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WO2023242598A1 - Molécules bifonctionnelles pour la dégradation ciblée de protéines - Google Patents

Molécules bifonctionnelles pour la dégradation ciblée de protéines Download PDF

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Publication number
WO2023242598A1
WO2023242598A1 PCT/GB2023/051594 GB2023051594W WO2023242598A1 WO 2023242598 A1 WO2023242598 A1 WO 2023242598A1 GB 2023051594 W GB2023051594 W GB 2023051594W WO 2023242598 A1 WO2023242598 A1 WO 2023242598A1
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Prior art keywords
substituted
alkyl
heteroaryl
aryl
heterocycloalkyl
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PCT/GB2023/051594
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English (en)
Inventor
Andrea TESTA
Callum Macgregor
Gregor MEIER
Callum HAMBY
Charlene FALLAN
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Amphista Therapeutics Limited
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Priority claimed from GBGB2208874.4A external-priority patent/GB202208874D0/en
Priority claimed from GBGB2219257.9A external-priority patent/GB202219257D0/en
Application filed by Amphista Therapeutics Limited filed Critical Amphista Therapeutics Limited
Publication of WO2023242598A1 publication Critical patent/WO2023242598A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms

Definitions

  • the present disclosure relates to a novel class of bifunctional molecules that are useful in a targeted or selective degradation of a protein, the protein being selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • TPD Targeted Protein Degradation
  • other drug modalities e.g. small molecule inhibitors, antibodies & proteinbased agents, antisense oligonucleotides and related knockdown approaches
  • potentiated pharmacology due to catalytic protein removal from within cells
  • ability to inhibit multiple functions of a specific drug target including e.g.
  • scaffolding function through target knockdown; opportunity for systemic dosing with good biodistribution; potent in vivo efficacy due to catalytic potency and prolonged duration of action limited only by de novo protein resynthesis; and facile chemical synthesis and formulation using application of small molecule processes.
  • UPS ubiquitin- proteasome system
  • the UPS can be repurposed to degrade specific proteins using bifunctional chemical molecules, commonly referred to as bifunctional degraders, as therapeutic agents. These molecules act by inducing the proximity of desired substrates with UPS proteins to initiate a cascade of events which ultimately leads to degradation, and removal of the protein from the cell by the proteasome.
  • PROTACs Proteolysis targeting chimeras constitute one such class of bifunctional degraders, which induce proximity of target proteins to the UPS by recruitment of specific ubiquitin E3 ligases.
  • PROTACs are composed of two ligands joined by a linker - one ligand to engage a desired target protein and another ligand to recruit a ubiquitin E3 ligase.
  • VHL von Hippel-Lindau
  • CRBN Cereblon
  • PROTACs recruiting VHL are typically based on hydroxyproline-containing ligands
  • PROTACs recruiting CRBN are typically characterised by the presence of a glutarimide moiety, such as thalidomide, pomalidomide and lenalidomide or close analogues to act as the warhead.
  • Other ligases including mdm2 and the IAP family have also shown utility in PROTAC design.
  • limitations of current PROTAC approaches include: inability to efficiently degrade some targets; poor activity of PROTACs in many specific cells due to low and variable expression of E3 ligases and other proteins required for efficient degradation; chemical properties which make it more difficult to prepare degraders with suitable drug-like properties including good drug metabolism & pharmacokinetic profiles; and high susceptibility to induced resistance mechanisms in tumours.
  • the present disclosure is based on the identification of a novel class of bifunctional molecules that are useful in a targeted and/or selective degradation of a desired protein, e.g. a “target protein”.
  • a target protein is selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • bifunctional molecules described herein comprise a general structure of:
  • TBL is a target protein binding ligand and L is a linker.
  • the moiety “Z” (a “warhead”) modulates, facilitates and/or promotes proteasomal degradation of the target protein and may, in some cases, be referred to as a modulator, facilitator and/or promoter of proteasomal degradation.
  • the TBL moiety of the bifunctional molecule binds to a target protein.
  • the moiety Z (which is joined or otherwise connected to the TBL via the linker) then modulates, facilitates and/or promotes the degradation of this target protein, e.g. by acting to bring the target protein into proximity with a proteasome and/or by otherwise causing the target protein to be marked for proteasomal degradation within a cell.
  • the bifunctional molecules described in the present disclosure may be considered to comprise: a target protein binding ligand (TBL) (i.e. a ligand capable of binding (e.g. specifically binding) to a target protein; a warhead or degradation tag (Z) (e.g. moiety Z which acts to modulate, facilitate and/or promote the degradation of this target protein) and a linker (e.g. a chemical linker) which conjugates, joins or connects TBL and Z.
  • TBL target protein binding ligand
  • Z warhead or degradation tag
  • linker e.g. a chemical linker
  • the bifunctional molecules described in the present disclosure have been shown to be effective degraders against a wide range of target proteins. Without being bound by theory, it is hypothesised that the Z moiety of the bifunctional molecules described herein does not bind to the ubiquitin E3 ligases typically relied on in the classical PROTAC approaches discussed above (such as CRBN and VHL). Accordingly, the bifunctional molecules described herein are believed to modulate, facilitate and/or promote proteasomal degradation via an alternative mechanism. Thus, the present class of bifunctional molecules may be useful against a wider range of diseases (including those that are resistant to many PROTAC degraders).
  • TBL is a target protein binding ligand selected from an: (i) estrogen receptor binding ligand; and (ii) androgen receptor binding ligand;
  • L is a linker
  • Z comprises a structure according to formula (Zl): wherein: ring A 2 is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl or an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S;
  • R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl)-; wherein R y is optionally substituted C 1-6 alkyl or H;
  • R 3 is selected from C 1-6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkyl heterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally wherein the C 1-6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S; and L shows the point of attachment of the linker; and further wherein Z is not: or a pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the bifunctional molecule of the first aspect, together with a pharmaceutically acceptable carrier, optionally wherein the bifunctional molecule is present in the composition as a pharmaceutically acceptable salt, solvate or derivative.
  • the invention provides a bifunctional molecule of the first aspect, or the pharmaceutical composition of the second aspect, for use in medicine, suitably, wherein the use comprises the treatment and/or prevention of any disease or condition which is associated with and/or is caused by an abnormal level of protein activity of the estrogen receptor or androgen receptor.
  • the invention provides a method of treating and/or preventing any disease or condition which is associated with and/or is caused by an abnormal level of protein activity of the estrogen receptor or androgen receptor, the method comprising administering a therapeutically effective amount of a bifunctional molecule of the first aspect, or the pharmaceutical composition of the second aspect to a subject in need thereof.
  • the invention provides a method of selectively degrading and/or increasing proteolysis of a target protein in a cell, the method comprising contacting and/or treating the cell with a bifunctional molecule of the first aspect or the pharmaceutical composition of the second aspect, wherein the target protein is selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • the invention provides a method of selectively degrading and/or increasing proteolysis of a target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bifunctional molecule of the first aspect or the pharmaceutical composition of the second aspect, wherein the target protein is selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • the invention provides for use of a moiety Z as defined herein in a method of targeted protein degradation of a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • the invention provides for use of a moiety Z as defined herein in the manufacture of a bifunctional molecule suitable for targeted protein degradation of a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • the invention provides a method of making a bifunctional molecule the first aspect.
  • the invention provides a method of screening the bifunctional molecules of the first aspect, comprising: a. providing a bifunctional molecule comprising:
  • a linker that covalently attaches the first and second ligands b. contacting a cell with the bifunctional molecule; c. detecting degradation of the target protein in the cell; d. detecting degradation of the target protein in the cell in the absence of the bifunctional molecule; and e. comparing the level of degradation of the target protein in the cell contacted with the bifunctional molecule to the level of degradation of the target protein in the absence of the bifunctional molecule; wherein an increased level of degradation of the target protein in the cell contacted with the bifunctional molecule indicates that the bifunctional molecule has facilitated and/or promoted the degradation of the target protein, optionally wherein detecting degradation of the target protein comprises detecting changes in the levels of the target protein in the cell.
  • the invention provides a compound library comprising a plurality of bifunctional molecules of the first aspect.
  • the linker may be appended to moiety Z via the R 2 group.
  • the linker may be attached to moiety Z by way of a covalent bond between an atom on the linker and an atom contained in the ring system of the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl of the R 2 group.
  • the linker may be attached to moiety Z by way of a covalent bond to the nitrogen atom of NR y or the benzylic carbon atom of the -CH(aryl)- or -CH(substituted aryl)-, for example by way of a covalent bond to the benzylic carbon atom of the -CH(aryl)- or - CH(substituted aryl)-.
  • R 2 may be absent.
  • the linker may be appended to moiety Z by way of a covalent bond between an atom on the linker and an atom contained in the heterocyclic ring (e.g. ring A 2 ).
  • the linker may be attached at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • the linker may be bonded at any position on the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)- or -CH(substituted aryl)- of the R 2 group or may replace a hydrogen atom at any position on the heterocyclic ring shown, for example, in formula (Zl).
  • ring A 2 is an optionally substituted 4- to 7-membered monocyclic N- heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S, such as N and O.
  • ring A 2 is bicyclic or tricyclic, and unless otherwise stated, it may comprise rings that are joined by a bond, rings that are fused, a bridged ring and/or rings that are joined at a spiro centre.
  • ring A 2 When ring A 2 is bicyclic, it may be a bridged bicyclic ring (i.e. it may comprise two rings that share three or more atoms) or it may be a spirocyclic bicyclic ring (i.e. it may comprise two rings that share one atom, e.g. the two rings may be joined at a spiro centre).
  • ring A 2 When ring A 2 is a bridged bicyclic ring, it may be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S. In some examples, ring A 2 is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S. In some examples, ring A 2 is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally containing one additional ring atom selected from N.
  • ring A 2 When ring A 2 is a spirocyclic bicyclic ring, it may be an optionally substituted 7- to 12- membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S. In some examples, ring A 2 is a 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S. In some cases, ring A 2 is bicyclic and comprises a first 5- to 7-membered ring and a second 3- to 7-membered ring.
  • ring A 2 may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, and optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • ring A 2 may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, and optionally containing one additional ring heteroatoms selected from N.
  • Z comprises a structure according to formula (Zla): wherein:
  • R 1 is absent (i.e. when m is 0) or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-5 cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl (e.g. 5- to 7-membered N-heterocycloalkyl), optionally wherein the C 3-5 cycloalkyl or the 5- to 7-membered heterocycloalkyl are joined to ring A at a spiro centre;
  • R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl)-; wherein R y is optionally substituted C 1-6 alkyl or H;
  • R 3 is selected from C 1 -C 6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkyl heterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkyl aryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkyl heteroaryl, substituted alkylheteroaryl, optionally wherein the C 1 -C 6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S;
  • X 1 is CH 2 ;
  • X 2 , X 3 and X 4 are each independently CH 2 , O or NR X ;
  • R x is H or C 1 to C 6 alkyl, or wherein one R 1 group and one R x group combine to form an optionally substituted C 1-3 bridge; n is 0, 1 , 2, or 3; m is 0, 1 , 2, 3 or 4; and
  • Z comprises a structure according to formula (Zlb): wherein:
  • R 1 is absent (i.e. when m is 0) or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-5 cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl (e.g. a 5- to 7-membered N- heterocycloalkyl), optionally wherein the C 3-5 cycloalkyl or the 5- to 7-membered heterocycloalkyl are joined to ring A at a spiro centre;
  • R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl)-; wherein R y is optionally substituted C 1-6 alkyl or H;
  • R 3 is selected from C 1 -C 6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkyl heterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkyl aryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkyl heteroaryl, substituted alkylheteroaryl, optionally wherein the C 1 -C 6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S;
  • X 1 and X 4 are each CH 2 ;
  • X 2 and X 3 are each independently CH 2 , O or NR X ; with the proviso that none or only 1 of X 2 and X 3 is O;
  • R x is H or C 1 to C 6 alkyl; or wherein one R 1 group and one R x group combine to form an optionally substituted C 1-3 bridge; n is 0, 1 , 2 or 3; m is 0, 1 , 2, 3 or 4; and
  • Z comprises a structure according to formula (Zlb’): wherein:
  • R 1 , R 3 , X 1 , X 2 , X 3 , X 4 , n, m and L are as defined above in respect of formula (Zla) and (Zlb).
  • Z comprises a structure according to formula (Zlb”): wherein:
  • R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , n and L are as defined above in respect of formula (Zla) and (Zlb).
  • an optionally substituted C 1-3 bridge may be formed by two R 1 groups or, in some cases, by one R 1 group and one R x group.
  • the C 1 -3 bridge may be a C 1 - C 3 alkylene bridging group, such as methylene, ethylene or propylene.
  • the C 1 -C 3 bridge may be methylene or ethylene.
  • the C 1-3 bridge may comprise from one to three (e.g. one or two) substituents (selected from any suitable substituent as described herein).
  • the C 1 to C 3 alkylene bridging group may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • Z may comprise a structure according to formula (I): wherein R 1 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl;
  • R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , -CH(aryl)-, -CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl)-; wherein R y is H or C 1 to C 6 alkyl;
  • R 3 is selected from C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 , or a heteroatom selected from O and NR X , wherein R x is H or C 1 to C 6 alkyl; n is 0, 1 , 2, or 3; and
  • L shows the point of attachment of the linker
  • the list of options for R 3 given above may be replaced with C 1 to C 6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkyl heterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S.
  • R 2 may be absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, - CH(substituted aryl)-, -CH(heteroaryl)- and -CH(substituted heteroaryl)-. In some examples, at least one of R 1 or R 2 is present.
  • R 2 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , - CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)- and -CH(substituted heteroaryl)-.
  • R 2 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, - CH(substituted aryl)-, -CH(heteroaryl)- and -CH(substituted heteroaryl)-.
  • R 1 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl.
  • At least one R 1 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge, optionally substituted Cs-ecycloalkyl or optionally substituted 5- to 7- membered N-heterocycloalkyl, optionally wherein the C 3-5 cycloalkyl or the 5-7-membered N- heterocycloalkyl are joined to ring A at a spiro centre.
  • both of R 1 and R 2 are present.
  • R 2 is present and at least one R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form a optionally substituted C 1-3 bridge, optionally substituted Cs-ecycloalkyl or optionally substituted 5- to 7- membered N-heterocycloalkyl.
  • R 1 and/or R 2 may be covalently attached to the heterocyclic ring (e.g. ring A) at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • R 1 and/or R 2 may replace a hydrogen atom at any position on the heterocyclic core, e.g. that shown in formula (I).
  • R 1 and R 2 may be covalently attached to the heterocyclic ring (e.g. ring A) at the same or different positions.
  • R 1 and R 2 may be covalently attached to the heterocyclic core by way of different carbon atoms.
  • R 1 and R 2 may be covalently attached to the heterocyclic core by way of the same carbon atom.
  • a double bond is present in Z.
  • the stereochemistry of this double bond may be either E or Z and this is indicated by the wavy line bond in formula (I) (and is similarly shown on the other formulae and structures disclosed herein).
  • this moiety may depend on the identity of the R 3 group.
  • Z may comprise a mixture of E and Z stereoisomers.
  • the present disclosure includes within its scope the use of each individual E and Z stereoisomers of any of the disclosed Z moieties according to formula (I) and any of the other formulae described herein (e.g. in a substantially stereopure form), as well as the use of mixtures of these E and Z isomers.
  • the stereochemistry of the double bond and the moieties bound to it is Z, i.e. the Z stereoisomer.
  • the stereochemistry of the double bond and the moieties bound to it is E, i.e. the E stereoisomer.
  • Z may be represented as either formula (la) or (lb): wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 and n are as defined above and herein.
  • the bifunctional molecules of the present disclosure may exist in different stereoisomeric forms.
  • the present disclosure includes within its scope the use of all stereoisomeric forms, or the use of a mixture of stereoisomers of the bifunctional molecules,
  • the bifunctional molecule comprises one or more chiral centres
  • the present disclosure encompasses each individual enantiomer of the bifunctional molecule as well as mixtures of enantiomers including racemic mixtures of such enantiomers.
  • the bifunctional molecule comprises two or more chiral centres
  • the present disclosure encompasses each individual diastereomer of the bifunctional molecule, as well as mixtures of the various diastereomers.
  • the various structures shown herein encompass all isomeric (e.g. enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure).
  • the present disclosure embraces the R and S configurations for each asymmetric centre, and Z and E double bond isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are to be understood to be within the scope of the present disclosure.
  • all tautomeric forms of the bifunctional molecules described herein are to be understood to be within the scope of the present disclosure.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • bifunctional molecules as described herein in which one or more hydrogen atoms have been replaced by deuterium or tritium, or in which one or more carbon atoms have been replaced by a 13 C- or 14 C-enriched carbon are to be understood to within the scope of the present disclosure.
  • Such molecules may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • a bifunctional molecule as described herein may be substituted with one or more deuterium atoms.
  • references to “a bifunctional molecule” may further embrace a pharmaceutically acceptable salt thereof.
  • Z may be represented as formula (lc’): wherein:
  • R 1 is absent (i.e. m is 0) or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms that is optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents; C 3 to C 8 cycloalkyl being optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents; C 1 to C 6 alkyl optionally substituted with one to three substituents; and/or wherein two R 1 groups combine to form a C 1-3 bridge optionally substituted with one to three substituents, C 3 - 5 cycloalkyl optionally substituted with one to three substituents or 5- to
  • R 2 is absent or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents; -NR y ; -CH(aryl)-, wherein the aryl has 6 to 10 carbon ring atoms and is optionally substituted with one to three substituents)-; and -CH(heteroaryl)-, wherein the heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three
  • R 3 is selected from the group consisting of: C 1 to C 6 alkyl optionally substituted with one to three substituents; C 3 to Cs cycloalkyl optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents; aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 , or a heteroatom selected from O and NR X , wherein R x is H or C 1 to C 6 alkyl, or wherein one R 1 group and one R x group combine to form a C 1-3 bridge optionally substituted with one to three substituents; with the proviso that none, or only 1 or 2 X 2 and X 3 is a heteroatom; and m is 0, 1 , 2 or 3; n is 0, 1 , 2, or 3; and
  • Z may be represented as formula (Ic): wherein:
  • R 1 is absent or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms that is optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents; C 3 to C 8 cycloalkyl; C 1 to C 6 alkyl optionally substituted with one to three substituents;
  • R 2 is absent or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents; -NR y ; -CH(aryl)-, wherein the aryl has 6 to 10 carbon ring atoms and is optionally substituted with one to three substituents)-; and -CH(heteroaryl)-, wherein the heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three
  • R 3 is selected from the group consisting of: C 1 to C 6 alkyl optionally substituted with one to three substituents; Cs to Cs cycloalkyl optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents; aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 , or a heteroatom selected from O and NR X , wherein R x is H or C 1 to C 6 alkyl; with the proviso that none, or only 1 or 2 X 2 and X 3 is a heteroatom; and n is 0, 1 , 2, or 3; and
  • Z may be represented as formula (Id’): wherein:
  • R 1 is absent (i.e. when m is 0) or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O and S; C 3 to Cs cycloalkyl; C 1 to C 6 alkyl and C 1 to C 6 haloalkyl; and/or wherein two R 1 groups combine to form a
  • R 2 is absent or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 al
  • R 3 is selected from the group consisting of C 1 to C 6 alkyl optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; C 3 to C 6 cycloalkyl optionally wherein the C 3 to C 6 cycloalkyl is substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; phenyl that is optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl,
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 , or a heteroatom selected from O and NR X , wherein R x is H or C 1 to C 6 alkyl, or wherein one R 1 group and one R x group combine to form a C 1-3 bridge; with the proviso that none or only 1 of X 2 and X 3 is a heteroatom; and m is 0, 1 , 2 or 3; n is 0, 1 , 2, or 3; and
  • Z may be represented as formula (Id): wherein:
  • R 1 is absent or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; C 3 to Cs cycloalkyl; C 1 to C 6 alkyl and C 1 to C 6 haloalkyl;
  • R 2 is absent or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 al
  • R 3 is selected from the group consisting of C 1 to C 6 alkyl optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; C 3 to Cs cycloalkyl optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents; phenyl that is optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 , or a heteroatom selected from O and NR X , wherein R x is H or C 1 to C 6 alkyl; with the proviso that none or only 1 of X 2 and X 3 is a heteroatom; and n is 0, 1 , 2, or 3; and
  • L shows the point of attachment of the linker.
  • Z may be represented as formula (le’): wherein:
  • R 1 is absent (i.e. when m is 0) or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms containing 1 or 2 heteroatoms each independently selected from N, O and S; C 3 to C7 cycloalkyl; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; C 1 to C 6 alkyl and C 1 to C 6 haloalkyl; wherein the phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy; and/or wherein two R 1 groups combine to form a C 1-3 bridge, C 3-5 cycloalkyl or 5- to 7- membered N-heterocycloalkyl (e.g. wherein the C 3-5 cycloalkyl or the
  • R 2 is absent or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; -NR y ; -CH(phenyl)-; and -CH(heteroaryl) wherein the heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O and S; and further wherein the phenyl, heteroaryl, heterocycloalkyl, - CH(phenyl)- and -CH(heteroaryl) are each optionally substituted with one substituent selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy; wherein R y is H or C 1 to C 6 alkyl;
  • R 3 is selected from the group consisting of C 1 to C 6 alkyl optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group the heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; C 3 to C 6 cycloalkyl; phenyl; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the C 3 to C 6 cycloalkyl, phenyl and heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 or O; with the proviso that none or only 1 of X 2 and X 3 is O; m is 0, 1 , 2 or 3; n is 1 , 2, or 3; and
  • Z may be represented as formula (le): wherein:
  • R 1 is absent or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms containing 1 or 2 heteroatoms each independently selected from N, O and S; C 3 to C 7 cycloalkyl; C 1 to C 6 alkyl and C 1 to C 6 haloalkyl; wherein the phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy;
  • R 2 is absent or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; -NR y ; -CH(phenyl)-; and -CH(heteroaryl) wherein the heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O and S; and further wherein the phenyl, heteroaryl, heterocycloalkyl, - CH(phenyl)- and -CH(heteroaryl) are each optionally substituted with one substituent selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy; wherein R y is H or C 1 to C 6 alkyl;
  • R 3 is selected from the group consisting of C 1 to C 6 alkyl optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group the heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; C 3 to C 6 cycloalkyl; phenyl; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the C 3 to C 6 cycloalkyl, phenyl and heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 or O; with the proviso that none or only 1 of X 2 and X 3 is O; and n is 1 , 2, or 3; and
  • Z comprises a structure according to formula (Zll): wherein R 2 is absent or is as described in any one of the embodiments disclosed herein;
  • R 3 is as described in any one of the embodiments disclosed herein;
  • X 5 is CR b 2, NR b , O or a 5- to 7-membered heterocycloalkyl (e.g. a 5- to 7-membered heterocycloalkyl); each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge or optionally substituted C 3-5 cycloalkyl (optionally wherein the C 3-5 cycloalkyl is joined to the heterocyclic ring shown in formula (Zll) at a spiro centre);
  • R b is H or optionally substituted C 1 . 3 alkyl; n1 is 0, 1 , 2 or 3; m is 0, 1 or 2; and
  • Z comprises a structure according to any one of formulae (Zlla) to (Zlle):
  • R 2 is as described in any one of the embodiments disclosed herein;
  • R 3 is as described in any one of the embodiments disclosed herein; each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 3-5 cycloalkyl (optionally wherein the C 3-5 cycloalkyl is joined to the heterocyclic ring shown in formula (Zlla) at a spiro centre);
  • X 5 is C(R b ) 2 , NR b or O;
  • R b is H or optionally substituted C 1 -salkyl; n1 is 0, 1 , 2 or 3; n’ is 1 or 2; m is 0, 1 or 2; and L shows the point of attachment of the linker.
  • Z may comprise a structure according to formula (Zllla) to (Zlllh): wherein:
  • R 2 is as described in any one of the embodiments disclosed herein;
  • R 3 is as described in any one of the embodiments disclosed herein; each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl;
  • X 5 is CH 2 , NR b or O
  • R b is H or optionally substituted C 1 -salkyl; n1 is 0, 1 or 2; n’ is 1 or 2; m is 0, 1 or 2; and
  • Z comprises a structure according to formula (ZlVa) to (ZlVj): wherein:
  • R 2 is absent or is as described in any one of the embodiments disclosed herein;
  • R 3 is as described in any one of the embodiments disclosed herein; each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl; n1 is 0, 1 or 2; n’ is 1 or 2; m is 0, 1 or 2; and L shows the point of attachment of the linker.
  • Z comprises a structure according to formula (If): wherein R 1 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl;
  • R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)- and -CH(substituted aryl)-;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted C 1 to C 6 alkyl, substituted aryl, and substituted heteroaryl; and wherein at least one of R 1 and R 2 is present; n is 0, 1 , 2, or 3; and
  • R 1 , R 2 and R 3 of formula (If) may be selected from those groups defined above, e.g. for any one or more of formulae (I c’) , (Ic), (Id’), (Id), (le’) or (le).
  • n may be 1 , 2 or 3 and/or n1 may be 0, 1 or 2.
  • Z may be represented by formula (II): wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl);
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a a heterocycloalkyl group;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 or O; with the proviso that none or only 1 of X 2 and X 3 is O; and
  • n is 0, 1 , 2 or 3;
  • L shows the point of attachment of the linker
  • Z may be represented by formula (Ila): wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl);
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a a heterocycloalkyl group; and n is 0, 1 , 2 or 3; and
  • n may be 1 or 2.
  • Z may be represented by formula (lib): o wherein R 2 is selected from aryl substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 or O; with the proviso that none or only 1 of X 2 and X 3 is O; n is 1 or 2; and
  • L shows the point of attachment of the linker
  • Z may be represented by formula (lle): wherein R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group;
  • X 1 is CH 2 ;
  • X 2 and X 3 are each independently CH 2 or O; with the proviso that none or only 1 of X 2 and X 3 is O; n is 1 or 2; and
  • Z may be represented by formula (lid): wherein R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2; and
  • Z may comprise a structure according to formula (lle): wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2; and
  • Z may comprise a structure according to formula (Ilf): wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and L shows the point of attachment of the linker.
  • Z may comprise a structure according to formula (III): wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 to C 6 alkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and n is 0,1 , 2 or 3; and
  • n may be 1 or 2.
  • Z may be represented by formula (Illa): wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 to C 6 alkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and L shows the point of attachment of the linker.
  • Z may be represented by formula (lllb): wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 -C 6 alkyl;
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and L shows the point of attachment of the linker.
  • bifunctional molecules of formula (lllb) comprise at least two stereocentres and so exist in several diastereomeric (and enantiomeric) forms.
  • the groups R 1 and L may exist in a trans relationship (e.g. these groups are held and/or oriented on opposite sides of the heterocyclic core).
  • the groups R 1 and L may exist in a cis relationship (e.g. these groups are held and/or oriented on the same side of the heterocyclic core).
  • bifunctional molecules of formula (lllb) may encompass at least the following diastereomeric forms:
  • Z may be represented by formula (IV): wherein R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; R 4 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; and n is 0, 1, 2 or 3; and
  • Z may comprise a structure according to formula (IVa):
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group;
  • R 4 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; and L shows the point of attachment of the linker.
  • R 4 may be selected from aryl or substituted aryl.
  • R 1 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl, and substituted C 1 to C 6 alkyl.
  • R 1 is an optionally substituted aryl or an optionally substituted heteroaryl.
  • the aryl or heteroaryl may comprise one or more substituents selected from the group consisting of C 1 to C 6 alkyl (e.g. methyl), C 1 to C 6 alkoxy (e.g. methoxy), C 1 to C 6 haloalkyl and halo.
  • R 1 may be phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy.
  • R 1 may be heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; C 3 to Cs cycloalkyl.
  • R 1 groups include but are not limited to phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl.
  • R 1 is a cycloalkyl, such as a C 3 to C7 cycloalkyl, or a Csto C 6 cycloalkyl.
  • R 1 is a C 1 to C 6 alkyl, such as a C 1 to C 3 alkyl that is optionally substituted with one to three substituents as defined herein.
  • R 1 groups are illustrated below:
  • the line intersected by a wavy line represents the covalent bond between the exemplary R 1 groups shown above and a carbon atom on the heterocycloalkyl core attached to the R 1 group in the parent structure of Z (as illustrated by the various formulae described herein).
  • a particular substitution pattern is shown in the exemplary aryl and heteroaryl structures above, it will be appreciated that other substitution patterns are also encompassed within the scope of the present disclosure.
  • two R 1 groups may combine to form a C 1-3 bridge or C 3-5 cycloalkyl.
  • two R 1 groups may combine to form a C 3 - scycloalkyl.
  • the C 3-5 cycloalkyl may be joined to the heterocyclic ring of the parent structure at a spiro centre.
  • R 2 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl) and -CH(substituted heteroaryl); wherein R y is optionally substituted C 1-6 alkyl (such as methyl) or H
  • R 2 is present in Z (and/or the bifunctional molecules described herein) as a divalent group.
  • the various groups defined for R 2 are covalently attached to an atom of the heterocyclic core of Z and also may be covalently attached to an atom of a linker. Thus, these groups may be considered as divalent radical species.
  • R 2 is selected from optionally substituted aryl and optionally substituted heteroaryl
  • R 2 may be selected from aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted with one to three substituents; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents.
  • R 2 may be selected from phenyl optionally substituted with one to three substituents selected from H, C 1 to C 6 alkyl, halo, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 or 2 N atoms, the heteroaryl being optionally substituted with one to three substituents selected from C 1 -C 6 alkyl (e.g. C 1 to C 3 alkyl), halo (e.g. F), C 1 -C 6 haloalkyl (e.g. C 1 to C 3 haloalkyl) and C 1 to C 6 alkoxy (e.g. C 1 to C 3 alkoxy).
  • suitable examples of R 2 include (but are not limited to) optionally substituted phenyl, and optionally substituted pyrazolyl.
  • the heterocycloalkyl may have 3 to 10 ring atoms and contain 1 to 3 heteroatoms each independently selected from N, O and S, and the heterocycloalkyl may be optionally substituted with one to three substituents.
  • the heterocycloalkyl may have 5 to 8 ring atoms (e.g. 6 ring atoms) and may contain 1 or 2 N atoms.
  • suitable examples include (but are not limited to) optionally substituted piperidinyl, and optionally substituted piperazinyl.
  • R 2 groups are shown below:
  • R 6 may be selected from H, C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy. In some examples, R 6 may be selected from H and C 1 -C 6 alkyl.
  • the line intersected by a wavy line represents the covalent bond between the exemplary R 2 groups shown above and a carbon atom on the heterocycloalkyl core attached to the R 2 group in the parent structure of Z (as illustrated by the various formulae described herein).
  • a particular substitution pattern is shown in the exemplary structures above, it will be appreciated that other substitution patterns are also encompassed within the scope of the present disclosure.
  • the bond to L shows the point of attachment to the linker.
  • the linker may replace a hydrogen atom at any suitable position on the aryl ring (e.g. provided it is chemically suitable and has the correct valency).
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted C 1 to C 6 alkyl, substituted aryl, and substituted heteroaryl.
  • R 3 may be selected from the group consisting of: C 1 to C 6 alkyl optionally substituted with a heterocycloalkyl group having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; aryl having 6 to 10 carbon ring atoms; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the aryl and the heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • the aryl and heteroaryl may be optionally substituted with one or two substituents selected from halo (e.g. F) and C 1 to C 3 alkyl (e.g. methyl).
  • R 3 groups include, but are not limited to, thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, oxetanyl, cyclobutanyl, cyclopropanyl, tert-butyl, imidazolyl, oxazolyl, thiophenyl, imidazo(1 ,2-a)pyridinyl, N-C 1 to C 6 alkylenemorpholine, and 4,5,6,7-tetrahydro-1 ,3-benzothiazolyl, such as thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, cyclobutanyl, cyclopropanyl and ter
  • R 3 groups may be substituted, such as substituted thiazolyl, substituted pyridinyl, substituted benzothiazolyl, substituted phenyl, substituted pyrazolyl, substituted isoxazolyl, substituted isothiazolyl, substituted tetrahydropyranyl, substituted tetrahydrofuranyl, substituted oxetanyl, substituted cyclobutanyl, substituted cyclopropanyl and substituted tert-butyl.
  • R 3 is a substituted heteroaryl or aryl group, there may be one or more substituents on the aromatic ring e.g. it may be mono-, di- or tri-substituted.
  • R 3 is optionally substituted pyrazolyl or imidazolyl, a nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted with C 1 to C 6 alkyl, such as methyl.
  • R 3 groups include, but are not limited to, optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted oxazoyl, optionally substituted isoxazolyl, tert-butyl, C 1 -C 6 alkyl comprising a morpholino substituent, optionally substituted benzothiazolyl and optionally substituted pyridinyl.
  • R 3 is a substituted aryl or heteroaryl group, there may be one or more substituents on the aromatic ring e.g. it may be mono-, di- or tri-substituted.
  • R 3 groups are shown below: ⁇ wherein the dotted line on the structures indicates the position that each of the respective R 3 groups may be joined to the structure shown in the formulae described herein. Where the dotted line is not shown connected directly to an atom, the R 3 group may be connected to the structure shown in formulae by a covalent bond to an atom at any position on the aromatic ring (provided that it has the correct valency and/or is chemically suitable). For example, a hydrogen at any position on the R 3 group may be replaced with a bond to the parent structures as shown in the formulae described herein.
  • R 5 may be any substituent as described herein or may be absent.
  • R 5 may be selected from halo (e.g. F, Cl, Br, I), CF 3 , -CH 2 F, -CHF 2 , OCF 3 , -OCH 2 F, -OCHF 2 , C 1 to C 6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO 2 Me, -NH 2 , -NHMe, -NMe 2 , CO 2 Me, -NO 2 , CHO, and COMe.
  • n may be 0 to 5, such as 0 to 4, 0 to 3, or 0 to 2). Where more than one substituent is present, each substituent may be independently selected from the R 5 groups noted above.
  • R 6 may be C 1 to C 6 alkyl, such as methyl.
  • G may be selected from CH 2 , O and NH.
  • Q may be C 1 to C 6 alkylene such as dimethylmethylene (-C(CH 3 ) 2 -) or dimethylethylene (- C(CH 3 ) 2 CH 2 -).
  • R 3 is selected from the group consisting of:
  • R 5 may be selected from C 1 to C 6 alkyl (e.g. methyl) and halo (e.g. F).
  • halo e.g. F
  • R 5 may be appended to the aryl or heteroaryl ring at any position (provided that it has the correct valency and/or is chemically suitable).
  • the line intersected by a wavy line represents the covalent bond between the exemplary R 3 groups shown above and the carbon atom of the parent structure of Z (as illustrated by the various formulae described herein).
  • R 3 is an aryl or heteroaryl group, this covalent bond (as illustrated in the various formulae described herein) may be formed at any position on the aromatic ring (provided that it has the correct valency and/or is chemically suitable).
  • a hydrogen at any position on the R 3 groups shown above may be replaced with a bond to the structure shown in formula (I).
  • a suitable R 3 group may be selected from the following:
  • a suitable R 3 group may be selected from the following:
  • a suitable R 3 group may be selected from the following:
  • the line intersected by a wavy line represents the covalent bond between the exemplary R 3 groups shown above and the carbon atom of the parent structure of Z (as illustrated by the various formulae described herein).
  • R 4 may be selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl.
  • R 4 may be selected from aryl having 6 to 10 carbon ring atoms; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the aryl and the heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • R 4 may be an optionally substituted phenyl.
  • a suitable R 4 group may be selected from the following:
  • R 7 may be any substituent as described herein or may be absent.
  • R 7 may be selected from C 1 to C 6 alkyl, halo, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy.
  • R 6 may be C 1 to C 6 alkyl or C 1 to C 3 alkyl (e.g. methyl).
  • R 7 may be covalently bonded to the aryl or heteroaryl ring at any position (provided that it has the correct valency and/or is chemically suitable).
  • R 3 may be selected from any of those R 3 groups disclosed herein. In some cases, in the exemplary structures shown above, R 3 may be selected from the group consisting of:
  • Z is not (or does not comprise) a structure selected from one or more of the following: In some examples, Z is not (or does not comprise) the following structure: wherein R 2 ’ is selected from H and C 1 to C 6 alkyl;
  • R 3 ’ is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; m is 3, 4 or 5; and
  • Z may be represented as shown in formula (ZV) or (V): wherein ring A 2 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , n and L are as defined in any one of the embodiments disclosed above.
  • the dotted line shown through the square brackets on formulae (ZV) and (V) indicates that the linker may be joined via a covalent bond to any atom on the Z moiety provided that it has the correct valency, is chemically suitable and/or provided that the attachment of the linker at this alternative position does not disrupt the function of the Z moiety in promoting and/or facilitating proteasomal degradation.
  • the TBL is linked or coupled to moiety Z via a linker L.
  • the linker may be a chemical linker (e.g. a chemical linker moiety) and, for example, may be a covalent linker, by which is meant that the linker is coupled to Z and/or TBL by a covalent bond.
  • the linker acts to tether the target protein binding ligand and Z moieties to one another whilst also allowing both of these portions to bind to their respect targets and/or perform their intended function.
  • the linker may act to tether the target protein binding ligand to Z whilst also mitigating the possibility of the Z moiety disrupting, interfering with and/or inhibiting the binding of the target protein binding ligand to the target protein.
  • the linker may act to tether Z to the target protein binding ligand whilst also mitigating the possibility of the target protein binding ligand disrupting, interfering with and/or inhibiting the cellular interactions of Z (e.g. its function in modulating, facilitating and/or promoting the proteasomal degradation of the target protein).
  • the linker may function to facilitate targeted protein degradation by allowing each end of the bifunctional molecule to be available for binding (or another type of interaction) with various components of the cellular environment.
  • the linker may be configured to allow the target protein binding ligand to bind to the target protein without interference, disruption and/or inhibition from the Z moiety of the bifunctional molecule.
  • the linker may be configured to allow the Z moiety to interact with the various components in the cellular environment to modulate, facilitate and/or promote the proteasomal degradation of the target protein without interference, disruption and/or inhibition from the target protein binding ligand of the bifunctional molecule.
  • linker may depend upon the protein being targeted for degradation (the target protein) and/or the particular target protein binding ligand.
  • the linker may be selected to provide a particular length and/or flexibility, e.g. such that the target protein binding ligand and the Z moiety are held within a particular distance and/or geometry.
  • the length and/or flexibility of the linker may be varied dependent upon the structure and/or nature of the target protein binding ligand.
  • the TBL is connected directly to moiety Z by a covalent bond i.e, the linker is a covalent bond.
  • the linker is a covalent bond.
  • Such a direct connection is also encompassed within the term “linker” within the context of the present disclosure (and unless otherwise stated).
  • the linker may comprise any number of atoms between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30 or between 1 and 10. In some cases the linker may comprise any number of atoms in a single linear chain of between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30 or between 1 and 10. In some examples of the disclosure, the linker may comprise any number of atoms in a single linear chain between 1 and 25, such as 3 and 25, or between 1 and 20, such as 3 and 20, or between
  • the degree of flexibility of the linker may depend upon the number of rotatable bonds present in the linker.
  • a rotatable bond is defined as a single non-ring bond, bound to a nonterminal heavy atom (e.g. non-hydrogen atom).
  • an amide (C-N) bond is not considered rotatable because of the high rotational energy barrier.
  • the linkers may comprise one or more moieties selected from rings, double bonds and amides to reduce the flexibility of the linker.
  • the linker may comprise a greater number and/or proportion of single bonds (e.g. may predominantly comprise single non-ring bonds) to increase the flexibility of the linker.
  • the length of the linker may affect the degree of flexibility. For example, a shorter linker comprising fewer bonds may also reduce the flexibility of a linker.
  • the number of rotatable bonds present in the linker may be any number between 1 and 20, between 1 and 15, 1 and 10 or between 1 and 8. In some examples, the number of rotatable bonds present in the linker may be any number between 2 and 9, between
  • the linker may comprise any number of atoms in a single linear chain between 10 and 20; and/or the number of rotatable bonds present in the linker may be any number between 2 and 8.
  • the structure of the linker (L) may be represented as follows:
  • each L x represents a subunit of L; and q is an integer greater than or equal to 1 .
  • q may be any integer between 1 and 30, between 1 and 20 or between 1 and 5.
  • the linker comprises only one L x subunit and may be represented as L 1 .
  • the linker comprises two L x subunits that are covalently linked to one another and which may be represented as L 1 - L 2 .
  • the linker comprises three L x subunits that are covalently linked to one another and may be represented as L 1 -L 2 -L 3 .
  • L may comprise the following subunits L 1 , L 2 , L 3 , L 4 ....up to L q .
  • R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 and R L9 may be independently selected from H, halo, C 1 to C 6 alkyl, C 1 to C 6 , haloalkyl, -OH, -O(C 1 to C 6 alkyl), -NH2, -NH(C 1 to C 6 alkyl), - NO 2 , -CN, -CONH2, -CONH(C 1 to C 6 alkyl), -CON(C 1 to C 6 alkyl) 2 , -S(O)OC 1 to C 6 alkyl, - C(O)OC 1 to C 6 alkyl, and -CO(C 1 to C 6 alkyl).
  • each of R L1 , R L2 , R L3 , R L4 , R L5 , R L6 R L7 , R L8 and R L9 may be independently selected from H and C
  • aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl groups are defined above.
  • the terminal L x subunits may link or couple the linker moiety to the TBL and Z moieties of the bifunctional molecule.
  • L 1 may link the linker to the TBL moiety
  • L q may link the linker to the Z moiety.
  • the one L x subunit e.g. L 1
  • the TBL and Z moieties may be covalently linked to L through any group which is appropriate and stable to the chemistry of the linker.
  • the linker may be covalently bonded to the TBL moiety via a carbon-carbon bond, keto, amino, amide, ester or ether linkage.
  • the linker may be covalently bonded to the Z moiety via a carbon-carbon bond, carbon-nitrogen bond, keto, amino, amide, ester or ether linkage.
  • each terminal L x subunit e.g.
  • At least one of L x comprises a ring structure and is, for example, selected from a heterocycloalkyl, heteroaryl, cycloalkyl or aryl group.
  • the linker may be or comprise an alkyl linker comprising, a repeating subunit of -CH 2 -; where the number of repeats is from 1 to 50, for example, 1-50, 1-40, 1-30, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11 , 1-10, 1-9. 1-8, 1-7, 1-6, 1-5, 1-4, 1- 3 and 1-2.
  • the linker may be or comprise a polyalkylene glycol.
  • the linker may be or comprise a polyethylene glycol (PEG) comprising repeating subunits of ethylene glycol (C2H4O), for example, having from about 1-50 ethylene glycol subunits, for example where the number of repeats is from 1 to 100, for example, 1-50, 1-40, 1-30, 1-20, 1-19 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12 or 1-5 repeats.
  • PEG polyethylene glycol
  • C2H4O ethylene glycol
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1a):
  • C 1A is absent or is selected from C 1 -C 6 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. - O(CH 2 )-, -O(CH 2 ) 2 -, -O(CH 2 ) 5 -, -CH 2 OCH 2 -) and
  • L 3A is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. -(CH 2 )O-, -(CH 2 )2O-, - (CH 2 )5O-, -CH 2 OCH 2 -) and C 1 -C 6 alkylamino (e.g. -(CH 2 )NR L2A -, -(CH 2 )2NR L2A -, -(CH 2 )5NR L2A -, -CH 2 NR L2A CH 2 -); wherein R L2A is H or C 1 -C 6 alkyl (e.g. C 1 .C 3 alkyl).
  • C 1 -C 6 alkoxy e.g. -(CH 2 )O-, -(CH 2 )2O-, - (CH 2 )5O-, -CH 2 OCH 2 -
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1b): wherein L 1 B is absent or is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. - O(CH 2 )-, -O(CH 2 ) 2 -, -O(CH 2 ) 5 -, -CH 2 OCH 2 -) and C 1 -C 6 alkylamino (e.g. -NR L2A (CH 2 )-, - NR L2A (CH 2 ) 2 -, -R L2A (CH 2 ) 5 -, -CH 2 R L2A CH 2 -);
  • L 1 B is absent or is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. - O(CH 2 )-, -O(CH 2 ) 2 -,
  • L 3B is selected from C 1 -C 1 5 alkylene, -[(CH 2 ) 2 O] 1-6 (CH 2 ) 2 -;
  • L 5B is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. -(CH 2 )O-, -(CH 2 ) 2 O-, - (CH 2 ) 5 O-, -CH 2 OCH 2 -) and C 1 -C 6 alkylamino (e.g. -(CH 2 )NR L2A -, -NR L2A (CH 2 ) 2 -, -(CH 2 ) 5 NR L2A -, -CH 2 NR L2A CH 2 -); wherein R L2A is H or C 1 -C 6 alkyl (e.g. C 1 .C 3 alkyl).
  • C 1 -C 6 alkoxy e.g. -(CH 2 )O-, -(CH 2 ) 2 O-, - (CH 2 ) 5 O-, -CH 2 OCH 2 -
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1c):
  • L1c wherein L 1C is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S;
  • L 2C is absent or is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. -(CH 2 )O-, - (CH 2 ) 2 O-, -(CH 2 ) 5 O-, -CH 2 OCH 2 -) and C 1 -C 6 alkylamino (e.g. -(CH 2 )NR L2A -, -(CH 2 ) 2 NR L2A -, - (CH 2 ) 5 NR L2A -, -CH 2 NR L2A CH 2 -);
  • C 1 -C 3 alkylene e.g. ethylene
  • C 1 -C 6 alkoxy e.g. -(CH 2 )O-, - (CH 2 ) 2 O-, -(CH 2 ) 5 O-, -CH 2 OCH 2 -
  • C 1 -C 6 alkylamino e.g. -
  • L 4C is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. -(CH 2 )O-, -(CH 2 ) 2 O-, - (CH 2 ) 5 O-, -CH 2 OCH 2 -) and C 1 -C 6 alkylamino (e.g. -(CH 2 )NR L2A -, -(CH 2 ) 2 NR L2A -, -(CH 2 ) 5 NR L2A -, -CH 2 NR L2A CH 2 -); wherein:
  • R L2A is H or C 1 -C 6 alkyl (e.g. C 1 .C 3 alkyl);
  • R L2B is NR L2A ; or an N-linked optionally substituted 4- to 7-membered monocyclic N- heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C and L 2C may be both absent.
  • R L2B in L 3C is an N-linked optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, optionally containing one or two additional ring heteroatoms selected from N, O and S, and L 3C is the terminal subunit of the linker attached, suitably covalently attached, to the TBL via R L2B .
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1d): wherein L 1 D is absent or is selected from C 1 -C 3 alkylene, CO, C 1 -C 3 alkylene(N(C 1 -Cs alkyl);
  • L 2D is NR L2A or an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S; wherein R L2A is H or C 1 -C 6 alkyl (e.g. C 1 .C 3 alkyl); and
  • L 3D is absent or is selected from C 1 -C 3 alkylene, -O-, -N(C 1 -C 3 alkyl)-, and CO.
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (Lie): wherein L 1 E is C 1 -C 3 alkylene (e.g. methylene) or CO;
  • L 2E is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S; and
  • L 3E is selected from C 1 -C 3 alkylene (e.g. methylene).
  • L 1A , L 1 B , L 1C , L 1 D , or L 1 E is the terminal subunit of the linker structure attached (i.e. covalently bonded) to the W moiety and L 3A , L 5B , L 4C , L 3D , L 3E , is the terminal subunit of the linker structure attached (i.e. covalently bonded) to the TBL portion.
  • L 2A , L 2B or L 2D is directly attached (i.e. covalently bonded) to the W moiety.
  • L 3D is absent, L 2D is directly attached (i.e. covalently bonded) to the TBL portion.
  • linker portions such as L 1C , L 2D , L 2E examples of R L2B and, may be bicyclic or tricyclic, and unless otherwise stated, these moieties may comprise rings that are joined by a bond, rings that are fused, a bridged ring and/or rings that are joined at a spiro centre.
  • L 1C , L 2D , L 2E examples of R L2B may be bicyclic, it may be a bridged bicyclic ring (i.e. it may comprise two rings that share three or more atoms) or it may be a spirocyclic bicyclic ring (i.e. it may comprise two rings that share one atom, e.g. the two rings may be joined at a spiro centre).
  • L 1C , L 2D , L 2E examples of R L2B may be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a 7- or 8-membered bridged bicyclic N- heterocycloalkyl optionally containing one additional ring atom selected from N.
  • L 1C , L 2D , L 2E , and examples of R L2B is a spirocyclic bicyclic ring, it may be an optionally substituted 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be bicyclic and comprises a first 5- to 7-membered ring and a second 3- to 7-membered ring.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, and optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6- membered ring and a second 3- to 6-membered ring, and optionally containing one additional ring heteroatoms selected from N.
  • L 1C , L 2D , L 2E , and examples of R L2B may be any one selected from:
  • L 1A and L 3A are as defined above;
  • X 5 is C(R b ) 2 , NR b or O;
  • R b is H or optionally substituted C 1 -salkyl; n1 is 0, 1 , 2 or 3; n’ is 1 or 2; m is 0, 1 or 2
  • L 1C , L 2D , L 2E , and examples of R L2B is any one selected from:
  • L 1 D is absent or is selected from C 1 -C 3 alkylene, -O-, -N(C 1 -C 3 alkyl)-, and CO.
  • L 3D is selected from C 1 -C 3 alkylene (e.g. methylene).
  • linker (L) may be, or comprise, a structure represented as shown in formula (L1f):
  • L 1 F (L1f) wherein L 1 F is selected from C 1 -C 3 alkylene, CO, and C 1 -C 3 alkylene(NR L1 c ); wherein R L1C is H or C 1 -C 3 alkyl. In some examples, L 1 F is selected from C 1 -C 3 alkylene (such as methylene).
  • the linker is or comprises one or more of:
  • q1 is any integer between 1 and 20, or between 1 and 10 (e.g. between 1 and 5).
  • the linker is or comprises one or more of: 1z9
  • q2 is any integer between 1 and 20, or between 1 and 10 (e.g. 3, 4, 5, 6 or 10).
  • the linker is or comprises
  • q1 is any integer between 1 and 20, or between 1 and 10 (e.g. between 1 and 5) and q2 is any integer between 1 and 20, or between 1 and 10 (e.g. 3, 4, 5, 6 or 10).
  • the linker is or comprises one or more of the following structures:
  • the linker is or comprises one or more of:
  • q3 is 1 to 8, such as 1 to 5, and q4 is 1 to 12, such as 1 to 10.
  • the linker is or comprises one or more of the following structures:
  • the structures shown above represent the entire linker.
  • the linker of the bifunctional molecule may comprise a plurality of the structures shown above.
  • the bond(s) that forms the link with the TBL and/or Z moieties is (are) attached to a ring structure.
  • this bond is shown as being attached at a particular position on the ring structure.
  • the disclosure also encompasses joining or coupling to the TBL and Z moieties at any chemically suitable position on these ring structures.
  • the present disclosure encompasses the use of any of the linkers disclosed herein in combination with any of the Z moieties and TBL moieties described herein.
  • a “target protein” is: (i) an estrogen receptor; or (ii) an androgen receptor that the skilled practitioner wishes to selectively degrade in a cell or a mammal, e.g., a human or animal subject.
  • a “target protein” is: (i) an estrogen receptor; or (ii) an androgen receptor that is selected by the skilled practitioner for increased proteolysis in a cell.
  • selected target protein may be (i) an estrogen receptor; or (ii) an androgen receptor which has been selected to be targeted for protein degradation and/or increased proteolysis.
  • androgen receptor means a protein with the UniProtKB designation of P10275 (ANDR_HUMAN).
  • estrogen receptor means a protein with the UniProtKB designation of P03372 (ESR1_HUMAN).
  • the bifunctional molecules disclosed herein are suitable for use and/or intended for use in the targeted degradation of a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • degradation of the target protein may occur when the target protein is subjected to and/or contacted with a bifunctional molecule as described herein, e.g. when the target protein is subjected to and/or contacted with any one of the bifunctional molecules in a cell.
  • the control of specific protein levels afforded by the bifunctional molecules described herein may provide treatment of a disease state or condition, which is modulated through or by the target protein by lowering the level of that protein in the cells of a subject.
  • TBL Target Protein Binding Ligand
  • the target protein binding ligand moiety is a target protein binding ligand selected from an: (i) estrogen receptor binding ligand; and (ii) androgen receptor binding ligand.
  • the target protein ligand comprised within the bifunctional molecules of the present disclosure is: (i) a ligand that selectively and/or specifically binds to an estrogen receptor; or (ii) is a ligand that selectively and/or specifically binds to an androgen receptor.
  • a bifunctional molecule according to this disclosure may comprise a target protein binding ligand, which binds to the target protein with sufficient binding affinity such that the target protein (i.e. the estrogen receptor or androgen receptor) is more susceptible to degradation or proteolysis than if unbound by the bifunctional molecule.
  • the target protein i.e. the estrogen receptor or androgen receptor
  • the target protein binding ligand may bind to the androgen receptor or estrogen receptor with a binding affinity of less than or equal to about 10 pM, less than or equal to about 1 pM, less than or equal to about 0.5 pM, or less than or equal to about 0.1 pM.
  • the ligand may bind to the androgen receptor or estrogen receptor with a binding affinity of about 0.01 nM to about 10 pM, such as about 0.01 nM to about 8 pM, about 0.01 nM to about 5 pM, about 0.01 nM to about 3 pM.
  • binding affinity is a measure of the propensity of an object comprising two components bound together to separate (dissociate) into the two components.
  • the binding affinity is the measure of the propensity of the complex formed when the target protein binding ligand binds to the target protein (i.e. the androgen receptor or estrogen receptor) to dissociate into separate components, i.e. the propensity of the target protein binding ligand to dissociate from the target protein.
  • the binding between the androgen receptor or the estrogen receptor and the target protein binding ligand may comprise one or more binding interactions, such as one or more of the group consisting of hydrogen bonding, dipole-dipole bonding, ion-dipole bonding, ion-induced dipole bonding, ionic bonding and covalent bonding.
  • the binding between the androgen receptor or the estrogen receptor and the target protein binding ligand may comprise a salt bridge (a combination of hydrogen and ionic bonding).
  • the observed DCso values would be less than about 1000 nM.
  • the observed DCso values would be less than about 1000 nM.
  • a target protein binding ligand may comprise or be derived from a small molecule (or analogue or fragment thereof) already known to act as a modulator, promoter and/or inhibitor of protein function (e.g. any small molecule known to bind to the estrogen receptor or androgen receptor).
  • the target protein binding ligand may comprise or be derived from a small molecule that is known to inhibit activity of the estrogen receptor or androgen receptor.
  • Non-limiting examples of compounds known to bind to: (I) Androgen Receptor (AR); or (II) Estrogen Receptor (ER) are described below.
  • R shows or indicates a site for linker attachment.
  • present disclosure also encompasses joining or coupling to the linker at any chemically suitable position on the various ligands.
  • the AR binder of the present disclosure is of formula Via: wherein:
  • V 2 is selected from: C 1 .6 alkyl; C 1 .8 cycloalkyl; heterocycloalkyl; aryl; or heteroaryl; each optionally substituted by 1 , 2 or 3 R V2 , wherein each R V2 is independently selected from: halo, C 1 .6 alkyl optionally substituted by one or more halo; OC 1-3 alkyl optionally substituted by one or more halo, OH, NR Y1 R Y2 , CN, C 2-4 alkenyl C 2-4 alkynyl;
  • A is selected from:
  • Y 1 and Y 2 are each independently selected from NR Y1 , O and S;
  • R V1 , R V2 are each independently selected from: H, C 1-6 alkyl optionally substituted by one or more halo; or R V1 and R V2 taken together with the atom to which they are attached, form a 3-7-membered cycloalkyl ring containing 0-2 heteroatoms selected from N, O and S;
  • Y 3 is selected from NR Y1 , O and S;
  • each R Q is independently selected from C 1-6 alkyl optionally substituted by one or more halo; or two R Q groups taken together with the atom to which they are attached, form a 3-7- membered cycloalkyl ring containing 0-2 heteroatoms selected from N, O and S;
  • R Y3 , R Y4 are each independently selected from: H, C 1-6 alkyl optionally substituted by one or more halo; n is 0, 1 , 2, 3, 4, 5 or 6; and m is 0, 1 , 2, 3, 4 or 5; and wherein the TBL is attached to the linker at any suitable position.
  • the TBL is attached to the linker via covalent coupling to V 2 .
  • V 1 is: wherein indicates the point of attachment to ring A;
  • R v1a is selected from: halo; C 1-4 alkyl optionally substituted with halo; -OC 1-4 alkyl optionally substituted with halo;
  • X v is N, or CR v1 b , wherein R v1 b is selected from: H; halo; C 1-4 alkyl optionally substituted with halo; -OC 1-4 alkyl optionally substituted with halo.
  • R v1a is selected from Cl and CF3.
  • V 2 comprises: wherein indicates the point of attachment to ring A, and L indicates the point of attachment of the linker; and
  • Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from: N, or CR V2b , wherein R V2b is selected from: H; halo; C 1-4 alkyl optionally substituted with halo; -OC 1-4 alkyl optionally substituted with halo.
  • Z 1 is N, or CH
  • Z 2 , Z 3 and Z 4 are each CH.
  • the AR binder has the Formula Vila:
  • V 2 , X v , Y 1 , Y 2 , R V1 , R V2 , R v1a and L are as defined for formula Via (and any sub-formula).
  • the AR binder has the Formula Vlla(i): wherein X v , Y 1 , Y 2 , R V1 , R V2 , R v1a , Z 1 , Z 2 , Z 3 , Z 4 and L are as defined for formula Via
  • the AR binder is of Formula Vlla(ii) or Vlla(iii):
  • X v , R v1a , Z 1 , Z 2 , Z 3 , Z 4 and L are as defined for formula Via (and any subformula).
  • the AR binder is of Formula Vlla(iv) or Vlla(v): wherein L is as defined for formula Via.
  • the AR binder is of Formula VI I b: wherein V 2 , X v , Y 3 , Y 4 , R v1a and L are as defined for formula Via; and wherein:
  • R Qa , R Qb , R Qc , R Qd are each independently selected from C 1-6 alkyl optionally substituted by one or more halo; or
  • R Qa and R Qb , or R Qc and R Qd taken together with the atom to which they are attached, form a 3-7-membered cycloalkyl ring containing 0-2 heteroatoms selected from N, O and S.
  • the AR binder is of the Formula Vllb(i): (Vllb(i)) wherein X v , Y 3 , R Qa , R Qb , R Qc , R Qd , R v1a , Z 1 , Z 2 , Z 3 , Z 4 and L are as defined for formula Vllb. iRel I
  • the AR binder TBL is of Formula Vllb(ii):
  • the AR binder is of Formula Vllb(iii): wherein X v , Y 3 , R Qa , R Qb , R Qc , R Qd , R v1a , Z 1 , Z 2 , Z 3 , Z 4 and L are as defined for formula Vllb.
  • the AR binder is of Formula Vllb(iv) or Vllb(v): wherein L is as defined for formula VI I b.
  • the AR binder is of Formula Vile: wherein X v , V 2 , Y 3 , Y 4 , R Q , R v1a and L are as defined for formula VI I b; and p v is 0, 1 or 2.
  • the AR binder is of Formula Vllc(i): wherein X v , V 2 , Y 3 , Y 4 , R Q , R v1a , p and L are as defined for formula Vile.
  • the AR binder is of Formula Vllc(ii): wherein X v , Y 3 , Y 4 , R Q , R v1a , Z 1 , Z 2 , Z 3 , Z 4 , p v and L are as defined for formula Vile. In some embodiments, the AR binder is of Formula Vllc(iii):
  • the AR binder is of Formula Vllc(iv): (Vllc(iv)) wherein L is as defined for formula Vile.
  • the TBL or ER binder of the present disclosure has the structure of:
  • Y s is CH 2 or NR 4 ;
  • Z s is selected from C 6-10 aryl; a 5- or 6- membered heteroaryl; C 3-8 cycloalkyl; C 5-8 cycloalkenyl; a 5- or 6- membered heterocycloalkyl containing up to two heteroatoms selected from the group consisting of -O-, -(NR S5 )2-, -S(O)- and S(O) 2 ; a bicyclic ring system consisting of a five or six membered alkyl or heterocycloalkyl ring fused to an aryl ring, the heterocyclic ring containing up to two heteroatoms selected from the group consisting of -O-, -(NR S5 ) 2 -, -S(O)- and S(O) 2 ; wherein Z is optionally substituted with (R s2 ) n s ; each R S1 is independently selected from OH, -O-C 1-4 alkyl, -O-C 1-4 haloal
  • each R S3 is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl;
  • R S4 is H, C 1-4 alkyl, C 1-4 haloalkyl; each R S5 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cyclohaloalkyl;
  • R S6 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, aryl, heteroaryl; m s is 0, 1 , 2 or 3; n s is 0, 1 , 2 or 3; p s is 0, 1 , 2 or 3 wherein the TBL is attached to the linker at any suitable position.
  • the linker may be attached to the top aryl group.
  • the linker (L) may substitute an H on the top aryl group, i.e. the TBL has the structure: wherein indicates the point of attachment of the linker.
  • the TBL is of formula Sil : wherein:
  • X, R S1 , R S2 , R S3 , R S4 , R S5 , R S6 , m s , n s and p s are as defined in Formula (SI); wherein indicates the point of attachment of the linker.
  • each X s is CH.
  • the TBL is of formula SIII:
  • R S1 , R S2 , R S3 , m s , n s and p s are as defined in Formula (SI) or Formula (SIl); wherein indicates the point of attachment of the linker.
  • the TBL is of Formula SI I la or Slllb:
  • the TBL is of Formula SI I la.
  • R S1 is OH.
  • n s is 0.
  • the TBL is of Formula SIV: wherein indicates the point of attachment of the linker.
  • the TBL is of Formula SV:
  • Cy is selected from C 6- 10 aryl; a 5- or 6-membered heteroaryl; C 3-7 cycloalkyl; a 5- or 6-membered heterocyloalkyl; wherein Cy is optionally substituted with 1-3 substituents independently selected from halogen, CN, OR Ta , N(R Ta ) 2 , C 1 .9 alkyl, C 3-7 cycloalkyl, 5- or 6- membered heterocyloalkyl, C 6- 10 aryl, a 5- or 6-membered heteroaryl, C(O)R Ta , C(O)NR Ta , SO 2 R Ta , and SO 2 NR Ta ;
  • R T1 is selected from H, C 1 .9 alkyl, C 1 -g haloalkyl; C 3-7 cycloalkyl, C ⁇ cyclohaloalkyl; a 5- or 6-membered heterocyloalkyl, C 6- 10 aryl, a 5- or 6-membered heteroaryl, -(C 1-6 alkyl)-(C 3-7 cycloalkyl), -(C 1-6 alkyl)-(a 5- or 6-membered heterocyloalkyl), C(O)R Tb , C(O)NR Ta , SO 2 R Ta , and SO 2 NR Ta , wherein when R T1 is not H, R T1 is optionally substituted with 1-3 substituents independently selected from halogen, CN, OR a , N(R a ) 2 , C 1 .9 alkyl, C 3-7 cycloalkyl, 5- or 6- membered heterocyloalkyl, C 6- 10
  • R Ta is selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and a 5- or 6-membered heterocyloalkyl, wherein R Ta is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH, OC 1 .6 alkyl, and SO 2 -C 1-6 alkyl;
  • R Tb is independently selected from H, -OR Ta , C 1-6 alkyl, -(C 1-6 alkyl)-(C 3-7 cycloalkyl), C 3 - 7 cycloalkyl, and 5- or 6-membered heterocyloalkyl, wherein R Tb is optionally substituted with 1-3 substituents independently selected from halogen, CN, C 1-6 haloalkyl, OH, OC 1 .6 alkyl, and SO 2 -C 1-6 alkyl,
  • R T2 and R T2 ’ are independently selected from H, halogen, -CN, C 1-6 alkyl, -OR Ta , -C 1-6 alkyl-OH, -C 1-6 alkyl-OR Ta , -C 1-6 alkyl-SO 2 -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl, 5- or 6- membered heterocyloalkyl, -N(R Ta ) 2 , -C 1-6 alkyl-NR Ta -C 1-6 alkyl, -C 1-6 alkyl-NH 2 , -C 1-6 alky- NHSO 2 -CI- 6 alkyl, -C 1-6 alkyl-CN, -CO 2 H, -COR Ta , -CO 2 R Ta , -CON(R Ta ) 2 , -C 1-6 alkyl-CONH 2 , - NR Ta CO-C 1 - 6 alkyl, -
  • R T3 is selected from halogen, -CN, C 1-6 alkyl, CH 2 OH, -C 1-6 alkyl-OR Ta , -C 1-6 alkyl-SO 2 - C 1-6 alkyl, C 1 .6 haloalkyl, C 3-7 cycloalkyl, C ⁇ cyclohaloalkyl, 5- or 6-membered heterocyloalkyl, -C 1-6 alkyl-NR Ta -C 1-6 alkyl, -C 1-6 alky-NHSO 2 -C 1-6 alkyl, -C 1-6 alkyl-CN, -CO 2 H, -CO-C 1 .6 alkyl, - CO 2 -C 1 - 6 alkyl, -CON(R Ta ) 2 , -C 1 - 6 alkyl-CONH 2 , -N(R Ta ) 2 , -NR Ta CO-C 1 - 6 alkyl, -NR Ta S(O) 2
  • R T4 is selected from H, C 1-3 alkyl, C 1-3 haloalkyl; and q T is 0, 1 , 2 or 3; wherein indicates the point of attachment of the linker.
  • the linker may be attached to the top aryl group.
  • the linker (L) may substitute an H on the top aryl group, i.e. the TBL has the structure: wherein indicates the point of attachment of the linker.
  • Cy is C 6- 10 aryl; a 5- or 6-membered heteroaryl.
  • R T4 is H.
  • the TBL is of Formula Til: wherein:
  • R T1 , R T2 , R T2 ’, R T3 and q T are as defined for Formula Tl; and Ring G is aryl or heteroaryl;
  • X T is CH or N
  • Y T is CR Tc or N, wherein R Tc is halogen or C 1-3 alkyl; wherein indicates the point of attachment of the linker.
  • each X T is N and each Y T is CH.
  • each X T is CH and each Y T is CR Tc .
  • ring G is selected from:
  • ring G is: wherein indicates the point of attachment of the linker; and wherein indicates the point of attachment to the remainder of the TBL structure.
  • R T2 is C 1-6 alkyl and R T2 ’ is H.
  • R T2 is Me and R T2 ’ is H.
  • R T6 and R T7 are each independently selected from H, Me or F, or R T6 and R T7 taken together with the carbon atom to which they are attached form a cyclopropyl ring or an oxetanyl ring;
  • R T8 is selected from H, Me, F, CH 2 F, CHF 2 , CF 3 , CN, CH 2 CN, CH 2 OMe, CH 2 OH, CO 2 H, CO 2 Me or SO 2 Me; and wherein '' indicates the point of attachment to the remainder of the TBL structure.
  • R T1 when R T1 is R T1 has a structure selected from: wherein indicates the point of attachment to the remainder of the TBL structure.
  • R T6 is Me.
  • R T7 is Me.
  • R T8 is F.
  • q T is 0.
  • the TBL is of Formula Till: wherein:
  • Ring G, X T , Y T , R T2 , R T2 ’, R T6 , R T7 and R T8 are as defined in Formula (Tl) and Formula (Til); and wherein indicates the point of attachment of the linker.
  • R T2 ’ is H
  • R T2 and ring G have a trans relative stereochemistry.
  • the TBL is of Formula TIV:
  • Ring G, X T , Y T , R T6 , R T7 and R T8 are as defined in Formula (TH) or (Till); and wherein indicates the point of attachment of the linker.
  • the TBL is of Formula TIVa or TIVb:
  • the bifunctional molecules of the present disclosure may exist in different stereoisomeric forms.
  • the present disclosure includes within its scope the use of all stereoisomeric forms, or the use of a mixture of stereoisomers of the bifunctional molecules,
  • the bifunctional molecule comprises one or more chiral centres
  • the present disclosure encompasses each individual enantiomer of the bifunctional molecule as well as mixtures of enantiomers including racemic mixtures of such enantiomers.
  • the bifunctional molecule comprises two or more chiral centres
  • the present disclosure encompasses each individual diastereomer of the bifunctional molecule, as well as mixtures of the various diastereomers.
  • the various structures shown herein encompass all isomeric (e.g. enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure).
  • the present disclosure embraces the R and S configurations for each asymmetric centre, and Z and E double bond isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are to be understood to be within the scope of the present disclosure.
  • all tautomeric forms of the bifunctional molecules described herein are to be understood to be within the scope of the present disclosure.
  • references to “a bifunctional molecule” may further embrace a pharmaceutically acceptable salt thereof.
  • the bifunctional molecule may comprise any combination of target binding protein (TBL), linker (L) and warhead (Z) (provided that it has the correct valency and/or is chemically suitable).
  • the bifunctional compound may comprise any combination of Z of formula (I), (II), (III), (IV), (V) (inc.
  • subgeneric formulae defined herein such as (la), (lb), (lc’), (Ic), (Id’), (Id), (le’), (le), (If), (Ila), (llaa), (lib), (lie), (lid), (lie), (Ilf), (Illa), (111 b) and IVa), L of any formula or subgeneric formula defined herein, such as any one of Formulae L1a to L1f, and TBL of any formula or subgeneric formula defined herein, for example any one of Formulae SI, SI I, SIH, Sllla, Slllb, SIV, SV, Tl, Til, Till or TIV, TIVa, TIVb, Via, Vila, Vlla(i) to (v), Vllb, Vllb(i) to (v), Vile or Vllc(i) to (iv).
  • the bifunctional compound comprises any combination of Z of formula (Zl), (Zll), (Zill), (ZIV), (ZV) (inc. corresponding subgeneric formulae defined herein, such as (Zla), (Zlb), (Zl b’), (Zl b”) (Zl la to e), (Zllla-h) and (ZlVa-j), L, such as any one of Formulae L1a to L1f, and TBL of any formula or subgeneric formula defined herein, for example any one of Formulae SI, Sil, SIH, Sllla, Slllb, SIV, SV, Tl, TH, Till or TIV, TIVa, TIVb, Via, Vila, Vlla(i) to (v), Vllb, Vllb(i) to (v), Vile or Vllc(i) to (iv).
  • i) Z is represented as formula (I), (II), (HI), (IV), (V), (Zl), (Zll), (ZHI), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above; and ii) TBL is represented by formula SI, SH, SHI, Sllla, Slllb, SIV, SV, Tl, TH, Till or TIV, TIVa, TIVb, Via, Vila, Vlla(i) to (v), Vllb, Vllb(i) to (v), Vile or Vllc(i) to (iv) as defined above.
  • Z is represented as formula (I), (II), (HI), (IV), (V), (Zl), (Zll), (ZHI), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above; wherein Z is not:
  • TBL is represented by formula SI, SH, SHI, Sllla, Slllb, SIV, SV, Tl, TH, Till or TIV,
  • TIVa, TIVb Via, Vila, Vlla(i) to (v), Vllb, Vllb(i) to (v), Vile or Vllc(i) to (iv) as defined above.
  • Z is represented as formula (I), (II), (III), (IV), (V), (Zl), (Zll), (Zill), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above;
  • TBL is represented by formula SI, SIl, SIII, SI I la, SI I lb, SIV or SV as defined above.
  • Z is represented as formula (I), (II), (III), (IV), (V), (Zl), (Zll), (Zill), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above; and ii) TBL is represented by formula SIV or SV as defined above.
  • Z is represented as formula (I), (II), (III), (IV), (V), (Zl), (Zll), (Zill), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above;
  • TBL is represented by formula Tl, TH, Till, TIV, TIVa or TIVb as defined above.
  • Z is represented as formula (I), (II), (HI), (IV), (V), (Zl), (Zll), (ZHI), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above; and ii) TBL is represented by formula TIVa or TIVb as defined above.
  • (iii) Z is represented as formula (I), (II), (III), (IV), (V), (Zl), (Zll), (Zill), (ZIV), (ZV) and
  • TBL is represented by formula Via, Vila, Vlla(i) to (v), VI lb, Vllb(i) to (v), Vile or
  • iii) Z is represented as formula (I), (II), (III), (IV), (V), (Zl), (Zll), (Zill), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above; and iv) TBL is represented by formula Vlla(iv), Vlla(v), Vllb(v) or Vllc(iv) as defined above.
  • L may be represented by formula L1a, L1 b, L1c, L1d, Lie or L1f.
  • i) (i) Z is represented as formula (I), (II), (III), (IV), (V), (Zl), (Zll), (Zill), (ZIV), (ZV) and (V) (inc. corresponding subgeneric formulae defined herein) as defined above;
  • TBL is represented by any one of formulae Formulae SI, SIl, SIII, Sllla, Slllb, SIV, SV, Tl, TII, TIll or TIV, TIVa, TIVb, Via, Vila, Vlla(i) to (v), Vllb, Vllb(i) to (v), Vile or Vllc(i) to (iv); and
  • L is represented by formula L1a, L1b, L1c, L1d, Lie or L1f as defined above.
  • the bifunctional molecule is any one of compounds 1 and 2 or any combination of TBL, L and Z represented in compounds 1 and 2 as shown in Table 1 below:
  • Table 1 showing structures of exemplary bifunctional molecules 1 and 2.
  • the disclosure also includes various deuterated forms of the compounds disclosed herein, or of any of the Formulae disclosed herein, including Formulae (Zl), (Zll), (Zill), (ZIV), (ZV), (I), (II) (III), (IV) and (V) (inc. corresponding subgeneric formulae defined herein), respectively, or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulas, as defined above) of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom.
  • deuterated forms of the compounds of any of the Formulae disclosed herein including Formulae (Zl), (Zll), (Zill), (ZIV), (ZV), (I), (II) (III), (IV) and (V) (inc. corresponding subgeneric formulae defined herein), respectively, or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulae, as defined above) of the present disclosure.
  • deuterated materials such as alkyl groups may be prepared by conventional techniques (see for example: methyl-d 3 -amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).
  • the disclosure also includes isotopically-labelled compounds which are identical to those recited in any of the Formulae disclosed herein, including Formulae (Zl), (Zll), (Zill), (ZIV), (ZV), (I), (II) (III), (IV) and (V) (inc. corresponding subgeneric formulae defined herein), respectively, or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulae, as defined above) of the present disclosure but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 2 H, 3 H, 11 C, 13 C, 14 C, 18 F, 123 l or 125 l.
  • Compounds of the present disclosure and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present disclosure.
  • I sotopically labelled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H or 14 C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).
  • Degradation may be determined by measuring the amount of a target protein (i.e. the estrogen receptor or the androgen receptor) in the presence of a bifunctional molecule as described herein and/or comparing this to the amount of the target protein observed in the absence of the bifunctional molecule. For example, the amount of target protein in a cell that has been contacted and/or treated with a bifunctional molecule as described herein may be determined. This amount may be compared to the amount of target protein in a cell that has not been contacted and/or treated with the bifunctional molecule (e.g. as a control). If the amount of target protein is decreased in the cell contacted and/or treated with the bifunctional molecule, the bifunctional molecule may be considered as facilitating and/or promoting the degradation and/or proteolysis of the target protein.
  • a target protein i.e. the estrogen receptor or the androgen receptor
  • the amount of the target protein can be determined using methods known in the art, for example, by performing immunoblotting assays, Western blot analysis and/or ELISA with cells that have been contacted and/or treated with a bifunctional molecule.
  • Selective degradation and/or increased proteolysis may be considered to have occurred if at least a 10% decrease in the amount of a target protein is observed compared to the control, for example, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% following administration of the bifunctional molecule to the cell.
  • selective degradation and/or increased proteolysis may be considered to have occurred if at least a 10% decrease in the amount of a target protein is observed, (e.g. at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% decrease) within 4 hours or more (e.g. 4 hours, 8 hours, 12 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 66 hours and 72 hours) following administration of the bifunctional molecule to the cell.
  • the bifunctional molecule may be administered at any concentration, e.g. a concentration between 0.01 nM to 10 M , such as 0.01nM, 0.1nM, 1 nM, 10nM, 100 nM, 1 ⁇ M, and 10 .M.
  • an increase of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or approximately 100% in the degradation of the target protein is observed following administration of the bifunctional molecule at a concentration of approximately 100 nM (e.g. following an incubation period of approximately 8 hours).
  • DCso is the concentration required to reach 50% of the maximal degradation of the target protein (i.e. the androgen receptor or the estrogen receptor).
  • the bifunctional molecules described herein may comprise a DCso of less than or equal to 10000 nM, less than or equal to 1000 nM, less than or equal to 500 nM, less than or equal to 100 nM or less than or equal to 75 nM. In some cases, the bifunctional molecules comprise a DCso less than or equal to 50 nM, less than or equal to 25 nM, or less than or equal to 10 nM.
  • D m ax represents the maximal percentage of target protein degradation.
  • the bifunctional molecules described herein may comprise a Dmax of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or about 100%.
  • the bifunctional molecules described herein may comprise an IC50 of less than 1000nM, less than 500nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 20 nM, or less than 10 nM. In some cases, the bifunctional molecules described herein may comprise an IC50 value of less than 5 nM.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the bifunctional molecules described herein.
  • the bifunctional molecule may be suitably formulated such that it can be introduced into the environment of the cell by a means that allows for a sufficient portion of the molecule to enter the cell to induce degradation of the target protein.
  • composition comprising a bifunctional molecule as described herein together with a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, phosphate buffer solutions and/or saline.
  • Pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • the pharmaceutical compositions described above may alternatively or additionally include, an appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • compositions may be present in any formulation typical for the administration of a pharmaceutical compound to a subject.
  • Representative examples of typical formulations include, but are not limited to, capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal and rectal administration.
  • compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), topical (including dermal, buccal and sublingual), rectal, nasal and pulmonary administration e.g., by inhalation.
  • the composition may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Methods typically include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free- flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent.
  • Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope.
  • the bifunctional molecules may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet.
  • Compositions suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.
  • Compositions for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release-controlling matrix, or is coated with a suitable release-controlling film.
  • compositions suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.
  • injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers, which are sealed after introduction of the formulation until required for use.
  • the bifunctional molecule may be in powder form, which is constituted with a suitable vehicle, such as sterile, pyrogen- free water, before use.
  • the pharmaceutical composition may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly.
  • Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins.
  • compositions suitable for topical formulation may be provided for example as gels, creams or ointments.
  • bifunctional molecules described herein may be present in the pharmaceutical compositions as a pharmaceutically and/or physiologically acceptable salt, solvate or derivative.
  • pharmaceutically acceptable salt refers to those salts, which are generally considered suitable for use in medicine (including in a veterinary context).
  • pharmaceutically acceptable salts may be those which can be contacted with the tissues of a mammalian subject (e.g. humans) without undue toxicity, irritation, allergic response or the like.
  • suitable pharmaceutically acceptable salts S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the entire contents of which are incorporated herein by reference.
  • Representative examples of pharmaceutically and/or physiologically acceptable salts of the bifunctional molecules of the disclosure may include, but are not limited to, acid addition salts formed with organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, malonic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, malonic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids
  • salts include (but are not limited to) adipate, alginate, ascorbate, aspartate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thi
  • salts that may be derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 -4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts may include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • compositions of the present invention are derivatives, which may be converted in the body into the parent compound. Such pharmaceutically and/or physiologically functional derivatives may also be referred to as "prodrugs" or “bioprecursors”. Pharmaceutically and/or physiologically functional derivatives of compounds of the present disclosure may include hydrolysable esters or amides, particularly esters, in vivo.
  • solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.
  • the moiety Z may form part of a bifunctional molecule intended for use in a method of targeted protein degradation, wherein the moiety Z acts to modulate, facilitate and/or promote proteasomal degradation of the target protein, wherein the target protein is selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • moiety Z or a compound comprising moiety Z as described herein (e.g. as defined in any one of Formulae (Zl), (Zll), (Zill), (ZIV), (ZV), (I), (II) (III), (IV) and (V)) in a method of targeted protein degradation of either the estrogen receptor or the androgen receptor (e.g. an in vitro or in vivo method of targeted protein degradation).
  • moiety Z may find particular application as a promoter or facilitator of targeted protein degradation of either the estrogen receptor or androgen receptor.
  • moiety Z or a compound comprising moiety Z e.g. as defined in any one of Formulae (Zl), (Zll), (Zill), (ZIV), (ZV), (I), (II) (III), (IV) and (V)) in the manufacture of a bifunctional molecule suitable for targeted protein degradation.
  • the bifunctional molecules of the present disclosure may modulate, facilitate and/or promote proteasomal degradation of a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • a method of selectively degrading and/or increasing proteolysis of a target protein in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a bifunctional molecule of the present disclosure.
  • the bifunctional molecules of the present disclosure may find application in medicine and/or therapy. Specifically, the bifunctional molecules of the present disclosure may find use in the treatment and/or prevention of any disease or condition, which is modulated through the estrogen receptor or androgen receptor.
  • the bifunctional molecules of the present disclosure may be useful in the treatment of any disease, which is modulated through the target protein by lowering the level of that protein in the cell, e.g. cell of a subject. Reduction of target protein levels in a cell following administration of a degrader of the present invention wherein activity of the selected protein is implicated in a disease state or a disorder, then it is to be understood that the degrader is useful in the treatment of that disease.
  • bifunctional molecules as described herein in the manufacture of a medicament for the treatment and/or prevention of any disease or condition, which is modulated through the estrogen receptor or androgen receptor.
  • a moiety Z e.g. as defined in any one of Formulae (Zl), (Zll), (Zill), (ZIV), (ZV), (I), (II) (III), (IV) and (V) in the manufacture of a medicament for the treatment and/or prevention of any disease or condition, which is modulated through the estrogen receptor or androgen receptor.
  • Diseases and/or conditions that may be treated and/or prevented by the molecules of the disclosure include any disease, which is associated with and/or is caused by an abnormal level of protein activity of the estrogen receptor or androgen receptor.
  • Such diseases and conditions include those whose pathology is related at least in part to an abnormal (e.g. elevated) level of the protein and/or the overexpression of the protein.
  • the bifunctional molecules may find use in the treatment and/or prevention of diseases where an elevated level of the target protein is observed in a subject suffering from the disease.
  • the diseases and/or conditions may be those whose pathology is related at least in part to inappropriate protein expression (e.g., expression at the wrong time and/or in the wrong cell), excessive protein expression or expression of a mutant protein.
  • a mutant protein disease is caused when a mutant protein interferes with the normal biological activity of a cell, tissue, or organ.
  • a method of treating and/or preventing a disease or condition, which is associated with and/or is caused by an abnormal level of protein activity of the estrogen receptor or androgen receptor which comprises administering a therapeutically effective amount of a bifunctional compound as described herein.
  • diseases and/or conditions that may be treated and/or prevented by the use of the described bifunctional compounds for the targeted degradation of the estrogen receptor include (but are not limited to) bone disorders, e.g., osteoporosis (including glucocorticoid-induced osteoporosis), osteopenia, Paget's disease and peridontal disease; cardiovascular diseases (including fibroproliferative conditions); hypercholesterolemia; hypertriglyceridemia; vasomotor disorders (e.g., hot flashes); urogenital disorders (e.g., urinary incontinence); prostatic hypertrophy; endometrial hyperplasia; cancer, including prostate cancer, uterine cancer, ovarian cancer, breast cancer, and endometrial cancer; multiple CNS disorders, such as neurodegenerative diseases (e.g., improvement of cognitive function and the treatment of dementia, including Alzheimer's disease and short-term memory loss).
  • bone disorders e.g., osteoporosis (including glucocorticoid-induced osteo
  • Representative examples of the diseases and/or conditions that may be treated and/or prevented by the use of the described bifunctional compounds for the targeted degradation of the androgen receptor include (but are not limited to) benign prostate hyperplasia, hirsutism, acne, hyperpilosity, seborrhea, endometriosis, polycystic ovary syndrome, androgenic alopecia, adenomas and neoplasies of the prostate, benign or malignant tumor cells containing the androgen receptor, hypogonadism, osteoporosis, suppression of spermatogenesis, libido, cachexia, anorexia, androgen supplementation for age related decreased testosterone levels in men, prostate cancer, breast cancer, endometrial cancer, uterine cancer, hot flashes, and Kennedy's disease.
  • the term “patient” or “subject” is used to describe an animal, such as a mammal (e.g. a human or a domesticated animal), to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided.
  • a mammal e.g. a human or a domesticated animal
  • the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc.
  • the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.
  • the disclosure also encompasses a method of screening bifunctional molecules to identify suitable target protein binding ligands and linkers for use in the bifunctional molecules described herein, e.g. a bifunctional molecule that is able to effectively modulate, facilitate and/or promote proteolysis of a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor.
  • This method may assist in identifying suitable linkers for a particular target protein binding partner such that the level of degradation is further optimised.
  • the method may comprise: a. providing a bifunctional molecule comprising:
  • a second ligand that binds to a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor (a target protein binding ligand);
  • This method may further comprise the steps of: d. detecting degradation of the target protein in the cell in the absence of the bifunctional molecule; and e. comparing the level of degradation of the target protein in the cell contacted with the bifunctional molecule to the level of degradation of the target protein in the absence of the bifunctional molecule; wherein an increased level of degradation of the target protein in the cell contacted with the bifunctional molecule indicates that the bifunctional molecule has facilitated and/or promoted the degradation of the target protein.
  • a step of detecting degradation of the target protein may comprise detecting changes in levels of a target protein in a cell. For example, a reduction in the level of the target protein indicates degradation of the target protein. An increased reduction in the level of the target protein in the cell contacted with the bifunctional molecule (compared to any reduction in the levels of target protein observed in the cell in the absence of the bifunctional molecule) indicates that the bifunctional molecule has facilitated and/or promoted the degradation of the target protein.
  • the method may further comprise providing a plurality of linkers, each one being used to covalently attach the first and second ligands together to form a plurality of bifunctional molecules.
  • the level of degradation provided by each one of the plurality of bifunctional molecules may be detected and compared. Those bifunctional molecules showing higher levels of target protein degradation indicate preferred and/or optimal linkers for use with the selected target protein binding partner.
  • the method may be carried out in vivo or in vitro.
  • the disclosure also provides a library of bifunctional molecules, the library comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of Z moieties covalently linked to a selected target protein binding partner.
  • the target protein binding partner may be pre-selected and the Z moiety may not be determined in advance.
  • the library may be used to determine the activity of a candidate Z moiety of a bifunctional molecule in modulating, promoting and/or facilitating selective protein degradation of a target protein.
  • the disclosure also includes a library of bifunctional molecules, the library comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of target protein binding ligands and a selected Z moiety.
  • the Z moiety of the bifunctional molecule may be pre-selected and the target protein may not be determined in advance.
  • the library may be used to determine the activity of a putative target protein binding ligand and its value as a binder of a target protein to facilitate target protein degradation.
  • the method of making the bifunctional molecule may comprise the steps of:
  • estrogen receptor binding ligand (i) estrogen receptor binding ligand; and (ii) androgen receptor binding ligand (e.g. a target protein binding ligand as defined herein); and
  • the method of making the bifunctional molecule may comprise the steps of:
  • a target protein binding ligand selected from an: (i) estrogen receptor binding ligand; and (ii) androgen receptor binding ligand (as defined herein);
  • aryl refers to a mono- or polycyclic aromatic hydrocarbon system having 6 to 14 carbon atoms, in some cases having 6 to 10 carbon atoms.
  • suitable "aryl” groups include, but are not limited to, phenyl, biphenyl, naphthyl, 1 -naphthyl, 2-naphthyl and anthracenyl.
  • substituted aryl refers to an aryl group as defined herein which comprises one or more substituents on the aromatic ring. When an aryl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • heteroaryl may be a single or fused ring system having one or more aromatic rings containing 1 or more, in some cases 1 to 3, in some cases 1 to 2, in some cases a single O, N and/or S heteroatom (s).
  • heteroaryl may refer to a mono- or polycyclic heteroaromatic system having 5 to 10 ring atoms.
  • heteroaryl groups may include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl etc.
  • substituted heteroaryl refers to a heteroaryl group as defined herein which comprises one or more substituents on the heteroaromatic ring.
  • alkyl refers to a straight or branched chain hydrocarbyl group.
  • the chain may be saturated or unsaturated, e.g. in some cases the chain may contain one or more double or triple bonds.
  • C 1 -C 6 alkyl refers to a straight or branched chain hydrocarbyl group containing from 1 to 6 carbon atoms.
  • a “C 1 -C 3 alkyl” refers to a straight or branched chain hydrocarbyl group containing from 1 to 3 carbon atoms. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, etc.
  • any hydrogen atom(s), CHs,CH 2 or CH group(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • a “cycloalkyl” is a ring containing 3 to 10 carbon atoms, in some cases 3 to 8, or in some cases 5 to 6 carbon atoms.
  • the ring may be saturated or unsaturated, e.g. in some cases the ring may contain one or more double or triple bonds.
  • a C 3 -C7 cycloalkyl is a cycloalkyl containing 3 to 7 carbon atoms in the ring.
  • a C 3 -C6 cycloalkyl is a cycloalkyl containing 3 to 6 carbon atoms in the ring.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynl etc.
  • substituted cycloalkyl refers to a cycloalkyl group as defined herein which comprises one or more substituents on the cycloalkyl ring. When a cycloalkyl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • alkenyl defines monovalent groups derived from alkenes by removal of a hydrogen atom from any carbon atom, wherein the term “alkene” is intended to define acyclic branched or unbranched hydrocarbons having the general formula CnH2n, wherein n is an integer >2.
  • alkenyl groups include ethenyl, n-propylenyl, iso-propylenyl, n-butylenyl, secbutylenyl, iso-butylenyl and tert-butylenyl.
  • any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • the alkenyl comprises a divalent hydrocarbon radical, this moiety may sometimes be referred to herein as an alkenylene.
  • alkynyl defines monovalent groups derived from alkynes by removal of a hydrogen atom from any carbon atom, wherein the term “alkyne” is intended to define acyclic branched or unbranched hydrocarbons having the general formula CnH2n-2, wherein n is an integer >2.
  • alkynyl groups include ethynyl, n-propylynyl, iso-propylynyl, n-butylynyl, secbutylynyl, iso-butylynyl and tert- butylynyl.
  • any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • the alkynyl comprises a divalent hydrocarbon radical, this moiety may sometimes be referred to herein as an alkynylene.
  • Benzyl as used herein refers to a -CH 2 Ph group.
  • a “substituted benzyl” refers to a benzyl group as defined herein which comprises one or more substituents on the aromatic ring.
  • any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • heterocycloalkyl refers to a monocyclic or polycyclic ring having in one or more rings of the ring system at least one heteroatom selected from O, N and S (e.g. from one to five ring heteroatoms independently selected from the group consisting of O, N and S).
  • the one or more rings may also contain one or more double bonds provided that the one or more rings are not fully aromaticized.
  • the one or more rings of the heterocycloalkyl may comprise 3 to 10 atoms, in some cases 3 to 8 atoms.
  • the one or more rings may be aliphatic.
  • the one or more rings may be saturated or unsaturated, e.g. in some cases the one or more rings may contain one or more double or triple bonds.
  • any N heteroatom present in the heterocycloalkyl group may be C 1 to C 6 alkyl-substituted.
  • the heterocycloalkyl is a monocyclic or bicyclic ring, such as a monocyclic ring.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, morpholinyl, dioxanyl, oxazolidinyl, tetrahydropyranyl, diazaspiroundecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, etc.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group as defined herein which comprises one or more substituents on the heterocyclo
  • -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)- and -CH(substituted heteroaryl) refers to a methylene moiety that comprises an aryl, substituted aryl, heteroaryl or substituted heteroaryl substituent and is the attachment point for the linker L.
  • heterocyclyl refers to a monovalent radical derived from a heterocycle.
  • a heterocycle is a cyclic compound (a compound comprising one or more rings of connected atoms) having as ring members atoms of at least two different elements (such as carbon and nitrogen).
  • a “carbocyclic ring” is a ring containing 3 to 10 carbon atoms, in some cases 3 to 8 carbon atoms, or in some cases 5 to 6 carbon atoms.
  • the ring may be aliphatic.
  • references to “carbocyclyl” and “substituted carbocyclyl” groups may refer to aliphatic carbocyclyl groups and aliphatic substituted carbocyclyl groups.
  • the ring may be saturated or unsaturated, e.g. in some cases the ring may contain one or more double or triple bonds.
  • carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynl etc.
  • substituted carbocyclyl refers to a carbocyclyl group as defined herein which comprises one or more substituents on the carbocyclic ring. When a carbocyclyl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • a “heterocyclic ring” may comprise at least 1 heteroatom selected from O, N and S.
  • the heterocyclic ring may be a monocyclic or polycyclic ring, each ring comprising 3 to 10 atoms, in some cases 3 to 8 atoms.
  • the one or more rings may be aliphatic.
  • references to “heterocyclyl” and “substituted heterocyclyl” groups may refer to aliphatic heterocyclyl groups and aliphatic substituted heterocyclyl groups.
  • the one or more rings may be saturated or unsaturated, e.g. in some cases the one or more rings may contain one or more double or triple bonds.
  • any N heteroatom present in the heterocyclic group may be C 1 to C 6 alkyl-substituted.
  • the heterocyclyl is a monocyclic or bicyclic ring, such as a monocyclic ring.
  • the heterocyclyl may be a bicyclic ring, which may, in some cases be a fused ring.
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, morpholinyl, dioxanyl, oxazolidinyl, tetrahydropyranyl, diazaspiroundecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, pyrrolizidinyl, etc.
  • substituted heterocyclyl refers to a heterocyclyl group as defined herein which comprises one or more substituents on the hetero
  • unsaturated As used herein, where a group comprising carbon atoms is defined as “saturated”, only single bonds bind the carbon atoms to one another. Where a group comprising carbon atoms is defined as “unsaturated”, at least two of the carbon atoms are connected by a double or triple bond. For the avoidance of doubt, unsaturated compounds may comprise any number of double and/or triple bonds.
  • Cycloalkene is used herein to refer to an unsaturated monocyclic hydrocarbon having one endocyclic double bond.
  • spiro is used to refer to moieties comprising two or more ring systems, wherein at least two of the ring systems are connected by just one atom (typically a quaternary carbon atom).
  • “Monocyclic” is used herein to refer to moieties comprising one ring of atoms.
  • Bicyclic is used herein to refer to moietes that feature two joined rings of atoms.
  • Te ricyclic is used herein to refer to moieties that feature three joined rings of atoms.
  • Polycyclic is used herein to refer to moieties that comprise two or more joined rings.
  • bicyclic and polycyclic systems may comprise a fused ring system (in which at least two rings share a common bond).
  • the two or more rings may be joined by a bond between atoms on each of the two or more rings.
  • the bicyclic system may comprise a spiro centre (as defined above).
  • bridged is used herein to refer to a cyclic compound, or ring, comprising two bridgehead atoms (typically two carbon atoms of the cyclic compound or ring) that are connected by one or more atoms lying outside of the ring (such as one to three atoms lying outside of the ring).
  • Bridged rings comprise two rings sharing three or more atoms.
  • the bridgehead atoms are separated within the ring by at least one carbon atom.
  • a ring may be bridged by between 1 and 3 bridging atoms which lie outside of the ring to form a bridging group (optionally wherein the bridging atoms are selected from C, N, O and S).
  • a “C 1-3 bridge” is a bridging group comprising between 1 and 3 carbon bridging atoms.
  • the bridging group may compirise one to three atoms lying outside of the ring, of which one, two or three of those atoms are carbon.
  • the bridging group may additionally comprise non-carbon atoms (such as a heteroatom selected from N, O and S).
  • a “C 1-3 bridge” may refer to a bridging group comprising between 1 and 3 atoms of which one, two or three are carbon and the remainder (if any) are selected from N, O and S.
  • the bridging group may be a C 1 to C 3 alkylene (such as methylene, ethylene or propylene).
  • the C 1 to C 3 alkylene bridging group may be optionally substituted with any suitable substituent as described herein.
  • C 1 to C 3 alkylene bridging group may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • fused is used to refer to moieties comprising two or more ring systems, wherein at least two of the ring systems are connected by a [1 ,2] ring junction, i.e. a moiety comprising two or more ring systems wherein two, or more, of the rings present share a bond in each respective ring structure.
  • aliphatic refers to acyclic or cyclic, saturated or unsaturated compounds, excluding aromatic compounds, where “aromatic” defines a cyclically conjugated molecular entity with a stability (due to delocalisation) significantly greater than that of a hypothetical localised structure.
  • the Huckel rule is often used in the art to assess aromatic character; monocyclic planar (or almost planar) systems of trigonally (or sometimes digonally) hybridised atoms that contain (4n+2) TT-electrons (where n is a non-negative integer) will exhibit aromatic character.
  • hydrocarbyl refers to a monovalent radical derived from a hydrocarbon by the removal of a hydrogen atom from the hydrocarbon.
  • a hydrocarbon is any molecule comprising only the elements carbon and hydrogen. Hydrocarbons may be aliphatic, aromatic, unsaturated or saturated.
  • an alkoxy refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-.
  • a C 1-4 alkoxy refers to a C 1-4 alkyl group (as defined above), appended to the parent molecular moiety through a oxy group, -O- .
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.
  • alkoxyalkyl may refer to a moiety derived from an alkyl moiety in which a hydrogen atom at any position of the alkyl is substituted with an alkoxy moiety.
  • alkoxyalkyl groups include methoxyethyl, methoxypropyl, ethoxymethyl and the like.
  • alkylcarbonyl refers to carbonyl having alkyl mentioned above.
  • alkylcarbonyl include C 1 - ealkylcarbonyl (-C(O)C 1-6 alkyl), such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tertbutylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, with methylcarbonyl being preferable.
  • alkylamino is used herein to refer to a moiety derived from an amino (NH2) moiety in which one or both hydrogen atom(s) of the amino is/are substituted with one or two alkyl moieties.
  • alkylamino groups include dimethylamino, diethylamino and the like.
  • alkylcarbonylaminoalkyl refers to aminoalkyl having alkylcarbonyl mentioned above.
  • alkylcarbonylaminoalkyl include C 1-6 alkylcarbonylaminoalkyl, such as methylcarbonylaminomethyl and ethylcarbonylaminomethyl.
  • alkylaminocarbonyl refers to carbonyl having at least one alkylamino group.
  • alkylaminocarbonyl include C 1-6 alkylamino-C 1-6 alkyl, such as methylaminocarbonyl, and ethylaminocarbonyl.
  • alkylaminoalkyl refers to alkyl mentioned above having at least one alkylamino group mentioned above.
  • alkylaminoalkyl include C 1-6 alkylamino-C 1 .
  • ealkyl such as methylaminomethyl, methylaminoethyl, ethylaminomethyl, and ethylaminopropyl.
  • alkoxyalkylene is used herein to refer to a moiety derived from an alkylene moiety in which a hydrogen atom at any position of the alkylene is substituted with an alkoxy moiety.
  • alkoxyalkylene groups include methoxyethylene, methoxymethylene and the like.
  • haloalkylene is used herein to refer to a moiety derived from an alkylene moiety in which one or more hydrogen atom(s) at any position(s) of the alkylene is/are substituted with one or more halo moieties.
  • haloalkylene groups include fluoroethylene, difluoromethoxymethylene, dichloroethylene and the like.
  • hydroxyalkylene is used herein to refer to a moiety derived from an alkylene moiety in which a hydrogen atom at any position of the alkylene is substituted a hydroxy moiety.
  • hydroxyalkylene groups include hydroxyethylene, hydroxymethylene and the like.
  • cycloalkoxy is used herein to refer to a moiety derived from a linear alkoxy moiety in which a bond forms between the oxygen atom of the OH moiety and the carbon atom at the end of the alkyl chain (by abstraction of the hydrogen atom of the OH moiety and a hydrogen atom at the end of the alkyl chain).
  • Examples of cycloalkoxy groups include oxacyclohexanyl, oxacyclopentanyl and the like.
  • carbocyclylamino is used herein to refer to a moiety derived from an linear monohydrocarbylamino moiety in which a bond forms between the nitrogen atom of the NH moiety and the carbon atom at the end of the hydrocarbyl chain (by abstraction of the hydrogen atom of the NH moiety and a hydrogen atom at the end of the hydrocarbyl chain).
  • Examples of carbocyclylamino groups include piperidinyl, pyrrolidinyl, pyridinyl, pyrrolyl and the like.
  • substituted means that the moiety comprises one or more substituents.
  • optionally substituted means that the moiety may comprise one or more substituents.
  • a “substituent” may include, but is not limited to, hydroxy, thiol, carboxyl, cyano (CN), nitro (NO2), halo, haloalkyl (e.g. a C 1 to C 6 haloalkyl or a C 1 to C4 haloalkyl), an alkyl group (e.g. C 1 to C 1 0 or C 1 to C 6 ), an alkenyl group (e.g.
  • alkynyl group e.g. C2 to C 6
  • aryl e.g. phenyl and substituted phenyl for example benzyl or benzoyl
  • morpholino N- C 1-6 alkylenylmorpholine
  • alkoxy group e.g. C 1 to C 6 alkoxy or C 1 to C4 alkoxy
  • haloalkoxy e.g. C 1 to C4 haloalkoxy
  • aryloxy e.g. phenoxy and substituted phenoxy
  • hydroxyalkynyl e.g. C2 to C 6
  • thioether e.g.
  • C 1 to C 6 alkyl or aryl thioether examples include alkylthio (e.g. C 1 to C 6 alkylthio), cyanoalkyl (e.g. C 1 to C 6 ), oxo, keto (e.g. C 1 to C 6 keto), ester (e.g. C 1 to C 6 alkyl or aryl ester, which may be present as an oxyester or carbonylester on the substituted moiety), thioester (e.g.
  • C 1 to C 6 alkyl or aryl thioester alkylene ester (such that attachment is on the alkylene group, rather than at the ester function which is optionally substituted with a C 1 to C 6 alkyl or aryl group), amine (including monoalkylamino, dialkylamino, a five- or six-membered cyclic alkylene amine optionally substituted with one or more halo, further including a C 1 to C 6 alkyl amine or a C 1 to C 6 dialkyl amine which alkyl groups may be substituted with one or two hydroxyl groups, and also including alkylphenylamino or alkylphenyl(alkyl)amino groups), amido (including -C(O)NH2, -C(O)NH(alkyl) such as -C(O)NH(C 1 -4alkyl), -C(O)N(alkyl)2 such as -C(O)N(C 1 .
  • -NHC(O)alkyl such as -NHC(O)C 1 - 4 alkyl, -NHC(O)(phenyl), - N(alkyl)C(O)(alkyl) such as -N(C 1 -4alkyl)C(O)(C 1 -4alkyl), -N(alkyl)C(O)(phenyl) such as -N(C 1 . 4alkyl)C(O)(phenyl), N-C 1-6 alkylenylamino, amido (e.g.
  • C 1 to C 6 alkyl groups including a carboxamide which is optionally substituted with one or two C 1 to C 6 alkyl groups
  • aminoalkyl e.g. C 1 to C4 aminoalkyl
  • alkanol e.g. C 1 to C 6 alkyl, C 1 to C4 alkyl or aryl alkanol
  • carboxylic acid e.g.
  • C 1 to C 6 alkyl or aryl carboxylic acid sulfoxide, sulfone, sulfinimide, sulfonamide, and urethane (such as -O-C(O)-NR2 or-N(R)- C(O)-O-R, wherein each R in this context is independently selected from C 1 to C 6 alkyl or aryl), a heteroaryl, arylalkyl (such as an arylC 1 -4alkyl) , heteroarylalkyl (such as a heteroarylC 1-4 alkyl), -OC 1 -4alkylphenyl, -C(O)alkyl such as -C(O)(C 1 -4alkyl), -C(O)alkylphenyl such as C(O)(C 1 .
  • a “substituent” may include, but is not limited to, halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy.
  • halo group may be F, Cl, Br, or I. In some examples, halo may be F.
  • haloalkyl may be an alkyl group in which one or more hydrogen atoms thereon have been replaced with a halogen atom
  • a C 1 -C 6 haloalkyl may be a C 1 to C 6 alkyl in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • a C 1 -C 6 haloalkyl may be a fluoroalkyl, such as trifluoromethyl (-CF3) or 1 ,1 -difluoroethyl (-CH 2 CHF2).
  • a cyclohaloalkyl refers to a cycloalkyl as defined above, in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • a “C 3 to C7 cyclohaloalkyl” refers to a C 3 to C7 cycloalkyl in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • C 1-4 haloalkoxy refers to a C 1-4 alkoxy as defined above, in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • aryl As used herein, the terms “aryl”, “substituted aryl”, “heteroaryl”, “substituted heteroaryl”, “cycloalkyl”, “C 1 to C 6 alkyl”, “heterocycloalkyl”, and “substituted heterocycloalkyl” may refer to either a monovalent radical species or a divalent radical species.
  • R 1 is typically a monovalent group that is attached to the heterocyclic core of Z and so the terms aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 to C 6 alkyl should be understood to represent a monovalent radical moiety.
  • R 2 for Z is typically a divalent group that is covalently attached to both the heterocyclic core of Z and also the linker.
  • the terms aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl should be understood to represent divalent radical moiety.
  • DIPEA N, N-Diisopropylethylamine, or Hunig's base
  • HATU 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • Flash column chromatography was performed using a Teledyne Isco Combiflash Rf or Rf200i. Prepacked columns RediSep Rf Normal Phase Disposable Columns were used.
  • NMR data was acquired in Bruker Avance Neo nano bay 400 MHz NMR Spectrometer. Chemical Shifts are reported in ppm relative to dimethyl Sulfoxide ( ⁇ 2.50), methanol ( ⁇ 3.31), chloroform ( ⁇ 7.26) or other solvent as indicated in NMR spectral data. A small amount (1-5 mg) of sample is dissolved in an appropriate deuterated solvent (0.6ml).
  • Preparative HPLC was performed on a Gilson Preparative HPLC System with a Waters X- Bridge C 1 8 column (100 mm x 19 mm; 5 pm particle size) and a gradient of 5 % to 95 % acetonitrile in water over 10 min, flow 25 mL/min, with 0.1 % formic acid in the aqueous phase.
  • Method-A Column: X-Select CSH C 1 8(3.0*50mm,2.5um), Mobile Phase A:0.05% FA in H2O Mobile Phase B :0.05%FA in ACN, Gradient %B: 0/2,0.3/2,2.0/98,2.8/98,3.0/2,3.7/2 Flow Rate:1.0ml/min
  • Method-B Column: Bakerbond Q2100 C 1 8 1.8um; 2.1x50mm Mobile Phase A :0.05% FA in Water Mobile Phase B : 0.05% FA in ACN Flow Rate:0.6 ml Gradient Program (Time/B%): 0/5,0.2/5,2.3/98,3.3/98,3.8/5,4.5/5
  • Method-C Column: X Select CSH C 1 8 2.5um; 3.0x50mm Mobile Phase A :2.5 mM Ammonium Bicarbonate Water + 5 %ACN Mobile Phase B : ACN Flow Rate: 1.2 ml Gradient Program (Time/B%): 0/0,1.5/100,2.4/100,2.6/0,3/0
  • Method-D Column: X-Bridge BEH C 1 8(3.0*50mm,2.5um), Mobile Phase A:0.05% FA in H2O:CAN (95:5), Mobile Phase B :0.05%FA in ACN, Gradient %B: 0/2,0.2/2,2.2/98,3/98,3.2/2,4/2 Flow Rate:1 ,2ml/min
  • Linker-Boc-amine 1A (1 equiv.) in DCM was added HCI (4M in dioxane) (10.0 equiv.) slowly at 0 °C.
  • HCI 4M in dioxane
  • the reaction was allowed to stir at RT for 2 h. After completion, the reaction mixture was concentrated under reduced pressure to get a crude solid, which was washed with MTBE and dried under vacuum, to afford Linker-amine.HCI 2A.
  • TBL-L-alklyl chloride 3A (1 equiv.) in DMF at 0 °C were sequentially added Amino-Boc-amine (3 equiv.) and Potassium Carbonate (3 equiv.) and heated to 80 °C for 12 h. After cooling to room temperature the mixture was diluted with EtOAc. The organic phase was washed with LiCI (5% aqueous solution), dried over MgSO4 and concentrated under reduced pressure. Purification by column chromatography yielded TBL-L-Boc amine 4A.
  • TBL-L-Acid 1.1 equiv.
  • DMF dimethyl sulfoxide
  • HATLI 2.3 equiv.
  • Resulting solution was stirred for 10 min before the addition of TBL-L-amine (1 equiv.) in DMF and stirred for overnight.
  • the reaction mixture was diluted by cold water and extracted with EtOAc, the organic layer was washed with water and brine, dried over Na2SC>4 and concentrated to afford TBL-L-Boc amine 5A.
  • bifunctional degraders comprising a piperidine- amino acid derivativebased moiety as Z are illustrated below. Overviews of various exemplary synthetic methods that may be used to provide these compounds are shown below.
  • 5-bromonicotinic acid is treated with the desired boronate or boronic acid X under Suzuki conditions ((PdCl2(dppf).DCM, K2CO3, in dioxane/water at 100 °C) in order to obtain the 5 substituted nicotinic acids, unless commercially available.
  • Hydrogenation under (H2, tC>2 in HCI or HOAc) affords the substituted nipecotic acids.
  • Acylation using 1 cyanoacetyl-3,5- dimethylpyrazole and DI PEA in dioxane or DMF affords the precursors for the Knoevenagel reaction, which can be carried on using aldehydes Y in ethanol at r.t. (or THF at 40 to 70 °C) using piperidine as catalyst.
  • reaction mixture was filtered through a celite bed and washed with EtOAc and water. The filtrate was concentrated completely and added ice cold water was added. The mixture was extracted with EtOAc. The aqueous layer was acidified with 1.5 N HCI at 0 °C and stirred for 30 min until precipitation was observed.
  • Example 10a 5-phenylpiperidine-3-carboxylic acid (see, for example, scheme 5)
  • N.B. 3-piperidine carboxylic acid is commercially available and, for example, can be obtained from Sigma-Aldrich.
  • Compounds 10a to 10k and 3-piperidine carboxylic acid are then reacted with DI PEA and 1- cyanoacetyl-3,5-dimethyl-1H-pyrazole (as illustrated in step iii, scheme 5).
  • Piperidine-acrylamide acids and amine-linker functionalised target protein binding ligand are dissolved in DMF and treated with HATU and DI PEA at room temperature to afford the bifunctional compounds.
  • Example compounds that are made in accordance with the method illustrated in scheme 6 are shown below.
  • Piperidine-pyrrolidine-based warheads Further examples of bifunctional degraders comprising a piperidine-pyrrolidine-based moiety as Z are illustrated below.
  • Cyanoacrylamide acids and amine-linker functionalised target protein binding ligand are dissolved in DMF and treated with HATLI and DI PEA at room temperature to afford the bifunctional compounds.
  • Example compounds that are made in accordance with the method illustrated in scheme 8 are shown below.
  • Acrylate esters are treated with /V-benzyl-1-methoxy-/V-((trimethylsilyl)methyl)methanamine and TFA in toluene to afford the trans-3,4-disubstituted /V-benzyl-pyrrolidines.
  • Cleavage of the benzyl group H2, Pd(OH)2/C in ethanol or methanol
  • Hydrolysis of the ester group (LiOH in THF/H2O) affords the free amino acids.
  • Example 11a Ethyl 1-benzyl-4-methylpyrrolidine-3-carboxylate (see step i, scheme 9)
  • ethyl (E)-but-2-enoate (1.154 g, 10.11 mmol) in toluene (20 ml)
  • N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (3.00 g, 12.64 mmol) at 0 °C.
  • the reaction mixture was stirred for 20 min and then a 1 M solution of TFA in DCM (0.097 ml, 1.264 mmol) was added slowly at 0 °C under inert atmosphere.
  • Example 12a Ethyl -4-methylpyrrolidine-3-carboxylate (see step ii, scheme 9)
  • Cyanoacrylamide acids and amine-linker functionalised target protein binding ligand are dissolved in DMF and treated with HATU and DI PEA at room temperature to afford the bifunctional compounds.
  • Example compounds that are made in accordance with the method illustrated in scheme 10 are shown below.
  • reaction was monitored by TLC; after completion of reaction, the reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SCU, filtered and the filtrate was concentrated under reduced pressure give crude compound.
  • the crude compound was purified by silica gel column chromatography, eluted with 20% ethyl acetate/ heptane to afford lnt-3 (2.0 g, 50%) as a brown solid.
  • reaction was monitored by TLC; after completion of reaction, the reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure give crude compound.
  • the crude compound was purified by silica gel column chromatography, eluted with 20% ethyl acetate/ heptane to afford lnt-5 (4.5 g, 75%) as a brown solid.
  • reaction was monitored by TLC; after completion of reaction, the reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure give crude compound.
  • the crude compound was purified by silica gel column chromatography, eluted with 15% ethyl acetate/ heptane to afford lnt-9 (0.15 g, 40%) as a brown solid.
  • SM-1 tert-butyl 4-fluorobenzoate
  • DMSO DMSO
  • K 2 CO 3 4.23 g, 30.58 mmol
  • SM-2 ethyl piperidine-4-carboxylate
  • the resulting reaction mixture was stirred at 90 °C for 16 h.
  • the reaction was monitored by TLC; after completion, the reaction mixture was cooled to RT, quenched with water (50 ml), extracted with ethyl acetate (3 x 50 ml) and washed with brine solution.
  • the bifunctional compounds were assayed to investigate their ability to degrade target proteins in accordance with the following general procedures.
  • MCF-7 cells were seeded at 5000 cells/well (45 pL) in sterile 384 well Phenoplates (Perkin Elmer 6057302) and incubated overnight at 37°C with 5% CO2. The next day, compounds were prepared at 1000x final concentration in DMSO and diluted 1 :100 in media (Phenol red- free DMEM PAN Biotech P04-03591 + 10% Charcoal stripped FBS Life Technologies 12676- 029). 5 pL compound was added to each well of the cell plate and incubated for 24 h at 37°C with 5% CO2.
  • Cells were fixed by adding 15 pL 16% paraformaldehyde (Thermo 28908) to every well and incubated at RT for 30 min. Well contents were aspirated using plate washer and 50 pL PBS containing 0.5% BSA and 0.5% Triton X-100 (antibody dilution buffer) was added to each well. Plate was incubated at RT for 30 min. Well contents were aspirated, and plate washed 3 times with 70 pL PBS. Immunofluorescence staining of ER was carried out using anti-ESR1 mAb (F10) (Santa Cruz sc-8002).
  • F10 Anti-ESR1 mAb
  • Antibody was diluted 1 :1000 in antibody dilution buffer and 25 pL added to every well, plate was then incubated overnight at 4°C. The next day, plate was washed 3 times with 70 pL PBS and secondary antibody solution was prepared by diluting Alexafluor 488 conjugate anti-mouse IgG (Life Technologies A2102) and 1 mg/mL Hoechst 33342 (Abeam ab228551) 1 :1000 in antibody dilution buffer. 25 pL was added to every well and plate incubated for 2 h in the dark at RT. Plate was washed 3 times with 70 pL PBS and the final PBS dispensed was left in the plate.
  • Quantitative fluorescence imaging was carried out on the Operetta (Perkin Elmer) using the Hoechst channel to define the nuclei and the Alexafluor 488 channel to measure ER signal.
  • ER intensity per nuclei was calculated on the Harmony software and data was imported into Dotmatics software for analysis.
  • DMSO and 1 pM Fulvestrant were used to define 0% ER degradation and 100% ER degradation respectively.
  • Table 2 data showing ER degradation efficiency of an exemplary compound:
  • VCaP cells were seeded at 50000 cells into 96 well microplates in a final volume of 150ml (Corning CellBind #3300) and incubated. Compounds were prepared at 1000x final concentration in DMSO and diluted 1 :100 in media (DM EM, 8% FBS, 1% Pen/Strep - Life Technologies). 20ml of diluted compound was transferred to the cell plate with DMSO (final concentration 0.10%) and Staurosporin (10mM) controls added manually and the plate incubated for 24 h at 37°C with 5% CO 2 .
  • DMSO final concentration 0.10%
  • Staurosporin (10mM) controls added manually and the plate incubated for 24 h at 37°C with 5% CO 2 .

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Abstract

La présente invention concerne une nouvelle classe de molécules bifonctionnelles qui sont utiles dans une dégradation ciblée ou sélective d'une protéine.
PCT/GB2023/051594 2022-06-16 2023-06-16 Molécules bifonctionnelles pour la dégradation ciblée de protéines WO2023242598A1 (fr)

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RU59063U1 (ru) 2006-05-30 2006-12-10 Государственное образовательное учреждение высшего профессионального образования "Ульяновский государственный технический университет" Режущий инструмент с многослойным покрытием
WO2018071606A1 (fr) * 2016-10-11 2018-04-19 Arvinas, Inc. Composés et procédés pour la dégradation ciblée du récepteur des androgènes
WO2018102725A1 (fr) * 2016-12-01 2018-06-07 Arvinas, Inc. Dérivés de tétrahydronaphtalène et de tétrahydroisoquinoléine en tant qu'agents de dégradation des récepteurs des œstrogènes
WO2019238816A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour cibler l'uchl5
WO2019238886A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour le ciblage de l'usp14
WO2019238817A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour cibler rpn11
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RU59063U1 (ru) 2006-05-30 2006-12-10 Государственное образовательное учреждение высшего профессионального образования "Ульяновский государственный технический университет" Режущий инструмент с многослойным покрытием
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WO2019238816A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour cibler l'uchl5
WO2019238886A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour le ciblage de l'usp14
WO2019238817A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour cibler rpn11
WO2022129925A1 (fr) 2020-12-18 2022-06-23 Amphista Therapeutics Limited Nouvelles molécules bifonctionnelles pour la dégradation ciblée de protéines

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