol (1.00 g, 5.61 mmol) were dissolved in DMSO (5 mL). The mixture was stirred at RT overnight. Water (20 mL) was then added to give a suspension. The suspension was stirred at RT for 20 mins. A solid was collected by filtration, washed with water (50 mL) and hexanes (50 mL) to give the title compound (1.58 g, 81 %) as a cream solid; >H NMR (CDCh) 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)phenyl1piperazin-l-yl1-2-(trifluoromethyl)benzonitrile
Figure imgf000151_0002
4-(4-(4-Hydroxyphenyl)piperazin-l-yl)-2-(trifluoromethyl)benzonitrile (0.520 g, 1.50 mmol), K2CO3 (0.248 g, 1.80 mmol) and 1 ,4-dibromobutane (0.358 mL, 2.99 mmol) were dissolved in anhydrous DMF (20 mL) under N2 and the mixture was stirred for 18h. The mixture was then warmed to 50°C for 16h. The mixture was then diluted with EtOAc (50 mL), washed with sat. Nal ICO;, (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; ‘H NMR (CDCI3) 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-dioxopiperidin-3-vD-5-fluoroisoindoline-l, 3-dione
Figure imgf000151_0003
To a solution of 5-fluoroisobenzofuran-l, 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 18h then concentrated. The residue was poured into water (200 mL) and stirred for 10 mins. A solid was collected by filtration, washed with water (2 x 50 mL) and dried under vacuum to give the title compound (11.8 g, 94 %) as a white solid; *H 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- [M-H]- 275.1.
Intermediate 63d: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazine-l- carboxylate
Figure imgf000152_0001
tert-Butyl piperazine- 1 -carboxylate (2.97 g, 15.9 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,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 2h. The mixture was then cooled to RT, 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 (Na2SO4) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (3.95 g, 62 %) as a yellow solid; >H 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-l-yl)isoindoline-l,3-dione
Figure imgf000152_0002
4M HCI in dioxane (22.3 mL, 89.3 mmol) was added to tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- isoindolin-5-yl)piperazine-l -carboxylate (3.95 g, 8.93 mmol) in DCM (100 mL) at RT and the mixture was stirred for 18h. Concentration under reduced pressure then gave the title compound as a hydrochloride salt (3.40 g, 100 %) as a pale yellow solid; >H 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-dihvdro-l/f-isoindol-5-
Figure imgf000153_0001
Intermediate 63b was reacted with Intermediate 63e using the general synthetic method illustrated by Example 5 to give the title compound after purification by EIPLC (Column A, Eluent A); *H NMR: (CDCI3) 1.71 (214, 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); Wz (ES-) [M-H]- = 742.1.
Figure imgf000153_0002
Intermediate 63b was reacted with Intermediate 2c using the general synthetic method illustrated by Example 5 to give the title compound (as a formate salt) after purification by EIPLC (Column A, Eluent A); *H NMR: (CDCI3) 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, dd), 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, dd), 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.
Figure imgf000153_0003
1 -Bromopyrrolidine-2, 5-dione (10.00 g, 56.18 mmol) was added to 3-phenylpyrrolidine (10.00 g, 67.93 mmol) and H2SO4 (53.00 g, 540.42 mmol) in water (53 mL) at RT. The resulting mixture was stirred at 70°C for 2h. The reaction was then quenched with sat. NaiCO, solution. The resulting mixture was extracted with EtOAc and the combined extract solution were dried QS^SCh) 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+EI]+ = 226.
Figure imgf000153_0004
Figure imgf000154_0001
CS2CO3 (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 RT. The resulting mixture was stirred at 60°C for 2h. The mixture was then concentrated and diluted with EtOAc. The resulting solution was washed with water, dried (Na2SC>4) and concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) gave material that was further purified by SFC (Column: CHIRALPAK AD-H SFC, 5*25cm, Sum: Mobile Phase A:CO2, Mobile Phase B:MeOH (2mM NHs-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 %) as a pale yellow solid and Intermediate 65c (2.200 g, 13 %) as a pale yellow solid. Intermediate 65b: >H 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: >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.
Figure imgf000154_0002
RockPhos Pd G3 (63.6 mg, 0.08 mmol) was added to (r)-4-(3-(4-bromophenyl)pyrrolidin-l-yl)-2-(trifluoro- methyl)benzonitrile (Intermediate 65b) (300 mg, 0.76 mmol), propane-1, 3-diol (87 mg, 1.14 mmol) and CS2CO3 (742 mg, 2.28 mmol) in 1,4-dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h. Purification by FSC (gradient: 0-10% MeOH in DCM) gave 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.
I
Figure imgf000154_0003
PPhs (282 mg, 1.08 mmol) was added to CBr i (357 mg, 1.08 mmol) and (r)-4-(3-(4-(3-hydroxypropoxy)- phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile (210 mg, 0.54 mmol) in DCM (5 mL) at RT and the mixture was stirred for 16h. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (135 mg, 55 %) as a yellow liquid. >H 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 (1H, 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-f(3r)-3-[4-(3-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5- yl1piperazin-l-yllpropoxy)phenyl1pyrrolidin-l-yll-2-(trifluoromethyl) benzonitrile (Absolute configuration not yet established.
Figure imgf000155_0001
Intermediate 2c was reacted with Intermediate 65e using the general synthetic method illustrated by Example 5 to give the title compound after purification by Cl 8- flash chromatography (gradient: 5-50% MeCN in water (0.1% formic acid));‘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[4.51decan-8-yl)phenyl)piperidin-l-yl)-2-
Figure imgf000155_0002
BrettPhos Pd G3 (177 mg, 0.20 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile (800 mg, 1.95 mmol), l,4-dioxa-8-azaspiro[4.5]decane (420 mg, 2.93 mmol) and CS2CO3 (1911 mg, 5.86 mmol) in 1,4-dioxane (30 mL) under N2. The resulting mixture was stirred at 100°C for 3h. The mixture was concentrated and diluted with EtOAc (50 mL). This solution was washed with water (50 mL x 2), dried (Na2SC>4) and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (750 mg, 81 %) as a yellow solid; >H NMR (CDCI3) 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-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000156_0001
Formic acid (17.08 mL, 445.36 mmol) was added to 4-(4-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)- piperidin-l-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 sat. Nal ICO;, (50 mL x 2), dried (Na2SO4) and concentrated to give the title compound (600 mg, 95 %) as a yellow gum; m/z ES+ [M+Na]+ = 450.
Example 66: 4-i4-|4-(4-i4-|2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l//-isoindol-5-yl|piperazin-l- yllpiperidin-l-yl)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000156_0002
Intermediate 2c was reacted with Intermediate 66b using the general synthetic method illustrated by Example 2 to give the title compound after purification by Cl 8- flash chromatography (0-100% MeCN in water); *H 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 (lH, d), 10.94 (1H, s); m/z ES+ [M+H]+ = 740.4.
Intermediate 67a: 5-(4-(4-(4-(Dimethoxymethyl)piperidin-l-yl)phenyl)piperidin-l-yl)-3-
(trifluoromethyl)picolinonitrile
Figure imgf000156_0003
Ruphos Pd G3 (65.3 mg, 0.08 mmol) was added to 5-(4-(4-bromophenyl)piperidin-l-yl)-3-(trifluoromethyl)- picolinonitrile (320 mg, 0.78 mmol), 4-(dimethoxymethyl)piperidine (124 mg, 0.78 mmol),Cs2CO3 (254 mg, 0.78 mmol) and Ruphos (36.4 mg, 0.08 mmol) in 1,4-dioxane (5 mL) at RT under N2. The resulting solution was stirred at 100°C for lOh and then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (200 mg, 53%) as a yellow solid; 'H 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-l-yl)phenyl)piperidin-l-yl)-3-
Figure imgf000157_0001
5-(4-(4-(4-(Dimethoxymethyl)piperidin-l-yl)phenyl)piperidin-l-yl)-3-(trifluoromethyl)picolinonitrile (190 mg, 0.39 mmol) was stirred in formic acid (2 mL) at RT for 2h. The mixture was then concentrated to dryness and the resulting residue was dissolved in EtOAc (25 mL). This solution was washed with sat. Nal ICO;, (20 mL x 3) then sat. brine (20 mL x 2), dried (Na2SO4) 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-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1piperazin-l-
-2-carbonitrile
Figure imgf000157_0002
Intermediate 2c was reacted with Intermediate 67b using the general synthetic method illustrated by Example 2 to give the title compound (as a formate salt) after purification preparative HPLC (Column: Sunfire prep C18 column, 30*150, 5um; Mobile Phase A:Water(0.1% formic acid), Mobile Phase BMeCN; Flow rate:60 mL/min; Gradient:26 B to 40 B in 7 min; 254/220 nm; RT1 .5.55 and MeCN as eluents); 'H 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-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000157_0003
5-Bromo-2-(piperidin-4-yl)pyridine (486 mg, 2.02 mmol) was added to 4-fhioro-2-(trifluoromethyl)- benzonitrile (400 mg, 2.12 mmol) and CS2CO3 (1.723 g, 5.29 mmol) in DMSO (5 mL) at RT. The resulting mixture was stirred at 60°C for 16h. The mixture was then diluted with EtOAc (50 mL), washed with water (50 mL x 3) then sat. brine (50 mL x 2), dried (Na2SO4) 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-l-yl)pyridin-2-yl)piperidin-l-yl)-2-
Figure imgf000158_0001
Ruphos Pd G3 (40.8 mg, 0.05 mmol) was added to 4-(dimethoxymethyl)piperidine (116 mg, 0.73 mmol), CS2CO3 (477 mg, 1.46 mmol) and 4-(4-(5-bromopyridin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (200 mg, 0.49 mmol) in dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h and then concentrated. Purification FSC (gradient: 0-80% EtOAc in petroleum ether) gave the title compound (0.160 g, 67 %) as a yellow solid; >H 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-l-yl)pyridin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000158_0002
4-(4-(5-(4-(Dimethoxymethyl)piperidin-l-yl)pyridin-2-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.31 mmol) was added to formic acid (5 mL, 0.31 mmol) at RT and the mixture was stirred for 4h. The reaction was then quenched with sat. Nal ICO3 and extracted with EtOAc. The combined organic solutions were dried (Na2SO4) and concentrated to give the title compound (0.160 g, 118 %) as yellow gum, which was used in the next step without further purification; *H 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-f5-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5-yl1piperazin-l- yllmethyl)piperidin-l-yl1pyridin-2-yllpiperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000159_0001
Intermediate 2c was reacted with Intermediate 68c using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5|im; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Flow rate:60 mL/min; Gradient:15 B to 25 B in 7 min; 254/220 nm; RTL7.52); ‘HNMR: (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), 3.25-3.60 (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-[(3r)-3-[4-[4-(2.2-Dimethoxyethyl)-l-piperidyl1phenyl1pyrrolidin-l-yl1-2-(trifluoro- methvDbenzonitrile
Figure imgf000159_0002
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), CS2CO3 (989 mg, 3.04 mmol) and 4-[(3r)-3-(4-bromophenyl)pyrrolidin-l- yl]-2-(trifhioromethyl)benzonitrile (Intermediate 65b) (400 mg, 1.01 mmol) in 1,4-dioxane (10 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h and then concentrated. Purification by FSC (gradient: 0-25% EtOAc in petroleum ether) gave the title compound (0.140 g, 28 %) as a yellow solid; *H 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), 3.36-3.51 (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-l-yl)phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000159_0003
4- [(3r)-3- [4-[4-(2,2-Dimethoxyethyl)- 1 -piperidyl]phenyl]pyrrolidin-l -yl]-2-(trifluoromethyl)benzonitrile (140 mg, 0.29 mmol) was added to formic acid (5 mL) at RT and the mixture was stirred for 2h. The reaction was then quenched with sat. Nal ICO;, and the resulting mixture was extracted with EtOAc. The combined organic solutions were dried (Na2SO4) and concentrated to give the title compound (0.157 g, 124 %) as yellow solid, which was used directly in the next step; >H 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-f4-[4-(2-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1- piperazin-l-yllethyl)piperidin-l-yl1phenyllpyrrolidin-l-yl1-2-(trifluoromethyl)benzonitrile (Ab solute stereochemistry not yet confirmed)
Figure imgf000160_0001
Intermediate 2c was reacted with Intermediate 69b using the general synthetic method illustrated by Example 2 to give the title compound after purification by EIPLC (Column: Sunfire prep C18 column, 30*150, 5|im; Mobile Phase A: Water (0.1% formic acid), Mobile Phase BMeCN; Flow rate:60 mL/min; Gradient:20 B to 30 B in 7 min; 254/220 nm; RT1 :8.33); >H 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); Wz ES+ [M+H]+ = 754.3.
Intermediate 70a: (5)-4-(3-(4-(3-Hvdroxypropoxy)phenyl)pyrrolidin-l-yl)-2-
(trifluoromethvDbenzonitrile (Absolute stereochemistry not yet confirmed)
Figure imgf000160_0002
RockPhos Pd G3 (63.6 mg, 0.08 mmol) was added to (s)-4-(3-(4-bromophenyl)pyrrolidin- 1-yl )-2-( trilluoro- methyl)benzonitrile (Intermediate 65c) (300 mg, 0.76 mmol), propane- 1,3 -diol (87 mg, 1.14 mmol) and CS2CO3 (742 mg, 2.28 mmol) in 1 ,4-dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h and then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (120 mg, 41 %) as a white solid; >H 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: (5)-4-(3-(4-(3-Bromopropoxy)phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000161_0001
PPha (134 mg, 0.51 mmol) was added to (s)-4-(3-(4-(3-hydroxypropoxy)phenyl )pyrrolidin- 1 -yl)-2-( tri lino ro- methyl)benzonitrile (100 mg, 0.26 mmol) and CBr i (170 mg, 0.51 mmol) in DCM (3 mL) at RT. The mixture was stirred for Ih, concentrated. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (101 mg, 87 %) as a colourless gum; 'HNMR: 2.01-2.14 (IH, m), 2.23 (2H, p), 2.37 (IH, dtd), 3.33-3.36 (IH, m), 3.41-3.56 (2H, m), 3.60 (IH, ddd), 3.66 (2H, t), 3.85 (IH, dd), 4.06 (2H, t), 6.87 (IH, dd), 6.91-6.96 (3H, m), 7.27 (2H, d), 7.79 (IH, d); m/z ES+ [M+H]+ = 453.
Example 70: 4-{(35)-3-[4-(3-{4-[2-(2.6-DioxoDiDeridin-3-yl)-l-oxo-2.3-dihvdro-l/f-isoindol-5- yl1piperazin-l-yllpropoxy)phenyl1pyrrolidin-l-yll-2-(trifluoromethyl) benzonitrile (Absolute stereochemistry not yet confirmed)
Figure imgf000161_0002
Intermediate 2c was reacted with Intermediate 70b using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5pm; Mobile Phase A: Water(0.1% formic acid), Mobile Phase B: MeCN: Flow rate:60 ml , /min: Gradient:30 B to 40 B in 7 min; 254/220 nm; RTE5.23); ‘HNMR: (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), 3.85 (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)DiDeridin-l-yl)phenyl)Dyrrolidin-l-yl)-2- i-benzonitrile
Figure imgf000161_0003
Ruphos Pd G3 (85 mg, 0.10 mmol) was added to Ruphos (47.2 mg, 0.10 mmol), 4-(dimethoxymethyl)- piperidine (259 mg, 1.49 mmol), CS2CO3 (989 mg, 3.04 mmol) and (r)-4-(3-(4-Bromophenyl)pyrrolidin-l-yl)- 2-(trifhioromethyl)benzonitrile (Intermediate 65b) (400 mg, 1.01 mmol) was added to 1,4-dioxane (10 mL) at RT. The resulting solution was stirred at 100°C for 16h. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (207 mg, 86 %) as a yellow solid; *H NMR (300 MHz) 0.85-0.97 (IH, m) 1.13-1.43 (3H, m), 1.70 (3H, d), 1.97-2.15 (IH, m), 2.36 (IH, d,), 2.60 (IH, d), 3.27 (6H, s), 3.46 (IH, d), 3.54-3.67 (2H, m), 3.69 (IH, s), 3.77-3.89 (IH, m), 4.08 (IH, d), 6.85-6.91 (3H, m), 7.17 (2H, d), 7.79 (IH, d); m/z ES+ [M+H]+ = 474.
Intermediate 71b: (r)-4-(3-(4-(4-Formylpiperidin-l-yl)phenyl)pyrrolidin-l-yl)-2-
Figure imgf000162_0001
(r)-4-(3-(4-(4-(Dimethoxymethyl)piperidin- 1 -yl)phenyl)pyrrolidin- 1 -yl)-2-(trifluoromethyl)benzonitrile (180 mg, 0.38 mmol) was added to formic acid (5 mL) at RT and the mixture was stirred for Ih. The reaction was then quenched with sat. Nal ICO;,. The resulting mixture was extracted with EtOAc, and the organic extract solution was dried (Na2SO4) and concentrated to give the title compound (204 mg, 126 %) as yellow gum, which was used in the next step without further purification; *H NMR (300 MHz) 1.48-1 .71 (3H, m), 1.86- 1.97 (2H, m), 1.96-2.12 (IH, m), 2.26-2.41 (IH, m), 2.74-2.85 (2H, m), 3.35-3.53 (2H, m), 3.56 (3H, dt), 3.76- 3.88 (IH, m), 4.22 (IH, t), 6.81-6.95 (4H, m), 7.18 (2H, d), 7.78 (IH, d), 9.63 (IH, s); m/z ES+ [M+H]+ = 428.
Example 71: 4-[(3r)-3-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1- in-l-yl}methyl)piperidin-l-yllphenyl}pyrrolidin-l-yll-2-( itrile (Absolute stereochemistry not yet confirmed)
Figure imgf000162_0002
Intermediate 2c was reacted with Intermediate 71b using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column A, Eluent A); *H 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 (IH, m), 3.40-3.51 (7H, m), 3.54-3.74 (4H, m), 3.83 (IH, dd), 4.16-4.41 (2H, m), 5.06 (IH, dd), 6.83-6.97 (4H, m), 7.08 (2H, d), 7.18 (2H, d), 7.54 (IH, d), 7.79 (IH, d), 10.96 (IH, s); m/z ES+ [M+H]+ = 740.3.
Intermediate 72a: 4-(4-(4-(Methylamino)phenvDpiperidin-l-vD-2-(trifluoromethvDbenzonitrile
Figure imgf000163_0001
CS2CO3 (1194 mg, 3.67 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluorom ethylbenzonitrile (500 mg, 1.22 mmol) and methanamine 2M solution in THF (794 Lil ,. 1.59 mmol) in 1 ,4-dioxane (5.3 mL). 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 under N2 at 80°C for 18h. The reaction was then quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the combined organic solutions were dried (MgSCL) and concentrated. Purification by FSC (gradient: 0-50% 3:1 EtOAc/EtOH in EtOAc) gave the title compound (318 mg, 72 %) as a beige solid; *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-(l,3-Dioxolan-2-yl)propyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-
:-l, 3-dione
Figure imgf000163_0002
2-(2,6-Dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l, 3-dione hydrochloride salt (250 mg, 0.66 mmol), 2-(3-bromopropyl)-l,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 4h. After cooling to RT, water (10 mL) was added. This mixture was extracted with DCM (2 x 50 mL) and the combined organic solutions were dried (Na2SC>4) and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (220 mg, 73 %) as a yellow solid; >H NMR (CDC13) 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 (2H, 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)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)butanal
Figure imgf000163_0003
Formic acid (2 mL) was added to 5-(4-(3-(l,3-dioxolan-2-yl)propyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l ,3-dione (125 mg, 0.27 mmol) at RT under air. The resulting solution was stirred at 40°C for 0.5h then diluted with toluene (3 mL). The solvent was removed under reduced pressure and the resulting residue was dissolved in toluene (3 mL) and 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. isoindol-5-
Figure imgf000164_0001
Intermediate 72a was reacted with Intermediate 72c using the general synthetic method illustrated by Example 2 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). 'H NMR:
I.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), 2.85 (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),
II .06 (1H, s); mz liS [M+H]+ = 756.0. ridin-2-
Figure imgf000164_0002
Intermediate 4c was reacted with Intermediate 56k using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN: Flowrate:60 ml, /min: Gradient:25 B to 35 B in 7 min; 254/220 nm; RT1 :6.95); ‘HNMR: (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), 2.52-2.77 (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: terZ-Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-l,4-diazepane-l- carboxylate
Figure imgf000164_0003
Pd-PEPPSI Ipent (0.123 g, 0.15 mmol) was added to 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (1.00 g, 3.09 mmol), tert-butyl 1,4-diazepane-l -carboxy late (0.806 g, 4.02 mmol) and CS2CO3 (3.02 g, 9.28 mmol) in 1 ,4-dioxane (15 mL) at RT under N2. The resulting mixture was stirred at 90°C for 16h. 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 (TfeSCh) and concentrated. Purification by FSC (gradient: 0-10% EtOH in EtOAc) gave the title compound (0.400 g, 29 %) as a white solid; m/z ES+ [M+H]+ = 443.
Intermediate 74b: 3-(5-(l,4-Diazepan-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000165_0001
tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-l,4-diazepane-l-carboxylate (390 mg, 0.88 mmol) was added to hydrochloric acid (0.134 mL, 4.41 mmol) in 1,4-dioxane (5 mL) at RT and the mixture was stirred for 2h. The mixture was then concentrated to give the title compound as a hydrochloride salt (300 mg, 99 %) as brown solid that was used in the next step without further purification; *H 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-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1-l,4- an-1-' in-1-' in-l-vD-2-i
Figure imgf000165_0002
Intermediate 4c was reacted with Intermediate 74b using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column: Sunfire prep C18 column, 30*150, 5|im; Mobile Phase A: Water (0.1% formic acid), Mobile Phase BMeCN; Flow rate:60 mL/min; Gradient:25 B to 35 B in 7 min; 254/220 nm; RT 1 :7.70); ‘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. idin-l-yll-2-
Figure imgf000166_0001
Rockphos Pd G3 (83.8 mg, 0.10 mmol) was added to CS2CO3 (975 mg, 2.99 mmol), butane- 1,4-diol (135 mg, 1.50 mmol) and 4-[(3r)-3-(4-bromophenyl)pyrrolidin-l-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 65b) (400 mg, 1.01 mmol) in dioxane (10 mL). The resulting mixture was stirred at 100°C for 16h 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; >H NMR: 1.51-1.59 (2H, m), 1.69-1.77 (2H, m), 2.02-2.14 (IH, m), 2.31-2.43 (IH, m), 3.39-3.53 (5H, m), 3.61 (IH, t), 3.85 (IH, dd), 3.96 (2H, t), 4.23 (IH, t), 6.84-6.92 (3H, m), 6.94 (IH, d), 7.23-7.28 (2H, m), 7.80 (IH, d).
Intermediate 75b: (r)-4-(3-(4-(4-Oxobutoxy)phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000166_0002
Dess- Martin periodinane (450 mg, 1.06 mmol) was added to (4-[(3r)-3-[4-(4- hydroxybutoxy)phenyl]pyrrolidin-l-yl]-2-(trifluoromethyl)benzonitrile (203.8 mg, 0.50 mmol) in DCM (5 mL) at RT and the mixture was stirred for Ih. The mixture was then quenched with sat. Nal ICO;,. The resulting mixture was extracted with DCM, and the organic extract solution was dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-25% EtOAc in petroleum ether) gave the title compound (0.094 g, 46 %) as a brown liquid; ‘H NMR: 1.91-2.02 (3H, m), 2.03-2.11 (IH, m), 2.37 (IH, dtd), 2.59 (2H, td), 3.41-3.55 (2H, m), 3.60 (IH, ddd), 3.84 (IH, dd), 3.96 (2H, t), 6.84-6.91 (3H, m), 6.94 (IH, d), 7.26 (2H, d), 7.79 (IH, d), 9.71 (IH, t); m/z ES+ [M+H]+ = 403.
Example 75: 4-f(3R)-3-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5- yl1piperazin-l-yllbutoxy)phenyl1pyrrolidin-l-yll-2-(trifluoromethyl) benzonitrile (Absolute stereochemistry not yet confirmed)
Figure imgf000166_0003
Intermediate 2c was reacted with Intermediate 75b using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column A, Eluent A); *H 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 (IH, m), 3.48-3.61 (5H, m), 3.85 (IH, m), 3.99 (2H, t), 4.21 (IH, d), 4.33 (IH, d), 5.05 (IH, m), 6.83-6.95 (4H, m), 7.06-7.08 (2H, s), 7.22-7.30 (2H, m), 7.53 (IH, d), 7.80 (IH, d), 10.96 (IH, s); Wz ES+ [M+H]+ = 715.3. Intermediate 76a: Methyl 4-(piperidin-4-yl)benzoate
Figure imgf000167_0001
SOCI2 (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) at 0°C under air. The resulting solution was then stirred at 70°C for 15h and then concentrated to give the title compound (8.70 g, 39.7 mmol); *H NMR (CD3OD) 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
Figure imgf000167_0002
LiAlEU (2.5M 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 RT for 2h then quenched by addition of Na2SO4.H2O. The mixture was then filtered and the filtrate was concentrated. Purification by FSC (gradient: 0- 20% MeOH in DCM (containing 0.3% Et3N)) gave the title compound (7.40 g, 97%) as a white solid; *H NMR (CD3OD, 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-(Hvdroxymethyl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000167_0003
4-Fhioro-2-(trifhioromethyl)benzonitrile (6.72 g, 35.55 mmol) was added to CS2CO3 (34.70 g, 106.65 mmol) and (4-(piperidin-4-yl)phenyl)methanol (6.80 g, 35.55 mmol) in DMF (50 mL) at RT under air and the mixture was stirred for 15h. The mixture was then diluted with EtOAc (150 mL), washed with sat. brine (100 mL x 3), dried (Na2SC>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; >H NMR (CD3OD, 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-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000168_0001
Dess- Martin Periodinane (15.36 g, 36.21 mmol) was added to 4-(4-(4-(hydroxymethyl)phenyl)piperidin-l-yl)- 2-(trifhioromethyl)benzonitrile (8.70 g, 24.14 mmol) in DCM (5 mL) at RT under air and the mixture was stirred for 3h. The mixture was then diluted with DCM (50 mL), washed with sat. brine (50 mL x 7), dried (Na2SC>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; 'H NMR ^DjOD) 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)-l-oxoisoindolin-5-yl)piperazin-l- vDpiperidine-1-carboxylate
Figure imgf000168_0002
NaBHfOAch (3.23 g, 15.23 mmol) was added to 3-(l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2,6- dione (1.0 g, 3.05 mmol), tert-butyl 4-oxopiperidine-l -carboxylate (0.607 g, 3.05 mmol) and Ti(OEt)4 (1.389 g, 6.09 mmol) in 1 ,2-dichloroethane (50 mL) at RT and the mixture was stirred for 3h. 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 (T^SCh) and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (0.500 g, 32 %) as a yellow solid; m/z ES+, [M+H]+ = 512.
Intermediate 76f: 3-(l-Oxo-5-(4-(piperidin-4-yl)piperazin-l-yl)isoindolin-2-yl)piperidine-2,6-dione
Figure imgf000168_0003
4M HC1 in 1 ,4-dioxane (1.955 mL, 7.82 mmol) was added dropwise to tert-butyl 4-(4-(2-(2,6-dioxopiperidin- 3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)piperidine-l-carboxylate (400 mg, 0.78 mmol) in DCM (20 mL) over a period of 2 mins and the mixture was stirred at RT for 2h. Concentration under reduced pressure then gave the title compound as a hydrochloride salt (300 mg, 79 %) as a white solid; m/z ES+, [M+H]+ = 412.
Example 76: 4-(4-!4-[(4-!4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro- isoindol-5-yl|piperazin-l-
Figure imgf000168_0004
Figure imgf000169_0001
Intermediate 76d was reacted with Intermediate 76f using the general synthetic method illustrated by Example 2 to give the title compound (as a formate salt) after purification by EIPLC (Column A, Eluent A), t; *H 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-Hvdroxyethoxy)ethoxy)ethyl)amino)-l-oxoisoindolin-2-yl)piperidine-
2,6-dione
Figure imgf000169_0002
3-(4-Amino-l -oxoisoindo lin-2-yl)piperidine-2, 6-dione (100 mg, 0.39 mmol) and 2-(2-(2-bromoethoxy)- ethoxy)ethan-l-ol (100 mg, 0.47 mmol) was added to DIPEA (0.067 mL, 0.39 mmol) inNMP (0.5 mL). The resulting mixture was stirred at 130°C for 12h and was then concentrated to give the title compound as a brown dry film which was used in the next step without further purification; *H NMR: 2.00-2.07 (114, 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)-l-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl methanesulfonate
Figure imgf000169_0003
Methane sulfonic anhydride (89 mg, 0.51 mmol) was added to 3-(4-((2-(2-(2-hydroxy ethoxy )ethoxy)ethyl)- amino)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (100 mg, 0.26 mmol) and EtaN (107 Lil,. 0.77 mmol) in DCM (10 mL) at 0°C. The resulting solution was stirred at RT for 1 ,5h. The mixture was then diluted with DCM (20 mL), washed with water (20 mL) then sat. brine (20 mL), dried (TS^SCL) 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-i2-|2-(2-il2-(2,6>-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l //-isoindol-4-yl|amino!- lin-l-vll-2-i
Figure imgf000170_0001
4-(4-(4-Hydroxyphenyl)piperidin-l-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 RT for 2h. 2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-l-oxo- isoindolin-4-yl)amino)ethoxy)ethoxy)ethyl methanesulfonate (122 mg, 0.26 mmol) was then added and the mixture was stirred for 2h. Purification by preparative HPLC (SunFire Prep C18 OBD column, 30x150mm 5|im; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN) gave the title compound (10 mg, 5%) as a white solid. >H 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), 7.10-7.18 (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.
Intermediates 78a: rac-4-(3-(4-Bromophenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000170_0002
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 3h. The mixture was the concentrated to dryness and the residue was dissolved in EtOAc (100 mL). This solution was washed with water (100 mL x 2) then sat. brine (100 mL), then dried (Na2SO4) and concentrated. Purification by FSC (gradient: 1-20% EtOAc in petroleum ether) gave the title compound (2.20 g, 50%) as a colourless oil which solidified on standing; m/z ES+ [M+H]+ = 395.
Intermediate 78b: 4-(3-(4-(4-(((terZ-butyldimethylsilyl)oxy)methyl)piperidin-l-yl)phenyl)pyrrolidin-l- yl)-2-(trifluoromethvDbenzonitrile
Figure imgf000171_0001
RuPhos Pd G3 (85 mg, 0.10 mmol) was added to 4-(3-(4-bromophenyl)pyrrolidin-l-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 CS2CO3 (989 mg, 3.04 mmol) in 1,4-dioxane (5 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h then concentrated. Purification FSC (0-100% EtOAc in heptane) gave the title compound (440 mg, 80 %) as a yellow liquid; *H 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-(Hvdroxymethyl)DiDeridin-l-yl)Dhenyl)pyrrolidin-l-yl)-2-
(trifluoromethyl)benzonitrile
Figure imgf000171_0002
Tetra-w-butylammonium fluoride (in THF, 2.94 mL, 2.94 mmol) was added to 4-(3-(4-(4-(((tert-butyldimethyl- silyl)oxy)methyl)piperidin-l-yl)phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile (400 mg, 0.74 mmol) in THF (10 mL) at RT. The resulting solution was stirred at RT for 1 ,5h. The mixture was then diluted with EtOAc, washed with water then sat. brine, then dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (239 mg, 75 %) as a white solid; *H NMR (300 MHz) 1.22 (2H, qd), 1.55-1.43 (IH, m), 1.77-1.66 (2H, m), 2.07 (IH, q), 2.35 (IH, tt), 2.59 (3H, td), 3.28 (2H, dd), 3.45 (2H, td), 3.61-3.54 (IH, m), 3.64 (2H, dd), 3.82 (IH, dd), 4.47 (IH, t), 6.96-6.81 (4H, m), 7.21-7.12 (2H, m), 7.78 (IH, d); Wz ES+ [M+H]+ = 430.
Intermediate 78d: 4-(3-(4-(4-Formylnirieridin-l-yl)rihenyl)riyrrolidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000171_0003
Dess- Martin periodinane (415 mg, 0.98 mmol) was added to 4-(3-(4-(4-(hydroxymethyl)piperidin-l-yl)- phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile (210 mg, 0.49 mmol) in DCM (5 mL) at RT. The resulting solution was stirred at RT for Ih. The mixture was then diluted with DCM, washed with sat.
Nal ICO;,, then sat. brine, dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (75 mg, 36 %) as a yellow solid; *H NMR (300 MHz) 1.57 (2H, dtd), 1.92 (2H, dd), 2.04 (IH, dd), 2.35 (IH, d), 2.54 (2H, s), 2.79 (2H, td), 3.27 (IH, s), 3.46 (3H, td), 3.56 (3H, dt), 3.82 (IH, dd), 6.96-6.81 (4H, m), 7.23-7.13 (2H, m), 7.78 (IH, d), 9.63 (IH, s); m/z ES+, [M+H]+ = 428.
Example 78: 4-(3-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1piperazin-l- lidin-l-vD-2-i
Figure imgf000172_0001
Intermediate 2c was reacted with Intermediate 78d using the general synthetic method illustrated by Example 2 to give the title compound after purification by EIPLC (Column: SunFire Cl 8 OBD Prep Column, , 100A, 5 pm, 19 mm x 250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Flow rate:25 mL/min; Gradient:30 B to 45 B in 7 min; 254/220 nm; RT1 :6.50); >H 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 (IH, m), 3.45-3.49 (4H, m), 3.62-3.65 (3H, m), 3.78-3.89 (IH, m), 4.21 (IH, d), 4.35 (IH, d), 5.06 (IH, dd), 6.85-6.98 (4H, m), 7.08 (2H, d), 7.18 (2H, d), 7.54 (IH, d), 7.80 (IH, d), 10.96 (IH, s); m/z ES+ [M+H]+ = 740.4.
Intermediate 79a: (5)-4-(3-(4-(4-Hvdroxybutoxy)phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile
(Absolute stereochemistry not yet confirmed)
Figure imgf000172_0002
RockPhos Pd G3 (85 mg, 0.10 mmol) was added to (s)-4-(3-(4-bromopheny l)pyrro lidin- l-yl)-2-(trifluoro- methyl)benzonitrile (Intermediate 65c) (400 mg, 1.01 mmol), 1 ,4-butanediol (137 mg, 1.52 mmol) and CS2CO3 (989 mg, 3.04 mmol) in 1,4-dioxane (10 mL) at RT under N2. The resulting mixture was stirred at 100°C for 16h then concentrated. Purification by FSC (gradient: 0-25% EtOAc in petroleum ether) gave the title compound (177 mg, 43 %) as a yellow gum; >H NMR: 1.55 (2H, dq), 1.72 (2H, dq), 2.01-2.12 (IH, m), 2.29-2.42 (IH, m), 3.33-3.35 (IH, m), 3.41-3.53 (4H, m), 3.60 (IH, ddd), 3.84 (IH, dd), 3.95 (2H, t), 4.44 (IH, t), 6.83-6.93 (3H, m), 6.94 (IH, d), 7.25 (2H, d), 7.79 (IH, d).
Intermediate 79b: (5)-4-(3-(4-(4-Oxobutoxy)phenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000172_0003
Dess- Martin periodinane (236 mg, 0.56 mmol) was added to (s)-4-(3-(4-(4-hydroxybutoxy)phenyl)pyrrolidin- l-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.37 mmol) in DCM (5 mL) at RT. The resulting mixture was stirred at RT for Ih. The mixture was then diluted with DCM, washed with sat. Na HCC);, then sat. brine, dried (Na2SO4) 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-{(35)-3-[4-(4-{4-[2-(2.6-DioxoDiDeridin-3-yl)-l-oxo-2.3-dihvdro-l/7-isoindol-5- yl1piperazin-l-yllbutoxy)phenyl1pyrrolidin-l-yll-2-(trifluoromethyl) benzonitrile (Absolute stereochemistry not yet confirmed)
Figure imgf000173_0001
Intermediate 2c was reacted with Intermediate 79b using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column: SunFire Cl 8 OBD Prep Column, 100A, 5 pm, 19 mm x 250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Flow rate:25 mL/min; Gradient: 42 % to 50 % in 7 min; 254/220 nm; RT1 :5.56); >H 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-l-yl)phenyl)piperidin-l-yl)-2-(trifluoro-
Figure imgf000173_0002
4-(4-(4-Bromophenyl)piperidin-l-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 N2 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 solutions were dried (IS^SCL) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.393 g, 33 %) as a pale yellow solid; >H NMR (CDCI3) 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 (3aR,6a>y)-5-(l-oxo-l,3-dihvdroisobenzofuran-5-yl)hexahvdropyrrolo[3,4- c] pyrrole-2( 1/D-carboxylate
Figure imgf000174_0001
tert-Butyl (3aR,6aN)-hexahydropyrrolo[3,4-c]pyrrole-2( 17/)-carboxylate (4.19 g, 19.72 mmol) was added to 5- lliioroisobenzoliiran-l (3//)-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 40h. The reaction mixture was then poured into water. A precipitate was collected by filtration, washed with water (100 mL) and dried under vacuum. Purification by FSC (gradient: 0-40% EtOAc in DCM) gave the title compound (5.10 g, 75 %) as a white solid; *H 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.
Figure imgf000174_0002
NaOH (2.32 g, 58.07 mmol) was added to tert-butyl (3aR,6aS)-5-(l-oxo-l,3-dihydroisobenzofuran-5-yl)hexa- hydropyrrolo[3,4-c]pyrrole-2(177)-carboxylate (5.00 g, 14.52 mmol) in THF (10 mL), MeOH (10 mL) and water (10 mL). The resulting solution was stirred at RT for 2h. The mixture was then diluted with water (50 mL) and washed with EtOAc (150 mL x 4). The combined organic solutions were dried (MgSCh) and concentrated to give the title compound which was used in the next step without further purification; *H 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.
Figure imgf000174_0003
Figure imgf000175_0001
Trimethylsilyldiazomethane (20.69 mL, 41.39 mmol) was added in one portion to 4-((3aR,6a<S)-5-(tert- butoxycarbonyl)-hexahydropyrrolo[3,4-c]pyrrol-2(l//)-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 2h. The mixture was then quenched with water (600 mL) and extracted with EtOAc (3 x 300 mL). The combined organic solution 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 (3aR,6a>y)-5-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)hexahvdro- pyrrolo[3,4-c1pyrrole-2(l/D-carboxylate
Figure imgf000175_0002
PPha (4.44 g, 16.92 mmol) was added in one portion to tert-butyl (3aR,6a<S)-5-(3-(hydroxymethyl)-4- (methoxy-carbonyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(l//)-carboxylate (4.90 g, 13.02 mmol) and CBr i (5.61 g, 16.92 mmol) in THF (80 mL) at RT. The resulting solution was stirred at RT for 16h. 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.
Figure imgf000175_0003
DIPEA (5.02 mL, 28.76 mmol) was added in one portion to tert-butyl (3aR,6aS)-2-(l-(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 RT. The resulting solution was stirred at 80°C for 35h. 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.
Figure imgf000176_0001
A solution of tert-butyl (3aR,6aS)-2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-l ,3,3a,4,6,6ahexahydro- pyrrolo[3,4-c]pyrrole-5-carboxylate (4.00 g, 8.80 mmol) in formic acid (20.4 mL) was stirred at RT for 16h. 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.
Figure imgf000176_0002
Formic acid (3 mL) was added to 4-(4-(4-(4-(dimethoxymethyl)piperidin-l-yl)phenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (70 mg, 0.14 mmol) and 3-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(l//)- yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (50.9 mg, 0.14 mmol) at RT under air. The resulting solution was stirred at 40°C for 0.5h 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 RT. The resulting suspension was stirred for 0.5h under air at RT. The mixture was then diluted with EtOAc (20 mL), washed with sat. Nal ICO;, (2 x 5 mL) then sat. brine (5 mL), dried (MgSO.4) and concentrated. Purification by preparative HPLC (Column A, Eluent A) was carried out. Fractions containing the desired compound were concentrated to remove the MeCN and basified with sat. aq. Nal ICO;, to pH 9. This solution was then extracted with DCM (4 x 20 mL), the combined extracts were dried (MgSO.4) and concentrated to dryness to give the title compound (26.0 mg, 23 %) as a white solid; 'H NMR ^DCh) 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 (1H, 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 (2H, 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 (1H, 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 (l/?,4/?)-5-(l-oxo-l,3-dihvdroisobenzofuran-5-yl)-2,5-
Figure imgf000177_0001
DIPEA (10.33 mL, 59.16 mmol) was added to (lR,4R)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (4.69 g, 23.66 mmol) and 5-fluoroisobenzofuran-l(377)-one (3.00 g, 19.72 mmol) in DMSO (30 mL) at RT. The resulting mixture was stirred at 120°C for 16h. 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; H NMR (300 MHz, CDCh) 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-((1R,4R)-5-(tert-Butoxycarbonyl)-2,5-diazabicvclo[2.2.11heptan-2-yl)-2- (hvdroxymethyl)benzoic acid
Figure imgf000177_0002
NaOH (2.42 g, 60.54 mmol) was added to tert-butyl (lR,4R)-5-(l-oxo-l,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 RT and the mixture was stirred at RT for 16h. The solvent was removed under reduced pressure. The residue was acidified with 2M HC1. 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 (1R,4R)-5-(3-(hvdroxymethyl)-4-(methoxycarbonyl)phenyl)-2,5- diazabicvclo [2.2.11heptane-2-carboxylate
Figure imgf000178_0001
Trimethylsilyldiazomethane (21.5 mL, 43.05 mmol) was added in one portion to 4-((1R,4R)-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 2h then water (600 mL) was added. This mixture was extracted with EtOAc (3 x 300 mL), 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.
Figure imgf000178_0002
I’h;, I’ (5.65 g, 21.53 mmol) was added to tert-butyl (1R, 4R)-5-(3-(hydroxymethyl)-4-(methoxy carbonyl)- phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.20 g, 14.35 mmol) and CBr i (7.14 g, 21.53 mmol) in THF (50 mL) at RT and the mixture was stirred at RT for 2h. The mixture was then filtered and the filtrate concentrated. Purification by FSC (gradient: 0-10% EtOAc in petroleum ether) gave the title compound (4.30 g, 71 %) as a white solid; *H NMR (300 MHz, CDC13) 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.
Figure imgf000178_0003
Figure imgf000179_0003
DIPEA (1.77 mL, 10.11 mmol) was added to tert-butyl (lR,4R)-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 2h then concentrated. Purification by FSC (gradient: 0-50% EtOAc in DCM) gave the title compound (2.20 g, 49 %) as a green solid; >H NMR (300 MHz, CDC13) 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-|(l/?,4/?)-2,5-Diazahicvclo|2.2.1 |heptan-2-yl|-l-oxo-isoindolin-2-yl|piperidine-2,6- dione
Figure imgf000179_0001
tert-Butyl ( lR,4R)-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 RT for 2h. Concentration under reduced pressure then gave the title compound (1.50 g, 63 %) as a black solid; *H 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 (1H, 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.
Figure imgf000179_0002
Formic acid (3 mL) was added to 4-(4-(4-(4-(dimethoxymethyl)piperidin-l-yl)phenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (70 mg, 0.14 mmol) and 3-[5-[( lR,4R)-2,5-Diazabicyclo[2.2.1 ]heptan-2-yl]-l- oxo-isoindolin-2-yl]piperidine-2, 6-dione (49 mg, 0.14 mmol) at RT under air. The resulting solution was stirred at 40°C for 0.5h 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 RT. The resulting suspension was stirred for 18h under air at RT. The mixture was then diluted with EtOAc (20 mL), washed with sat. Nal ICO3 (2 x 5 mL) then sat. brine (5 mL), dried (MgSO.4) and concentrated. Purification by preparative HPLC (Column A, Eluent A, Basic Work-Up A) gave the title compound (41.0 mg, 37 %) as a white solid; *H NMR: (CDCI3) 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), 2.31 (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)-l-oxoisoindolin-5-yl)-3,9-diazaspiro[5.51- undecane-3-i
Figure imgf000180_0001
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-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (0.90 g, 2.79 mmol) and CS2CO3 (2.72 g, 8.36 mmol) in 1,4-dioxane (30 mL) at RT under N2. The resulting suspension was vacuum degassed, backfilling with N2 and stirred at 110°C for 3h. The mixture was then cooled to RT, diluted with DCM (100 mL) and washed with 5% AcOH in water (50 mL), then brine (50 mL). The organic layer was dried (MgSCL) 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. 'H NMR ^DCh) 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-f4-[4-(f9-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1-3,9-diaza- spiro[5.51undecan-3-yllmethyl)piperidin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000180_0002
Intermediate 80a was reacted with Intermediate 82a using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H NMR: (CDClj) 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 (3H, 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), 7.61 (1H, d), 7.71 (1H, d), 7.86 (1H, s); m/z ES+ [M+H]+ = 822.5.
Intermediate 83a: tert-Butyl methyl(l-(l-oxo-l,3-dihvdroisobenzofuran-5-yl)piperidin-4-yl)carbamate
Figure imgf000181_0001
DIPEA (6.89 mL, 39.44 mmol) was added in one portion to 5-lliioroisobenzol'uran- l(3/7)-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 RT. The resulting solution was stirred at 120°C for 16h. The mixture was then poured into water (100 mL). This mixture was extracted with EtOAc (3 * 75 mL) and the combined organic solutions were dried ( MgSO i ) and concentrated. Trituration with EtOAc and petroleum ether (1 :5) to give a solid which was collected by filtration and dried under vacuum to give the title compound (5.82 g, 85 %) as a white solid; 'H NMR (CDCL) 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-l-yl)-2-(hvdroxymethyl)benzoic acid
Figure imgf000181_0002
NaOH (0.716 g, 17.90 mmol) was added in one portion to tert-butyl methyl(l-(l-oxo-l,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 2h then IM HC1 (70 mL) was added. The mixture was extracted with EtOAc (3 x 300 mL) and the combined organic solutions were dried (MgSCL) 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; 11 NMR (300 MHz. CDCL) 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-l-yl)-2- (hvdroxymethyl)benzoate
Figure imgf000182_0001
Trimethylsilyldiazomethane (25.5 mL, 51.04 mmol) was added in one portion to 4-(4-((tert-butoxycarbonyl)- (methyl)-amino)piperidin-l-yl)-2-(hydroxymethyl)benzoic acid (6.20 g, 17.01 mmol) in MeOH (40 mL) and EtOAc (40 mL) at -10°C. The resulting solution was stirred at -10°C for 2h then 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; >H NMR (300 MHz, CDC13) 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), 4.28 (1H, s), 4.72 (2H, s), 6.70-6.87 (1H, m), 6.87 (1H, d), 7.91 (1H, d); Wz ES+, [M+H]+ = 379.2.
Intermediate 83d: Methyl 2-(bromomethyl)-4-(4-((ter<-butoxycarbonyl)(methyl)amino)DiDeridin-l-
Figure imgf000182_0002
PPha (4.96 g, 18.89 mmol) was added in one portion to methyl 4-(4-((tert-butoxycarbonyl)(methyl)amino)- piperidin-l-yl)-2-(hydroxymethyl)benzoate (5.50 g, 14.53 mmol) and CBr i (6.27 g, 18.89 mmol) in THF (80 mL) at RT. The resulting solution was stirred at RT for 16h and 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; *H NMR (300 MHz, CDCh) 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 (l-(2-(2,6-dioxoriirieridin-3-yl)-l-oxoisoindolin-5-yl)riirieridin-4-yl)-
Figure imgf000182_0003
DIPEA (5.94 mL, 33.99 mmol) was added in one portion to methyl 2-(bromomethyl)-4-(4-((tert-butoxy- carbonyl)(methyl)amino)piperidin-l-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 RT. The resulting solution was stirred at 80°C for 2 days then stirred overnight at RT. A precipitate was collected by filtration, washed with MeCN (100 mL) and dried under vacuum. Purification by FSC (gradient: 0-50% EtOAc in DCM) gave the title compound (3.30 g, 64 %) as a black solid; >H 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); Wz ES+, [M+H]+ = 457.2.
Figure imgf000183_0001
4M HC1 in 1,4-dioxane (30 mL, 120.00 mmol) was added dropwise to butyl-(l-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperidin-4-yl)(methyl)carbamate (3.30 g, 7.23 mmol) in 1,4-dioxane (10 mL) at RT under N2. The resulting mixture was stirred at RT for 16h. The mixture was then diluted with EtOAc (120 mL). A precipitate was collected by filtration, washed with EtOAc (300 mL) and dried under vacuum to give the title compound (2.90 g, 93 %) as a white solid; *H 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); Wz ES+, [M+H]+ = 357.2.
Figure imgf000183_0002
Intermediate 80a was reacted with Intermediate 83f using the general synthetic method illustrated by Example
2 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H NMR:
(CDClj) 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), 5.19 (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); Wz ES+ [M+H]+ = 782.5.
Intermediate 84a: tert-Butyl 4-((4-(4-(l-(4-cvano-3-(trifluoromethvDphenvDpiperidin-4-vDphenvD- piperazin-1-vDmethvDpiperidine-l-carboxylate
Figure imgf000184_0001
BrettPhos Pd G3 (0.222 g, 0.24 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile (2.00 g, 4.89 mmol), tert-butyl 4-(piperazin-l-ylmethyl)piperidine-l -carboxylate (1.524 g, 5.38 mmol) and CS2CO3 (4.78 g, 14.66 mmol) in 1,4-dioxane (20 mL) at RT under N2. The resulting solution was stirred at 100°C for 2h 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-l-yl)phenyl)piperidin-l-yl)-2-
(trifluoromethvDbenzonitrile
Figure imgf000184_0002
4M HC1 in 1,4-dioxane (12.26 mL, 49.04 mmol) was added slowly to tert-butyl 4-((4-(4-(l-(4-cyano-3- (trifluoromethyl)phenyl)piperidin-4-yl)phenyl)piperazin-l-yl)methyl)piperidine-l -carboxylate (1.50 g, 2.45 mmol) in DCM (50 mL). The resulting mixture was stirred at RT for 2h then concentrated. Purification by flash C18-flash chromatography (gradient: 0-100% MeCN in water (0.1 NH4OH)) gave the title compound (0.950 g, 76 %) as a yellow solid; m/z ES+, [M+H]+ = 512.
84: 4-(4-f4-[4-(fl-[2-(2,6-Dioxopiperidin-3-vl)-l-oxo-2,3-dihvdro-lZT-isoindol-5-vllpiperidin-4- yllmethyl)piperazin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000184_0003
Pd-PEPPSI-IPent (107 mg, 0.14 mmol) was added to 4-(4-(4-(4-(piperidin-4-ylmethyl)piperazin-l-yl)phenyl)- piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (700 mg, 1.37 mmol), 3-(5-bromo-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione (442 mg, 1.37 mmol) and CS2CO3 (892 mg, 2.74 mmol) in DMF (20 mL) under N2. The resulting mixture was stirred at 100°C for 15h. The mixture was then filtered through celite. Purification by flash C18-flash chromatography (gradient: 0- 90% MeCN in water (containing 0.5% formic acid)) gave material that was further purified by preparative HPLC (Column: Xselect CSH OBD Column 30*150mm Sum: Mobile Phase A:Water(0.1% formic acid), Mobile Phase BMeCN: Flow rate:60 ml, /min: Gradient: 34%B to 44%B in 7 min; 254 nm) to give the title compound as a formate salt (71.0 mg, 7%) as a yellow solid; ‘HNMR: 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.
Figure imgf000185_0001
Intermediate 56f was reacted with Intermediate 63e using the general synthetic method illustrated by Example 2 to give the title compound after purification by EIPLC (Column A, Eluent A, Basic Work-Up A); '14 NMR: (CDCI3) 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.
Figure imgf000185_0002
Intermediate 2c was reacted with Intermediate 56f using the general synthetic method illustrated by Example 2 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-Up A); *H NMR: (CDCI3) 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), 6.87 (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-f4-[4-(fl-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-l/T-isoindol-5- yl1piperidin-4-yllmethyl)piperazin-l-yl1phenyllpiperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000186_0001
DIPEA (0.319 mL, 1.82 mmol) was added to 4-(4-(4-(4-(piperidin-4-ylmethyl)piperazin-l- yl)phenyl)piperidin-l-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 3h. The mixture was then diluted with EtOAc (50 mL), washed with water (50 mL) and then sat. brine (50 mL), dried (IS^SCL) and concentrated. Purification by preparative HPLC (Column A, Eluent A) gave the title compound (30.0 mg, 11 %) as a yellow solid; 'H 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), 7.20-7.30 (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-Hvdroxypentyl)oxy)pyridin-3-yl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000186_0002
4-(4-(6-Chloropyridin-3-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (0.50 g, 1.37 mmol), CS2CO3 (1.55 g, 4.78 mmol) and pentane- 1,5-diol (0.72 mL, 6.83 mmol) were dissolved in toluene (15 mL) at degassed with
N2. Rockphos Pd G3 (0.057 g, 0.07 mmol) was then added and the mixture was heated at 90°C for 2h.
The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL) and then sat. brine (100 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.375 g, 64 %) as a pale yellow oil; >H NMR (CDCI3) 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);
Figure imgf000187_0001
Dess- Martin periodinane (205 mg, 0.48 mmol) was added to 4-(4-(6-((5-hydroxypentyl)oxy)pyridin-3-yl)- piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (190 mg, 0.44 mmol) in DCM (5 mL) at RT. The resulting mixture was stirred at RT for Ih. The mixture was then diluted with DCM (15 mL) and poured into mixture of sat. NaHCOa (25 mL) and sodium thiosulfate solution (25 mL). The resulting suspension was stirred vigorously for 10 mins and the layers were separated. The organic solution was dried ( Na^SO i) 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; >H NMR (CDCh) 1.75 (2H, td), 1.8-1.83 (3H, m), 1.98 (2H, d), 2.52 (2H, td), 2.75 (IH, ddt), 3.06 (2H, td), 3.93-4.09 (2H, m), 4.19-4.35 (2H, m), 6.69 (IH, d), 7.00 (IH, dd), 7.16 (IH, d), 7.42 (IH, dd), 7.62 (IH, d), 7.96-8.03 (2H, m), 9.79 (IH, t); m/z\ ES+ [M+H]+ 432.2. -
Figure imgf000187_0002
Intermediate 63e was reacted with Intermediate 88b using the general synthetic method illustrated by Example 2 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). *H NMR: (CDClj) 1.51 (2H, p), 1.65-1.76 (3H, m), 1.76-1.86 (3H, m), 1.97 (2H, d), 2.14 (IH, ddq), 2.62-2.71 (2H, m), 2.71-2.74 (IH, m), 2.77 (IH, dd), 2.8-2.86 (IH, m), 2.89 (5H, dt), 3.06 (2H, td), 3.53-3.58 (4H, m), 3.71 (IH, s), 4.03 (2H, d), 4.27 (2H, t), 4.94 (IH, dd), 6.71 (IH, s), 7.00 (IH, dd), 7.07 (IH, dd), 7.16 (IH, d), 7.30 (IH, d), 7.43 (IH, dd), 7.62 (IH, d), 7.72 (IH, d), 8.01 (IH, d), 8.16 (2H, s); m/z\ ES+ [M+H]+ = 758.5.
Figure imgf000187_0003
Figure imgf000188_0001
Intermediate 2c was reacted with Intermediate 88b using the general synthetic method illustrated by Example 2 to give the title compound (as a formate salt) after purification by HPLC (Column A, Eluent A). *H NMR: (CDCI3) 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.
Figure imgf000188_0002
4-(4-(6-Chloropyridin-3-yl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 56d) (0.500 g, 1.37 mmol), CS2CO3 (1.56 g, 4.78 mmol) and tert-butyl 4-(3-hydroxypropyl)piperazine-l -carboxylate (0.835 g, 3.42 mmol) were dissolved in toluene (15 mL) and degassed with N2. Rockphos Pd G3 (0.057 g, 0.07 mmol) was added and the mixture was then heated at 90°C for 18h. The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL) and then sat. brine (100 mL), dried (T^SCh) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.285 g, 36 %) as a pale yellow solid; 'H NMR ^DCh) 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), 3.37-3.46 (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-l-yl)propoxy)pyridin-3-yl)piperidin-l-yl)-2-
(trifluoromethvDbenzonitrile
Figure imgf000189_0001
4M HC1 in 1,4-dioxane (1.24 mL, 4.97 mmol) was added to tert-butyl 4-(3-((5-(l-(4-cyano-3- (trifluoromethyl)-phenyl)piperidin-4-yl)pyridin-2-yl)oxy)propyl)piperazine-l-carboxylate (285 mg, 0.50 mmol) in DCM (25 mL) and the mixture was stirred for Ih. Concentration under reduced pressure then gave the title compound as a bis-hydrochloride salt (255 mg, 101 %) as a white solid which was used directly in next step; ‘H NMR (CDCh) 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 (IH, d), 7.00 (IH, dd), 7.16 (IH, d), 7.42 (IH, dd), 7.62 (IH, d), 8.00 (IH, d), 9.62 (IH, s); Wz: ES+ [M+H]+ 474.3.
Example 90: 4-f4-[6-(3-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5-yl1piperazin-l- yllpropoxy)pyridin-3-yl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000189_0002
CS2CO3 (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-l-yl)propoxy)pyridin-3-yl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile (226 mg, 0.48 mmol) and 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (154 mg, 0.48 mmol) in 1 ,4-dioxane (8 mL) under N2. The resulting mixture was stirred at 90°C for 5h. The mixture was then cooled to RT, diluted with DCM (50 mL), washed with 5% AcOH in water (50 mL), then water (50 mL), then dried (MgSCL) and concentrated. Purification by preparative HPLC (Colum A, Eluent A) was carried out. 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 (MgSOy) and concentrated. Further purification by preparative HPLC (Column A, Eluent A) gave the title compound as a formate salt (4.00 mg, 1 %) as a colourless gum. >H NMR: (CDCh) 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 (1H, 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-(l-(4-cvano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenoxyl- ethvDpiperazine-l-carboxylate
Figure imgf000190_0001
RockPhos Pd G3 (0.102 g, 0.12 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile (1.00 g, 2.44 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-l -carboxylate (0.844 g, 3.67 mmol) and CS2CO3 (1.59 g, 4.89 mmol) in toluene (20 mL) under N2. The resulting mixture was stirred overnight at 100°C 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-l-yl)ethoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000190_0002
4M HC1 in dioxane (10 mL, 40.00 mmol) was added to tert-butyl 4-(2-(4-(l-(4-cyano-3-(trifluoromethyl)- phenyl)piperidin-4-yl)phenoxy)ethyl)piperazine-l -carboxylate (750 mg, 1.34 mmol) in DCM (20 mL). The resulting mixture was stirred at RT for 2h. 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-f4-[4-(2-f4-[2-(2.6-Dioxopiperidin-3-yl)-l-oxo-2.3-dihvdro-l/T-isoindol-5-yl1piperazin-l- yllethoxy)phenyl1piperidin-l-yll-2-(trifluoromethvDbenzonitrile
Figure imgf000190_0003
Pd-PEPPSI-IPent (4.32 mg, 5.45 nmol ) was added to 4-(4-(4-(2-(piperazin-l-yl)ethoxy)phenyl)piperidin-l- yl)-2-(trifhioromethyl)benzonitrile (50 mg, 0.11 mmol), 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (35.2 mg, 0.11 mmol) and CS2CO3 (107 mg, 0.33 mmol) in DMF (3 mL) at RT under N2. The resulting solution was stirred at 90°C for 16h. The mixture was then diluted with EtOAc (10 mL), washed with water (10 mL x 3) then sat. brine (10 mL x 2), dried (Na2SO4) and concentrated. Purification by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30*150mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3+O. E/oNHs.EBO), Mobile Phase BMeCN) gave the title compound (11 mg, 14 %) as a white solid; ‘HNMR: 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-l-carboxylate
Figure imgf000191_0001
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) at 0°C over 5 mins. The resulting mixture was stirred at RT for 3h. The mixture was then diluted with DCM (100 mL), washed with water (200 mL x 2), dried (IS^SCL) 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; *H NMR (CDCh, 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.
Figure imgf000191_0002
RockPhos Pd G3 (0.336 g, 0.40 mmol) was added to benzyl 4-(4-bromophenyl)piperidine-l -carboxylate (3.00 g, 8.02 mmol), tert-butyl 4-(3-hydroxypropyl)piperazine-l -carboxylate (1.96 g, 8.02 mmol) and CS2CO3 (5.22 g, 16.03 mmol) in toluene (60 mL) under N2. 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 (2.30 g, 53 %) as a yellow oil which solidified on standing; m/z\ ES+ [M+H]+= 538.
Figure imgf000191_0003
tert-Butyl 4-(3-(4-(l -((benzyloxy )carbonyl)piperidin-4-yl)phenoxy)propyl)piperazine-l -carboxylate (2.800 g, 5.21 mmol) and Pd(OH)2 (0.366 g, 0.26 mmol) in EtOAc (50 mL) were stirred under H2 (with balloon) at RT for 15h. The mixture was then filtered through celite and the filtrate was concentrated to dryness to give the title compound (1.80 g, 86 %) as a yellow solid; >H NMR (CDC13, 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.
Figure imgf000192_0001
CS2CO3 (1.45 g, 4.46 mmol) was added to tert-butyl 4-(3-(4-(piperidin-4-yl)phenoxy)propyl)piperazine-l- 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 15h. The mixture was then diluted with EtOAc (100 mL), washed with water (100 mL) then sat. brine (100 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (0.850 g, 65 %) as a yellow oil which solidified on standing; m/z\ ES+ [M+H]+ = 583.
Figure imgf000192_0002
PdC12(dppf) (50.2 mg, 0.07 mmol) was added to a mixture of tert-butyl 4-(3-(4-(l-(3-bromo-4-cyanophenyl)- piperidin-4-yl)phenoxy)propyl)piperazine-l -carboxylate (400 mg, 0.69 mmol), 2-cyclopropyl-4,4,5,5-tetra- methyl-l,3,2-dioxaborolane (173 mg, 1.03 mmol) and K3PO4 (291 mg, 1.37 mmol) in 1,4-dioxane (15 mL) under N2. The resulting mixture was stirred at 90°C for 15h. The mixture was then concentrated and the residue dissolved in EtOAc (50 mL). This solution was washed with water (50 mL) then sat. brine (50 mL), dried (Na2SO4) 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.
Figure imgf000193_0001
4M HC1 in 1,4-dioxane (3.86 mL, 15.42 mmol) was added to tert-butyl 4-(3-(4-(l-(4-cyano-3-cyclopropyl- phenyl)piperidin-4-yl)phenoxy)propyl)piperazine-l -carboxylate (280 mg, 0.51 mmol) in DCM (20 mL). The resulting mixture was stirred at RT for 2h. 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.
Figure imgf000193_0002
Intermediate 63 c was reacted with Intermediate 92f using the general synthetic method illustrated by Example 87 to give the title compound after purification by EIPLC (Column A, Eluent A). *H 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-(l-(4-cvano-3-(difluoromethyl)phenyl)piperidin-4-yl)phenoxy)- propyDpiperazine-l-carboxylate
Figure imgf000194_0001
Bis(dibenzylideneacetone)palladium (39.4 mg, 0.07 mmol) was added to tert-butyl 4-(3-(4-(l-(3-bromo-4- cyanophenyl)piperidin-4-yl)phenoxy)propyl)piperazine-l-carboxylate (Intermediate 92d) (400 mg, 0.69 mmol), (oxydi-2,l-phenylene)bis(diphenylphosphine) (73.8 mg, 0.14 mmol) and (l,3-bis(2,6- diisopropylphenyl)imidazolidin-2-yl)(difluoromethyl)silver (377 mg, 0.69 mmol) in toluene (10 mL) under N2. The resulting solution was stirred at 80°C for 18h. The mixture was then concentrated and diluted with EtOAc (50 mL). This solution was then washed with water (50 mL x 2) and sat. brine (50 mL), dried (Na2SO4) 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-l-yl)propoxy)phenyl)piperidin-l-
Figure imgf000194_0002
4M HC1 in 1,4-dioxane (2.70 mL, 10.82 mmol) was added to tert-butyl 4-(3-(4-(l-(4-cyano-3- (difluoromethyl)-phenyl)piperidin-4-yl)phenoxy)propyl)piperazine-l -carboxylate (300 mg, 0.54 mmol) in DCM (10 mL) at RT. The resulting mixture was stirred at RT for 3h. The solvent was then removed under reduced pressure to give the title compound as a hydrochloride salt (253 mg, 95 %) as a yellow solid; m/z\ ES+ [M+H]+ = 455.
Example 93: 2-(Difluoromethyl)-4-f4-[4-(3-f4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-l //- isoindol-5-yl1piperazin-l-yllpropoxy)phenyl1piperidin-l-yll benzonitrile
Figure imgf000195_0001
Intermediate 63c was reacted with Intermediate 93b using the general synthetic method illustrated by Example 87 to give the title compound after purification by HPLC (Column A, Eluent A). *H 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), 7.69 (2H, dd), 11.08 (1H, s); 19F NMR: (376 MHz) -110.7; m/z\ ES+ [M+H]+ = 711.4.
Intermediate 94a: tert-Butyl 4-((4-(2-(2.6-dioxopiperidin-3-vD-l-oxoisoindolin-5-vDpiperazin-l- yl)methvDpiperidine-l-carboxylate
Figure imgf000195_0002
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-(l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2,6- dione hydrochloride salt (1.00 g, 2.74 mmol) in DCM (100 mL) at RT under air. The resulting suspension was stirred for Ih at RT and then NaBH(OAch (0.871 g, 4.11 mmol) was added and the mixture was stirred at RT for Ih. The mixture was then diluted with water (20 mL). The organic phase was separated, washed with sat. Nal ICCL solution (20 mL) and sat. brine (20 mL), dried ( NaiSO i ) 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+ [M-H]' 524.2.
Intermediate 94b: 3-(l-Oxo-5-(4-(piperidin-4-ylmethyl)piperazin-l-yl)isoindolin-2-yl)piperidine-2,6- dione
Figure imgf000195_0003
HC1 (4M in 1,4-dioxane) (6.85 mL, 27.40 mmol) was added to tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperazin-l -yl)methyl)piperidine-l -carboxylate (1.44 g, 2.74 mmol) in DCM (25 mL) and the mixture was stirred for Ih. 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+ [M-H]+ 426.0.
Example 94: 4-[4-(6-f4-[(4-f2-[(3R)-2,6-Dioxopiperidin-3-yl1-l-oxo-2,3-dihvdro-l/T-isoindol-5-yll-
Figure imgf000196_0001
Anhydrous DMF (5mL) was added to a mixture of 4-(4-(6-chloropyridin-3-yl)piperidin-l-yl)-2-(trifluoro- methyl)benzonitrile (Intermediate 56d) (143 mg, 0.39 mmol), 3-(l-oxo-5-(4-(piperidin-4-ylmethyl)piperazin- l-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). This mixture was degassed, under N2, and stirred at 70°C for Ih. 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 sat. Nal ICO;, solution (50 mL) and brine (50 mL) then dried (Na2SO4) and concentrated. Preparative HPLC (Column A, Eluent A, Basic Work-Up A) gave the title compound (15.0 mg, 6 %) as a white solid; 'H NMR: (CDCI3) 1.30- 1.45 (2H, m), 1.68-1.8 (3H, m), 1.85-1.99 (4H, m), 2.15-2.24 (IH, m), 2.27 (2H, d), 2.3-2.4 (IH, m), 2.53-2.64 (4H, m), 2.69 (IH, t), 2.76-2.87 (3H, m), 2.91 (IH, d), 3.05 (2H, t), 3.26-3.37 (4H, m), 4.01 (2H, d), 4.25 (3H, d), 4.41 (IH, d), 5.19 (IH, dd), 6.64 (IH, d), 6.88 (IH, s), 6.99 (2H, dd), 7.16 (IH, d), 7.31 (IH, dd), 7.62 (IH, d), 7.73 (IH, d), 7.84 (IH, s), 8.06 (IH, d); m/z\ ES+ [M+H]+= 755.0.
Figure imgf000196_0002
Intermediate 63 c was reacted with Intermediate 91b using the general synthetic method illustrated by Example 87 to give the title compound after purification by HPLC (Column: Sunfire prep Cl 8 column, 30*150, 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN: Flow rate:60 ml , /min: Gradient: 30 B to 50 B in 7 min; 254/220 nm; RT1 :6.62). ‘HNMR: (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-(l-(4-cvano-3-(trifluoromethyl)phenyl)piperidin-4- yl)phenyl)amino)ethyl)piperazine-l -carboxylate
Figure imgf000197_0001
Brettphos Pd G3 (0.222 g, 0.24 mmol) was added to 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile (1.00 g, 2.44 mmol), tert-butyl 4-(2-aminoethyl)piperazine-l -carboxylate (0.62 g, 2.69 mmol) and CS2CO3 (2.39 g, 7.33 mmol) in 1 ,4-dioxane (10 mL) at RT under N2. The resulting mixture was stirred at 100°C for 15h under N2. The mixture was then diluted with EtOAc (75 mL), and washed with sat. brine (50 mL x 3). The organic solution was dried (Na2SC>4) and concentrated. Purification by FSC (gradient: 30-50% EtOAc in petroleum ether) gave the title compound (1.12 g, 82 %) as a white solid; *H 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-l-yl)ethoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000197_0002
tert-Butyl 4-(2-((4-(l-(4-cyano-3-(trifluoromethyl)phenyl)piperidm-4-yl)phenyl)amino)ethyl)piperazine-l- carboxylate (200 mg, 0.36 mmol) was added to 4M HC1 solution in 1 ,4-dioxane (1.00 mL, 4.00 mmol) in MeOH (2 mL) at RT under air. The resulting mixture was stirred at RT for 3h. The solvent was removed under reduced pressure to give the title compound (159 mg, 97 %) as a white solid; *H 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-f4-[(2-f4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-l/T-isoindol-5- in-l-vD-2-i
Figure imgf000197_0003
Intermediate 63 c was reacted with Intermediate 96b using the general synthetic method illustrated by Example 87 to give the title compound after purification by HPLC (Column B, Eluent A); *H NMR: 1.51-1.65 (2H, m), I.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),
II .07 (1H, s); 2 protons underneath solvent peak; m/z\ ES+ [M+H]+ = 714.4.
Figure imgf000198_0001
4-(4-(4-Bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (0.573 g, 1.40 mmol), tert-butyl piperazine- 1-carboxylate (leq), 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 filled with N2, and the mixture stirred at 60°C overnight. After cooling and concentrating to dryness, water (10 mL) was added. This mixture was extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried (T^SCh) and concentrated. Purification by FSC (gradient: hexanes to 100% EtOAc) gave the title compound (0.614 g, 85 %) white solid; 1H NMR (500 MHz, CDC13) 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.
Figure imgf000198_0002
4 tert-Butyl 4-(4-(l-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)piperazine-l-carboxylate (1.71 g, 3.32 mmol) was dissolved in DCM (8 mL) and TFA (4 mL). The mixture was stirred at RT for 3h. After concentrating, DCM (20 mL) was added and the mixture was washed with sat. Nal ICO;, (2 x 5 mL), dried (Na2SO4) and concentrated to dryness to give the title compound (1.37 g, 99 %) as a dry film; *H NMR (500 MHz, CDCh) 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-hvdroxyisoindoline-l,3-dione
Figure imgf000199_0001
NaOAc (0.50 g, 6.09 mmol) was added to 5-hydroxyisobenzofuran-l, 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 RT. The resulting mixture was stirred at 120°C for 3h then at RT overnight. A precipitate was then collected by filtration, washed with water (10 mL) and Et2O (10 mL) and dried at 50°C to give the title compound (0.60 g, 72 %); *H 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(lH,s); m/z\ ES+, [M+H]+ = 275.
Intermediate 97d: 2-(2,6-Dioxopiperidin-3-yl)-5-(2-hvdroxyethoxy)isoindoline-l,3-dione
Figure imgf000199_0002
DMF (0.5 mL) was added to a mixture of 2-bromoethan-l-ol (114 mg, 0.91 mmol), K2CO3 (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 5h 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 (Na2SO4) and concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (34 mg, 12 %); *H NMR (500 MHz, CDCI3) 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
Figure imgf000199_0003
EtaN (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 CH2CI2 (1 mL) at 0°C then stirred at RT overnight. The mixture was then diluted with DCM (10 mL), washed with water (10 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (15 mg, 35 %); >H NMR (500 MHz, CDCI3) 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 (1H, 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-f4-[4-(2-f[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-l/7-isoindol-5- ylloxylethvDpiperazin-l-yl]phenyllpiperidin-l-yl)-2-(trifluoromethvDbenzonitrile
Figure imgf000200_0001
DMF (0.5 mL) was added to a mixture of Nal (6 mg, 0.04 mmol), DIPEA (0.020 mL, 0.11 mmol), 4-(4-(4- (piperazin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (16 mg, 0.04 mmol) and 2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)ethyl methanesulfonate (15 mg, 0.04 mmol). The resulting solution was stirred at 60-90°C for 3h then concentrated. DCM (10 mL) was added and the resulting solution was washed with water, sat. Nal ICO;, (2 mL), then dried (Na2SO4) and concentrated. Purification by FSC (hexanes to EtOAc) gave the title compound (7 mg, 23 %); 'H 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-hvdroxypiperidin-l-yl)isoindoline-l,3-dione
Figure imgf000200_0002
2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-l ,3-dione (0.200 g, 0.72 mmol) was dissolved in DMA (1 mL). DIPEA (0.253 mL, 1.45 mmol) and piperidin-4-ol (0.081 g, 0.80 mmol) were then added. The mixture was then stirred at 100°C for 18h then concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (0.200 g, 77 %); 'El 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-l-yl)isoindoline-l, 3-dione
Figure imgf000200_0003
2-(2,6-Dioxopiperidin-3-yl)-5-(4-hydroxypiperidin-l-yl)isoindoline-l, 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 RT for 2h then concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (18 mg, 72 %); 'H NMR (500 MHz, CDC13) 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.
Figure imgf000201_0001
Intermediate 97b was reacted with Intermediate 98b using the general synthetic method illustrated by Example 2 to give the title compound (as a formate salt) after purification by flash C- 18 chromatography (Eluent A); *H NMR: (500 MHz, CDCh) 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), 4.06 (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.
Figure imgf000201_0002
DMF (1 mL) was added to a mixture of 4-bromobutan-l-ol (112 mg, 0.73 mmol), K2CO3 (111 mg, 0.80 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-l, 3-dione (200 mg, 0.73 mmol). The resulting suspension was stirred at 50°C overnight 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 (Na2 SO4) and concentrated. Purification by FSC (gradient: hexanes to EtOAc) and further purification using a 30g Cl 8 column (Eluent A) gave the title compound (35 mg, 14 %); *H 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.
Figure imgf000201_0003
I A,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-l, 3-dione (33 mg, 0.10 mmol) in anhydrous DCM (1 mL) at 0°C. The mixture was then stirred at RT for 0.5h, diluted with DCM (10 mL) washed with water (1 mL), dried (Na2SC>4) and concentrated to give the title compound; *H NMR (500 MHz, CDCh) 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.
Figure imgf000202_0001
DMF (0.5 mL) was added to a mixture of Nal (12.71 mg, 0.08 mmol), DIPEA (0.044 mL, 0.25 mmol), 4-(4- (4-(piperazin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (35 mg, 0.08 mmol) and 4-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)butyl methane sulfonate (36 mg, 0.08 mmol). The resulting solution was stirred at 60°C for Ih then concentrated to dryness. DCM (10 mL) was added and the resulting mixture was washed with water, sat. Nal ICO;, (2 mL), dried (Na2SC>4) and concentrated. Purification by FSC (eluents: hexanes to EtOAc then 5% MeOH in EtOAc) gave the title compound (12 mg, 19% ): *H NMR: (500 MHz, CDCh) 1.50-1.55 (2H, m), 1.76 (3H, qd), 1.90-2.01 (4H, m), 2.14-2.22 (IH, m), 2.46-3.29 (15H, m), 4.03 (2H, br d), 4.12-4.17 (2H, m), 4.97 (IH, dd), 6.90 (2H, d), 6.97-7.02 (lH, m), 7.11-7.15 (2H, m), 7.16 (IH, d), 7.20 (IH, dd), 7.34 (IH, d), 7.62 (IH, d), 7.79 (IH, d), 7.97 (IH, s); m/z\ ES+ [M+H]+ = 743.3.
Figure imgf000202_0002
DMF (0.5 mL) was added to a mixture of 3 -bromopropan- l-ol (84 mg, 0.60 mmol), K2CO3 (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 5h and then concentrated under reduced pressure. Water (10 mL) was added, and the phases separated. The aqueous portion was extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (50.0 mg, 28 %); *H NMR (500 MHz, CDCh) 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.
Figure imgf000202_0003
DCM (1 mL) was added to a mixture of />-toluenesulfonyl chloride (33.6 mg, 0.18 mmol), 2-(2,6-dioxo- piperidin-3-yl)-5-(3-hydroxypropoxy)isoindoline-l, 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 RT overnight. After diluting with DCM (5 mL), the resulting solution was washed with water, dried (Na2SO4) and concentrated. Purification by FSC (gradient: hexanes to EtOAc) gave the title compound (27 mg, 41 %) as a sticky film; *H NMR (500 MHz, CDCh) 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), 7.19-7.26 (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.
Figure imgf000203_0001
DMF (0.5 mL) was added to a mixture of Nal (14 mg, 0.10 mmol), DIPEA (0.051 mL, 0.29 mmol), 4-(4-(4- (piperazin-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 97b) (40 mg, 0.10 mmol), 3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)propyl 4-methylbenzenesulfonate (47 mg, 0.10 mmol). The resulting solution was stirred at 60°C for Ih. The mixture was then concentrated to dryness then DCM (10 mL) was added. This solution was washed with water then sat. Nal ICO;, (2mL), dried (Na2SO4) and concentrated. Purification by FSC (eluent: hexanes to EtOAc then 5% MeOH in EtOAc) gave the title compound (39 mg, 54.0 %); ‘H 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 (IH, m), 2.51-2.64 (7H, m), 2.68-2.75 (IH, m), 2.84-2.91 (IH m), 2.98-3.12 (7H, m), 4.16 (2H, br d), 4.23 (2H, br t), 5.06-5.17 (IH, m), 6.85 (2H, br d), 7.08 (2H, br d), 7.23-7.28 (IH, m), 7.31 (IH, br s), 7.33-7.37 (IH, m), 7.43 (IH, br d), 7.75-7.86 (2H, m), 11.10 (IH, s), 2 protons underneath solvent peak; m/z\ ES+ [M+H]+ = 729.3.
Figure imgf000203_0002
4-(4-(4-Hydroxyphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.43 mmol), ITh; (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 N2. The mixture was cooled to 0°C and di-tert-butyl (E)-diazene- 1 ,2- dicarboxylate (0.199 g, 0.87 mmol) was added. This mixture was stirred at RT overnight, then washed with sat. Nal ICO;, (2 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: hexanes to DCM) gave the title compound (0.200 g, 79 %) as a colourless oil; >H NMR (500 MHz, CDC13) 1.48-1.55 (2H, m), 1.69- 1.85 (6H, m), 1.99 (2H, br d), 2.45 (3H, s), 2.75 (IH, tt), 3.07 (2H, td), 3.90 (2H, t), 4.00-4.09 (4H, m), 6.83 (2H, d), 7.02 (IH, dd), 7.13 (2H, d), 7.19 (IH, d), 7.34 (2H, d), 7.57-7.69 (IH, m), 7.80 (2H, d); m/z\ ES+, [M+H]+ = 587.
Figure imgf000204_0001
Intermediate 63 e was reacted with Intermediate 101a using the general synthetic method illustrated by Example 12 to give the title compound after purification by FSC (gradient: 0-100% EtOAc in hexanes); *H 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 (1H, 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.
Figure imgf000204_0002
Intermediate 2c was reacted with Intermediate 101a using the general synthetic method illustrated by Example 12 to give the title compound after purification by C- 18 chromatography (Eluent A, Basic Work-up A); *H 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), 4.27-4.37 (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.
Figure imgf000204_0003
DMF (2 mL) was added to a mixture of tert-butyl (4-bromobutyl)carbamate (256 mg, 1.01 mmol), 3-(l-oxo-5- (piperazin-l-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 24h, then cooled to RT and the solvents removed under reduced pressure. Purification by FSC (eluting with hexanes to DCM then 10% MeOH in DCM) gave the title compound (340 mg, 67 %); >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 (1H, 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.
Figure imgf000205_0001
HC1 4M 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)-l-oxoisoindolin-5-yl)piperazin-l-yl)butyl)carbamate (340 mg, 0.68 mmol) to give a suspension. The resulting suspension was stirred at RT for Ih then concentrated to dryness. Et2O (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 %); >H NMR (500 MHz) 1.59-1.69 (2H, m), 1.77-1.85 (2H, m), 1.93-2.03 (IH, m), 2.30-2.41 (IH, m), 2.54-2.66 (2H, m), 2.77-2.96 (3H, m), 3.06-3.23 (4H, m), 3.26-3.38 (2H, m), 3.96-4.04 (2H, m), 4.07-4.25 (2H, m), 4.32-4.40 (IH, m), 5.00-5.12 (IH, m), 7.08-7.25 (2H, m), 7.58 (IH, d), 7.97 (3H, br s), 10.93 (IH, s); m/z: ES+, [M+H]+ = 400.
Figure imgf000205_0002
4-(4-(4-Bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (73 mg, 0.18 mmol), sodium tert- butoxide (78 mg, 0.81 mmol), 3-(5-(4-(4-aminobutyl)piperazin-l-yl)-l-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 a flask. The mixture was degassed, the flask filled with N2 and the mixture was then stirred at 100°C for 1 ,5h. After cooling to RT 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 by 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 %); >H NMR: (500 MHz) 1.49-1.65 (7H, m), 1.79 (2H, br d), 1.92- 2.00 (IH, 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 (IH, m), 4.28-4.41 (IH, m), 5.03 (IH, br dd), 6.49 (2H, br d), 6.93 (2H, br d), 7.00-7.08 (2H, m), 7.24 (IH, br d), 7.30 (IH, s), 7.51 (IH, d), 7.79 (IH, d), 8.02-8.18 (IH, m), 10.92 (IH, s); m/z: ES+ [M+H]+ = 728.4.
Intermediate 104a: 4-(4-(4-((7-Bromoheptyl)oxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000206_0001
4-(4-(4-Hydroxyphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (0.170 g, 0.49 mmol), ITh; (0.283 g, 1.08 mmol) and 7-bromoheptan-l-ol (0.144 g, 0.74 mmol) were dissolved in anhydrous DCM (4.9 mL) under N2 and cooled to 0°C. Di-tert-butyl ( / j-diazene- 1 ,2-dicarboxylate (0.170 g, 0.74 mmol) was added dropwise. The mixture was then stirred at RT for Ih. Additional di-tert-butyl ( / j-diazene- 1 ,2-dicarboxylate (40 mg), PPha (40 mg) and 7-bromoheptan- 1 -ol (0.144 g, 0.74 mmol) were then added and the mixture stirred at RT overnight. The mixture was then washed with sat. Nal ICO;, (2 mL) and dried (Na2SO4). Purification by FSC (gradient: hexanes to DCM) gave the title compound (0.170 g, 66 %) as white solid; *H NMR (500 MHz, CDCh) 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 (IH, 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 (IH, dd), 7.11- 7.15 (2H, m), 7.18 (IH, d), 7.63 (IH, d); m/z: ES+, [M+H]+ = 523.
Example 104: 4-(4-f4-[(7-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/7-isoindol-5-yl1piperazin- l-yllheptvDoxy]phenyllpiperidin-l-vD-2-(trifluoromethvDbenzonitrile
Figure imgf000206_0002
Intermediate 2c was reacted with Intermediate 104a using the general synthetic method illustrated by Example 12 to give the title compound as a formate salt after purification by C-18 chromatography (Eluent A); *H 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 (IH, 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 (IH, s), 5.04 (IH, dd), 6.83 (2H, d), 7.05-7.11 (2H, m), 7.13 (2H, d), 7.25 (IH, dd), 7.31 (IH, d), 7.54 (IH, d), 7.80 (IH, d), 8.12 (IH, s), 10.93 (IH, s), 4 protons under solvent peak; m/z\ ES+ [M+H]+= 771.5.
Example 105: 4-f4-[4-(4-f4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-l/7-isoindol-5- yllpiperazin-l-yllbutoxy)phenyl]piperidin-l-yll-2-(trifluoromethvDbenzonitrile
Figure imgf000206_0003
Intermediate 50a was reacted with Intermediate 63e using the general synthetic method illustrated by Example 5 to give the title compound as a formate salt after purification by C-18 chromatography (Eluent A); *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 (IH, m), 2.38 (2H, br t), 2.53- 2.65 (2H, m), 2.68-2.80 (IH, m), 2.80-2.96 (IH, 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 (IH, m), 6.85 (2H, d), 7.14 (2H, d), 7.21-7.28 (2H, m), 7.31 (2H, dd), 7.66 (IH, d), 7.80 (IH, d), 8.13 (IH, s), 11.06 (IH, s), 3 protons under solvent peak; m/z\ ES+ [M+H]+ = 743.3.
Intermediate 106a: 4-(4-(4-((6-Bromohexyl)oxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000207_0001
4-(4-(4-Hydroxyphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (0.170 g, 0.49 mmol), PPha (0.257 g, 0.98 mmol) and 6-bromohexan-l-ol (0.133 g, 0.74 mmol) were dissolved in anhydrous DCM (4.9 mL) under N2 and cooled to 0°C. Di-tert-butyl ( / j-diazene- 1 ,2-dicarboxylate (0.170 g, 0.74 mmol) was then added and the mixture stirred at RT for Ih. Further di-tert-butyl ( / j-diazene- 1 ,2-dicarboxylate (40 mg), PPM (40 mg) and 6-bromohexan-l-ol (1 eq) were then added. This mixture was stirred at RT for 6h then washed with sat. NaHCOa (2 mL) and dried (NaaSCU). Purification by FSC (gradient: hexanes to DCM) gave the title compound (0.150 g, 60 %) as white solid; *H NMR (500 MHz, CDCh) 1.48-1.57 (4H, m), 1.77-1.94 (6H, m), 2.00 (2H, br d), 2.71-2.82 (IH, m), 3.03-3.14 (2H, m), 3.39-3.46 (2H, m), 3.96 (2H, t), 4.02 (2H, br d), 6.86 (2H, d), 7.10 (IH, dd), 7.14 (2H, d), 7.22-7.25 (IH, m), 7.65 (IH, d); m/z\ ES+, [M+H]+ = 509.
Example 106: 4-(4-f4-[(6-f4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-l/T-isoindol-5-yl1- piperazin-l-yllhexyl)oxy1phenyllpiperidin-l-yl)-2-(trifluoromethyl) benzonitrile
Figure imgf000207_0002
Intermediate 63 e was reacted with Intermediate 106a using the general synthetic method illustrated by Example 5 to give the title compound (as a formate salt) after purification by C- 18 chromatography (Eluent A); ‘HNMR: (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-
I.74 (2H, m), 1.79-1.86 (2H, m), 1.98-2.03 (IH, m), 2.30-2.37 (2H, m), 2.52-2.64 (4H, m), 2.71-2.79 (IH, m), 2.83-2.92 (IH, m), 2.99-3.06 (2H, m), 3.37-3.47 (4H, m), 3.91 (2H, t), 4.15 (2H, br d), 5.06 (IH, dd), 6.78- 6.90 (2H, m), 7.13 (2H, d), 7.21-7.27 (2H, m), 7.31 (2H, dd), 7.66 (IH, d), 7.76-7.85 (IH, m), 8.12 (IH, s),
II .05 (IH, s); m/z\ ES+ [M+H]+ = 771.5.
Intermediate 107a: 2-[2-[2-(tert-butoxycarbonylamino)ethoxy1ethoxy1ethyl methanesulfonate
Figure imgf000208_0001
EtaN (2.24 mL, 16.04 mmol) was added slowly 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 RT for Ih. The mixture was then diluted with DCM (100 mL) and washed with water (10 mL) then sat. brine (10 mL). The organic solution was then dried (Na2SO4) and concentrated to give the title compound (2.10 g, 80 %) as a pale yellow oil; >H NMR (CDC13) 1.36 (9H, s), 2.67 (4H, d), 4.36 (3H, s), 5.00 (6H, s), 5.29 (2H, s), 7.32 (IH, s); m/z ES+, [M+H]+ = 328.
Figure imgf000208_0002
CS2CO3 (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-(l-oxo-5-(piperazin-l-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 2h. The solvent was then removed under reduced pressure. DCM (15 mL) was added to the residue and the mixture was filtered. 4M HC1 in 1 ,4-dioxane (20 mL) was then added dropwise to the filtrate and the mixture was stirred at RT for Ih. Purification by flash Cl 8-flash chromatography (eluent: 100% water) gave the title compound (0.699 g, 85 %) as a pale yellow solid; m/z ES+, [M+H]+ = 460.
Figure imgf000208_0003
4-(4-(4-Bromophenyl)piperidin-l-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-l-yl)-l-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 Lil , ) were added to a flask. The mixture was degassed, the flask filled with N2 then the mixture was stirred at 100°C for 1 ,5h. After cooling to RT the mixture was quenched using 2M AcOH in THF (362 pL, 0.72 mmol) to give a cloudy solution. The THF was removed under reduced pressure. DMSO (1 mL) was added and the mixture was filtered. Purification by Cl 8 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%); *H NMR: (500 MHz) 1.48-1.61 (2H, m), 1 .73-1.80 (2H, m), 1.91-2.00 (IH, 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), exchangeable protons missing; m/z\ ES+ [M+H]+ = 788.3.
Figure imgf000209_0001
DIPEA (4.79 mL, 27.41 mmol) was added to 3-(l-oxo-5-(piperazin-l-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 RT for 40h. The mixture was then diluted with EtOAc (100 mL), and washed with water (20 mL) then sat. brine (20 mL). The organic solution was then dried (Na2SC>4) and concentrated to give the title compound which was used in the next step without further purification; m/z\ ES+ [M+H]+ = 472.
Figure imgf000209_0002
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 4M HC1 in 1 ,4-dioxane (1 mL). The resulting mixture was stirred at RT for 2h. 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.
Figure imgf000209_0003
4-(4-(4-Bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (77 mg, 0.19 mmol), sodium tert- butoxide (91 mg, 0.95 mmol), 3-(5-(4-(2-aminoethyl)piperazin-l-yl)-l-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 N2 then stirred at 100°C for 1 ,5h. After cooling to RT the reaction was quenched with AcOH (2M in THF, 473 Lil ,. 0.95 mmol) to give a cloudy solution. The THF was removed under reduced pressure. DMSO (1 mL) was added and the mixture was filtered. Purification by reverse phase (Cl 8) 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 %); *H 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), 6.59 (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.
Figure imgf000210_0001
Intermediate 2c was reacted with Intermediate 106a using the general synthetic method illustrated by Example 12 to give the title compound after purification by C- 18 chromatography (Eluent A); *H 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 (IH, m), 2.31-2.42 (IH, m), 2.56-2.64 (2H, m), 2.71-2.80 (IH, m), 2.85-2.95 (IH, 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 (IH, m), 4.31-4.44 (IH, m), 4.98-5.12 (IH, m), 6.84 (2H, br d), 7.12-7.18 (3H, m), 7.26 (IH, br d), 7.31 (IH, br s), 7.57-7.60 (IH, m), 7.80 (IH, br d), 10.93 (IH, s); one exchangeable not observed; m/z\ ES+ [M+H]+ = 757.4.
Figure imgf000210_0002
EtaN (1.28 mL, 9.20 mmol) was added slowly 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 RT for Ih. The mixture was then diluted with DCM (50 mL) and washed with water (10 mL) then sat. brine (10 mL). The organic solution was then dried (TS^SCL) and concentrated to give the title compound (1.350 g, 99 %) as a colourless oil; *H NMR (300 MHz, CDC13) 1.46 (15H, s), 1.76 (2H, dt), 3.03 (3H, s), 3.13 (2H, dd), 4.24 (2H, t), 4.54 (IH, s).
Intermediate 110b: tert-Butyl (6-(4-(2-(2.6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-vDpiperazin-l- yllhexyDcarbamate
Figure imgf000211_0001
CS2CO3 (4.47 g, 13.70 mmol) was added to 6-((tert-butoxy carbonyl )amino )hexyl methanesulfonate (4.32 g, 14.62 mmol), 3-(l-oxo-5-(piperazin-l-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 3h. 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.
Figure imgf000211_0002
4M HC1 in 1,4-dioxane (15 mL, 1.52 mmol) was added dropwise to tert-butyl (6-(4-(2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)hexyl)carbamate (800 mg, 1 .52 mmol) in DCM (10 mL). The resulting mixture was stirred at RT for Ih. Purification by Cl 8- flash chromatography (eluent: 100% water) gave the title compound (425 mg, 66 %) as a pale yellow solid; m/z ES+, [M+H]+ = 428.
Figure imgf000211_0003
4-(4-(4-Bromophenyl)piperidin-l-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-l-yl)-l-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 nl . ). The mixture was degassed, filled withN2 then stirred at 100°C for 1.5h. The mixture was then cooled to RT, 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 on 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. ‘H 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 (IH, m), 2.33-2.42 (IH, m), 2.54-2.69 (3H, m), 2.84-3.20 (12H, m), 4.14 (2H, br d), 4.18-4.28 (IH, m), 4.34 (IH, br d), 5.05 (IH, dd), 6.48 (2H, br d), 6.94 (2H, d), 7.00-7.20 (2H, m), 7.22-7.26 (IH, m), 7.30 (IH, d), 7.58 (IH, d), 7.79 (IH, d), 8.12 (IH, s), 10.93 (IH, s); m/z: ES+ [M+H]+ = 756.5.
Figure imgf000212_0001
EtaN (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 RT for Ih. The mixture was then diluted with DCM (50 mL) and washed with water (10 mL) then sat. brine (10 mL). The organic solution was dried (Na2SO4) and concentrated to give the title compound (1.35 g, 98%) as a colourless oil; *H NMR (300 MHz, CDCh) 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 (IH, s).
Figure imgf000212_0002
CS2CO3 (1.49 g, 4.57 mmol) was added to 5-((tert-butoxycarbonyl)amino)pentyl methanesulfonate (1.71 g, 6.09 mmol) and 3-(l-oxo-5-(piperazin-l-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 12h. Purification by C-18 (eluent: water) gave the title compound (800 mg, 66%) as a brown oil; m/z'. ES+ [M+H]+ = 514.
Figure imgf000212_0003
4M HC1 in 1,4-dioxane (20 mL, 2.53 mmol) was added dropwise to tert-butyl (5-(4-(2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)pentyl)carbamate (1.30 g, 2.53 mmol) in DCM (15 mL). The resulting mixture was stirred at RT for 1 h. Purification by flash C 18- flash chromatography (eluent: 100% water) gave the title compound (1.00 g, 96 %) as a pale yellow solid; >H NMR (CD3OD) 1.54 (2H, p), 1.77 (2H, h), 1.97- 1.86 (2H, m), 2.23-2.10 (IH, m), 2.50 (IH, qd), 2.85-2.70 (IH, m), 2.96-2.87 (IH, m), 2.99 (2H, q), 3.31-3.22 (4H, m), 3.37 (2H, s), 3.74 (2H, d), 7.71 (IH, d), 4.08 (2H, d), 4.53-4.37 (2H, m), 5.13 (IH, dd), 7.23-7.16 (2H, m); m/z\ ES+ [M+H]+ = 414.
Example 111: 4-(4-f4-[(5-(4-[2-(2,6-Dioxopiperidin-3-vl)-l-oxo-2,3-dihvdro-l/T-isoindol-5-vllpiperazin- l-vllpentyl)aminolphenyl}piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000213_0001
Intermediate 4a was reacted with Intermediate 111c using the general synthetic method illustrated by Example 110 to give the title compound (as a bis-formate salt) after purification by C- 18 chromatography (Eluent A). ‘HNMR: (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 dd), 6.48 (2H, br d), 6.92 (2H, br d), 7.21-7.27 (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.
Figure imgf000213_0002
Intermediate 2c was reacted with Intermediate 13a using the general synthetic method illustrated by Example 5 to give the title compound after purification by HPLC (Column A, Eluent A, Basic Work-up 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 (1H, 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, dd), 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), 3 protons under solvent peak; m/z\ ES+ [M+H]+ = 715.3.
Example 113: 4-!4-[4-(3-!4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-l//-isoindol-5- yllpiperazin-l-yllpropoxy)phenyl]piperidin-l-yll-2-(trifluoromethvDbenzonitrile
Figure imgf000214_0001
Intermediate 13a was reacted with Intermediate 63e using the general synthetic method illustrated by Example 5 to give the title compound after purification by FSC (eluent: 0-10% MeOH in EtOAc). *H 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.
Figure imgf000214_0002
Intermediate 2c was reacted with Intermediate 4c using the general synthetic method illustrated by Example 2 to give the title compound after purification by flash alumina chromatography (eluent: 0-100% EtOAc in heptane then 20% EtOH in EtO Ac); ‘H NMR: (CDC13) 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), 2.55-2.62 (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.
Figure imgf000214_0003
3-(l-Oxo-5-(piperazin-l-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 RT for 10 mins. Then NaBH(OAc)a (1.63 g, 7.67 mmol) was added and the mixture was stirred at RT for Ih. Additional benzyl (3-oxopropyl)carbamate (1.19 g, 5.76 mmol) was then added. The mixture was stirred at RT for 10 min and additional NaBH(OAc)a (1.63 g, 7.67 mmol) was added and stirring continued at RT for Ih. After concentrating under reduced pressure, EtOAc (20 mL) was added to the residue. The resulting solution was washed with sat. Nal ICO;, solution (10 mL), brine (10 mL) and dried (Na2SO4) and concentrated. Purification by FSC (gradient: hexanes to DCM then 10% MeOH in DCM) gave the title compound (0.800 g, 80 %) colourless dry film; *H NMR (500 MHz, CDCI3) 1.76 (2H, br s), 2.14-2.26 (IH, m), 2.33 (IH, br dd), 2.49-2.57 (2H, m), 2.58-2.72 (4H, m), 2.78-2.87 (IH, m), 2.88-2.96 (IH, m), 3.32 (6H, br s), 4.26 (IH, d), 4.42 (IH, d), 5.11 (2H, s), 5.18-5.25 (IH, m), 5.68 (IH, br s), 6.87 (IH, s), 6.98 (IH, br d), 7.35 (5H, br s), 7.74 (IH, d), 8.02-8.25 (IH, m); m/z ES+, [M+H]+ =520.
Figure imgf000215_0001
Benzyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)proyl)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 and the suspension was degassed, filled with H2 (balloon used), and stirred at RT for 3h. The mixture was then filtered through celite and washed through 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 %); *H 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.
Figure imgf000215_0002
Intermediate 4a was reacted with Intermediate 115b using the general synthetic method illustrated by Example 110 to give the title compound after purification by C-18 chromatography (Eluent A); The title compound was converted to a hydrochloride salt by mixing with 0. ImL of IN HC1 water solution and then concentrating the solution to dryness. ‘HNMR: (500 MHz) 1.55-1.69 (2H, m), 1.75-1.89 (2H, m), 1.91-1.99 (IH, m), 2.33-2.45 (2H, m), 2.54-2.65 (2H, m), 2.67-2.80 (IH, m), 2.83-2.95 (IH, 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 (IH, m), 4.98-5.12 (IH, 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); 2 exchangeable protons not observed; m/z\ ES+ [M+H]+ = 714.5.
Figure imgf000216_0001
Intermediate 4b was reacted with Intermediate 29g using the general synthetic method illustrated by Example 1 to give the title compound after purification by HPLC (Column A, Eluent A). *H 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); 2 exchangeable protons not observed; m/z\ ES+ [M+H]+ = 769.3.
Figure imgf000216_0002
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 RT for 16h. The mixture was then poured into crushed ice, and the pH was adjusted to 4-5 using 2N AcOH. The mixture was then extracted with DCM (50 mL x 2). The combined organic solutions were washed with water (30 mL), dried (Na2SC>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.
Figure imgf000216_0003
To a stirred solution of 6-chloro-4-methoxy-2-methylnicotinic acid (2.50 g, 12.40 mmol) in DMF (30 mL) was added K2CO3 (2.06 g, 14.88 mmol) and Mel (1.16 mL, 18.60 mmol) at RT. The mixture was then stirred at RT for 16h. 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 (TS^SCL) and concentrated under reduced pressure (bath temperature: 45°C) to give the title compound (2.50 g, 7.04 mmol, 57 % yield) as yellow solid which was used in the next step without further purification; m/z\ ES+ [M+H]+ = 216.1.
Figure imgf000217_0001
tert-Butyl acetate (30 mL) was added to methyl 6-chloro-4-methoxy-2-methylnicotinate (1 .50 g, 6.96 mmol) in under N2 at RT. NBS (1.610 g, 9.04 mmol) and AIBN (0.228 g, 1.391 mmol) were then added at RT. The mixture was then stirred at 110°C for 16h. The mixture was then diluted with water (30 mL) and extracted with EtOAc (40 mL x 2). The combined organic solutions were washed with brine (30 mL), dried (TS^SCL) and concentrated under reduced pressure (bath temperature: 45°C) give the title compound (2.00 g, 35 % yield) as brown liquid which was used in the next step without further purification; m/z\ ES+ [M+H]+ = 294.
Figure imgf000217_0002
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) under N2 at RT. The mixture was then heated to 85°C for 18h. The mixture was then cooled slowly to RT and the resulting solids were collected by filtration, washed with MeCN (5 mL) and dried under vacuum to give the title compound (0.44 g, 66%) as brown solid; *H 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 (1H, dd), 7.30 (1H, s), 10.99 (1H, s). Wz: ES+ [M+H]+ = 310.1.
Figure imgf000217_0003
Pd-PEPPSI-IHept (Cl) (47.1 mg, 0.048 mmol) was added to tert-butyl piperazine- 1 -carboxylate (541 mg, 2.91 mmol), CS2CO3 (947 mg, 2.91 mmol) and 3-(2-chloro-4-methoxy-5-oxo-5,7-dihydro-677-pyrrolo[3,4- />]pyridin-6-yl)piperidine-2, 6-dione (300 mg, 0.969 mmol) in 1,4-dioxane (10 mL) at RT under N2. The resulting suspension was stirred for 2h at 120°C. The mixture was then diluted with DCM (20 mL) and washed with 5% AcOH in water (20 mL), water (20 mL), sat. Nal ICO;, (20 mL) and then sat. brine (20 mL). The organic solution was then dried (Na2SO4) and concentrated. Trituration with EtOAc (4 mL) and washing with MTBE (16 mL) gave a solid which was collected by filtration and dried under vacuum to give the title compound (340 mg, 70 % yield) as brown powder; *H 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.
Figure imgf000218_0001
To a stirred solution of tert-butyl 4-(6-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-oxo-6,7-dihydro-5/7- pyrrolo[3,4-b]pyridin-2-yl)piperazine-l-carboxylate (340 mg, 0.740 mmol) in DCM (10 mL) was added 4M HC1 (3.70 mL, 14.80 mmol) in 1,4-dioxane at 0°C. The mixture was then stirred at RT for Ih under N2.
Concentration of the mixture then gave the title compound as a hydrochloride salt (300 mg, 88 %) as a brown solid; ‘HNMR: 1.88-1.99 (IH, m), 2.29-2.38 (IH, m), 2.59 (IH, br s), 2.84-2.96 (IH, m), 3.17-3.20 (4H, m), 3.92-4.00 (7H, s), 4.01-4.08 (IH, m), 4.18 (IH, s), 5.02 (IH, dd), 6.41 (IH, s), 9.35 (2H, br s), 10.92 (IH, s);
Wz: ES+ [M+H]+ = 360.2.
Figure imgf000218_0002
Intermediate 117f was reacted with Intermediate 50a using the general synthetic method illustrated by Example 5 to give the title compound after purification by HPLC (Column; Zorbax- Cl 8, 5|im; 50 * 21.2 mm, Eluent C, Basic Work-Up A); >H 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), 6.27 (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-(l-(4-cvano-3-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)-3,9- diaz aspiro [5.51 undecane-3-carboxylate
Figure imgf000219_0001
4-(4-(4-Bromophenyl)piperidin-l-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-olate (0.352 g, 3.67 mmol) were weighed into a microwave vial. Anhydrous 1 ,4-dioxane (8 mL) was then added. The mixture was degassed by bubbling N2 through the mixture for 5 mins and was then heated and stirred at 100°C for 2h in a microwave. The mixture was then cooled to RT and water (20 mL) was added. A precipitate formed which was collected by filtration. The cake was washed with Et2O (2 x 15 mL) to give the title compound (0.578 g, 81 %) as a grey solid; ‘HNMR: 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.
Figure imgf000219_0002
Intermediate 118a was reacted with Intermediate 27f using the general synthetic method illustrated by Example 1 to give the title compound after purification (Column A, Eluent A); *H NMR (CDCh) 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-l-oxo-isoindolin-5-yl1piperazin-l- yl1pentoxy1phenyl1-l-piperidyl1-2-(trifluoromethyl)benzonitrile
Figure imgf000220_0001
Prepared from 4-(4-(4-bromophenyl)piperidin-l-yl)-2-(trifluoro-methyl)benzonitrile (Intermediate 4a) using the general synthetic method illustrated by Example 12 but using pentane- 1,5-diol to give the title compound after purification (Column A, Eluent A); ‘H NMR (CDCh) 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+ [M+H]+= 773.5.
Intermediate 120a: 6-Chloro-2-methoxy-4-methylnicotinic acid
Figure imgf000220_0002
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 16h. After cooling to RT the mixture was acidified with a 1.5N aq. HC1 to pH 3-4, then extracted with EtOAc (60 mL x 2). The combined organic solutions were washed with water and brine, dried (NajSO/i) and concentrated to give the title compound (4.00 g, 76 %) which was used in the next step without further purification; ’H 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
Figure imgf000220_0003
To a stirred solution of 6-chloro-2-methoxy-4-methylnicotinic acid (4.40 g, 20.19 mmol) in DMF (50 mL) was added K2CO3 (3.35 g, 24.23 mmol) and Mel (1.89 mL, 30.3 mmol) at RT. The mixture was then stirred at RT for 16h. 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 (Na2SO4) and concentrated under reduced pressure (bath temperature: 45°C) to give the title compound (4.00 g, 76 %) as pale yellow solid; 'll 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
Figure imgf000221_0003
tert-Butyl acetate (150 mL) was added to methyl 6-chloro-2-methoxy-4-methylnicotinate (8.00 g, 37.1 mmol) under N2. NBS (9.24 g, 51.9 mmol) and benzoyl peroxide (1.80 g, 7.42 mmol) were then added at RT. The mixture was stirred at 110°C for 14h. Further NBS (2.64 g, 14.84 mmol) was then added and stirring continued at 110°C for 12h. The mixture was then diluted with 10% Nal ICC);, solution (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic solutions were washed with brine (80 mL), dried ( Na;SO i ) and concentrated under reduced pressure to give the title compound (11.00 g, 27%) as brown liquid, which was used directly in the next step without further purification; m/z\ ES+ [M+H]+ = 294.
Figure imgf000221_0002
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 RT under N2. The mixture was then stirred at 85°C for 16h then cooled slowly to RT. The mixture was then diluted with DCM (200 mL) and washed with 5% AcOH in water (200 mL), water (200 mL), sat. Nal ICO;, (200 mL) and then sat. brine (200 mL). The organic solution was dried (Na2SO4) and concentrated. Trituration with EtOAc (10 mL) and washing with MTBE (30 mL) gave a solid which was collected by filtration and dried under vacuum to give the title compound (1.60 g, 44%) as brown solid; *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.
Figure imgf000221_0001
Pd-PEPPSI-IHept (Cl) (47.1 mg, 0.048 mmol) was added to tert-butyl piperazine- 1 -carboxylate (541 mg, 2.91 mmol), CS2CO3 (947 mg, 2.91 mmol) and 3-(6-chloro-4-methoxy-3-oxo-l,3-dihydro-277-pyrrolo[3,4- c]pyridin-2-yl)piperidine-2, 6-dione (300 mg, 0.969 mmol) in 1 ,4-dioxane (10 mL) at RT under N2. The resulting suspension was stirred for 2h at 120°C. After cooling the reaction mixture was diluted with DCM (20 mL) and washed with 5% AcOH in water (20 mL), water (20 mL), sat. Nal ICO;, (20 mL) and then sat. brine (20 mL). The organic portion was dried (Na2SO4) and concentrated. Trituration using EtOAc (4 mL) and washing with MTBE (16 mL) gave a solid which was collected by filtration and dried under vacuum to give the title compound (260 mg, 50%) as brown solid; ‘HNMR: 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.
Figure imgf000222_0001
To a stirred solution of tert-butyl 4-(2-( 2,6-dioxopiperidin-3-yl )-4-methoxy-3-oxo-2,3-dihydro- 177-pyrrolo- [3, 4-c]pyridin-6-yl)piperazine-l -carboxylate (260 mg, 0.566 mmol) in DCM (10 mL) was added 4M HC1 (2.83 mL, 11.32 mmol) in 1,4-dioxane at 0°C. The mixture was stirred at RT for 12h under N2. The mixture was then concentrated under reduced pressure to give the title compound as a hydrochloride salt (240 mg, 63 % yield), as brown solid; m/z\ ES+ [M+H]+ = 360.2.
Figure imgf000222_0002
Intermediate 50a was reacted with Intermediate 120f using the general synthetic method illustrated by Example 5 to give the title compound after purification (Column: Zorbax-Cl 8, 5|im; 50 x 21.2 mm, Eluent C, Basic Work-Up A); ‘HNMR: 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.
Figure imgf000222_0003
K2CO3 (421 mg, 3.05 mmol) and 1 ,4-dibromobutane (910 Lil,. 7.62 mmol) were added consecutively to a solution of tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperidine-l -carboxylate (Intermediate 38B) (450 mg, 1.52 mmol) in DMF (5 mL). The resulting mixture was stirred overnight at 70°C. After cooling to RT the mixture was diluted with EtOAc (20 mL) and water (20 mL) then brine (20 mL). The organic portion was collected and washed with further portions of brine (3 x 20 mL), dried (MgSO.4) and concentrated. Purification by FSC (gradient: 0-25% EtOAc in heptane) gave the title compound (0.305 g, 47 %) as an colourless oil; *H NMR (CDCh) 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.
Figure imgf000223_0001
DIPEA (729 Lil,. 4.18 mmol) was added to a mixture of 3-(7-methoxy-l-oxo-5-(piperazin-l-yl)isoindolin-2- yl)piperidine-2, 6-dione hydrochloride salt (303 mg, 0.77 mmol) (Intermediate If), tert-butyl 4-(4-(4- bromobutoxy)-2-fluorophenyl)piperidine-l -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 4h. The mixture was cooled to RT and diluted with water (20 mL) and EtOAc (20 mL). The organic portion was collected and the aqueous portion was washed with further EtOAc (20 mL). The combined organics were washed with water (2 x 20 mL), brine (2 x 20 mL), dried (MgSO.4) and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (0.200 g, 41 %) as a pale yellow liquid; >H NMR (CDCh) 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.
Figure imgf000223_0002
4M HC1 in 1 ,4-dioxane (706 Lil ,. 2.83 mmol) was added in one portion to 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 (200 mg, 0.28 mmol) in DCM (1 mL) at RT. The resulting mixture was stirred at RT for 0.5h. The mixture was then concentrated under reduced pressure to give a mixture of the title compounds 121c and biproduct 121 d in 1 :2 ratio. as a pale 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-l-oxoisoindolin-5- yl)piperazin-l-yl)butoxy)-2-fluorophenyl)piperidin-l-yl)-2-(trifluoromethyl) benzonitrile
Figure imgf000224_0001
A ( 1 : 2) mixture of Intermediates 121c and 121 d was reacted with 4-fluoro-2-(trifluoromethy l)benzonitrile using the general synthetic method illustrated by Example 16 to give the title compound (as a formate salt) after purification (Column A, Eluent A); ‘H NMR (CDC13) 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), 7.61 (1H, d), 8.33 (1H, s); Wz: ES+ [M+H]+ = 811.6.
Example 122: 4-(4-(4-(4-(4-(2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazin-l- yl)butoxy)-2-fluorophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000224_0002
A ( 1 : 2) mixture of Intermediates 121c and 121 d was reacted with 4-fluoro-2-(trifluoromethy l)benzonitrile using the general synthetic method illustrated by Example 16 to give the title compound as a formate salt after purification (Column A, Eluent A); >H NMR (CDC13) 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-hvdroxy-2-methylphenyl)-3,6-dihvdropyridine-l(2/D-carboxylate
Figure imgf000225_0001
NaiCO;, (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-l ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2//)-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 mins. PdC12(dppf)-DCM (0.799 g, 0.978 mmol) was then added under N2 at RT and then the mixture was stirred at 110°C for 16h. After cooling the mixture was filtered through celite and washed through with EtOAc. The filtrate was concentrated under reduced pressure to give gummy mass which was dissolved in EtOAc (100 mL). This solution was washed with water (30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. Purification by FSC (gradient: 5-17% EtOAc in hexane) gave the title compound (2.27 g, 72%) as pale yellow solid; ‘HNMR: 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), 6.87 (1H, d), 9.21 (1H, s); m/z\ ES+[M-Boc]+ 190.4.
Figure imgf000225_0002
A solution of tert-butyl 4-(4-hydroxy-2-methylphenyl)-3,6-dihydropyridine-l(2/f)-carboxylate (2.25 g, 7.78 mmol) in EtOAc (40 mL) hadN2 gas bubbled through it for a period of 10 mins. Pd-on-C (10 % dry basis, 0.80 g, 7.52 mmol) was then added under N2. The mixture was then stirred under H2 at RT for 24h. The mixture was then filtered through celite and washed through with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (2.22 g, 95%) as an off white solid; *H 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.
Figure imgf000225_0003
4M HC1 in 1,4-dioxane (10 mL, 40.0 mmol) was added to a mixture of tert-butyl 4-(4-hydroxy-2-methyl- phenyl)piperidine-l -carboxylate (500 mg, 1.72 mmol) in DCM (5 mL) at RT under N2. The mixture was then stirred at RT for 24h. Removal of solvent under reduced pressure then gave the title compound as a hydrochloride salt (390 mg, 96%) as an off-white solid; m/z\ ES+[M+H]+ 192.2.
Intermediate 123d: 4-(4-(4-Hvdroxy-2-methylphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000226_0001
DIPEA (3.95 mL, 22.61 mmol) was added to a mixture of 3-methyl-4-(piperidin-4-yl)phenol hydrochloride salt (1.03 g, 4.52 mmol) and 4-lliioro-2-(trilliiorometh\ l (benzonitrile (1.00 g, 5.29 mmol) in DMSO (10 mL) at RT under air for 18h. The mixture was then poured into water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0- 50% EtOAc in petroleum ether) gave the title compound (0.880 g, 54 %) as a yellow solid; *H 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-(l,3-Dioxolan-2-yl)propoxy)-2-methylphenyl)piperidin-l-yl)-2-
(trifluoromethvDbenzonitrile
Figure imgf000226_0002
2-(3-Bromopropyl)-l,3-dioxolane (0.364 mL, 2.69 mmol) was added in one portion to 4-(4-(4-hydroxy-2- methylphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (0.88 g, 2.44 mmol) and K2CO3 (1.012 g, 7.33 mmol) in MeCN (10 mL) at RT under N2. The resulting suspension was stirred at 80°C for 24h. The mixture was then filtered after cooling to RT. The filtrate was diluted with water (50 mL) and a resulting yellow precipitate was collected by filtration to give the title compound (1.10 g, 95%); *H 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 (lH, 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-(4-(2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxoisoindolin-5-yl)piperazin-l- yl)butoxy)-2-methylphenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000227_0001
Intermediate 123e was reacted with Intermediate le using the general synthetic method illustrated by Example 1 to give the title compound after purification (Column A, Eluent A, Basic Work-Up A); *H 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 (lH, 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-Hvdroxybut-l-vn-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)- benzonitrile
Figure imgf000227_0002
But-3-yn-l-ol (154 mg, 2.20 mmol) and diethylamine (357 mg, 4.89 mmol) were added to a mixture of 4-(4- (4-bromophenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (Intermediate 4a) (500 mg, 1.222 mmol) and DMF (5 mL) at RT under N2. Bis(triphenylphosphine)palladium(II) chloride (42.9 mg, 0.061 mmol), PPha (22.43 mg, 0.086 mmol) and Cui (11 .63 mg, 0.061 mmol) were then added under N2. The mixture was then stirred at 80°C for 16h. After cooling, the mixture was filtered through celite and washed through with DCM (20 mL x 3). The filtrate was then concentrated under reduced pressure then diluted with DCM (50 mL). This solution was washed with water (20 mL x 2) and brine (20 mL), dried (T^SCh) and concentrated. Purification by FSC (gradient: 5-40% EtOAc in hexane) gave the title compound (220 mg, 29%) as a yellow solid; m/z\ ES+ [M+H]+ 399.0.
Intermediate 124b: 4-(4-(4-(4-Hvdroxybutyl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000227_0003
A solution of 4-(4-(4-(4-hydroxybut-l-yn-l-yl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (200 mg, 0.502 mmol) in EtOH (10 mL) had N2 gas bubbled through it for a period of 10 mins. 10% Pd-on-C (150 mg, 1.410 mmol) was then added under N2. The mixture was then stirred under H2 at RT for 5h. The mixture was then filtered through celite and washed through with EtOH. Concentration of the filtrate gave the title compound as a gummy mass (160 mg, 46%); m/z\ ES+ [M+H]+ 403.4.
Figure imgf000228_0001
PPha (201 mg, 0.765 mmol) and CBr i (254 mg, 0.765 mmol) were added to a solution of 4-(4-(4-(4-hydroxy- butyl)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (154 mg, 0.383 mmol) in DCM (5 mL) at 0°C then the mixture was stirred at RT for 3h. 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 (N^SOa) and concentrated. Purification by FSC (Snap- ultra silica-gel, 100-200 mesh size, gradient: 5- 15% EtOAc in hexane) gave the title compound (71 mg, 32 % yield) as brown gummy liquid; m/z\ ES+ [M+H]+ 467.
Figure imgf000228_0002
Intermediate 124c was reacted with Intermediate 2c using the general synthetic method illustrated by Example 5 to give the title compound after purification (Column B, Eluent A, Basic Work-up A); *H 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: ((lr,3r)-3-((4-(l-(4-Cvano-3-(trifluoromethyl)phenyl)piperidin-4- yllphenoxylmethvD-cvclobutvDmethyl methanesulfonate
Figure imgf000229_0001
To a stirred solution of 4-(4-(4-(((lr,3r)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (Intermediate 36b) (90 mg, 0.202 mmol) in DCM (2 mL) was added l'U,N (41.0 mg, 0.405 mmol) and methanesulfonyl chloride (46.4 mg, 0.405 mmol) at 0°C. The mixture was then stirred for Ih at RT. The reaction was then quenched with water (25 mL). The mixture was then extracted with DCM (30 mL x 2) and the combined organic solutions were washed with brine (20 mL), dried (Na2SC>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.
Figure imgf000229_0002
Intermediate 125a was reacted with Intermediate If using the general synthetic method illustrated by Example 12 to give the title compound after purification (Column B, Eluent A, Basic Work-Up A); *H 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.
Figure imgf000229_0003
To a stirred solution of 4-(4-(4-(((ls,3s)-3-(hydroxymethyl)cyclobutyl)methoxy)phenyl)piperidin-l-yl)-2- (trifluoromethyl)benzonitrile (Intermediate 36c) (100 mg, 0.225 mmol) in DCM (2 mL) was added EtaN (0.063 mL, 0.450 mmol) and methanesulfonyl chloride (0.035 mL, 0.450 mmol) at 0°C, followed by stirring for Ih at RT. The reaction was then quenched with water (25 mL) and extracted with DCM (30 mL x 2). The combined organic solutions were washed with brine (20 mL), dried (NaiSO^ 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.
Figure imgf000230_0001
Intermediate 126a was reacted with Intermediate If using the general synthetic method illustrated by Example 12 to give the title compound after purification (Column B, Eluent A, Basic Work-Up A); *H 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.
Figure imgf000230_0002
To a stirred solution of 1 -(benzyloxy )-4-bromobenzene (4.00 g, 15.20 mmol) in THF (40 mL) was added w-BuLi (1 ,6M in hexane, 14.25 mL, 22.80 mmol) at -78°C then the mixture was stirred for Ih at -78°C. tert- Butyl 4-oxoazepane-l -carboxylate (3.89 g, 18.24 mmol) was then added at -78°C. The mixture was stirred for 2h at -78°C then stirred for Ih at RT. The reaction was quenched with sat. NH4CI solution and extracted with EtOAc (2 x 20 mL). The combined organic solutions were dried QS^SCL) and concentrated. Purification by FSC (gradient: 20-30% EtOAc in hexane) gave the title compound (3.50 g, 55%) as pale yellow liquid; *H NMR: 1.42 (9H, d), 1.63-1.92 (4H, m), 2.01-2.14 (IH, m), 3.10-3.29 (2H, m), 3.39-3.62 (3H, m), 4.89 (IH, 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).
Figure imgf000230_0003
To a solution of tert-butyl 5-(4-(benzyloxy)phenyl )-2,3,4,7-tetrahydro- 1 /7-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 2h while warming slowly to RT. Concentration under reduced pressure and washing with MTBE gave the title compound as a TFA salt (2.98 g, 100 % yield); ‘H 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).
Figure imgf000231_0001
To a stirred solution of 5-( 4-( ben/vlox vjphenvl (-2.3.4.7-tetrahvdro- l /7-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 RT. The mixture was then stirred at 100°C for 16h. After cooling, the mixture was poured ice-cold water and extracted with EtOAc (100 mL x 2). The combined organic solutions were washed with brine (100 mL), dried QS^SCL) and concentrated. Purification by FSC (gradient: 25-35 % EtOAc in hexane) gave the title compound (2.30 g, 64 %) as an off-white solid; >H 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 (2H, 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.
Figure imgf000231_0002
A solution of 4-(5-(4-(benzyloxy)phenyl)-2,3,4,7-tetrahydro-l/7-azepin-l-yl)-2-(trifluoromethyl)benzonitrile (2.3 g, 5.13 mmol) in MeOH (25 mL) was bubbled withlSh for 5 mins. To this mixture 10% Pd-on-C (1.092 g, 10.26 mmol) was added under N2. The mixture was then stirred under H2 using a H2 bladder at RT for 3h. The mixture was then filtered through celite and washed through with MeOH (150 mL). The filtrate was concentrated to obtain a pale yellow sticky liquid. Trituration with MTBE gave the title compound as a racemic mixture (1.80 g, 92 %) which was separated by chiral SFC (Column: LUX A3, (LUXA3_MeOH_3- 40_CHIRALHPLC-SFCME), Eluent CO2/MeOH) to give enantiomer 1 (eluting first) (500 mg) and enantiomer 2 (500 mg);
Enantiomer 1 (127d): ‘H NMR: 1.43-1.64 (lH, 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): ‘HNMR: 1.46-1.61 (lH, 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); Wz: ES+ [M+H]+= 361.0.
Figure imgf000232_0001
To a stirred solution of 4-(4-(4-hydroxyphenyl)azepan-l-yl)-2-(trifluoromethyl)benzonitrile (enantiomer 1, 127d) (300 mg, 0.832 mmol) in MeCN (3 mL) was added K2CO3 (230 mg, 1.67 mmol) and 1,4- dibromobutane (270 mg, 1.249 mmol) at RT and the mixture was stirred for 6h at 70°C. 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 (TS^SCL) and concentrated. Purification by FSC (gradient: 0-20% EtOAc in hexane) gave the title compound (255 mg, 60 %) as pale yellow gummy material; *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); Wz: ES+ [M+H]+= 496.9.
Figure imgf000232_0002
Intermediate 127e was reacted with Intermediate 2c using the general synthetic method illustrated by Example 5 to give the title compound after purification (Column B, Eluent A, Basic Work-Up A); *H 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.
Figure imgf000232_0003
K2CO3 (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-l-yl)-2-(trifluoromethyl)benzonitrile (enantiomer 2, 127e) (300 mg, 0.832 mmol) in MeCN (3 mL) at RT then the mixture was stirred for 6h at 70°C. 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 (Na2SO4) and concentrated. Purification by FSC (gradient: 0-20% EtOAc in hexane) gave the title compound (250 mg, 58 % yield) as pale yellow gummy material; *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); Wz: ES+ [M+H]+ = 496.8.
Figure imgf000233_0001
Intermediate 128a was reacted with Intermediate 2c using the general synthetic method illustrated by Example 5 to give the title compound after purification (Column B, Eluent A, Basic Work-Up A); *H 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.
Figure imgf000233_0002
tert-Butyl 4-( 4.4.5.5-tetramethvl- 1 ,3,2-dioxaborolan-2-yl )-3,6-dihydropyridine- 1 ( 2/7)-carboxvlate (574 mg, 1.86 mmol) and CS2CO3 (1008 mg, 3.09 mmol) were added to a solution of 3 -(5-bromo-l -oxoisoindo lin-2- yl)piperidine-2, 6-dione (500 mg, 1.55 mmol) in 1,4-dioxane (10 mL) that was purged withN2 for 15 mins. PdCi2(dppf)-CH2C12 adduct (126 mg, 0.155 mmol) was then added and the mixture was stirred at 120°C for 5h. After cooling, the crude mixture was diluted with DCM and filtered through celite. The filtrate was washed with water. The organic layer was separated and dried (Na2SO4) and concentrated to give the title compound as brown gummy liquid (600 mg, 38%); m/z\ ES+ [M+H]+= 426.1.
Figure imgf000233_0003
4M HC1 in 1,4-dioxane (2.0 mL, 8.00 mmol) was added to a solution of tert-butyl-4-(2-(2,6-dioxopiperidin-3- vl )- 1 -oxoisoindolin-5-vl )-3.6-dihvdropvridine- 1 ( 2/7)-carboxvlate (200 mg, 0.47 mmol) in DCM (5 mL) at 0°C. After stirring for 2h 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.
Figure imgf000234_0001
Intermediate 50a was reacted with Intermediate 129b using the general synthetic method illustrated by Example 5 to give the title compound after purification (Column B, Eluent C, Basic Work-Up A); *H NMR: 1.43-1.69 (5H, m), 1.69-1.90 (4H, m), 1.97-2.06 (IH, m), 2.30-2.41 (IH, m), 2.59-2.67 (3H, m), 2.70-2.84 (IH, 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 (IH, m), 6.32 (IH, s), 6.87 (2H, d), 7.15 (2H, d), 7.24-7.36 (2H, m), 7.59 (IH, d), 7.63-7.71 (2H, m), 7.82 (IH, d), 10.83-11.22 (IH, m);w/z: ES+ [M+H]+= 726.4.
Figure imgf000234_0002
10% Pd-on-C (75 mg, 0.705 mmol) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)-3,6-dihydropyridine-l(2//)-carboxylate (Intermediate 129a) (150 mg, 0.353 mmol) in MeOH (5 mL) and the mixture was stirred under H2 for 16h. Removal of solvent under reduced pressure gave the title compound (140 mg, 93%) which was used directly in the next step without further purification; m/z\ ES+ [M-Boc]+= 328.0.
Figure imgf000234_0003
To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidine-l -carboxylate (150 mg, 0.351 mmol) in DCM (5 mL) add 4M HC1 in 1,4-dioxane (2 mL, 8.00 mmol) and the mixture was stirred for Ih. Concentration under reduced pressure gave the title compound (120 mg, 85%) which was used directly in the next step.
Figure imgf000234_0004
Figure imgf000235_0001
Intermediate 50a was reacted with Intermediate 130b using the general synthetic method illustrated by Example 5 to give the title compound after purification C-18 chromatography (Eluent C, Basic Work-Up A); ‘HNMR: 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.
Figure imgf000235_0002
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 CHCh (72 mL) and the reaction stirred at 80°C under reflux. After 3h, additional NBS (1.62 g, 9.11 mmol) and AIBN (0.187 mg, 1.14 mmol) were added and heating continued at reflux for a further 0.5h. The mixture was then cooled to RT. Water (150 mL) was added. The mixture was extracted with DCM (2 x 150 mL). The combined organic solutions were dried (Na2SC>4) and concentrated to give the title compound which was used without further purification; *H NMR (500 MHz, CDCI3) 3.99 (3H, s), 4.44 (2H, s), 7.49 (1H, d), 7.54 (1H, d).
Figure imgf000235_0003
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) at RT under air. The resulting mixture was stirred at 80°C for 20h then cooled to RT with stirring. The resulting solid was collected by filtration, washed with MeCN (2 x 10 mL) and dried to give the title compound (1.49 g, 37 %) as a grey/purple solid; *H 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-vD-l-oxoisoindolin-5-vDpiperazine-l- carboxylate
Figure imgf000236_0001
tert-Butyl piperazine- 1 -carboxylate (40.1 mg, 0.22 mmol), 3-(5-bromo-7-chloro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (70 mg, 0.20 mmol) and oven-dried CS2CO3 (191 mg, 0.59 mmol) were placed in an oven-dried micro wave vial and the tube flushed with N2. DMF (1.75 mL) was added and the mixture was purged withN2. diMeiHept-Cl-Pd(cinnamyl)Cl (10.45 mg, 9.79 nmol) was added and the mixture again purged withN2. The tube was sealed and the mixture heated at 100°C for 4 h then cooled to RT. The mixture was diluted with DCM (50 mL), poured into 5% AcOH in water (50 mL) and shaken. Sat. brine (5 mL) was added to separate the layers. The aqueous layer was extracted with DCM (30 mL) and the extracts combined with the organic layer. The combined organic fractions were washed with water (2 x 50 mL) and filtered through a phase-separating paper. The crude product was purified by preparative HPLC (Column A, Eluent A). Fractions containing the desired compound were concentrated to a volume such that the MeCN had been removed. The resulting aqueous suspension was basified to pH 7 and extracted with DCM (3 x 15 mL). The combined DCM extracts were dried (T^SCh) and concentrated to give the title compound (0.028 g, 27 %) as a white solid; >H NMR (500 MHz) 1.43 (9H, s), 1.93-2.01 (IH, m), 2.31-2.42 (IH, m), 2.59 (IH, d), 2.90 (IH, ddd), 3.33-3.37 (4H, m), 3.42-3.51 (4H, m), 4.20 (IH, d), 4.32 (IH, d), 5.02 (IH, dd), 7.01 (IH, d), 7.04 (IH, s), 10.96 (IH, s); m/z\ ES+ [M+H]+ 463.0.
Figure imgf000236_0002
4-(4-(4-(3-(l,3-Dioxolan-2-yl)propoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (Example Ih) (28.8 mg, 0.06 mmol) and tert-butyl-4-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine- 1-carboxylate (29 mg, 0.06 mmol) were heated at 60°C in formic acid (2 mL) for Ih. The mixture was then concentrated and then diluted in NMP (2 mL) at RT under air. NaBH(OAc)a (33.2 mg, 0.16 mmol) was added in one portion after 5 mins and the resulting suspension was stirred at RT for 18h. Purification by preparative HPLC (Column A, Eluent A) gave the title compound as a formate salt (0.034 g, 67 %) as a beige solid; *H NMR: 1.64-1.89 (6H, m), 1.97 (2H, d), 2.09-2.22 (IH, m), 2.31 (IH, qd), 2.66-3 (9H, m), 3.07 (2H, d), 3.26- 3.57 (4H, m), 3.93-4.14 (4H, m), 4.20 (IH, d), 4.33 (IH, d), 5.12 (IH, dd), 6.75 (IH, s), 6.78-6.88 (3H, m), 6.95-7.04 (IH, m), 7.06-7.18 (3H, m), 7.60 (IH, d), 8.28 (IH, s), 8.54-8.94 (IH, m); m/z\ ES+ [M+H]+ 763.2.
Intermediate 132a: 4-Bromo-2-hvdroxy-6-methylbenzoic acid
Figure imgf000237_0001
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 l,3-dimethylimidazolidin-2-one (33.4 mL, 308.96 mmol). The mixture was heated to 120°C for 3h. The mixture was then cooled to RT and was poured into water (400 mL). The mixture was acidified to pH3 with 2M HC1 with stirring. A resulting solid was collected by filtration, washed with water and dried under vacuum to give the title compound (2.13 g, 72 %) as a white solid; *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- [M-H]’ 229.
Figure imgf000237_0002
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 and stirred for 5 days and then concentrated to 15 mL volume. This mixture was diluted with EtOAc (100 mL) and ice (100 g) was added, followed by sat. NaHCOa solution (60 mL). The mixture was shaken; the organic layer was separated and washed with sat. NaHCOa solution (60 mL) and sat. brine (30 mL), dried (NaaSOy) and concentrated.
Purification by FSC (20% EtOAc in heptane) gave the title compound (1.43 g, 90 %) as a beige crystalline solid; H 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- [M-H]- 243.
Figure imgf000237_0003
8.2M 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 N2. The 2-phase mixture was stirred at -35°C for 10 mins then diethyl (bromodifluoromethyl)phosphonate (2.06 mL, 11.59 mmol) was added dropwise, keeping the temperature at -35°C. The cooling bath was removed and the resulting solution was allowed to warm with stirring. At -10°C, a rapid exotherm began; the cooling bath was reapplied at 5°C and a maximum temperature of 32°C was reached. The mixture was then stirred at RT for a further 90 mins. TLC showed almost complete conversion to a new product. The reaction was quenched with water (125 mL) and adjusted to pH=2 with 2M HC1. The mixture was extracted with EtOAc (2 x 125 mL); the combined organic solutions were washed with sat. brine (75 mL), dried (NaaSO^ and concentrated. Purification by FSC (gradient: 0-10% EtOAc in heptane) gave the title compound (1.16 g, 68 %) as a white crystalline solid; *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
Figure imgf000238_0001
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 stirred at 100°C for 35 mins. The mixture was then cooled to RT. 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 (TS^SCL) and concentrated to give the title compound (1.52 g, 100 %), as a beige gum, which was used without further purification; >H NMR (500 MHz, CDC13) 3.97 (3H, s), 4.51 (2H, s), 6.49 (1H, t), 7.36 (1H, d), 7.48 (lH, d).
Intermediate 132e: 3-(5-Bromo-7-(difluoromethoxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000238_0002
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) at RT under air. The resulting mixture was stirred at 80°C for 16h. The mixture was then cooled to RT and concentrated to 10 mL volume. Diethyl ether (30 mL) was added followed by stirring and sonication, causing precipitation of a dark solid. The solid was collected by filtration and washed with MeCN. The filtrates were concentrated to give a brown gum. The gum was treated with DCM (30 mL) and was warmed and sonicated. A brown precipitate remained out of solution. This was collected by filtration and washed with DCM to give product as a brown solid. The filtrate was purified by FSC (gradient: 0-3% MeOH in DCM) gave the title compound (1.145 g, 72%) as a brown solid; *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 (lH, t), 7.53 (1H, s), 7.78 (lH, s), 11.01 (1H, s); m/z\ ES+ [M+H]+ 389.
Intermediate 132f: tert-Butyl-4-(7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-vD-l-oxoisoindolin-5- yl)piperazine-l-carboxylate
Figure imgf000239_0001
Pd-PEPPSI-IHept.Cl (11.25 mg, 0.01 mmol) was added to a N2-purged mixture of 3-(5-bromo-7-(difluoro- m ethoxy )-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (90 mg, 0.23 mmol), tert-butyl piperazine- 1 -carboxylate (129 mg, 0.69 mmol) and in 1,4-dioxane (7.5 mL) and heated at 90°C for 5h. The mixture were then diluted with DCM (100 mL) and washed with 5% AcOH in water (100 mL), water (100 mL) and then sat. brine (50 mL). The organic solution was dried (Na2SC>4) and concentrated. Purification by FSC (gradient: 0-3% MeOH in DCM) gave (after concentration and azeotroping with MeCN) the title compound (0.090 g, 32 %) as a grey solid; *H NMR (500 MHz) 1.43 (9H, s), 1.97 (IH, ddd), 2.37 (IH, ddd), 2.59 (IH, d), 2.89 (IH, ddd), 3.33- 3.37 (4H, m), 3.43-3.50 (4H, m), 4.24 (IH, d), 4.35 (IH, d), 5.01 (IH, dd), 6.74 (IH, d), 6.96 (IH, d), 7.42 (IH, t), 10.96 (IH, s); m/z\ ES+ [M+H]+ 495.1.
Figure imgf000239_0002
4-(4-(4-(3-(l,3-Dioxolan-2-yl)propoxy)phenyl)piperidin-l-yl)-2-(trifluoromethyl)benzonitrile (Example Ih) (50 mg, 0.11 mmol) and tert-butyl-4-(7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazine-l -carboxylate (62.2 mg, 0.12 mmol) were heated at 60°C in formic acid (2 mL) for 0.5h. The mixture was then concentrated and the crude residue was stirred in NMP (2 mL) at RT under air. NaBH( OAcy (57.5 mg, 0.27 mmol) was then added in one portion after 5 mins and the resulting suspension was stirred at RT for 2h. Purification by preparative HPLC (Waters XSelect CSH Cl 8 ODB column, 5pm silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents gave the title compound (0.073 g, 85 %) as a white solid; *H NMR: 1.55-1.69 (4H, m), 1.69- 1.8 (2H, m), 1.85 (2H, d), 1.91-2.03 (IH, m), 2.36-2.46 (2H, m), 2.53-2.64 (2H, m), 2.77 (IH, tt), 2.89 (IH, ddd), 3.05 (2H, td), 3.26-3.37 (8H, m), 3.97 (2H, t), 4.17 (2H, d), 4.23 (IH, d), 4.34 (IH, d), 5.00 (IH, dd), 6.72 (IH, d), 6.83-6.9 (2H, m), 6.93-6.98 (IH, m), 7.12-7.19 (2H, m), 7.27 (IH, dd), 7.32 (IH, d), 7.41 (IH, t), 7.81 (IH, d), 10.94 (IH, s); m/z\ ES+ [M+H]+ 795.3.
Intermediate 133a: Methyl 4-bromo-3-methoxy-2-methylbenzoate
Figure imgf000240_0001
To a stirred solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (1 .00 g, 4.08 mmol) in MeCN (10 mL) was added K2CO3 (1.69 g, 12.24 mmol) and Mel (0.38 mL, 6.12 mmol) at 0°C. The mixture was then stirred at RT for 16h. The reaction was then quenched with water (10 mL) and the mixture extracted with EtOAc (20 mL x 2). The combined organic solutions were washed with brine (10 mL), dried (T^SCh) and concentrated. Purification by FSC (eluent: EtOAc-hexane 20%-35%) gave the title compound (600 mg, 57 %) as off-white solid; 'H NMR ^DCh) 2.58 (3H, s), 3.83 (3H, s), 3.91 (3H, s), 7.46 (1H, d), 7.53 (1H, d).
Figure imgf000240_0002
CHCI3 (80 mL) was added to ethyl 4-bromo-3-methoxy-2-methylbenzoate (4.10 g, 15.82 mmol) underN2.
NBS (3.94 g, 22.15 mmol) and AIBN (520 mg, 3.16 mmol) were then added at RT and the mixture was stirred at 75°C for 3h. 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 (Na2SC>4) and concentrated to give the title compound (5.00 g, 86 %) as brown liquid that was used directly without further purification; *H NMR: 3.88 (3H, s), 3.92 (3H, s), 5.01 (2H, s), 7.60 (1H, d), 7.80 (1H, d).
Figure imgf000240_0003
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 RT under N2. The mixture was then stirred at 85°C for 16h under N2. The mixture was then cooled slowly to RT, solids were 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; *H 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-l-oxoisoindolin-5-yl)piperazine- 1-carboxylate
Figure imgf000241_0001
Pd-PEPPSI-IHeptCl (83 mg, 0.085 mmol) was added to tert-butyl piperazine- 1 -carboxylate (949 mg, 5.10 mmol), CS2CO3 (1661 mg, 5.10 mmol) and 3-(5-bromo-4-methoxy-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (600 mg, 1.699 mmol) in 1,4-dioxane (20 mL) at RT under N2. The resulting suspension was stirred for 2h at 120°C. The mixture was then diluted with DCM (20 mL) and washed with 5% AcOH in water (20 mL), water (20 mL), sat. Nal ICO, (20 mL) and then sat. brine (20 mL). The organic solution was dried (Na2SO4) and concentrated. Trituration with EtOAc (8 mL) and washing with MTBE (25 mL) gave a solid which was collected by filtration and dried under vacuum to give the title compound (700 mg, 77 %) as dark brown solid; *H 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.
Figure imgf000241_0002
To a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-l-oxoisoindolin-5-yl)piperazine- 1-carboxylate (700 mg, 1.527 mmol) in DCM (10 mL) was added 4M HC1 (7.63 mL, 30.5 mmol) in 1,4- dioxane at 0°C. The mixture was stirred at RT for 2h under N2. The mixture was then concentrated to give the title compound (600 mg, 78 %) as brown solid; >H 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); Wz: ES+ [M+H]+ = 359.
Figure imgf000241_0003
Intermediate 133e was reacted with Intermediate 50a using the general synthetic method illustrated by Example 5 to give the title compound after purification by HPLC (Column: Zorbax-C18, 5|im; 50 x 21.2 mm, Eluent C, Basic Work-Up A); >H 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.
Figure imgf000242_0001
THF (10 mL) was added to 4-bromo-5-methoxy-2-methylaniline (1.00 g, 4.63 mmol) then water (2.4 mL) and HC1 (37%, 2.40 mL) were added at RT. The mixture was stirred at RT for Ih and was 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 the drop wise addition of KI (1.306 g, 7.87 mmol) solution in water (2 mL). The mixture was then warmed slowly to RT and stirred for 16h. The reaction was then quenched with sat. NaiCO;, solution and the pH was adjusted to 7-8. The mixture was then extracted with DCM (20 mL x 3). Combined organic solutions were washed with brine (20 mL), dried (Na2SO4) and concentrated. Purification by FSC using hexane (100 %) as the eluent gave the title compound (1.07 g, 62 %) as yellow solid; >H NMR: 2.29 (3H, s), 3.82 (3H, s), 7.45 (IH, s), 7.54 (IH, s); m/z\ ES+ [M+H]+ = 328.2.
Figure imgf000242_0002
THF (10 mL) was added to l-bromo-4-iodo-2-methoxy-5-methylbenzene (1.05 g, 3.21 mmol), then iPrMgCl
(4.82 mL, 9.63 mmol) was added dropwise at -78°C. The mixture was stirred at -50°C to -20°C for 40 min. Solid carbon dioxide (excess) was added and then the mixture was warmed slowly to RT and stirred for Ih. The reaction was then quenched with 1 ,5M HC1 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 (Na2SO4) and concentrated to give the title compound (0.80 g, 74%) as brown solid; m/z\ ES+ [M+H]+ = 245.9.
Figure imgf000242_0003
DMF (3 mL) was added to 4-bromo-5-methoxy-2-methylbenzoic acid (750 mg, 3.06 mmol). K2CO3 (846 mg,
6.12 mmol) and Mel (0.287 mL, 4.59 mmol, dropwise) were then added at RT and the mixture was then stirred at RT for 24h. 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 (Na2SO4) and concentrated under reduced pressure to give the title compound (730 mg, 92%); *H NMR (CDCI3) 2.58 (3H, s), 3.83 (3H, s), 3.91 (3H, s), 7.46 (IH, d), 7.53 (IH, d). Intermediate 134d: Methyl 4-bromo-2-(bromomethyl)-5-methoxybenzoate
Figure imgf000243_0001
CHCI3 (10 mL) was added to methyl 4-bromo-5-methoxy-2-methylbenzoate (720 mg, 2.78 mmol) under N2 then NBS (692 mg, 3.89 mmol) and AIBN (91 mg, 0.556 mmol) were added at 0°C. The mixture was then stirred at 75°C for 32 h then quenched with sat. 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 QS^SCL) and concentrated to give the title compound as a brown liquid; *H NMR: 3.89 (3H, s), 3.93-4.00 (3H, m), 4.97 (2H, s), 7.48 (1H, s), 7.90 (1H, s).
Figure imgf000243_0002
MeCN (10 mL) was added to methyl 4-bromo-2-(bromomethyl)-5-methoxybenzoate (860 mg, 2.54 mmol) under N2. 3-Aminopiperidine-2, 6-dione hydrochloride (419 mg, 2.54 mmol) and DIPEA (1.78 mL, 10.18 mmol) were then added at RT and the mixture was stirred at 85°C for 16h. After cooling to RT, a precipitate was collected by filtration and washed with 5 mL MeCN then dried under reduced pressure to give the title compound (430 mg, 31 %) as grey solid; ‘HNMR: 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.
Figure imgf000243_0003
1,4-Dioxane (20 mL) was added to 3-(5-bromo-6-methoxy-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (430 mg, 1.22 mmol) under N2. To this mixture, tert-butyl piperazine- 1 -carboxylate (680 mg, 3.65 mmol) and CS2CO3 (1.19 g, 3.65 mmol) were added under N2 at RT. To this mixture Pd-PEPPSLIHeptCl (71.1 mg, 0.073 mmol) was charged under N2 then the mixture was stirred at 120°C for 2h. The mixture was then diluted with DCM (20 mL) and washed with 5% AcOH in water (25 mL), water (25 mL), sat. Nal ICO3 (25 mL) and then sat. brine (20 mL). The organic layer was dried (Na2SC>4) and concentrated. Trituration with EtOAc (5 mL) and washing with MTBE (20 mL) gave a solid which was collected by filtration and dried under vacuum to the title compound (253 mg, 36 % yield) as green solid; *H 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-l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2,6-dione
Figure imgf000244_0001
DCM (2 mL) was added to tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-methoxy-l-oxoisoindolin-5- yl)piperazine-l -carboxylate (250 mg, 0.545 mmol), then 4M HC1 in 1,4-dioxane (2.73 mL, 10.90 mmol) was added at 0°C and the mixture was then stirred at RT for 2h. The organic solvent was then removed under reduced pressure to give the title compound (250 mg, 99 %) as grey solid; *H 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), 5.05-5.12 (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-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-methoxy-l-oxoisoindolin-5-yl)piperazin-l- idin-l-yl)-2-i
Figure imgf000244_0002
Intermediate 50a was reacted with Intermediate 134g using the general synthetic method illustrated by Example 5 to give the title compound after purification (Column: X Select C18 150 x 21.1, Eluent C, Basic Work-Up A); ‘H 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), 7.13-7.20 (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-((4-(2-(2.6-Dioxopiperidin-3-yl)-4-methoxy-3-oxo-2.3-dihvdro-lg-pyrrolo[3.4- c]pyridin-6-vDpiperazin-l-vDmethvDpiperidin-l-vDphenvDpiperidin-l-vD-2-
(trifluoromethvDbenzonitrile
Figure imgf000244_0003
Intermediate 4b was reacted with Intermediate 120e using the general synthetic method illustrated by Example 1 to give the title compound after purification (Column A, Eluent A); 'H 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.
Figure imgf000245_0001
PPha (757 mg, 2.89 mmol) was added to 4-(4-(4-hydroxyphenyl)piperidin-l-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 Lil ,. 1.88 mmol) in THF (16 mL) at RT under N2. The resulting mixture was stirred at RT for 16h. Concentration and purification by FSC (gradient 0-20% EtOAc in petroleum ether) gave the title compound (0.560 g, 65 %) as a yellow gum; *H 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.
Figure imgf000245_0002
Intermediate 27f was reacted with Intermediate 136a using the general synthetic method illustrated by Example 1 to give the title compound after purification by preparative TLC (DCM:MeOH, 15:1); *H 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.
Figure imgf000245_0003
3-Bromo-4-iodophenol (5.0 g, 16.73 mmol) was added to 2-(3-bromopropyl)-l,3-dioxolane (4.7 g, 24.33 mmol) and K2CO3 (6.3 g, 45.62 mmol) in MeCN (100 mL). The mixture was stirred at 80 °C for 1 h, cooled to RT, filtered through silica and the solvent was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% DCM in MeOH to give the title compound (5.0 g, 80 %) as a colourless oil; ‘H NMR: 5 1.65-1.73 (2H, m), 1.7-1.8 (2H, m), 1.76-1.95 (1H, m), 3.7-3.99 (5H, m), 4.8^1.87 (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.
Figure imgf000246_0001
PdCh(dtbpf) (0.472 g, 0.65 mmol) was added to K2CO3 (2.20 g, 16.14 mmol), 2-[3-(3-bromo-4- iodophenoxy)propyl]-l,3-dioxolane (4.00 g, 9.68 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-vl)-3.6-dihvdropvndine- l (2/7)-carboxvlate (1.99 g, 6.46 mmol) in l,4-dioxane:water (4:1, 50 mL) at RT under nitrogen. The mixture was stirred at 80 °C for 1 h, cooled to RT, filtered through Celite® and the solvent was evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in Et2O to give the title compound (2.3 g, 76 %) as a yellow oil; ‘H NMR: 5 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 (lH, m), 7.11-7.18 (2H, m); m/z: ES+ [M+H]+ = 468.1.
Figure imgf000246_0002
Rhodium on carbon (5%, 2.1 g, 1.02 mmol) and tert-butyl 4- {2-bromo-4-[3-(l ,3-dioxolan-2- yl)propoxy]phenyl}-3,6-dihydropyridine-l(2/f)-carboxylate (2.1 g, 4.48 mmol) in EtOAc (10 mL) and MeOH (1 mL) was stirred under an atmosphere of hydrogen at RT 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; >H NMR: 5 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), 3.35-3.47 (1H, m), 3.71-3.8 (2H, m), 3.84-3.9 (2H, m), 3.94^1.01 (2H, m), 4.09 (2H, d), 4.75-4.87 (1H, m), 6.91 (1H, dd), 7.14 (1H, d), 7.23 (1H, d).
Figure imgf000247_0002
Copper(I) cyanide (0.38 g, 4.34 mmol) was added to tert-butyl 4-{2-bromo-4-[3-(l,3-dioxolan-2- yl)propoxy]phenyl}piperidine-l-carboxylate (1.7 g, 3.61 mmol) inNMP (14 mL) at RT. The mixture was stirred at 150 °C for 3 h.The reaction was cooled to RT and diluted with EtOAc (100 mL), washed with water (50 mL), saturated brine (50 mL), dried over Na2SC>4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in Et2O to give the title compound (0.500 g, 33.2 %) as a yellow gum; >H NMR: 5 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), 3.99^1.11 (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.
Figure imgf000247_0001
TMS-I (327 pl, 2.40 mmol) was added to tert-butyl 4-{2-cyano-4-[3-(l,3-dioxolan-2- yl)propoxy]phenyl}piperidine-l-carboxylate (500 mg, 1.20 mmol) in MeCN (1 mL). The mixture was stirred at RT for 1 min. The solvent was removed under reduced pressure to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 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-f2-Cvano-4-[3-(1.3-dioxolan-2-yl)propoxylphenyllpiperidin-l-yl)-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000248_0003
Copper(I) cyanide (61.3 mg, 0.68 mmol) was added to l-bromo-3,4-difluoro-2-(trifluoromethyl)benzene (170 mg, 0.65 mmol) in NMP (2 mL) at RT and stirred at 150 °C for 3 h. DIPEA (228 pl, 1.30 mmol) and 5-[3- (l,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 Ih. The reaction mixture was cooled to RT and diluted with EtOAc (20 mL), washed with water (10 mL), saturated brine (10 mL), dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in Et2O to give the title compound (0.150 g, 45.7 %) as a yellow solid; 'H NMR: 5 1.67-1.74 (IH, 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 (IH, t), 7.24 (IH, dd), 7.37 (IH, d), 7.44-7.53 (2H, m), 7.83 (IH, d); m/z: ES+ [M+H]+ = 504.3.
Figure imgf000248_0001
4-(4-{2-Cyano-4-[3-(l,3-dioxolan-2-yl)propoxy]phenyl}piperidin-l-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 RT and evaporated to dryness. tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-l-oxo-2,3- dihvdro- 1 //-isoindol-5-vl |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 two residues were dissolved in NMP (1.5 mL) and the solution was stirred at RT for 16 h. The reaction mixture was purified by Cl 8- flash chromatography, elution gradient 5 to 100% MeCN in water (1% NH4HCO3) to give the title compound (78 mg, 33 %) as a white solid; ‘H NMR: 5 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 (1H, 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.
Figure imgf000248_0002
tert-Butyl 4-( 4.4.5.5-tetramethvl- 1 ,3,2-dioxaborolan-2-yl )-3,6-dihydropyridine- 1 ( 2//)-carboxvlate was reacted with 5-bromo-l ,3-difluoro-2-iodobenzene using the general synthetic method illustrated by intermediate 9a to give the title compound; 'H NMR CCDCh): 8 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-/Bu| = 318.0
Intermediate 138b: 4-(4-Bromo-2,6-difluorophenyl)-l,2,3,6-tetrahvdropyridine
Figure imgf000249_0001
tert-Butyl 4-(4-bromo-2,6-difluorophenyl)-3,6-dihydropyridine-l(2//)-carboxylate was reacted using the general synthetic method illustrated by intermediate 26c to give the title compound in the form of an HC1 salt which was used without further purification; *H NMR: 5 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-dihvdropyridin-l(2/D-yl1-2-
(trifluoromethvDbenzonitrile
Figure imgf000249_0002
4-(4-Bromo-2,6-difluorophenyl)- 1,2, 3 ,6- tetrahydropyridine was reacted with 4-fluoro-2-
(trifluoromethyl)benzonitrile using the general synthetic method illustrated by intermediate 4a to give the title compound; >H NMR: 5 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- lin-l-vll-2,6-di -3,6-dil
-2-i
Figure imgf000249_0003
4-[4-(4-Bromo-2,6-difluorophenyl)-3,6-dihydropyridin-l(2//)-yl]-2-(trifluoromethyl)benzonitrile was reacted with 4-(dibutoxymethyl)piperidine (intermediate 27e) using the general synthetic method illustrated by intermediate 27c to give the title compound; *H NMR: 8 0.93 (6EI, t), 1.35 - 1.47 (4H, m), 1.53 - 1.6 (6EI, 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 - 7.71 (1H, m); m/z: ES+ [M+H]+ = 606.3.
Figure imgf000250_0001
4- [4- {4-[4-(Dibutoxymethyl)piperidin- 1 -yl]-2,6-difluorophenyl} -3 ,6-dihydropyridin- 1 (277)-yl]-2- (trifluoromethyl)benzonitrile was hydrogenated using the general synthetic method illustrated by intermediate 9b to give the title compound; >H NMR: 5 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.
Figure imgf000250_0002
4-(4-{4-[4-(Dibutoxymethyl)piperidin-l-yl]-2,6-difluorophenyl}piperidin-l-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-lH-pyrrolo[3,4-c]pyridin-6-yl)piperazine-l-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 RT, evaporated and the residue was suspended in NMP (2 mL). The reaction mixture was stirred for 5 mins followed by addition of sodium triacetoxyhydroborate (56.7 mg, 0.27 mmol). The suspension was stirred at RT for 2 h. Purification by preparative HPLC (Column A, Eluent A) gave the title compound in the form of a formate salt (25 mg, 28.5 %) as a yellow solid; >H NMR: 5 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 - 2.76 (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.
Figure imgf000250_0003
Figure imgf000251_0001
Benzyl (2S)-2-methylpiperazine-l -carboxylate was reacted with 4-fluoro-2-(trifluoromethyl)benzonitrile using the general synthetic method illustrated by intermediate 137f to give the title compound; *H NMR: 5 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>y)-3-methylpiperazin-l-yl1-2-(trifluoromethyl)benzonitrile
Figure imgf000251_0002
Benzyl (2S)-4-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]-2-methylpiperazine-l-carboxylate was reacted with hydrogen gas using the general synthetic method illustrated by intermediate 123b to give the title compound; 'H NMR: 5 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>y)-3-methyl-4-(4-nitrophenyl)piperazin-l-yl1-2-
Figure imgf000251_0003
3-Fluoro-4-[(3S)-3-methylpiperazin-l-yl]-2-(trifluoromethyl)benzonitrile was reacted with l-fluoro-4- nitrobenzene using the general synthetic method illustrated by intermediate 29a to give the title compound; *H NMR: 5 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>y)-4-(4-AminophenvD-3-methylpiperazin-l-yl]-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000252_0001
3-Fluoro-4-[(3S)-3-methyl-4-(4-nitrophenyl)piperazin-l-yl]-2-(trifluoromethyl)benzonitrile was reacted with iron and ammonium chloride using the general synthetic method illustrated by intermediate 29b to give the title compound; ‘HNMR: 5 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.
Figure imgf000252_0002
Copper bromide (682 mg, 4.76 mmol) was added to 4-[(3>S)-4-(4-aminophenyl)-3-methylpiperazin-l-yl]-3- fluoro-2-(trifluoromethyl)benzonitrile (600 mg, 1.59 mmol) and tert-butylnitrite (491 mg, 4.76 mmol) in MeCN (15 mL) at RT and was stirred at RT for 3 h. The reaction mixture was diluted with DCM, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in Et2O to give the title compound (130 mg, 18.5 %) as a yellow solid; *H NMR: 5 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), 4.09^1.15 (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.
Figure imgf000252_0003
PdlZ-Bud’h (0.11 g, 0.02 mmol) was added to 4-|(3.S>4-(4-bromophenvl )-3-methylpiperazin- 1-yl ]-3-fluoro-2- (trifluoromethyl)benzonitrile (0.1 g, 0.03 mmol), 4-(l,3-dioxolan-2-yl)piperidine (0.039 g, 0.25 mmol), CS2CO3 (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 was stirred at 100 °C for 2 h. The mixture was then cooled to RT and the solvent evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in Et2O to give the title compound (0.80 g, 68 %) as a yellow solid; *H NMR 5 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. -
Figure imgf000253_0001
4-[(3>S)-4-{4-[4-(l ,3-Dioxolan-2-yl)piperidin-l-yl]phenyl}-3-methylpiperazin-l-yl]-3-fluoro-2- (trifluoromethyl)benzonitrile was reacted with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3- dihydro-lH-isoindol-5-yl]piperazine-l-carboxylate (intermediate le) using the general synthetic method illustrated by example 137 and purified by flash silica chromatography, elution gradient 0 to 8 % MeOH in DCM to give the title compound; ‘HNMR: 5 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 (7H, 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 - 3.78 (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.
Figure imgf000253_0002
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) inNMP (12 mL) and was stirred at 100 °C for 24 h. The reaction mixture cooled to RT, diluted with EtOAc (50 mL), washed with water (50 mL), saturated brine (20 mL), dried over MgSCh, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in Et2O to give the title compound (1.5 g, 77 %) as a yellow solid; ‘H NMR: 5 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.
Figure imgf000254_0001
Benzyl 4-[4-cyano-3-(trifluoromethyl)phenyl]-3-methylpiperazine-l-carboxylate was reacted with hydrogen gas using the general synthetic method illustrated by intermediate 123b to give the title compound; *H NMR: 5 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.
Figure imgf000254_0002
IThldbay (175 mg, 0.19 mmol) was added to Xantphos (110 mg, 0.19 mmol), Cs2CO3 (3.1 g, 9.54 mmol), 1- bromo-4-iodobenzene (1.1 g, 4.20 mmol) and 4-(l,3-dioxolan-2-yl)piperidine (600 mg, 3.82 mmol) in 1,4- di oxane (20 mL) under nitrogen. The mixture was stirred at 80 °C for 3 h and then cooled to RT. The solvent was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 55% EtOAc in Et2O to give the title compound (0.30 g, 25.2 %) as a yellow solid; *H NMR 5 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 (IH, m), 6.84 - 6.91 (2H, m), 7.27 - 7.36 (2H, m); m/z: ES+ [M+H]+ = 312.1.
Figure imgf000254_0003
l-(4-Bromophenyl)-4-(l,3-dioxolan-2-yl)piperidine was reacted with 4-[2-methylpiperazin-l-yl]-2- (trifluoromethyl)benzonitrile using the general synthetic method illustrated by intermediate 139f to give racemic compound which was purified by preparative chiral-HPLC on a Column: CHIRALPAK IH, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH (0.1% 2M NI E-MeOH ): Flow rate: 100 mL/min; Gradient: isocratic 40% B; to give the title compounds; Intermediate 140d (isomer 1) elutes first: ‘H NMR: 5 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): ‘H NMR: 5 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), 4.57^1.63 (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-[(2R*)-4-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro-lg- isoindol-5-yl1piperazin-l-yllmethyl)piperidin-l-yl1phenyll-2-methylpiperazin-l-yl1-2-
(trifluoromethvDbenzonitrile (absolute stereochemistry not yet confirmed)
Figure imgf000255_0001
4-[(27(*)-4-{4-[4-(l,3-Dioxolan-2-yl)piperidin-l-yl]phenyl}-2-methylpiperazin-l-yl]-2- (trifluoromethyl)benzonitrile was reacted with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3- dihydro-lH-isoindol-5-yl]piperazine-l-carboxylate (intermediate le) using the general synthetic method illustrated by example 137 to give the title compound; 'H NMR: 5 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-|(2.$,*)-4-f4-[4-(f4-[2-(2,6>-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro-l//- isoindol-5-yl1piperazin-l-yllmethyl)piperidin-l-yl1phenyll-2-methylpiperazin-l-yl1-2-
(trifluoromethyl)benzonitrile (absolute stereochemistry not yet confirmed)
Figure imgf000255_0002
4- [(2S'*)-4- { 4- [4-( 1 ,3 -Dioxolan-2-yl)piperidin- 1 -y 1] phenyl } -2-methy Ipiperazin- 1 -y 1] -2- (trifluoromethyl)benzonitrile was reacted with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3- dihydro-lEI-isoindol-5-yl]piperazine-l-carboxylate (intermediate le) using the general synthetic method illustrated by example 137 to give the title compound; ‘El NMR: 5 1.18-1.29 (6EI, 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), 2.53-2.76 (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), 4.96 (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-l-yl)-2-(trifluoromethyl)benzonitrile
Figure imgf000256_0001
Copper(I) cyanide (1.80 g, 20.12 mmol) was added to l-bromo-3,4-difhioro-2-(trifluoromethyl)benzene (5.0 g, 19.16 mmol) inNMP (2 mL) and was stirred at 150 °C for 3 h, 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 a further 1 h. The reaction was cooled to RT and was diluted with EtOAc (200 mL) and water (200 mL), dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in Et2O to give the title compound (3.3 g, 57.4 %) as a white solid; >H NMR (CDC13): 8 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: l-[4-Cvano-2-fluoro-3-(trifluoromethyl)phenyl1-3-methyl-1.2.3.6-tetrahvdroDyridin-
4-yl trifluoromethanesulfonate
Figure imgf000256_0002
Lithium bis(trimethylsilyl)amide (15.0 mL, 14.99 mmol) was added to 3-fluoro-4-(3-methyl-4-oxopiperidin-l- yl)-2-(trifhioromethyl)benzonitrile (1.5 g, 5.00 mmol) in THF (30 mL) under nitrogen at -65 °C for 1 h. N-(5- chloropyridin-2-yl)-l,l,l-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.92 g, 9.99 mmol) was added and continued to stir at -65 °C for 2 h. The reaction mixture was quenched with MeOH and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in Et2O to give the title compound (0.410 g, 18.98 %) as a yellow solid; *H NMR (CDClj): 8 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-(l,3-Dioxolan-2-vD-l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yllphenyllpiperidine
Figure imgf000257_0001
4-(l,3-Dioxolan-2-yl)piperidine was reacted with 2-(4-bromophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane using the general synthetic method illustrated by intermediate 139f to give the title compound; *H NMR (CDC13): 5 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.
Figure imgf000257_0002
1 - [4-Cy ano-2-fluoro-3-(trifluoromethyl)phenyl]-3-methyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl trifluoromethanesulfonate was reacted with 4-(l,3-dioxolan-2-yl)-l-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperidine using the general synthetic method illustrated by intermediate 92e to give the title compound; 'H NMR CCDClj): 5 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.
Figure imgf000257_0003
3-Ethenyl-4-fluoro-2-(trifluoromethyl)benzonitrile was reacted with hydrogen gas using the general synthetic method illustrated by intermediate 9b to give the title compound as a racemic mixture which was purified by preparative chiral-HPLC on a Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NHa-MeOH), Mobile Phase B: EtOH-HPLC; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 20 mins to give the title compounds as white solids;
Intermediate 142e (cis-isomer 1) (elutes first): >H NMR (CDC13): 8 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): >H NMR (CDC13): 8 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.
Figure imgf000258_0001
Intermediate 142e was reacted with intermediate le using the general synthetic method illustrated by example 137 to give the title compound; >H NMR (CDC13): 8 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), 7.96 (1H, s); m/z: ES+ [M+H]+ = 816.4.
Figure imgf000258_0002
Figure imgf000259_0001
Intermediate 143a was reacted with intermediate le using the general synthetic method illustrated by example 137 to give the title compound; >H NMR (CDC13): 8 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), 7.12 (3H, t), 7.50 (1H, d), 7.96 (1H, s); m/z: ES+ [M+H]+ = 816.4.
Figure imgf000259_0002
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 mins under nitrogen. I2 (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 NH4CI solution (25 mL), extracted with EtOAc (3 x 25 mL), dried over Na2SC>4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in Et2O to give the title compound (1.00 g, 60.0 %) as a yellow solid; *H NMR (CDCI3): 8 7.31 - 7.41 (1H, m), 7.81 - 7.95 (1H, m).
Figure imgf000259_0003
4-Fluoro-3-iodo-2-(trifluoromethyl)benzonitrile was reacted with 2-ethenyl-4,4,5,5-tetramethyl-l,3,2- dioxaborolane using the general synthetic method illustrated by intermediate 35a to give the title compound; *H NMR (CDCh): 8 5.70 - 5.87 (2H, m), 6.68 (1H, m), 7.40 (1H, t), 7.74 (1H, dd).
Figure imgf000259_0004
3-Ethenyl-4-fluoro-2-(trifluoromethyl)benzonitrile was reacted with hydrogen gas using the general synthetic method illustrated by intermediate 9b to give the title compound; *H NMR (CDCla): 8 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-l-carboxylate
Figure imgf000260_0001
Benzyl carbonochloridate (14.27 mL, 96.17 mmol) was added dropwise over 5 mins 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. The resulting mixture was stirred at RT 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 using MgSCh, filtered and evaporated to afford crude product as a colourless oil. The oil was diluted with IPA:water (1 :1, 200 mL) and was stirred at RT 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 give the title compound (32.9 g, 91 %) as a white solid; *H NMR 5 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-(l, 3-dioxolan-2-yl )piperidin-l -yll phen yllpiperidine-1 -carboxylate
Figure imgf000260_0002
To 4-(l,3-dioxolan-2-yl)piperidine (15.02 g, 95.52 mmol), benzyl 4-(4-bromophenyl)piperidine-l -carboxylate (32.5 g, 86.83 mmol) and CS2CO3 (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 followed by addition of PdlZ-Bud’h (2.21 g, 4.34 mmol). The resulting mixture was stirred at 100 °C for 20 h, cooled to RT and the solid was filtered under vacuum. The solid was washed with 1,4-dioxane (3x 65 mL) and the filtrate was evaporated to afford a pale yellow solid. The solid was suspended in cyclopentyl methyl ether:heptane (1 :10, 300 mL), stirred at 50 °C for 30 mins and then left to cool to RT for a further 2 h. The solid was filtered to give the title compound (28.9 g, 73.9 %) as a cream solid; *H NMR 5 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-(l,3-Dioxolan-2-vD-l-[4-(piperidin-4-vDphenyl]piperidine
Figure imgf000261_0001
Benzyl 4-{4-[4-(l,3-dioxolan-2-yl)piperidin-l-yl]phenyl}piperidine-l-carboxylate (762 mg, 1.69 mmol) was dissolved in EtOEI (20 mL) and Pd/C (10%, 180 mg, 0.17 mmol) was added under nitrogen. The reaction was stirred under an atmosphere of hydrogen at 4 bar for 16 h. The catalyst was then filtered off through a pad of Celite®, 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; *H NMR 5 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.
Figure imgf000261_0002
3-Ethyl-4-fluoro-2-(trifluoromethyl)benzonitrile was reacted with 4-(l,3-dioxolan-2-yl)-l-[4-(piperidin-4- yl)phenyl] piperidine using the general synthetic method illustrated by intermediate 140a to give the title compound; >H NMR (CDCh): 5 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.
Figure imgf000261_0003
4-(4-{4-[4-(l,3-Dioxolan-2-yl)piperidin-l-yl]phenyl}piperidin-l-yl)-3-ethyl-2-(trifluoromethyl)benzonitrile was reacted with intermediate 2b using the general synthetic method illustrated by example 137 to give the title compound; ‘HNMR: 5 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.
Figure imgf000262_0001
Intermediate 38d (1.0 g, 2.74 mmol), K2CO3 (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 RT and filtered under vacuum. The filtrate was evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane to give the title compound (1.03 g, 75 %) as a yellow oil which solidified on standing; 'El NMR (CDCh): 5 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.
Figure imgf000262_0002
4-Nitro-l //-indole (5x 95.0 g, 585 mmol), tert-butyl 4-[(methanesulfonyl)oxy]piperidine-l-carboxylate (5x 409.0 g, 1.46 mol) and CS2CO3 (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 extracting with EtOAc (6.0 L). The organic layer was washed with NaCl solution (10.0 L x3) and dried with Na2SO4. The solvent was evaporated and the crude product was purified by re-crystallisation from MTBE:Et2O (1 :4, 500.0 mL) at RT for 20 mins. The solid was filtered and dried under vacuum to give the title compound (910.0 g) as a brown solid; 'H NMR 5 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).
Figure imgf000262_0003
Figure imgf000263_0001
tert-Butyl 4-(4-nitro- 1 /7-indol- 1 -vl (piperidine- 1 -carboxylate (7x 140.0 g, 405 mmol) was added to 7 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 for 12 h under an atmosphere of hydrogen (30 PSI). The 7 batches were combined by filtering off Pd/C and evaporating the solvent. The resulting solid was used without further purification to give the title compound (770.0 g, 86%) as a brown solid; >H NMR 5 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).
Figure imgf000263_0002
tert-Butyl 4-(4-anuno- 1 //-indol- 1 -vl (piperidine- 1 -carboxylate (5x 175.0 g, 555 mmol) was added to 5 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 was stirred at 80 °C for 18 h. The batches were combined and the solvent was evaporated to afford crude product which was extracted with EtOAc (10.0 L) and washed with NaHCOa (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 with NaiSO i. The solvent was evaporated to give the title compound (1 .08 kg, crude) as a black oil and was used without further purification; *H NMR 5 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), 7.23 (s, 1H), 11.89 (s, 1H).
Intermediate 145e: tert-Butyl 4-f4-[carbamoyl(3-methoxy-3-oxopropyl)amino1-l/T-indol-l- yllpiperidine-l-carboxylate
Figure imgf000264_0001
tert-Butyl 4-{4-[(3-methoxy-3-oxopropyl)amino]-l/f-indol-l-yl}piperidine-l-carboxylate (6x 200 g, 498 mmol) were 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 RT for 2 h. The 6 batches were combined and water (5.0 L) was added to the mixture. DCM (8 L x2) was added to the extraction which was washed with NaCl solution. The organic layer was dried with Na2SC>4 and evaporated. The residue was purified by column chromatography, elution gradient 30:1 to 1 :1 Et2O:EtOAc to give the title compound (260.0 g, 19.6%) as a brown solid; >H NMR 5 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), 4.66-4.78 (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-l,3-diazinan-l-yl)-l//-indol-l-yl|piperidine-l -carboxylate
Figure imgf000264_0002
tert-Butyl 4- {4-[carbamoyl(3-methoxy-3-oxopropyl)ammo]-lrt-indol-l-yl}piperidine-l -carboxylate (3x 105.0 g, 236 mmol) in MeOH (3x 779.0 g, 24.3 mol, 3x 984 mL) were added to 3 separate vessels of MeOH (1.0 L) followed by MeONa/MeOH (42.5 g, 236 mmol, 30% purity). The reaction was stirred at RT 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 give the title compound (180 g, 70.7%) as a white solid; *H NMR 5 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), 4.59-4.60 (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: l-[l-(Piperidin-4-yl)-l/T-indol-4-yl1-l,3-diazinane-2,4-dione TsOH
Figure imgf000265_0001
tert-Butyl 4-[4-(2,4-dioxo-l,3-diazinan-l-yl)-l/f-indol-l-yl]piperidine-l-carboxylate (140.0 g, 339.41 mmol) in a solution of MeCN (300 mL) was added to p-toluenesul fonic acid hydrate (82.6 g, 434 mmol) in MeCN (560 mL) dropwise at RT. The reaction was stirred at 60 °C for 1 h. Additional p-toliieriesul fonic acid hydrate (6.46 g, 33.9 mmol) was added to the mixture and stirred continued at 60 °C for a further 1 h. The reaction was then filtered and dried under vacuum to give the title compound (120.0 g, 70.8%) as a grey solid; *H NMR: 5 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), 4.42-4.79 (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-f4-[4-(4-f4-[4-(2,4-Dioxo-l,3-diazinan-l-yl)-l/T-indol-l-yl1piperidin-l-yllbutoxy)-2- fluorophenyllpiperidin-l-yll-2-ltrifluoromethvDbenzonitrile
Figure imgf000265_0002
l-[l-(Piperidin-4-yl)-177-indol-4-yl]-l,3-diazinane-2, 4-dione TsOH (0.040 g, 0.13 mmol), 4-{4-[4-(4- bromobutoxy)-2-fhiorophenyl]piperidin-l-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 4h. The reaction mixture was cooled to RT, filtered under vacuum and the filtrate was evaporated to dryness to afford 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; *H NMR: 5 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 - 7.56 (2H, 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)ethvnyl1piperidine-l-carboxylate
Figure imgf000266_0001
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-l -carboxylate (2.1 g, 10.04 mmol) and copper(I) iodide (0.229 g, 1.20 mmol) in triethylamine (17 mL) at RT under nitrogen. The mixture was stirred at 80 °C for 16 h, cooled to RT and the solvent was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in DCM to give the title compound (3.0 g, 79 %) as a yellow solid; ‘H NMR (CDC13) 8 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-l//-pyrrolo|3,2-b|pyridin-2-yl)piperidine-l -carboxylate
Figure imgf000266_0002
Dichlorobis(MeCN)palladium(II) (0.409 g, 1.58 mmol) was added to tert-butyl 4-[(3-amino-5-bromopyridin- 2-yl)ethynyl]piperidine-l -carboxylate (3.0 g, 7.89 mmol) in DMF (30 mL) at RT under nitrogen. The resulting mixture was stirred at 120 °C for 16 h and then cooled to RT. The reaction mixture was diluted with EtOAc (75 mL), washed with Nal ICO;, solution (100 mL), dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash alumina chromatography, elution gradient 0 to 50% EtOAc in Et2O to give the title compound (1.5 g, 50.0 %) as a yellow oil; *H NMR 5 1.42 (9H, s), 1.96 (2H, d), 2.73 (2H, s), 2.89 (2H, s), 4.02M.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.
Figure imgf000266_0003
Sodium hydride (60 % in mineral oil, 0.22 g, 5.52 mmol) was added to tert-butyl 4-(6-bromo-l/7-pyrrolo[3,2- b]pyridin-2-yl)piperidine-l -carboxylate (1.4 g, 3.68 mmol) in DMF (15 mL) at 0 °C under nitrogen, lodomethane (0.229 mL, 3.68 mmol) was added after 15 mins. The resulting mixture was stirred at RT 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 Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in DCM to give the title compound (0.62 g, 42.7 %) as a yellow solid; >H NMR (CDCh) 8 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.
Figure imgf000267_0001
Ephos Pd G4 (280 mg, 0.30 mmol) was added to tert-butyl 4-(6-bromo-l-methyl-lrt-pyrrolo[3,2-b]pyridin-2- yl)piperidine-l -carboxylate (600 mg, 1.52 mmol), CS2CO3 (992 mg, 3.04 mmol), EPhos (163 mg, 0.30 mmol) and l,3-diazinane-2, 4-dione (521 mg, 4.56 mmol) in 1,4-dioxane (8 mL) under nitrogen. The mixture was stirred at 100 °C for 2 h, cooled to RT and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4 % MeOH in DCM to give the title compound (400 mg, 61.5 %) as a red solid; >H NMR 5 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.
Figure imgf000267_0002
l-Bromo-3,4-difluoro-2-(trifluoromethyl)benzene was reacted with l-bromo-3,4-difluoro-2-
(trifluoromethyl)benzene and copper cyanide using the general synthetic method illustrated by intermediate
137f to give the title compound; >H NMR: 5 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.
Figure imgf000267_0003
4-[4-(4-Bromophenyl)piperidin-l-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile was reacted with 4-(l,3- dioxolan-2-yl)piperidine using the general synthetic method illustrated by intermediate 139f to give the title compound; 'H NMR: 5 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.
Figure imgf000267_0004
Figure imgf000268_0001
4-(4-{4-[4-(l,3-Dioxolan-2-yl)piperidin-l-yl]phenyl}piperidin-l-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (100 mg, 0.20 mmol) was added to tert-butyl 4-[6-(2,4-dioxo-l ,3-diazinan-l-yl)- l-methvl- l //-pvrrolo| 3.2- b]pyridin-2-yl]piperidine-l-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 afford a residue. The residue diluted with NMP (2 mL) and stirred at RT for 16 h. The reaction mixture was diluted with DCM (10 mL), washed with saturated NaHCOa solution (20 mL), saturated brine (10 mL), dried over MgSO i. filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 11% MeOH in DCM and then purified by preparative TLC (DCMMeOH, 10:1) to give the title compound (0.065 g, 42 %) as a white solid; *H NMR (100 °C): 5 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-l-carboxylate
Figure imgf000268_0002
Intermediate 138a was reacted with hydrogen gas using the general synthetic method illustrated by intermediate 137c to give the title compound; >H NMR (CDC13): 8 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
Figure imgf000268_0003
tert-Butyl 4-(4-bromo-2,6-difluorophenyl)piperidine-l -carboxylate was reacted with HC1 using the general synthetic method illustrated by intermediate 24d to give the title compound; *H NMR: 8 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-l-yl1-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000269_0001
4-(4-Bromo-2,6-difluorophenyl)piperidine was reacted with 4-(4-bromophenyl)piperidine and copper cyanide using the general synthetic method illustrated by example 137d to give the title compound; *H NMR (CDCh): 8 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-t4-!4-|4-tl,3-Dioxolan-2-yl)piperidin-l-yl|-2,6-difluorophenyl!piperidin-l-yl)-3- fluoro-2-(trifluoromethyl)benzonitrile
Figure imgf000269_0002
4-[4-(4-Bromo-2,6-difluorophenyl)piperidin-l-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile was reacted with 4- (l,3-dioxolan-2-yl)piperidine using the general synthetic method illustrated by intermediate 139f to give the title compound; >H NMR (CDC13): 8 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 - 4.02 (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-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro-l/7-isoindol-5- yl1piperazin-l-yllmethyl)piperidin-l-yl1-2,6-difluorophenyllpiperidin-l-yl)-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000269_0003
4-(4-{4-[4-(l,3-Dioxolan-2-yl)piperidin-l-yl]-2,6-difluorophenyl}piperidin-l-yl)-3-fluoro-2- (trifluoromethyl)benzonitrile was reacted with intermediate 1 e using the general synthetic method illustrated by example 138 and purified by preparative EIPLC (Column A, Eluent D) to give the title compound; *H NMR: 8 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 (1H, 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.
Figure imgf000270_0001
4-Bromo-2-fluoro-l -iodobenzene was reacted with benzyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine- 1 ( 2/7)-carboxvlate using the general synthetic method illustrated by intermediate 35a to give the title compound; ‘HNMR: 5 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.
Figure imgf000270_0002
Pd-PEPPSI-IHeptcl (0.312 g, 0.32 mmol) was added to benzyl 4-(4-bromo-2-fluorophenyl)-3,6- dihydropyridine-l(2EI)-carboxylate (2.5 g, 6.41 mmol), 4-(l,3-dioxolan-2-yl)piperidine (1.1 g, 7.05 mmol) and CS2CO3 (5.2 g, 16.02 mmol) in dioxane (50 mL) under nitrogen and stirred at 80 °C for 24h. The reaction was cooled to RT and the solvent was evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 35% EtOAc in Et2O followed by 0 to 10% EtOAc in DCM to give the title compound (0.950 g, 31.8 %) as a yellow solid; ‘H NMR: 5 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), 3.71 - 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.
Figure imgf000270_0003
Benzyl 4-{4-[4-(l,3-dioxolan-2-yl)piperidin-l-yl]-2-fluorophenyl}-3,6-dihydropyridine-l(2H)-carboxylate was reacted with hydrogen gas using the general synthetic method illustrated by intermediate 9b to give the title compound; ‘HNMR: 5 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-(l,3-Dioxolan-2-yl)piperidin-l-yl|-2-tluorophenyl!piperidin-l-yl)-3- fluoro-2-(trifluoromethvI)benzonitrile
Figure imgf000271_0001
4-(l,3-Dioxolan-2-yl)-l-[3-fluoro-4-(piperidin-4-yl)phenyl]piperidine was reacted with 1 -bromo-3 ,4-difluoro- 2-(trilluoroineth\ l (benzene and copper cyanide using the general synthetic method illustrated by example 137f to give the title compound; >H NMR: 5 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 (4H, 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-f4-[4-(f4-[2-(2,6-Dioxopiperidin-3-yl)-7-methoxy-l-oxo-2,3-dihvdro-l/7-isoindol-5- yllpiperazin-l-yllmethyl)piperidin-l-yl]-2-fluorophenyllpiperidin-l-yl)-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000271_0002
4-(4- {4-[4-(l ,3-Dioxolan-2-yl)piperidin- l-yl]-2-fluorophenyl}piperidin-l -yl)-3-fluoro-2- (trifluoromethyl)benzonitrile was reacted with intermediate 1 e using the general synthetic method illustrated by example 146 to give the title compound; *H NMR: 5 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), 2.77 - 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-l-methyl-l,3-dihvdro-2/7-benzimidazol-2-one
Figure imgf000271_0003
Pd(dppf)2C12-DCM (0.575 g, 0.70 mmol) was added to 7-bromo-l-methyl-l,3-dihydro-277-benzimidazol-2- one (2.0 g, 8.81 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (2.03 g, 13.21 mmol) and K2CO3 (3.04 g, 22.02 mmol) in l,4-dioxane:water (4:1, 48 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 18 h. The reaction was cooled to RT and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in Et2O to give the title compound (1.1 g, 71.7 %) as a white solid; >H NMR 5 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-dihvdro-l/7-benzimidazole-4-carbaldehvde
Figure imgf000272_0001
Potassium osmate dihydrate (0.212 g, 0.57 mmol) was added to 7-ethenyl-l -methyl- 1.3-dihvdro-2/7- 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 l,4-dioxane:water (3:1, 40 mL) at RT and stirred for 2 h. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (3 x 100 mL), dried over Na2SC>4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM to give the title compound (0.95 g, 94 %) as a grey solid; *H NMR 5 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.
Figure imgf000272_0002
LHMDS (153 mL, 153.26 mmol) was added to 3-methyl-2-oxo-2,3-dihydro-l/f-benzimidazole-4- carbaldehyde (9.0 g, 51.09 mmol) in THF (80 mL) at 0 °C under nitrogen. The resulting mixture was stirred at RT for Ih. 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 RT. The mixture was stirred at 60 °C for 3 h, then was cooled to 10 °C and quenched with saturated NH4CI 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 was extracted with EtOAc (300 mL) and the solvent was evaporated to afford a brown solid. The brown solid was triturated with water to give a solid which was collected by filtration and dried under vacuum to give crude product. The two solid batches were combined, triturated with Et2O, collected by filtration and dried under vacuum to give the title compound (10.0 g, 68.1 %) as a grey solid; >H NMR 5 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.
Figure imgf000273_0001
Sodium triacetoxyborohydride (3.69 g, 17.40 mmol) was added to l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3 -dihydro- l/f-benzimidazole-4-carbaldehy de (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 RT 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 Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in Et2O to give the title compound (0.800 g, 50.2 %) as a yellow solid; >H NMR 5 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 (lH, m), 6.94 - 7.01 (1H, m), 7.06 - 7.12 (1H, m), 11.11 (1H, s); m/z\ ES+ [M+H]+ = 458.3.
Figure imgf000273_0002
TFA (2.5 mL) was added to tert-butyl 4-{[l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-l/f- benzimidazol-4-yl]methyl}piperazine-l -carboxylate (750 mg, 1.64 mmol) in DCM (10 mL) and stirred at RT for 1 h. The solvent was evaporated to give the title compound (1.1 g, 96 %) as yellow oil which was used without further purification; >H NMR 5 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-f4-[(4-f[l-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihvdro-l/7-benzimidazol-
4-yl1methyllpiperazin-l-yl)methyl1piperidin-l-yllphenyl)piperidin-l-yl1-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000274_0001
3- {3-Methyl-2-oxo-4-[(piperazin-l-yl)methyl]-2,3-dihydro-l/f-benzimidazol- l-yl}piperidine-2, 6-dione was reacted with intermediate 146f using the general synthetic method illustrated by example 138 to give the title compound; >H NMR (CDC13): 5 1.44 (2H, qd), 1.75 - 2.04 (8H, m), 2.13 - 2.28 (1H, m), 2.58 - 3.12 (17H,
1, 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,
1, 7.48 (1H, d), 8.38 (1H, s); m/z: ES+ [M+H]+ = 801.5.
Figure imgf000274_0002
Lithium bis(trimethylsilyl)amide (IM in THF, 11.01 mL, 11.01 mmol) was added dropwise over 5 mins to a suspension of 7-bromo-l-methyl-l,3-dihydro-2/f-benzimidazol-2-one (1.0 g, 4.40 mmol) in THF (5.00 mL) at RT under nitrogen for 20 minutes at RT. This solution was then was added portionwise over 5 mins to a separate flask containing a solution of 3-bromopiperidine-2, 6-dione (1.78 g, 8.81 mmol) in THF (10 mL) and was stirred at 60 °C for 4 h. The reaction was cooled to RT and was diluted with saturated NH4CI solution (10 mL), water (10 mL), saturated brine solution (5 mL), dried with MgSO i and was evaporated to dryness to afford crude product. The crude product was triturated with IPA:Heptane (1 :1 20 mL) and was heated to 50 °C for 30 mins. The mixture was cooled to RT and filtered under vacuum to give the title compound (743 mg, 50 %) as a grey solid; >H NMR (CDCI3): 5 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.
Figure imgf000274_0003
3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-l/f-benzimidazol-l-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 RT, diluted with DCM (100 mL), washed with NH4CI solution (50 mL), water (50 mL), Nal ICO;, solution (50 mL) and NaCl solution (50 mL). The organic layer was dried with Na2SO4, filtered and evaporated to afford crude product. The crude product was triturated with Hexane:EtOAc (1 :1, 100 mL) and filtered under vacuum. The solid was then slurried in EtOH (50 mL) for 20 mins, 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; ‘H NMR: 5 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-l-yl)-2.3-dihvdro-l/7-benzimidazol-l-yl1piperidine-
2,6-dione
Figure imgf000275_0001
tert-Butyl 4-[ 1 -( 2,6-dioxopiperidin-3-yl )-3-methyl-2-oxo-2,3-dihydro- 1 K-benzimidazol-4-yl ]piperazine- 1 - carboxylate was reacted with HC1 using the general synthetic method illustrated by intermediate 34d to give the title compound isolated as an HC1 salt; >H NMR: 5 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-f4-[4-(f4-[l-(2.6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihvdro-l/7-benzimidazol-
4-yl|piperazin-l-yl!methyl)piperidin-l-yl|phenyl!piperidin-l-yl)-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000275_0002
3- [3-Methyl-2-oxo-4-(piperazin- 1 -yl)-2,3-dihydro- 1 H-benzimidazol- 1 -yl]piperidine-2, 6-dione was reacted with intermediate 146f using the general synthetic method illustrated by example 138 and purified by preparative HPLC (Column A, Eluent D) to give the title compound; *H NMR (CDCla): 5 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.
Figure imgf000276_0001
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-l -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 was stirred to RT for 2 h. The reaction was then washed with citric acid (IM, 2x 100 mL), saturated Na HCO;, solution (100 mL), saturated brine (100 mL), dried over MgSO; and evaporated to dryness to give the title compound (28.0 g, 99 %) as a light brown oil, which was used without further purification; *H NMR (CDCh): 5 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).
Figure imgf000276_0002
Intermediate 1g (1.9 g, 4.50 mmol) was stirred with K;CO;, (1.865 g, 13.49 mmol) and tert-butyl 3-
{ [(methanesulfonyl)oxy] methyl} azetidine- 1 -carboxy late (1.45 g, 5.5 mmol) in MeCN (45.0 mL) at RT for 48 h. The reaction was then cooled to RT and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in heptane to give the title compound (2.2 g, 95 %) as a colourless gum; >H NMR (CDCh): 5 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.
Figure imgf000276_0003
TFA (0.6 mL, 7.79 mmol) was added to tert-butyl 3-[(4-{l-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4- yl}phenoxy)methyl]azetidine-l-carboxylate (230 mg, 0.45 mmol) in DCM (6 mL) and was stirred at RT for 2 h. The solvent was evaporated to dryness to give the title compound in the form of a TFA salt (0.23 g, 97 %) as a yellow oil and was used without further purification; *H NMR (CDCh): 5 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-il l-(2,2-Dimethoxyethyl)azetidin-3-yl|methoxy! phenyl)piperidin-l-yl|-2-
(trifluoromethvDbenzonitrile
Figure imgf000277_0001
2-Bromo- 1,1 -dimethoxy ethane (0.206 mL, 1.74 mmol), 4-(4-{4-[(azetidin-3-yl)methoxy]phenyl}piperidin-l- yl)-2-(trifluoromethyl)benzonitrile (0.602 g, 1.45 mmol) and DIPEA (0.631 mL, 3.63 mmol) were stirred in NMP (10 mL) under nitrogen at RT for 8 h. The reaction mixture was purified by preparative HPLC (Column A, Eluent D). The product was extracted with DCM (300 mL), dried over a phase separating cartridge and evaporated to give the title compound (0.055 g, 6.37 %) as a dry film; *H NMR (CDCla): 5 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-f[l-(2-f4-[2-(2,6-Dioxopiperidin-3-yl)-l-oxo-2,3-dihvdro-l/T-isoindol-5- yl I pipe razin-1 -ylleth yl)azetidin-3-yl I methoxy l pheny l )piperidin- l-yll-2-(tritluoromethyl)benzonitrile
Figure imgf000277_0002
4- [4-(4- { [ 1 -(2,2-Dimethoxyethyl)azetidin-3-yl]methoxy }phenyl)piperidin- 1 -yl] -2- (trifluoromethyl)benzonitrile (55 mg, 0.11 mmol) wase stirred in 2-MeTHF (1 mL) and HC1 (IM, 1 mL) at 60 °C for 1 h, cooled to RT 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 was stirred at RT for 1 h. The reaction mixture was purified by preparative HPLC (Column A, Eluent A) to give the title compound in the form of a formate salt (0.013 g, 14.59 %) as a colourless film; *H NMR (CDCI3): 8 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, ddd), 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), 5.18 (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
Figure imgf000278_0001
To a stirred solution 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 was then stirred at 70 °C for 16 h. The reaction was then cooled to RT and acidified with a HC1 (2M, aq) to pH 3-4, then extracted with EtOAc (160 mL). The organic layer was washed with water (100 mL), NaCl solution (100 mL), dried over Na2SO4, filtered and evaporated to dryness to give the title compound (8.0 g, 78 % yield) which was used without further purification; >H NMR 5 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
Figure imgf000278_0002
To a stirred solution of 6-chloro-2-methoxy-4-methylpyridine-3-carboxylic acid (8.0 g, 39.7 mmol) in DMF (80 mL) was added K2CO3 (6.58 g, 47.6 mmol) and methyl iodide (8.45 g, 59.5 mmol) which was stirred at RT 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 Na2SC>4, filtered and evaporated to dryness to give the title compound (8.5 g, 37.1 mmol, 93 % yield) as pale yellow solid; *H NMR 5 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
Figure imgf000278_0003
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 RT and was then stirred at 110 °C for 14 h. Additional NBS (2.64 g, 14.84 mmol) was added and was continued to stir at 110 °C for 12 h. The reaction mixture was cooled to RT and diluted with Na HCO;, solution
(10%, 50 mL) and extracted with EtOAc (120 mL). The organic layer was washed with NaCl solution (80 mL), dried over Na2SC>4, filtered and evaporated to dryness to give the title compound (11.0 g, 10.01 mmol, 27.0 % yield) as brown liquid which was used without further purification; m/z\ ES+ [M+EI]+ = 294.0.
Intermediate 152d: 3-(6-Chloro-4-methoxy-3-oxo-l,3-dihvdro- pyrrolo[3,4-c|pyridin-2-yl)piperidine-
Figure imgf000278_0004
2,6-dione
Figure imgf000279_0001
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 RT, diluted with DCM (200 mL), washed AcOH (5%, aq 200 mL), water (200 mL), Nal ICO;, solution (200 mL), NaCl solution (200 mL), dried with Na2SO4, filtered and evaporated to afford crude product. The crude product was triturated with EtOAc (10 mL) and washed with MTBE (30 mL) to afford solid which was collected by filtration and dried under vacuum to give the title compound (1.6 g, 4.35 mmol, 43.5 % yield) as brown solid; >H NMR 5 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 4-12-12, 6-dioxopiperidin-3-yl)-4-methoxy-3-oxo-2,3-dihvdro-l //- pyrrolo [3,4-c1pyridin-6-yl1piperazine-l-carboxylate
Figure imgf000279_0002
Pd-PEPPSI-IPent (47.1 mg, 0.048 mmol) was added to tert-butyl piperazine- 1 -carboxylate (541 mg, 2.91 mmol), CS2CO3 (947 mg, 2.91 mmol) and 3-(6-chloro-4-methoxy-3-oxo-l .3-dihvdro-2//-pvrrolo|3.4- c]pyridin-2-yl)piperidine-2, 6-dione (300 mg, 0.969 mmol) in 1,4-dioxane (10 mL) at RT under nitrogen. The resulting suspension was stirred at 120 °C for 2 h. The reaction mixture was cooled to RT and diluted with DCM (20 mL), washed with AcOH (5%, aq 20 mL), water (20 mL), Nal ICO;, solution (20 mL), NaCl solution (20 mL), dried with Na2SO4, filtered and evaporated to afford crude product. The crude product was triturated with EtOAc (4 mL) and washed with MTBE (16 mL) to afford solid which was collected by filtration and dried under vacuum to give the title compound (260 mg, 0.485 mmol, 50.1 % yield) as brown solid; *H NMR: 5 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.
Example 152: 4-14- 14-14-114-12-12, 6-Dioxopiperidin-3-yl )-4-methoxy-3-oxo-2, 3-dih vdro-1 H-pyrrolo 13, 4- c1pyridin-6-yl1piperazin-l-yllmethyl)piperidin-l-yl1phenyllpiperidin-l-yl)-3-fluoro-2-
(trifluoromethvDbenzonitrile
Figure imgf000280_0001
tert-Butyl 4-[ 2-( 2,6-dioxopiperidin-3-yl )-4-methoxy-3-oxo-2,3-dihydro- 1 //-pvnolo|3.4-c|pvridin-6- yl]piperazine-l -carboxylate was reacted with intermediate 146f using the general synthetic method illustrated by example 138 to give the title compound; *H NMR (CDCL): 5 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, td), 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.
Figure imgf000280_0002
PdChCPPha)? (3.36 g, 4.78 mmol) was added in to tert-butyl 4-ethynylpiperidine-l -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) under nitrogen. The dark brown solution was stirred at RT for 18 h. The reaction mixture was diluted with water (150 mL) and extracted into MTBE (150 mL). The organic layer was washed with water (150 mL), NaCl solution (50 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 20% EtOAc in heptane to give the title compound (24.1 g, 70 %) as an orange oil; *H NMR (CDCL): 5 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.
Figure imgf000280_0003
Potassium tert-butoxide (13.3 g, 118.48 mmol) was added to tert-butyl 4-[(2-amino-4- bromophenyl)ethynyl]piperidine-l -carboxylate (21.4 g, 39.49 mmol) in NMP (200 mL) at RT and was stirred for 3 h. lodomethane (7.38 mL, 118.48 mmol) was then added over 10 mins to the reaction flask, keeping the internal temperature below 35 °C which was then left to stir for 1 h. The reaction mixture was quenched with NH4CI 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 i. filtered and evaporated to afford crude. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane to give the title compound (13.74 g, 88 %) as a white solid; >H NMR (CDCI3): 5 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.
Figure imgf000281_0001
tert-Butyl 4-(6-bromo-l-methyl-lrt-indol-2-yl)piperidine-l-carboxylate (10.82 g, 27.51 mmol) was dissolved in 1,4-dioxane (180 mL) and added to a flask containing l,3-diazinane-2, 4-dione (9.42 g, 82.53 mmol), K2CO3 (11.41 g, 82.53 mmol) and tert-butylBrettPhos (1.33 g, 2.75 mmol). The mixture was degassed with nitrogen followed by the addition of tert-butylBrettPhos Pd G3 (2.35 g, 2.75 mmol). The mixture stirred at 100 °C for 42 h and then cooled to RT. Water (180 mL) and 2-MeTHF (180 mL) was added and stirred for 5 mins. The layers were separated and the organic layer was washed with water (180 mL), NaCl solution (50 mL), dried with MgSCL, filtered and evaporated to afford crude product. The crude product was slurried in EtOAc (30 mL) and the resulting brown suspension was filtered, the solid was washed with EtOAc (10 mL) to give the title compound (6.59 g, 56.2 %) as a pale brown solid; *H NMR: 5 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).
Figure imgf000281_0002
tert-Butyl 4-[ 6-( 2,4-dioxo- 1 ,3-diazinan- 1 -yl )- 1 -methyl- 1 H-indo 1-2-yl Jpiperidine- 1 -carboxylate was reacted with intermediate 138e using the general synthetic method illustrated by example 138 to give the title compound; >H NMR (CDC13): 8 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 (4H, 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.
Figure imgf000282_0001
Intermediate 138e was reacted with intermediate le using the general synthetic method illustrated by example 138 to give the title compound; >H NMR (CDC13): 5 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.
Figure imgf000282_0002
Intermediate 146f was reacted with intermediate 153c using the general synthetic method illustrated by example 138 and purified by preparative HPLC (Column A, Eluent D) to give the title compound; *H NMR (CDCh): 5 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.
Figure imgf000283_0001
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 was stirred at 80 °C for 6 h. The reaction was cooled to RT, filtered through Celite® and evaporated to afford crude product. The crude product was purified by silica gel chromatography (0-8% EtOAc/Hexane) to give the title compound (0.350 g, 24.5 %); m/z: ES+ [M+H]+ = 264.0.
Figure imgf000283_0002
DIPEA (475 pL, 2.72 mmol) was added to methyl 2-(bromomethyl)-6-chloropyridine-3-carboxylate (240 mg, 0.91 mmol) and 3-aminopiperidine-2, 6-dione, HC1 (119 mg, 0.73 mmol) in DMF (2 mL). The mixture was stirred at 40 °C for 2 h followed by 100 °C for 16 h. The reaction was cooled to RT and evaporated to dryness to afford crude product. The crude product was purified by silica gel chromaotgraphy (0-10% MeOH:DCM) followed by crystallisation from EtOAc to give the title compound (0.140 g, 55.2 %) as a purple solid; *H NMR: 5 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.
Figure imgf000283_0003
DIPEA (1.27 mL, 7.15 mmol) was added to 3-(2-chloro-5-oxo-5,7-dihydro-677-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, dried under vacuum for 48 h to give the title compound (1.06 g, 69.5 %) as a beige solid; >H NMR: 5 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' [M-H]’ = 428.4.
Intermediate 156d: 3-[5-Oxo-2-(piperazin-l-yl)-5.7-dihvdro-6/7-pyrrolo[3.4-blpyridin-6-yllpiperidine- 2,6-dione
Figure imgf000284_0001
HC1 (4M in dioxane, 2 mL, 8.00 mmol) was added to tert-butyl 4-[6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7- dilwdro-5//-pvrrolo|3.4-b|pvridin-2-vl Ipiperazine- 1 -carboxvlate (92 mg, 0.21 mmol) at RT and was stirred for 2 h. The reaction was evaporated to dryness to give the title compound as a HC1 salt which was used without further purification.
Figure imgf000284_0002
Intermediate 146f (0.075g, 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) with 3-[5-oxo-2-(piperazin-l-yl)-5,7-dihydro-6/f- pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (0.060 g, 0.17 mmol) at RT. Sodium triacetoxyborohydride (0.067 g, 0.32 mmol) was added after 5 mins and suspension was stirred at RT for 10 mins. The reaction mixture was purified by preparative HPLC (Column A, Eluent A) gave the title compound in the form of a formate salt (0.054 g, 51.9 %) as pale solid; >H NMR (CDC13): 5 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.
Figure imgf000284_0003
Intermediate 153c was reacted with TFA using the general synthetic method illustrated by intermediate 149e to give the title compound in the form of a TFA salt and was used without further purification; *H NMR: 5 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.
Figure imgf000285_0001
l-[l-Methyl-2-(piperidin-4-yl)-lE/-indol-6-yl]-l,3-diazinane-2, 4-dione was reacted with intermediate 145a in the general synthetic method illustrated by example 12 to give the title compound; *H NMR: 5 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.
Figure imgf000285_0002
tert-Butyl 4- [(methanesulfonyl)oxy]piperidine-l -carboxylate (534 g, 1912.81 mmol) and potassium tert- butoxide (258 g, 2295.37 mmol) were added portion wise to 5-bromo- 1 //-indole (150 g, 765.12 mmol) in heptane (2400 mL) and stirred at 80 °C for 3 h. The reaction mixture cooled to RT and was 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 Na2SC>4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in Et2O to give a colourless foam which was crystallised from MTBE:Et2O (1 :5) to give the title compound (85 g, 29.3 %) as a white solid; >H NMR (CDCh) 5 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.
Figure imgf000285_0003
[Pd(cinnamyl)Cl]2 (0.913 g, 1.65 mmol) was added to tert-butyl 4-( 5-bromo- 1 //-indol- 1 -yl )piperidine- 1 - carboxylate (25 g, 65.91 mmol), l,3-diazinane-2, 4-dione (15.04 g, 131.82 mmol), tert-butylBrettPhos (1.59 g, 3.30 mmol) and CS2CO3 (43 g, 131.82 mmol) in 1,4-dioxane (750 mL) at RT under nitrogen. The resulting mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to RT and diluted with EtOAc (2 L) and water (2 L). The organic layer was dried over Na2SC>4, filtered and evaporated to afford crude product. The crude product was purified by crystallisation from MTBE to give the title compound (44.0 g, 57.1 %) as a white solid; >H NMR (CDC13) 5 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.
Figure imgf000286_0001
The title compound was prepared using methodology described in intermediate 145g using tert-butyl 4-[5- ( 2,4-dioxo- 1 ,3-diazinan- 1 -yl )- 1 /7-indol- 1 -yl Jpiperidine- 1 -carboxylate to give the title compound as a tosylate salt (73 g, 82 %) as a white solid; >H NMR 5 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.
Figure imgf000286_0002
l-[l-(Piperidin-4-yl)-l/7-indol-5-yl]-l,3-diazinane-2, 4-dione was reacted with intermediate 145a in the general synthetic method illustrated by example 12 to give the title compound; *H NMR: 5 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 (OH, s), 10.26 (1H, s); m/z: ES+ [M+H]+ = 731.4.
Figure imgf000286_0003
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) at RT under nitrogen. The mixture was stirred at 100 °C for 2 h, cooled to RT and then evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 35% EtOAc in Et2O to give the title compound (4.0 g, 80 %) as a yellow solid; ‘HNMR: 5 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), 6.58 (1H, dd), 6.69 - 6.74 (1H, m); m/z: ES+ | M-/Bu| = 341.1.
Figure imgf000287_0001
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-l -carboxylate (3.8 g, 9.56 mmol) in DMF (40 mL) under nitrogen. The mixture was stirred at 120 °C for 3 h and then cooled to RT. The mixture was diluted with water (125 mL), and EtOAc (300 mL), washed with saturated brine (100 mL, dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 35% EtOAc in Et2O to give the title compound (1.35 g, 35.5 %) as a yellow solid; *H NMR: 5 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.
Figure imgf000287_0002
NaH (60% in mineral oil, 0.196 g, 4.91 mmol) was added to tert-butyl 4-(6-bronw-4-lliioro- l /7-indol-2- yl)piperidine-l -carboxylate (1.3 g, 3.27 mmol) in THF (20 mL) at 0 °C under nitrogen. lodomethane (0.204 mL, 3.27 mmol) was added after 15 mins and was stirred to RT 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 Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in Et2O to give the title compound (1.15 g, 85 %) as a red solid; *H NMR: 5 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.
Figure imgf000287_0003
tert-Butyl 4-(6-bromo-4-fluoro- 1-methyl- 1 //-indol-2-vl (piperidine- 1 -carboxylate was reacted using the general synthetic method illustrated by intermediate 146d to give the title compound; m/z: ES+ [M-tBu+H]+ = 389.3.
Figure imgf000288_0001
/e/7- Butv I 4- [6-(2,4-dioxo- 1 ,3 -diazinan- 1 -y l)-4-fluoro- 1 -methyl- 1 K-indol-2-y 1] piperidine- 1 -carboxy late (500 mg, 1.12 mmol) was added to formic acid (1 mL) and was stirred at RT for 1 h. The reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NI h/MeOH to give the title compound (0.300 g, 77 %) as a yellow solid; *H NMR: 5 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.
Figure imgf000288_0002
Intermediate 1g (2.0 g, 5.77 mmol) was added to 1,3 -dibromopropane (3.5 g, 17.32 mmol) and K2CO3 (1.59 g, 11.55 mmol) in MeCN (30 mL) at RT. The mixture was stirred at 80 °C for 16 h and then cooled to RT and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in Et2O to give the title compound (1.9 g, 70.4 %) as a white solid; *H NMR: 5 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 (2H, 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.
Figure imgf000288_0003
4-{4-[4-(3-Bromopropoxy)phenyl]piperidin-l-yl}-2-(trifluoromethyl)benzonitrile was reacted with l-[4- fluoro-l-methyl-2-(piperidin-4-yl)-lH-indol-6-yl]-l,3-diazinane-2, 4-dione in the general synthetic method illustrated by example 12 to give the title compound; *H NMR: 5 *H NMR: 5 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-IY2-amino-4-bromo-5-fluorophenvDethvnyl 1 piperidine-1 -carboxylate
Figure imgf000289_0001
5-Bromo-4-fluoro-2-iodoaniline and tert- butyl 4-ethynylpiperidine-l -carboxylate were reacted using the general synthetic method illustrated by intermediate 159a to give the title compound; *H NMR: 5 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-/Bu| = 341.1.
Intermediate 160b: tert- Butyl 4-(6>-bromo-5-fluoro-l//-indol-2-yl)piperidine-l-carboxylate
Figure imgf000289_0002
tert-Butyl 4-[(2-amino-4-bromo-5-fluorophenyl)ethynyl]piperidine-l-carboxylate was reacted using the general synthetic method illustrated by intermediate 159b to give the title compound; *H NMR: 5 1.42 (9EI, 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+ [MrtBu]+ = 341.1.
Intermediate 160c: tert-Butyl 4-(6>-bromo-5-fluoro-l-methyl-l//-indol-2-yl)piperidine-| -carboxylate
Figure imgf000289_0003
tert-Butyl 4-(6-bromo-5-fluoro-lE/-indol-2-yl)piperidine-l -carboxylate was reacted using the general synthetic method illustrated by intermediate 159c to give the title compound; *H NMR: 5 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-/Bu| = 355.1.
Intermediate 160d: tert-Butyl 4-16-12, 4-dioxo-l,3-diazinan-l-yl)-5-fluoro-l-methyl-l//-indol-2- yllpiperidine-l-carboxylate
Figure imgf000289_0004
tert-Butyl 4-( 6-bromo-5-lluoro- 1 -methyl- 1 //-indol-2-vl )piperidine- 1 -carboxylate was reacted using the general synthetic method illustrated by intermediate 146d to give the title compound; *H NMR: 5 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), 4.54 - 4.60 (2H, m), 7.07 - 7.17 (1H, m), 7.46 - 7.57 (1H, m), 7.67 (1H, s); m/z: ES+ [M-/Bu]+ = 389.2.
Intermediate 160e: 1 -15-Fluoro-l -meth yl-2-(nirieridin-4-yl )- indol-6-yl 1-1, 3-diaz inane-2, 4-dione
Figure imgf000290_0001
Figure imgf000290_0002
tert-Buty 1 4- [6-(2,4-dioxo- 1 ,3 -diazinan- 1 -y l)-5-fluoro- 1 -methyl- 1 //-indo 1-2-yl] piperidine- 1 -carboxy late was reacted using the general synthetic method illustrated by intermediate 80g to give the title compound; *H NMR: 5 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-f4-[4-(3-f4-[6-(2,4-Dioxo-l,3-diazinan-l-yl)-5-fluoro-l-methyl-l/7-indol-2-yl1piperidin- l-yllpropoxy)phenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000290_0003
Intermediate 159f was reacted with l-[5-fluoro-l-methyl-2-(piperidin-4-yl)-l //-indol-6-vl |- l ,3-diazinane-2,4- dione in the general synthetic method illustrated by example 12 to give the title compound; *H NMR: 5 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 (2H, 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 (lH, m), 7.81 (1H, d), 10.41 (1H, s); m/z: ES+ [M+H]+ = 73E3.
Example 161: 4-f4-[4-(4-f4-[6-(2.6-Dioxopiperidin-3-yl)-5-oxo-6.7-dihvdro- pyrrolo[3.4-b1pyridin-2-
Figure imgf000290_0004
yl1piperazin-l-yllbutoxy)-2-fluorophenyl1piperidin-l-yll-2-(trifluoromethyl)benzonitrile
Figure imgf000290_0005
Intermediate 156d was reacted with intermediate 38e in the general synthetic method illustrated by example 138 to give the title compound in the form of a formate salt; *H NMR (CDCR): 5 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-hvdroxyphenyl)-3,6-dihvdropyridine-l(2/D-carboxylate
Figure imgf000291_0001
tert-Butyl 4-( 4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl )-3,6-dihydropyridine- 1 ( 2// (-carboxylate was reacted with 4-bromo-3,5-difluorophenol in the general synthetic method illustrated by intermediate 9a to give the title compound; >H NMR: 5 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-/Bu| = 256.1.
Intermediate 162b: tert- Butyl 4-(2,6-difluoro-4-hvdroxyphenyl)piperidine-l-carboxylate
Figure imgf000291_0002
tert-Butyl 4-( 2,6-difluoro-4-hydroxyphenyl )-3,6-dihydropyridine- 1 ( 2// (-carboxy late was reacted with hydrogen gas in the general synthetic method illustrated by intermediate 9b to give the title compound; *H NMR (CDC13): 8 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-/Bu| = 258.1.
Intermediate 162c: 3,5-Difluoro-4-(piperidin-4-vDphenol
Figure imgf000291_0003
tert-Butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperidine-l -carboxylate (130 mg, 0.41 mmol) was suspended in DCM (2 mL) and TFA (317 pl, 4.15 mmol) and was stirred at RT for 1 h. The solution was evaporated to dryness to afford crude product. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using I M NI B/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-hvdroxyphenvDpiperidin-l-yl1-2-(trifluoromethvDbenzonitrile
Figure imgf000292_0001
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 pl, 0.43 mmol) in NMP (1 mL) were stirred at 100 °C for 1 h. The reaction was cooled to RT and diluted with EtOAc (10 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried with MgSO i. filtered and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in heptane to give the title compound (0.143 g, 96 %) as a white solid; >H NMR: 5 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' [M-H]' = 381.2.
Figure imgf000292_0002
To 4-[4-(2,6-difluoro-4-hydroxyphenyl)piperidin-l-yl]-2-(trifluoromethyl)benzonitrile (140 mg, 0.37 mmol) in MeCN (5 mL) was added K2CO3 (253 mg, 1.83 mmol) and 2-(3-bromopropyl)-l ,3-dioxolane (99 pl, 0.73 mmol). The reaction was stirred at 80 °C for 2 h. The mixture was cooled to RT, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in heptane to give the title compound (0.127 g, 69.9 %) as a white solid; *H NMR: 5 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.
Figure imgf000292_0003
4-(4-{4-[3-(l,3-Dioxolan-2-yl)propoxy]-2,6-difluorophenyl}piperidin-l-yl)-2-(trifluoromethyl)benzonitrile was reacted with intermediate 2b in the general synthetic method illustrated by example 138 to give the title compound in the form of a formate salt; *H NMR (CDCI3): 5 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.
Figure imgf000293_0001
Intermediate 162e was reacted with intermediate le in the general synthetic method illustrated by example 138 to give the title compound in the form of a formate salt; *H NMR (CDCI3): 5 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 (2H, 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.
Figure imgf000293_0002
Intermediate 38c was reacted with l-bromo-3,4-difluoro-2-(trifluoromethyl)benzene in the general synthetic method illustrated by intermediate 137f to give the title compound; *H NMR (CDCh): 5 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.
Figure imgf000293_0003
3-Fluoro-4-[4-(2-fluoro-4-hydroxy-phenyl)-l-piperidyl]-2-(trifluoromethyl)benzonitrile was reacted with 2-(3- bromopropyl)-l,3-dioxolane in the general synthetic method illustrated by intermediate 38e to give the title compound; m/z: ES+ [M+H]+ = 497.3.
Figure imgf000294_0001
4-(4-{4-[3-(l,3-Dioxolan-2-yl)propoxy]-2-fluorophenyl}piperidin-l-yl)-3-fluoro-2- (trifluoromethyl)benzonitrile was reacted with intermediate 2b in the general synthetic method illustrated by example 138 to give the title compound in the form of a formate salt; *H NMR (CDCla): 5 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.
Figure imgf000294_0002
Intermediate 123c was reacted with l-bromo-3,4-difluoro-2-(trifluoromethyl)benzene in the general synthetic method illustrated by intermediate 137f to give the title compound; *H NMR: 5 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.
Figure imgf000294_0003
Figure imgf000295_0001
3-Fluoro-4-[4-(4-hydroxy-2-methylphenyl)piperidin-l-yl]-2-(trifluoromethyl)benzonitrile was reacted with 2- (3 -bromopropyl)- 1 ,3 -dioxolane in the general synthetic method illustrated by intermediate 38e to give the title compound; >H NMR: 5 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.
Figure imgf000295_0002
4-(4-{4-[3-(l,3-Dioxolan-2-yl)propoxy]-2-methylphenyl}piperidin-l-yl)-3-fluoro-2- (trifluoromethyl)benzonitrile was reacted with intermediate 2b in the general synthetic method illustrated by example 138 to give the title compound in the form of a formate salt; *H NMR (CDC13): 5 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.
Figure imgf000295_0003
Intermediate 164b was reacted with intermediate le in the general synthetic method illustrated by example 138 to give the title compound in the form of a formate salt; *H NMR (CDCla): 5 E66 - 2.01 (8EI, 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 - 3.42 (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.
Figure imgf000296_0001
4-bromo-2-fluoro-l -iodobenzene was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3.6-dilwdropvridine- 1 ( 2//)-carboxvlate in the general synthetic method illustrated by intermediate 8a to give the title compound; >H NMR: 5 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).
Figure imgf000296_0002
To tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-l(2//)-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 RT and was degassed for 5 mins followed by addition of Pdifdbay (0.129 g, 0.140 mmol) and BINAP (0.175 g, 0.281 mmol). The mixture was stirred for 6 h at 120 °C and was then cooled to RT and quenched with water. The product was extracted with EtOAc (200 mL), washed with saturated brine (50 mL), dried over Na2SC>4, filtered and evaporated to dryness to afford 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 yellow solid; m/z: ES+ [M+H]+ = 433.2.
Figure imgf000296_0003
tert-Butyl 4- {4-[4-( ethoxy carbonyl )piperidin- 1 -yl ]-2-fluorophenyl}-3,6-dihydropyridine- 1 ( 2//)-carboxvlate was reacted with hydrogen gas in the general synthetic method illustrated by intermediate 123b to give the title compound; m/z: ES+ [M+H]+ = 435.0.
Intermediate 167d: Ethyl l-[3-fluoro-4-(piperidin-4-vDphenyl1piperidine-4-carboxylate
Figure imgf000297_0001
To tert-butyl 4-{4-[4-(ethoxycarbonyl)piperidin-l-yl]-2-fluorophenyl}piperidine-l-carboxylate (0.4 g, 0.920 mmol) in DCM (20 mL) was added HC1 (4M in dioxane, 10 mL, 40.0 mmol) dropwise at 0 °C. The reaction was stirred at RT for 4 h and then evaporated to dryness to afford crude product. The crude product was triturated in MTBE (30 mL) and filtered under vacuum to give the title compound in the form of an HC1 salt and was used without further purification; m/z: ES+ [M+H]+ = 335.5.
Figure imgf000297_0002
To ethyl l-[3-fluoro-4-(piperidin-4-yl)phenyl]piperidine-4-carboxylate hydrochloride (0.518 g, 1.396 mmol) in DMSO (7 mL) was added K2CO3 (0.386 g, 2.79 mmol) and 2-cyclopropyl-4-fluorobenzonitrile (0.15g, 0.931 mmol) and stirred at 120 °C for 16 h. The reaction was then cooled to RT and quenched with water. The product was extracted with EtOAc (200 mL), washed with saturated brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness to afford 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 yellow solid; m/z: ES+ [M+H]+ = 476.0.
Figure imgf000297_0003
To ethyl l-{4-[l-(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 i (0.239 g, 6.31 mmol) at 0 °C and was stirred to RT for 4h. the reaction was quenched with saturated NH4CI solution and extracted with DCM (10 mL). The organic layer was washed with saturated brine (50 mL), dried over Na2SC>4, filtered and evaporated to dryness to afford 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; *HNMR: 5 0.76 - 0.92 (2H, m), 0.97 - 1.11 (2H, m), 1.11 - 1.28 (2H, m), 1.45 - 1.56 (lH, 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-Cvclopropyl-4-f4-[2-fluoro-4-(4-formylpiperidin-l-yl)phenyl1piperidin-l- yllbenzonitrile
Figure imgf000298_0001
2-Cyclopropyl-4-(4-{2-fluoro-4-[4-(hydroxymethyl)piperidin-l-yl]phenyl}piperidin-l-yl)benzonitrile was reacted with Dess-Martin periodinane in the general synthetic method illustrated by intermediate 53b to give the title compound which was isolated crude and used without further purification.
Example 167: 2-Cvclopropyl-4-(4-f4-[4-(f4-[2-(2.6-dioxopiperidin-3-yl)-7-methoxy-l-oxo-2.3-dihvdro- l/7-isoindol-5-yl1piperazin-l-yllmethyl)piperidin-l-yl1-2-fluorophenyllpiperidin-l-yl)benzonitrile
Figure imgf000298_0002
To intermediate If (0.16 g, 0.405 mmol) and 2-cyclopropyl-4-{4-[2-fluoro-4-(4-formylpiperidin-l- yl)phenyl]piperidin-l-yl}benzonitrile (0.175 g, 0.405 mmol) in DCM (10 mL) was added sodium acetate (0.066 g, 0.810 mmol) and was stirred at RT for 3 h followed by the addition of sodium triacetoxyborohydride (0.172 g, 0.810 mmol). The mixture was stirred at RT for 16 h and was extracted with DCM (80 mL). The solution was washed with water (100 mL), dried overNa2SO4, filtered and evaporated to afford crude product. Purification by preparative HPLC (Column A, Eluent A) was performed and the fractions containing product were evaporated followed by neutralization with saturated Nal ICO;, solution and extracted with DCM (2x 50 mL). The organic layer was dried with Na2SO4, filtered and evaporated to dryness to give the title compound (0.025 g, 7.81 %) as a white solid; ‘H NMR: 5 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 (3H, 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 Assay
This cell-based imaging assay uses immuno-fluorescence to measure both cell number and endogenous nuclear AR staining in the prostate cancer cell line LNCaP (expressing AR-full length). The purpose of the assay is to identify compounds that regulate AR protein level according to the protocol laid out in the steps below.
All work was performed in a sterile tissue culture hood up to the point of cell fixation. LNCaP cells were cultured at 6-8 *106 per T175 flask and split 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 (Cedex™ Cell counter, Beckmann & Coulter), 40LII , per well, using a Multidrop (ThermoFisher).
Cells were dosed with test compound diluted in DMSO using an Echo 555™ (Labcyte) and the final concentration of DMSO in the well was 0.3%. A neutral control (DMSO) and a positive AR degrader control at 3pM (a prior art AR PROTAC) were included. The Echo uses acoustic technology to perform direct microplate- to-microplate transfers of DMSO compound solutions to assay plates. The system can be programmed to transfer volumes as low as 2.5 nL in multiple increments between microplates and in so doing generates a serial dilution of compound in the assay plate which is then back-filled to normalise the DMSO concentration across the dilution range. Compounds were dispensed onto the cell plates with a compound source plate prepared as above producing a 12 point dose response curve with 3-fold dilutions and one final 10-fold dilution, and a top concentration of 3 or 30LIM using the Integrated Echo workcell. The plates were incubated at 37°C / 5% CO2 for 24h and then fixed and stained as below.
40|iL of 8% paraformaldehyde solution (v/v) in phosphate buffered saline (PBS) was added on top of the media already in the well using a Multidrop to fix plates giving a final concentration of 4% PFA (v/v) for 20-30 minutes (keep in fume hood to minimise PFA exposure). After 20-30 mins, the plates were washed with 3 x PBS using a BioTek washer.
The cells were incubated with a Mouse monoclonal Anti-AR antibody AR441 (DAKO M3562) (1 :1000), diluted in modified blocking buffer (PBS+1% BSA+0.1% TritonX ): 15 Lil, / well for 2h at RT. The plates were then washed with 3 x PBS using a BioTek washer. Cells were then incubated with Goat antimouse secondary antibody 488 (Invitrogen Al 1001) (1 :500) and nuclear stain, DRAQ5 (Abeam Abl08410) (1 :2000) diluted in modified blocking buffer for 45 mins at room temperature 15 Lil , / well. Plates are then washed with 3 x PBS using a BioTek washer and sealed with black plate seals.
Plates are read using a Cellomics Cellinsight to measure the Androgen Receptor level in each well. The data is exported into Genedata to perform curve fitting analysis. All data are normalized as % of positive control and any data points that fall on the hook of the curve are masked before fitting. Down-regulation of AR is expressed as a DC50 value and determined by calculation of the concentration of compound that is required to give 50% of maximum degradation of AR as per the curve fit for that compound. The maximum degradation observed for each compound is expressed as Dmax. The AR degradation data for compounds is shown in the table below and may be a result from a single experiment or an average of two or more experiments.
Figure imgf000299_0001
Figure imgf000299_0002
Figure imgf000300_0001
Figure imgf000300_0002
Figure imgf000301_0001
LNCaP Androgen Receptor L702H Imaging Assay
While treatment with AR antagonists has been shown to be of patient benefit, 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 mutation. One of the point mutations observed in patient populations is L702H in the AR Ligand Binding Domain. LNCAP cells have been engineered to introduce the mutation L702H into the AR gene using CRISPR/Cas9. The previously described imaging-based AR assay will monitor nuclear AR (L702H) levels in these cells to identify compounds that regulate AR (L702H). Down-regulation of AR (L702H) is expressed as a DC50 value and determined by calculation of the concentration of compound that is required to give 50% of maximum degradation of AR (L702H) as per the curve fit for that compound. The maximum degradation observed for each compound is expressed as Dmax. The AR and AR (L702H) degradation data for compounds is shown in the table below and may be a result from a single experiment or an average of two or more experiments.
Figure imgf000302_0001
Figure imgf000303_0001
STATEMENTS
1. A compound of Formula (I) :
Figure imgf000304_0001
or a pharmaceutically acceptable salt thereof, wherein:
X1 is C & 0, 1 or 2 of X2, X3 & X4 is/are N, and are otherwise C: or
X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and with Xs attached to Xs, where 1 or 2 of X1, X2, Xs, X6, X7 & Xs is/are N, and are otherwise C:
P is 1 or 2 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-; and otherwise p is 0, 1 or 2: where: each R1 is a substituent on any C atom at X1, X2, X3 & X4, (or at X1, X2, Xs, X6, X7 & Xs when X3 & X4 are substituted by -X5=X6- X7=X8— ), and is independently selected from F, Cl, C _;,alkvl and Ci-aalkoxy, wherein said C i-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F; n is 0, 1 or 2; m is 0 or 1 ;
Q is CH or N when n & m are both other than 0 and otherwise Q is CH;
R2a and R2b are substituents on the same or different C atoms other than at Q, each independently selected from H, F and Ci-aalkyl, or R2a & R2b together form a -(CH2)r- group where r is 1 , 2 or 3 ;
0, 1 or 2 of Y1, Y2, Y3 & Y4 is/are N, and are otherwise C; each R3 is a substituent on any C atom at Y1, Y2, Y3 & Y4, and is independently selected from F, Cl, CN, C _;,alkvl and Ci-aalkoxy, wherein said Ci-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F; q is 0, 1 or 2;
Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and a minimum length of from 6 to 26 atoms between ‘a’ and ‘b’ ; wherein said framework may include one or more straight and/or branched chains and/or rings and is optionally substituted on any available C atom(s) by one or more F; and W is an E3 ubiquitin ligase cereblon binder unit. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to statement 1 wherein the Linker is a saturated or partially unsaturated framework. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to statement 1 or statement 2 wherein the Linker comprises C and H atoms and at least two heteroatoms. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to statement 1 or statement 2 wherein the Linker comprises C and H atoms and at least one nitrogen heteroatom in the form of a secondary or tertiary amine. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to statement 1 or statement 2 wherein the Linker includes at least one nitrogen-containing saturated or partially unsaturated heterocyclic group having from 4 to 12 ring atoms, or a A'-CI h-CI h-A2 unit where A1 and A2 are each independently selected from N and O. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to any one of statements 1 to 5 wherein the Linker has the Formula: a -QA-QB-QC- b wherein:
‘a’ and ‘b’ represent the end points of attachment;
QA is -G-QH- or -G-(Ci.5alkylene)-;
QB is a direct bond, -QB1-QB2-QB3- or C .vilkvlene optionally substituted by one or more F (e.g. 1 or 2); where:
QB1 & QB3 each independently represent a direct bond or C ^alkylene;
QB2 is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJ is H or Ci.3alkyl;
Qc is -QH-G- or -(Ci.5alkylene)-G-; each G is independently a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci.3alkyl; each QH is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA, QB and Qc are selected so that the Linker does not contain any N-N or N-O bonds. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to statement 6 wherein QB2 is QH, -O-CH2CH2-O- or -N(RJ)- where RJ is Ci-jalkyl. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to statement 6 or statement 7 wherein Qc is -QH-G- or -(Ci-2alkylene)-G-. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to any one of statements 6 to 8, wherein each QH is independently selected from piperazin- 1,4-diyl, azetidin-l,3-diyl, piperidin-l,4-diyl, 1 ,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-1,3- diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2. l]heptan-2,5-diyl, 1 , 3, 3a, 4, 6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3.6-dihvdro-2/7-pvridin- 1 .4-divl and 9-azaspiro[5.5]undecan- 3,9-diyl. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to any one of statements 1 to 9, wherein the Linker is selected from any of Linkers 1 to 46 or 1 to 48 as shown in the description. A PROTAC compound or a pharmaceutically acceptable salt thereof, containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) :
Figure imgf000306_0001
where R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q are as defined in statement 1. The PROTAC compound or a pharmaceutically acceptable salt thereof, according tostatement 11 , containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) of Formula (lb):
Figure imgf000306_0002
where: QA is -G-QH- or -G-(Ci.5alkylene)-;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or C].3alkyl; and
QH is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group.
13. The PROTAC compound or a pharmaceutically acceptable salt thereof, according tostatement 12, containing an E3 ubiquitin ligase cereblon binder unit and an AR binding unit of Formula (la) of Formula (Ic):
Figure imgf000307_0001
where:
QB is a direct bond, -QB1-QB2-QB3- or C .vilkvlene optionally substituted by one or more F (e.g. 1 or 2 ): where:
QB1 & QB3 each independently represent a direct bond or C .lalkvlene:
QB2 is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJ is H or Ci.3alkyl; and each QH is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA and QB are selected so that Formula (Ic) does not contain any N-N or N-O bonds.
14. The PROTAC compound or a pharmaceutically acceptable salt thereof, according tostatement 12 or statement 13, where:
QA is -GA-QHA- or -GA-(Ci-5alkylene)- where:
GA is selected from a direct bond, -CH2-, -O- or -N(RG)-;
RG is H or Ci-salkyl; and
QHA is a 4 to 11 -membered nitrogen-containing saturated heterocyclic group.
15. A compound of Formula (II):
Figure imgf000307_0002
or a salt thereof, wherein:
QA is -G-QH- or -G-(Ci-5alkylene)-; G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-jalkyl;
QH is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group;
QD is a direct bond or Ci.2alkylene optionally substituted by one or more F (for example 1 or 2 F); and
(i) RL1 & RL2 together form “=O” and RL3 is H or Ci-ealkoxy;
(h) RL1 & RL2 are each independently Ci-salkoxy, and RL3 is H;
(iii) RL1 & RL2 together form -O-(CH2)k-O- where k is 2 or 3, and RL3 is H; or
(iv) RL1 is OH or LG1 where LG1 is a leaving group, and RL2 & RL3 are both H; where when QD is a direct bond and QA is -G-QH-, the value of QH is selected so that QD connects to a C atom of QH; and R1, p, X1, X2, X3, X4, n, m, Q, R2a, R2b, Y1, Y2, Y3, Y4, R3 and q are as defined in statement 1.
16. The compound of Formula (II) or a salt thereof, according to statement 15, wherein LG1 is selected from Cl, Br, I, trifluoromethanesulfonate and C .-Iwdrocarbvlsiill'onate.
17. A compound of Formula (IV):
Figure imgf000308_0001
or a salt thereof, wherein:
J is H or PG2 where PG2 is a nitrogen protecting group (for example a tert-butoxycarbonyl group);
QA is -G-QH- or -G-(Ci.5alkylene)-;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-salkyl;
QB is a direct bond, -QB1-QB2-QB3- or C .vilkvlene optionally substituted by one or more F (e.g. 1 or 2); where:
QB1 & QB3 each independently represent a direct bond or Chalky lene;
QB2 is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJ is H or Ci.3alkyl; and each QH (including the “QH Ring” attached to J) is independently a 4-12-membered nitrogencontaining saturated or partially unsaturated heterocyclic group; where the values of QA, QB and QH Ring are selected so that Formula (IV) does not contain any N-N or N-O bonds; and R1, p, X1, X2, X3, X4, n, m, R2a R2b, Q, Y1, Y2, Y3, Y4, R3 and q are as defined in statement 1.
18. The compound of Formula (IV), or a salt thereof, as statemented in statement 17, wherein PG2 is Ci-ealk oxycarbonyl.
19. A compound of Formula (V):
Figure imgf000309_0001
or a salt thereof, wherein:
Xx is selected from:
(i) N substituted by J where J is H or PG3 where PG3 is a protecting group; and
(ii) C substituted by oxo, or by RU1 and RU2; where RU1 and RU2 are each C ...alkoxv: or RU1 and RU2 together represent -O-(CH2)U-O- where u is 2 or 3;
G is a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci-jalkyl;
QH Ring is a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of G and QH Ring are selected so that Formula (V) does not contain any N-N or N-O bonds; and R1, p, X1, X2, X3, X4, n, m, R2a, R2b, Q, Y1, Y2, Y3, Y4, R3 and q are as defined in statement 1. The compound of Formula (V), or a salt thereof, according to statement 19, wherein PG3 is
Ci-ealk oxycarbonyl. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of statements 1 to 10, wherein W is W1 which is: -Z-(RA)h where Z is:
Figure imgf000309_0002
wherein: represents a single covalent bond or a double covalent bond;
0, 1 or 2 of XA, XB, Xc, XD, XE & XE is/are N, where XE & XF are not both N, and are otherwise C;
1 ofXG, XH & XJ is C(O);
1 ofXG, XH & XJ is N-(2,6-dioxopiperidin-3-yl) (Y); and
1 ofXG, XH & XJ is selected from C(RT)2, -CH2CH2-, C(O), N(Ci.3alkyl), -O- and -N=, wherein each RT is selected from H, F, Me or together with the carbon of C(RT)2 forms a cycloprop- 1 , 1 -diyl group ; where XG, XH & XJ are selected such that there are not two C(O) groups present at adjacent positions, and that the N-(2,6-dioxopiperidin-3-yl) is not at an adjacent position to either N(Ci-3alkyl) or O: each RA is independently a substituent on any available C atom at XA, XB, Xc or XD selected from F, Cl, Chalky 1, Ci-salkoxy wherein said C i.vilkvl and Ci-salkoxy is independently optionally substituted by one or more F; h is 0, 1 or 2; and wherein the Linker is attached to any C atom at XA, XB, Xc or XD. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to statement 21 where each RA is a substituent on any available C at XA, XB, Xc or XD selected from F, Cl and
C i-aalkoxy optionally substituted by one or more F. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to statement 21 or statement 22 where XG-XH-XJ is:
(i) XG-NY-C(O) where XG is -CH2-, -CH2CH2-, =N- or C(O);
(ii) XG-C(O)-NY where XG is -O- or N(Ci.3alkyl); or
(iii) C(O)-NY-CH2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of statements 21 to 23 where -Z-(RA)h together represent any of the groups 1 to 21 as shown in the description. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of
Figure imgf000310_0001
statements 1 to 10, wherein W is W2 which is
Figure imgf000310_0002
wherein: represents a single covalent bond or a double covalent bond;
1 of XA2, XB2, XC2 & XD2 is C and covalently bound to Y ;
0, 1 or 2 of XA2, XB2, XC2, XD2, XE2 & XE2 is/are N (where XE2 & XE2 are not both N) and are otherwise C;
1 or 2 of XG2, XH2 & XJ2 is/are N; and are otherwise C; each RAA is a substituent on any available C or N atom of Z - in each case independently selected from RAAI optionally substituted by one or more RAA2: where RAA is further selected from RAA2 when RAA is a substituent on an available C atom of ZA; each RAAI is independently Ci-4alkyl, C2-3alkenyl, C2-3alkynyl,
Ci-salkoxyCi-salkyl, carboxyCi-salkyl, Cj.ycarbocyclyl or a 4-6 membered heterocyclyl; each RAA2 is independently selected from F, Cl, Br, CN, NH2, Chalky 1,
O(C].3alkyl), NH(Ci-3alkyl) and N(Ci-3alkyl)2; wherein said Ci-salkyls are optionally substituted by one or more F; v is 0, 1 or 2;
Y is N-(2,6-dioxopiperidin-3-yl).
26. The compound or salt thereof according to statement 25, wherein
1 of XA2 & XB2 is C and covalently bound to Y and the other of XA2 & XB2 is C;
0 or 1 of XC2 & XD2 is N and is/are otherwise C;
1 of XG2 & XJ2 is N and the other of XG2 & XJ2 is C; and
X H2 X E2 & XF2 are all C.
27. The compound or salt thereof according to statement 25, wherein W is W2-1
Figure imgf000311_0001
wherein:
XK and XL are either N-linker and CH or NMe and C-linker respectively;
1 ofXM and X° is N-(2,6-dioxopiperidin-3-yl) (Y);
0 or 1 of XM and XN is C-F;
XN may be N if XM is not C-F ; the remainder of XN, XM and X° are CH.
28. The compound or salt thereore according to statement 27, wherein W represents any of the groups 22 to 26 shown below:
Figure imgf000312_0001
The compound or salt thereof, according to any preceding statement wherein X1 is C and 0 or 1 of X2, X3 & X4 is N and are otherwise C; or X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and Xs attached to Xs, where 1 of X1, X2, Xs, X6, X7 & Xs is N, and are otherwise C. The compound or salt thereof, according to any preceding statement wherein R2a and R2b are substituents on the same or different C atoms adjacent Q. The compound or salt thereof according to any preceding statement wherein R2a and R2b are substituents on the same or different C atoms, each independently selected from H and Ci-aalkyl. The compound or salt thereof according to any preceding statement wherein Y1, Y2, Y3 & Y4 are respectively selected from (C, C, C, C), (N, C, C, C), (C, N, C, C) and (N, C, N, C). The compound or salt thereof according to any preceding statement wherein q is 0, 1 or 2 and R3 (when present) is a substituent on any C atom at Y1, Y2, Y3 & Y4 selected from F and Ci-aalkyl. The compound or salt thereof according to any preceding statement wherein p is 1 ; X3 & X4 are not substituted by -X5=X6-X7=X8- X1, X2, X3 & X4 are all C and R1 is a substituent on X1 and is CFs. The compound or salt thereof according to any one of statements 1 to 33 wherein p is 2; X3 & X4 are not substituted by -X5=X6-X7=X8- X1, X2, X3 & X4 are all C; one R1 substituent is on X1 and is CT), and the other R1 substituent is on X2 and is F or ethyl. The compound of salt thereof according to any preceding statement wherein n is 1 , m is 1 , Q is CH,
R2a is H and R2b is H. 37. The compound of salt thereof according to any preceding statement wherein 0 or 1 of Y1, Y2, Y3 & Y4 is N and are otherwise C.
38. The compound of salt thereof according to any preceding statement wherein Y1, Y2, Y3 & Y4 are all C.
39. The compound of salt thereof according to any preceding statement wherein q is 0.
40. The compound of salt thereof according to any one of statements 1 to 38, wherein q is 1 and R3 is attached to C at Y1, and R3 is selected from F, CN and Me.
41. The compound of salt thereof according to any one of statements 1 to 38, wherein q is 2 and each R3 group is F, which are attached to C at Y1 and Y3.
42. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof according to one of statements 1-14 or 21-41, in association with a pharmaceutically acceptable excipient.
43. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of cancer.
44. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of a solid tumour.
45. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of an AR- sensitive tumour type.
46. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of tumour types that harbour one or more mutated forms of the androgen receptor.
47. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of prostate cancer. 48. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of castrate-resistant prostate cancer.
49. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of metastatic castrate-resistant prostate cancer.
50. A pharmaceutical composition, which comprises a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of AR-mutated cancer.
51. The compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use as a medicament.
52. The compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in therapy.
53. The compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in a method of treatment of the human or animal body by therapy.
54. The compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the production of an antiproliferative effect in a warm-blooded animal such as man.
55. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for the production of an anti-proliferative effect in a warm-blooded animal such as man.
56. A method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such effect, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41. 57. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
58. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
59. A method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease, in a warm-blooded animal, such as man, in need of such effect, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.
60. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the prevention or treatment of cancer.
61. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for the prevention or treatment of cancer.
62. A method for the prevention or treatment of cancer in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.
63. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the prevention or treatment of solid turnouts).
64. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-1, for the manufacture of a medicament for the prevention or treatment of solid tumour(s).
65. A method for the prevention or treatment of solid tumour(s) in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.
66. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the prevention or treatment of tumour types that are sensitive to degradation of androgen receptors.
67. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for the prevention or treatment of those tumour types that are sensitive to degradation of androgen receptors.
68. A method for the prevention or treatment of those tumour types that are sensitive to degradation of androgen receptors in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.
69. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in providing a degrading effect on androgen receptors in a warm-blooded animal such as man.
70. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for providing a degrading effect on androgen receptors in a warm-blooded animal such as man.
71. A method for providing a degrading effect on androgen receptors in a warm-blooded animal, such as man, in need of such effect, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.
72. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in providing a selective degrading effect on androgen receptors in a warm-blooded animal such as man.
73. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for providing a selective degrading effect on androgen receptors in a warm-blooded animal such as man. 74. A method for providing a selective degrading effect on androgen receptors in a warm-blooded animal, such as man, in need of such effect, which comprises administering an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.
75. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of tumour types that harbour androgen receptor mutations.
76. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for the prevention or treatment of those tumour types that harbour androgen receptor mutations.
77. A method for the prevention or treatment of those tumour types that harbour androgen receptor mutations in a warm-blooded animal, such as man, in need of such prevention or treatment, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.
78. A compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for use in the treatment of prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC)).
79. Use of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41, for the manufacture of a medicament for the treatment of prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC).
80. A method for treating prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC) in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of Formula (I) or PROTAC of Formula (la), or a pharmaceutically acceptable salt thereof, according to any one of statements 1-14 or 21-41.

Claims

1. A compound of Formula (I) :
Figure imgf000318_0001
or a pharmaceutically acceptable salt thereof, wherein:
X1 is C & 0, 1 or 2 of X2, X3 & X4 is/are N, and are otherwise C; or
X3 & X4 are both C and are substituted by -X5=X6-X7=XS- with Xs attached to X3 and with Xs attached to Xs, where 1 or 2 of X1, X2, Xs, X6, X7 & Xs is/are N, and are otherwise C:
P is 1 or 2 and X1 is C attached to R1 when X3 & X4 are not substituted by -X5=X6-X7=X8-; and otherwise p is 0, 1 or 2: where: each R1 is a substituent on any C atom at X1, X2, X3 & X4, (or at X1, X2, Xs, X6, X7 & Xs when X3 & X4 are substituted by -X5=X6- X7=X8— ), and is independently selected from F, Cl, C _;,alkvl and Ci-aalkoxy, wherein said C i-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F; n is 0, 1 or 2; m is 0 or 1 ;
Q is CH or N when n & m are both other than 0 and otherwise Q is CH;
R2a and R2b are substituents on the same or different C atoms other than at Q, each independently selected from H, F and Ci-aalkyl, or R2a & R2b together form a -(CH2)r- group where r is 1 , 2 or 3 ;
0, 1 or 2 of Y1, Y2, Y3 & Y4 is/are N, and are otherwise C; each R3 is a substituent on any C atom at Y1, Y2, Y3 & Y4, and is independently selected from F, Cl, CN, C _;,alkvl and Ci-aalkoxy, wherein said Ci-aalkyl and C i-aalkoxy may be independently optionally substituted by one or more F; q is 0, 1 or 2;
Linker is a saturated or a partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein said framework has end points of attachment ‘a’ and ‘b’ and a minimum length of from 6 to 26 atoms between ‘a’ and ‘b’ ; wherein said framework may include one or more straight and/or branched chains and/or rings and is optionally substituted on any available C atom(s) by one or more F; and W is an E3 ubiquitin ligase cereblon binder unit.
2. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to claim 1 wherein the Linker has the Formula: a -QA-QB-QC- b wherein:
‘a’ and ‘b’ represent the end points of attachment;
QA is -G-QH- or -G-(Ci.5alkylene)-;
QB is a direct bond, -QB1-QB2-QB3- or Cj.vilkvlene optionally substituted by one or more F (e.g. 1 or 2); where:
QB1 & QB3 each independently represent a direct bond or C ^alkylene;
QB2 is QH, -O-CH2CH2-O-, -O- or -N(RJ)- where RJ is H or Ci.3alkyl;
Qc is -QH-G- or -(Ci-5alkylene)-G-; each G is independently a direct bond, -CH2-, -O-, or -N(RG)- where RG is H or Ci.3alkyl; each QH is independently a 4-12-membered nitrogen-containing saturated or partially unsaturated heterocyclic group; where the values of QA, QB and Qc are selected so that the Linker does not contain any N-N or N-O bonds.
3. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to claim 2 wherein QB2 is QH, -O-CH2CH2-O- or -N(RJ)- where RJ is Ci-jalkyl.
4. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to claim 2 or claim 3 wherein Qc is -QH-G- or -(Ci-2alkylene)-G-.
5. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to any one of claims 2 to 4, wherein each QH is independently selected from piperazin- 1,4-diyl, azetidin-l,3-diyl, piperidin-l,4-diyl, 1 ,4-diazepan- 1,4-diyl, 12-oxa-3,9-diazaspiro[5.6]dodecan-3,9-diyl, pyrrolidin-1,3- diyl, 3,9-diazaspiro[5.5]undecan-3,9-diyl, 2,5-diazabicyclo[2.2. l]heptan-2,5-diyl, 1 , 3, 3a, 4, 6,6a- hexahydropyrrolo[3,4-c]pyrrol-2,5-diyl, 3.6-dihvdro-2//-pvridin- 1 .4-divl and 9-azaspiro[5.5]undecan- 3,9-diyl.
6. The compound of Formula (I), or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the Linker is selected from any of Linkers 1 to 46 or 1 to 48:
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein W is W1 which is: -Z-(RA)h where Z is:
Figure imgf000322_0002
wherein: represents a single covalent bond or a double covalent bond;
0, 1 or 2 of XA, XB, Xc, XD, XE & XF is/are N, where XE & XE are not both N, and are otherwise C; 1 of XG, XH & XJ is C(O); 1 ofXG, XH & XJ is N-(2,6-dioxopiperidin-3-yl) (Y); and
1 ofXG, XH & XJ is selected from C(RT)2, -CH2CH2-, C(O), N(Ci.3alkyl), -O- and -N=, wherein each RT is selected from H, F, Me or together with the carbon of C(RT)2 forms a cycloprop- 1 , 1 -diyl group ; where XG, XH & XJ are selected such that there are not two C(O) groups present at adjacent positions, and that the N-(2,6-dioxopiperidin-3-yl) is not at an adjacent position to either N(Ci-3alkyl) or O: each RA is independently a substituent on any available C atom at XA, XB, Xc or XD selected from F, Cl, Ci-jalkyl, Ci-salkoxy wherein said Ci-salkyl and Ci-salkoxy is independently optionally substituted by one or more F; h is 0, 1 or 2; and wherein the Linker is attached to any C atom at XA, XB, Xc or XD. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to claim 7 where each RA is a substituent on any available C at XA, XB, Xc or XD selected from F, Cl and
C i-aalkoxy optionally substituted by one or more F. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to claim 7 or statement 22 where XG-XH-XJ is:
(i) XG-NY-C(O) where XG is -CH2-, -CH2CH2-, =N- or C(O);
(ii) XG-C(O)-NY where XG is -O- or N(Ci-3alkyl); or
(iii) C(O)-NY-CH2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6 where W is any one of groups 1 to 21 :
Figure imgf000324_0001
11. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of
Figure imgf000325_0001
claims 1 to 6, wherein W is W2 which is
ZA is:
Figure imgf000325_0002
wherein:
* represents a single covalent bond or a double covalent bond;
1 of XA2, XB2, XC2 & XD2 is C and covalently bound to Y ;
0, 1 or 2 of XA2, XB2, XC2, XD2, XE2 & XE2 is/are N (where XE2 & XE2 are not both N) and are otherwise C;
1 or 2 of XG2, XH2 & XJ2 is/are N; and are otherwise C; each RAA is a substituent on any available C or N atom of Z - in each case independently selected from RAAI optionally substituted by one or more RAA2: where RAA is further selected from RAA2 when RAA is a substituent on an available C atom of ZA; each RAAI is independently Ci.4alkyl, C2-3alkenyl, C2-3alkynyl,
Ci-salkoxyCi-salkyl, carboxyCi-salkyl, Cj-ycarbocyclyl or a 4-6 membered heterocyclyl; each RAA2 is independently selected from F, Cl, Br, CN, NH2, Chalky 1,
O(Ci-3alkyl), NH(Ci-3alkyl) and N(Ci-3alkyl)2; wherein said Ci-salkyls are optionally substituted by one or more F; v is 0, 1 or 2;
Y is N-(2,6-dioxopiperidin-3-yl).
12. The compound or salt thereof according to claim 11, wherein
1 of XA2 & XB2 is C and covalently bound to Y and the other of XA2 & XB2 is C;
0 or 1 of XC2 & XD2 is N and is/are otherwise C;
1 of XG2 & XJ2 is N and the other of XG2 & XJ2 is C; and
X H2 X E2 & XF2 are all C.
13. The compound or salt thereof according to claim 11, wherein W is W2-1
Figure imgf000326_0001
wherein:
XK and XL are either N-linker and CH or NMe and C-linker respectively;
1 ofXM and X° is N-(2,6-dioxopiperidin-3-yl) (Y);
0 or 1 of XM and XN is C-F;
XN may be N if XM is not C-F ; the remainder of XN, XM and X° are CH.
14. The compound or salt thereore according to any one of claims 1 to 6, wherein W represents any of the groups 22 to 26 shown below:
Figure imgf000326_0002
15. The compound or salt thereof, according to any one of claims 1 to 14 wherein R2a and R2b are substituents on the same or different C atoms adjacent Q.
16. The compound or salt thereof according to any one of claims 1 to 15 wherein R2a and R2b are substituents on the same or different C atoms, each independently selected from H and Ci-aalkyl.
17. The compound or salt thereof according to any one of claims 1 to 16 wherein p is 1 ; X3 & X4 are not substituted by -X5=X6-X7=X8-; X1, X2, X3 & X4 are all C and R1 is a substituent on X1 and is CFs.
18. The compound or salt thereof according to any one of claims 1 to 16 wherein p is 2; X3 & X4 are not substituted by -X5=X6-X7=X8-; X1, X2, X3 & X4 are all C; one R1 substituent is on X1 and is CFs, and the other R1 substituent is on X2 and is F or ethyl.
19. The compound of salt thereof according to any one of claims 1 to 18 wherein n is 1 , m is 1 , Q is CH, R2a is H and R2b is H.
20. The compound of salt thereof according to any one of claims 1 to 19 wherein Y1, Y2, Y3 & Y4 are all C.
21. The compound of salt thereof according to any one of claims 1 to 20 wherein q is 0.
22. The compound of salt thereof according to any one of claims 1 to 20, wherein q is 1 and R3 is attached to C at Y1, and R3 is selected from F, CN and Me.
23. The compound of salt thereof according to any one of claims 1 to 21 , wherein q is 2 and each R3 group is F, which are attached to C at Y1 and Y3.
24. The compound or salt thereof according to claim 1 which is of Formula (VI):
Figure imgf000327_0001
or a pharmaceutically acceptable salt thereof, wherein:
RZ1 is H or F;
RZ2 is H or F;
RZ3 is H or F;
Lz is a linker selected from 1, 3, 45 and 47:
Figure imgf000327_0002
Figure imgf000328_0001
Figure imgf000329_0002
where Y is N-(2,6-dioxopiperidin-3-yl).
25. The compound or salt thereof according to claim 1 which is of Formula (VI-1):
Figure imgf000329_0001
or a pharmaceutically acceptable salt thereof, wherein:
RZ1 is H or F;
Lz is a linker selected from 1 and 3:
Figure imgf000330_0002
and Wz is selected from 1, 2 and 10:
Figure imgf000330_0003
where Y is N-(2,6-dioxopiperidin-3-yl).
26. The compound or salt thereof according to claim 1 which is of Formula (VI- 2):
Figure imgf000330_0001
or a pharmaceutically acceptable salt thereof, wherein:
RZ1 isHorF;
RZ2 isHorF;
RZ3 is H or F; Lz is a linker selected from 3, 45 and 47 :
Figure imgf000331_0001
and Wz is selected from 1, 3, 16, 22, 23, 24 and 26:
Figure imgf000331_0002
Figure imgf000332_0001
where Y is N-(2,6-dioxopiperidin-3-yl).
27. A pharmaceutical composition, which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to one of claims 1 to 26, in association with a pharmaceutically acceptable excipient.
28. A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to one of claims 1 to 26 or a pharmaceutical composition according to claim 24, for use in the prevention or treatment of tumour types that are sensitive to degradation of androgen receptors or for use in the treatment of prostate cancer (for example castrate-resistant prostate cancer (CRPC), for example metastatic CRPC)).
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