WO2023115150A1 - Bifunctional arylsulphonamide compounds - Google Patents

Bifunctional arylsulphonamide compounds Download PDF

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Publication number
WO2023115150A1
WO2023115150A1 PCT/AU2022/051576 AU2022051576W WO2023115150A1 WO 2023115150 A1 WO2023115150 A1 WO 2023115150A1 AU 2022051576 W AU2022051576 W AU 2022051576W WO 2023115150 A1 WO2023115150 A1 WO 2023115150A1
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Prior art keywords
optionally substituted
compound
alkyl
mmol
formula
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PCT/AU2022/051576
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English (en)
French (fr)
Inventor
Jean-Marc Daniel GARNIER
Christopher Gardner
Guillaume Laurent Lessene
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Anaxis Pharma Pty Ltd
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Anaxis Pharma Pty Ltd
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Priority claimed from AU2021904198A external-priority patent/AU2021904198A0/en
Priority to AU2022422212A priority Critical patent/AU2022422212A1/en
Priority to JP2024538382A priority patent/JP2025501766A/ja
Priority to CA3241619A priority patent/CA3241619A1/en
Priority to MX2024007887A priority patent/MX2024007887A/es
Priority to EP22908912.3A priority patent/EP4452978A4/en
Application filed by Anaxis Pharma Pty Ltd filed Critical Anaxis Pharma Pty Ltd
Priority to CN202280091779.5A priority patent/CN119032091A/zh
Priority to KR1020247024219A priority patent/KR20240148322A/ko
Priority to US18/722,099 priority patent/US20250115598A1/en
Publication of WO2023115150A1 publication Critical patent/WO2023115150A1/en
Anticipated expiration legal-status Critical
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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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Definitions

  • the present disclosure relates to compounds which treat necroptosis and/or inhibit and/or degrade mixed lineage kinase domain-like protein (MLKL), and methods for their use.
  • MLKL mixed lineage kinase domain-like protein
  • necrosis In many diseases, cell death is mediated through apoptotic and/or necrotic pathways. While much is known about the mechanisms of action that control apoptosis, control of necrosis is not as well understood. Understanding the mechanisms in respect of both necrosis and apoptosis in cells is essential to being able to treat conditions, such as neurodegenerative diseases, stroke- coronary heart disease, kidney disease, liver disease, AIDS and the conditions associated with AIDS.
  • Cell death has traditionally been categorized as either apoptotic or necrotic based on morphological characteristics (Wyllie et al., Int. Rev. Cytol. 68: 251 (1980)). These two modes of cell death were also initially thought to occur via regulated (caspase-dependent) and non-regulated processes, respectively. More recent studies, however, demonstrate that the underlying cell death mechanisms resulting in these two phenotypes are much more complicated and under some circumstances interrelated. Furthermore, conditions that lead to necrosis can occur by either regulated caspase-independent or non-regulated processes.
  • necroptosis One regulated caspase-independent cell death pathway with morphological features resembling necrosis, called necroptosis, has been described (Degterev et al., Nat. Chem. Biol. 1 :112, 2005).
  • This cell death modality can be initiated with various stimuli (e.g., TNF- [alpha] and Fas ligand) and in an array of cell types (e.g., monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells and neurons).
  • stimuli e.g., TNF- [alpha] and Fas ligand
  • monocytes e.g., monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells and neurons.
  • Necroptosis may represent a significant contributor to and in some cases predominant mode of cellular demise under pathological conditions involving excessive cell stress, rapid energy loss and massive oxidative species generation, where the highly energy-dependent apoptosis process is not operative.
  • WO2015/172203 we reported that particular compounds described in US2005/0085637 have been found to be suitable for inhibiting necroptosis. We also discussed particularly suitable compounds for inhibiting necroptosis in WO2016/127213.
  • E3L is an E3 ligase binding moiety
  • L is a linker covalently linking E3L to MLKLi
  • MLKLi is a radical of formula (I) wherein
  • J is selected from the following moieties J1 and J2:
  • a 1 and A 4 are independently selected from N and C;
  • a 2 and A 3 are independently selected from N, NR 1 , CH, O and S; wherein at least one of A 1 , A 2 , A 3 and A 4 is selected from N, NR 1 , O and S;
  • a 5 is CH or N;
  • a 6 is N or CR 2 ;
  • R 1 and R 3 are independently selected from H and an optionally substituted C 1-6 -alkyl
  • R 2 is selected from:
  • X is selected from optionally substituted C 1-6 alkyl, optionally substituted haloC 1-6 alkyl, optionally substituted C 2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C 1-6 alkylcycloalkyl and optionally substituted amino;
  • Y and Z are independently selected from H, R 4 , -OR 4 , -NR 4 R 4 ’ and halo; wherein at least one of Y and Z is H;
  • R 4 is selected from optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted C 1-6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1-6 alkylC C 3-10 cycloalkyl, optionally substituted C 3-10 cycloalkylaryl, optionally substituted C 3-10 cycloalkylheterocyclyl, optionally substituted C 3-10 cycloalkylC C 3-10 cycloalkyl, optionally substituted 3-6 membered non-aromatic heterocyclyl-aryl, optionally substituted 3-6 membered non-aromatic heterocyclyl C 3-10 cycloalkyl and optionally substituted 3-6 membered non-aromatic heterocyclyl-3-10 membered heterocyclyl;
  • R 4 is H or optionally substituted C 1-6 alkyl
  • R 5 is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 3-10 cycloalkyl and optionally substituted aryl.
  • R 2 is selected from:
  • MLKLi is a compound of formula (X) comprising a radical at: i) R 2 when J is J1 so that R 2 and L are covalently bound; or ii) R 5 when J is J2 so that R 5 and L are covalently bound.
  • the compound of formula (X) may be provided as a compound of formula (XX): wherein A 1 , A 2 , A 3 , A 4 , n, R 1 , R 2 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein.
  • the compound of formula (X) may be provided as a compound of formula (XXa): (XXa) wherein A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4 , R 5 , X, Y, Z, L and E3L are as defined herein.
  • the compound of the invention may be provided in the form of a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof.
  • compounds of Formula (I) are selective degraders of MLKL.
  • Degradation of MLKL may be preferred to inhibition of MLKL in some instances as degradation results in a loss of function of the degraded protein, while the effects of inhibition last only as long as the inhibitor interacts with the protein.
  • the compound of the invention is selected from any of compounds 1001 to 1031 , 1037, and 1039 to 1145 described herein, preferably from any of compounds 1001 to 1031 , 1037, and 1039 to 1137.
  • the compound of the invention is selected from any of compounds 1001 to 1031 , preferably from any of compounds 1001 to 1023 and 1029 to 1031 , more preferably from any of compounds 1003, 1005, 1006, 1008 to 1012, 1014, 1015, 1017 and 1022.
  • the compound of the invention comprises a radical of any of compounds 1-173 described herein.
  • the compound of the invention comprises a radical of any of compounds 7, 9, 12, 13, 14, 15, 16, 18, 19, 20 and 72.
  • the compound of the invention comprises a radical of any of compounds 1 , 7, 9, 12-16, 18-21 , 23-32, 35-46, 48, 50-52, 55-62, 72-89, 92-109, 111 , 113, 115-117, and 119-123, preferably a radical of any of compounds 19, 29-31 , 36, 38, 40-41 . 75-77, 81 , 100-101 , 103-104, 109, 120 and 123.
  • the compound of the invention comprises a radical of any of compounds 1 , 5, 7-9, 11-16, 18-21 , 23-32, 35-46, 48, 50-52, 55-62, 66, 69, 70, 72-89, 92- 109, 111 , 113, 115-117, and 119-123, preferably a radical of any of compounds 5, 7-9, 11- 13, 15, 18-20, 60, 61 , 66, 69, 70 and 72.
  • the compound of the invention comprises a radical of any of compounds 3, 11 , 13, 19, 29, 30, 46, 79, 80, 81 , 97, 98, 99, 103, 104, 109, 113, 116, 120, 121 and 122.
  • a medicament comprising a compound of the invention, and the use of the compound of the invention in the preparation of a medicament.
  • That medicament may be for treating necroptosis; the medicament may also be for degrading MLKL.
  • composition comprising a compound of the invention and optionally a pharmaceutically acceptable excipient.
  • a method of treating necroptosis comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • a method of degrading MLKL comprising contacting a cell with a compound of the invention.
  • a compound of the invention for use in treating necroptosis, and for use in degrading MLKL.
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • C 1-6 alkyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl and the like.
  • C 1-6 alkyl also encompasses alkyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent.
  • C 1-4 alkyl and C 1-3 alkyl including methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl are preferred with methyl being particularly preferred.
  • C 2-6 alkenyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1 -propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. Unless the context requires otherwise, the term “ C 2-6 alkenyl” also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. “C 2-4 alkenyl” and “ C 2-3 alkenyl” including ethenyl, propenyl and butenyl are preferred with ethenyl being particularly preferred.
  • C 2-6 alkynyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl and the like. Unless the context indicates otherwise, the term “C 2-6 alkynyl” also encompasses alkynyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. C 2-4 alkynyl or C 2-3 alkynyl are preferred.
  • C 3-10 cycloalkyl refers to non-aromatic cyclic groups having from 3 to 10 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl. C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferred. Cycloalkyl groups also include polycyclic carbocycles and include fused, bridged and spirocyclic systems.
  • hydroxy and “hydroxyl” refer to the group -OH.
  • C 1-6 alkoxy refers to an alkyl group as defined above covalently bound via an O linkage containing 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy and pentoxy.
  • C 1-4 alkoxy and “C 1-3 alkoxy” including methoxy, ethoxy, propoxy and butoxy are preferred with methoxy being particularly preferred.
  • haloC 1-6 alkyl and “C 1-6 alkylhalo” refer to a C 1-6 alkyl which is substituted with one or more halogens.
  • HaloC 1-3 alkyl groups are preferred, such as for example, -CH 2 CF 3 , and - CF 3 .
  • haloC 1-6 alkoxy and “C 1-6 alkoxyhalo” refer to a C 1-6 alkoxy which is substituted with one or more halogens.
  • C 1-3 alkoxyhalo groups are preferred, such as for example, - OCF 3 .
  • carboxylate or “carboxyl” refers to the group -COO- or -COOH.
  • esters refers to a carboxyl group having the hydrogen replaced with, for example a C 1-6 alkyl group (“carboxylC 1-6 alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
  • CO 2 C 1-3 alkyl groups are preferred, such as for example, methylester (CO 2 Me), ethylester (CO 2 Et) and propylester (CO 2 Pr) and includes reverse esters thereof (e.g. -OC(O)Me, -OC(O)Et and -OC(O)Pr).
  • cyano and “nitrile” refer to the group -CN.
  • nitro refers to the group -NO 2 .
  • amino refers to the group -NH 2 .
  • substituted amino refers to an amino group having at least one hydrogen replaced with, for example a C 1-6 alkyl group (“C 1-6 alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) and so on.
  • Substituted amino groups include “monosubstituted amino” (or “secondary amino”) groups, which refer to an amino group having a single hydrogen replaced with, for example a C 1-6 alkyl group, an aryl or aralkyl group and so on.
  • Preferred secondary amino groups include C 1-3 alkylamino groups, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).
  • Substituted amino groups also include “disubstituted amino” (or “tertiary amino”) groups, which refer to amino groups having both hydrogens replaced with, for example C 1-6 alkyl groups, which may be the same or different (“dialkylamino”), aryl and alkyl groups (“aryl(alkyl)amino”) and so on.
  • Preferred tertiary amino groups include di(C 1-3 alkyl)amino groups, such as for example, dimethylamino (NMe 2 ), diethylamino (NEt 2 ), dipropylamino (NPr 2 ) and variations thereof (e.g. N(Me)(Et) and so on).
  • acyl and “acetyl” refers to the group -C(O)CH 3 .
  • ketone refers to a carbonyl group which may be represented by -C(O)-.
  • substituted ketone refers to a ketone group covalently linked to at least one further group, for example, a C 1-6 alkyl group (“C 1-6 alkylacyl” or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), an aralkyl group (“aralkylketone) and so on.
  • C 1-3 alkylacyl groups are preferred.
  • substituted amido or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a C 1-6 alkyl group (“C 1-6 alkylamido” or “C 1-6 alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on.
  • C 1-3 alkylamide groups are preferred, such as for example, methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt) and propylamide (-C(O)NHPr) and includes reverse amides thereof (e.g. -NHMeC(O)-, - NHEtC(O)- and -NHPrC(O)-).
  • disubstituted amido or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a C 1-6 alkyl group (“di(C 1-6 alkyl)amido” or “di(C 1- 6 alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on.
  • Di(C 1-3 alkyl)amide groups are preferred, such as for example, dimethylamide (-C(O)NMe 2 ), diethylamide (-C(O)NEt 2 ) and dipropylamide ((-C(O)NPr 2 ) and variations thereof (e.g. -C(O)N(Me)Et and so on) and includes reverse amides thereof.
  • thiol refers to the group -SH.
  • C 1-6 alkylth io refers to a thiol group having the hydrogen replaced with a C 1-6 alkyl group.
  • C 1-3 alkylthio groups are preferred, such as for example, thiolmethyl, thiolethyl and thiolpropyl.
  • substituted sulfinyl or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a C 1-6 alkyl group (“C 1-6 alkylsulfinyl” or “C 1-6 alkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on.
  • C 1-3 alkylsulfinyl groups are preferred, such as for example, -SOmethyl, -SOethyl and -SOpropyl.
  • sulfonyl refers to the group -SO 2 H.
  • substituted sulfonyl refers to a sulfonyl group having the hydrogen replaced with, for example a C 1-6 alkyl group (“sulfonylC 1-6 alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on.
  • SulfonylC 1-3 alkyl groups are preferred, such as for example, - SO 2 Me, -SO 2 Et and -SO 2 Pr.
  • sulfonylamido or “sulfonamide” refers to the group -SO 2 NH 2 .
  • substituted sulfonamido or “substituted sulphonamide” refers to an sulfonylamido group having a hydrogen replaced with, for example a C 1-6 alkyl group (“sulfonylamidoC 1- 6 alkyl”), an aryl (“arylsulfonamide”), aralkyl (“aralkylsulfonamide”) and so on.
  • SulfonylamidoC 1-3 alkyl groups are preferred, such as for example, -SO 2 NHMe, -SO 2 NHEt and -SO 2 NHPr and includes reverse sulfonamides thereof (e.g. -NHSO 2 Me, -NHSO 2 Et and - NHSO 2 Pr).
  • disubstituted sufonamido or “disubstituted sulphonamide” refers to an sulfonylamido group having the two hydrogens replaced with, for example a C 1-6 alkyl group, which may be the same or different (“sulfonylamidodi(C 1-6 alkyl)”), an aralkyl and alkyl group (“sulfonamido(aralkyl)alkyl”) and so on.
  • Sulfonylamidodi(C 1-3 alkyl) groups are preferred, such as for example, -SO 2 NMe 2 , -SO 2 NEt 2 and -SO 2 NPr 2 and variations thereof (e.g. -SO 2 N(Me)Et and so on) and includes reserve sulfonamides thereof (e.g. - N(Me)SO 2 Me and so on).
  • sulfate refers to the group OS(O) 2 OH and includes groups having the hydrogen replaced with, for example a C 1-6 alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on.
  • alkylsulfates groups having the hydrogen replaced with, for example a C 1-6 alkyl group
  • arylsulfate an aryl
  • aralkyl aralkyl
  • C 1-3 sulfates are preferred, such as for example, OS(O) 2 OMe, OS(O) 2 OEt and OS(O) 2 OPr.
  • sulfonate refers to the group SO 3 H and includes groups having the hydrogen replaced with, for example a C 1-6 alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on.
  • alkylsulfonate a C 1-6 alkyl group
  • arylsulfonate an aryl
  • aralkyl aralkylsulfonate
  • C 1-3 sulfo nates are preferred, such as for example, SO 3 Me, SO 3 Et and SO 3 Pr.
  • aryl refers to a carbocyclic (non-heterocyclic) aromatic ring or mono-, bi- or tri- cyclic ring system.
  • Poly-cyclic ring systems may be referred to as “aryl” provided at least 1 of the rings within the system is aromatic.
  • the aromatic ring or ring system is generally composed of 6 to 10 carbon atoms.
  • Examples of aryl groups include but are not limited to phenyl, biphenyl, naphthyl and tetrahydronaphthyl. 6-membered aryls such as phenyl are preferred.
  • alkylaryl refers to C 1-6 alkylaryl such as benzyl.
  • alkoxyaryl refers to C 1-6 alkyloxyaryl such as benzyloxy.
  • heterocyclyl refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 10 ring atoms (unless otherwise specified), of which 1 , 2, 3 or 4 are ring heteroatoms each heteroatom being independently selected from O, S and N.
  • Heterocyclyl groups include monocyclic and polycyclic (such as bicyclic) ring systems, such as fused, bridged and spirocyclic systems, provided at least one of the rings of the ring systm contains at least one heteroatom.
  • the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10- membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms.
  • the term “3-10 membered heterocylyl”, as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms.
  • heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.
  • Examples of monocyclic heterocyclyl groups include, but are not limited to, those containing one nitrogen atom such as aziridine (3-membered ring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5-membered rings) , piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), and azepine (7-membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5-membered rings), piperazine (6-membered ring); those containing one oxygen atom such as oxirane (3-membered ring
  • Heterocyclyls encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.
  • aromatic heterocyclyl may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”.
  • the heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O.
  • the aromatic heterocyclyl groups may comprise 1 , 2, 3, 4 or more ring heteroatoms. In the case of fused aromatic heterocyclyl groups, only one of the rings may contain a heteroatom and not all rings must be aromatic.
  • Heteroaryl is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (e.g. bicyclic) ring systems containing one or more aromatic rings.
  • aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls.
  • the term “pseudoaromatic” refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
  • aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non- aromatic ring.
  • heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclic aromatic ring systems.
  • 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1 ,2,3 and 1 ,2,4 oxadiazolyls and furazanyl i.e.
  • thiazolyl isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1 ,2,3, 1 ,2,4 and 1 ,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1 ,2,3 and 1 ,3,4 thiadiazolyls) and the like.
  • 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like.
  • 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens).
  • Aromatic heterocyclyl groups may also be bicyclic or polycyclic heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1 H thieno[2,3- c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like).
  • fused ring systems including purine, pteridinyl, napthyridinyl, 1 H thieno[2,3- c]pyrazolyl, thieno[2,3-b]furyl and the like
  • linked ring systems such as oligothiophene, polypyrrole and the like.
  • Fused ring systems may also include aromatic 5-membered or 6- membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphtyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5-membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • aromatic 5-membered or 6- membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphtyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5-membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a
  • 6-membered ring containing 1 or 2 ring heteroatoms h) an isoxazole ring fused to a 5- or 6- membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6- membered ring containing 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6- membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6- membered ring containing 1 , 2 or 3 ring heteroatoms; I) a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1- b]thiazole) and imidazoimidazole (e.g. imidazo[1 ,2-a]imidazole).
  • imidazothiazole e.g. imidazo[2,1- b]thiazole
  • imidazoimidazole e.g. imidazo[1 ,2-a]imidazole
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.
  • pyrazolo[1 ,5-a]pyrimidine e.g. benzodioxole and pyrazolopyridine (e.g. pyrazolo[1 ,5-a]pyridine) groups.
  • pyrazolopyridine groups e.g. pyrazolo[1 ,5-a]pyridine
  • a further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1 ,4]dioxine, benzo[1 ,3]dioxole, 4, 5,6,7- tetrahydrobenzofuran, indoiine, isoindoline and indane groups.
  • aromatic heterocyclyls fused to carbocyclic aromatic rings may therefore include but are not limited to benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.
  • non-aromatic heterocyclyl encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom selected from the group consisting of N, S and O.
  • the ring may contain 1 , 2 or 3 heteroatoms.
  • the ring may be a monocyclic ring or part of a polycyclic ring system.
  • Polycyclic ring systems include fused rings and spirocycles. Not every ring in a non-aromatic heterocyclic polycyclic ring system must contain a heteroatom, provided at least one ring contains one or more heteroatoms.
  • Non-aromatic heterocyclyls may be 3-7 membered mono-cyclic rings.
  • Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1-pyrrolinyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetra hydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and the like.
  • 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1 ,4-dioxinyl, 1 ,4-dithianyl, 1 ,3,5-triozalanyl, 1 ,3,5- trithianyl, 1 ,4-morpholinyl, thiomorpholinyl, 1 ,4-oxathianyl, triazinyl, 1 ,4-thiazinyl and the like.
  • Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl and the like.
  • Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems.
  • Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like.
  • non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and the like.
  • halo refers to fluoro, chloro, bromo or iodo.
  • the term “optionally substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1 , 2, 3, 4 or more groups, preferably 1 , 2 or 3, more preferably 1 or 2 groups selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxyl, oxo, C 1-6 alkoxy, aryloxy, C 1-6 alkoxyaryl, halo, C 1-6 alkylhalo (such as CF 3 ), C 1-6 alkoxyhalo (such as OCF 3 ), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, substituted ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, s
  • C 1-6 alkyl For optionally substituted “C 1-6 alkyl”, “C 2-6 alkenyl” and “C 2-6 alkynyl”, the optional substituent or substituents are preferably selected from halo, aryl, heterocyclyl, C 3-8 cycloalkyl, C 1- 6 alkoxy, hydroxyl, oxo, aryloxy, haloC 1-6 alkyl, haloC 1-6 alkoxyl and carboxyl.
  • Each of these optional substituents may also be optionally substituted with any of the optional substituents referred to above, where nitro, amino, substituted amino, cyano, heterocyclyl (including non- aromatic heterocyclyl and heteroaryl), C 1-6 alkyl, C 2-6 akenyl, C 2-6 alkynyl, C 1-6 alkoxyl, haloC 1- 6 alkyl, haloC 1-6 alkoxy, halo, hydroxyl and carboxyl are preferred.
  • suitable derivatives of aromatic heterocyclyls containing nitrogen include N-oxides thereof.
  • the direction of attachment of such a hybrid radical may be denoted by inclusion of a bond, for example, “-alkylaryl” or “arylalkyl-“ denotes that the point of attachment of the radical to the rest of the compound is via the alkyl moiety, and “alkylaryl-“ or “-arylalkyl” denotes that the point of attachment is via the aryl moiety.
  • the invention provides a compound of (X):
  • E3L is an E3 ligase binding moiety
  • L is a linker covalently linking E3L to MLKLi
  • MLKLi is a radical of formula (I) wherein
  • J is selected from the following moieties J1 and J2:
  • a 1 and A 4 are independently selected from N and C;
  • a 2 and A 3 are independently selected from N, NR 1 , CH, O and S; wherein at least one of A 1 , A 2 , A 3 and A 4 is selected from N, NR 1 , O and S;
  • a 5 is CH or N
  • a 6 is N or CR 2 ;
  • R 1 and R 3 are independently selected from H and an optionally substituted C 1-6 -alkyl
  • R 2 is selected from:
  • X is selected from optionally substituted C 1-6 alkyl, optionally substituted haloC 1-6 alkyl, optionally substituted C 2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C 1-6 alkylcycloalkyl and optionally substituted amino;
  • Y and Z are independently selected from H, R 4 , -OR 4 , -NR 4 R 4 and halo; wherein at least one of Y and Z is H;
  • R 4 is selected from optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted C 1-6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1-6 alkylC 3-10 cycloalkyl, optionally substituted C 3-10 cycloalkylaryl, optionally substituted C 3-10 cycloalkylheterocyclyl, optionally substituted C 3-10 cycloalkylC 3-10 cycloalkyl, optionally substituted 3-6 membered non-aromatic heterocyclyl-aryl, optionally substituted 3-6 membered non-aromatic heterocyclylC 3-10 cycloalkyl and optionally substituted 3-6 membered non-aromatic heterocyclyl-3-10 membered heterocyclyl;
  • R 4 is H or optionally substituted C 1-6 alkyl
  • R 5 is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 3-10 cycloalkyl and optionally substituted aryl.
  • the MLKLi is a radical of a compound of formula (I).
  • J is selected from the following moieties J1 and J2:
  • a 1 and A 4 are independently selected from N and C;
  • a 2 and A 3 are independently selected from N, NR 1 , CH, O and S; wherein at least one of A 1 , A 2 , A 3 and A 4 is selected from N, NR 1 , O and S;
  • a 5 is CH or N
  • a 6 is N or CR 2 ;
  • R 1 and R 3 are independently selected from H and an optionally substituted C 1-6 -alkyl
  • R 2 is selected from:
  • X is selected from optionally substituted C 1-6 alkyl, optionally substituted haloC 1-6 alkyl, optionally substituted C 2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C 1-6 alkylcycloalkyl and optionally substituted amino;
  • Y and Z are independently selected from H, R 4 , -OR 4 , -NR 4 R 4 and halo; wherein at least one of Y and Z is H;
  • R 4 is selected from optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted C 1-6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1-6 alkyl C 3-10 cycloalkyl, optionally substituted C 3-10 cycloalkylaryl, optionally substituted C 3-10 cycloalkylheterocyclyl, optionally substituted C 3-10 cycloalkylC 3-10 cycloalkyl, optionally substituted 3-6 membered non-aromatic heterocyclyl-aryl, optionally substituted 3-6 membered non-aromatic heterocyclylC 3-10 cycloalkyl and optionally substituted 3-6 membered non-aromatic heterocyclyl-3-10 membered heterocyclyl;
  • R 4 is H or optionally substituted C 1-6 alkyl
  • R 5 is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 3-10 cycloalkyl and optionally substituted aryl.
  • X is selected from C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, -(CH 2 ) n aryl, -(CH 2 ) n cycloalkyl, and -N(C 1-4 alkyl) 2 ; wherein n is 1 or 2, and each alkyl and alkynyl is optionally substituted with one or more groups selected from halo, nitrile, -OR 6 , -N(R 7 )R 8 ;
  • R 6 , R 7 and R 8 are independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl, and wherein each aryl and cycloalkyl is optionally substituted with one or more groups that are independently selected from halo, nitrile, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1- 4 alkoxy.
  • X is selected from optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-4 alkylnitrile, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted CialkylC 3-6 cycloalkyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted C 1 alkylaryl, optionally substituted haloCialkylaryl, optionally substituted haloCialkoxyaryl, optionally substituted benzyl, optionally substituted halobenzyl, optionally substituted Cialkylbenzyl, optionally substituted Cialkoybenzyl and optionally substituted haloCialkoybenzyl.
  • X is selected from an optionally substituted C 1-4 alkyl, an optionally substituted haloC 1-4 alkyl and a C
  • X is selected from an optionally substituted C 1-2 alkyl, an optionally substituted haloC 1-2 alkyl and a C 3 cycloalkyl.
  • X is an optionally substituted haloC 1-4 alkyl selected from -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 and -CH 2 CH 2 CF 3 .
  • X is an optionally substituted haloC 1-2 alkyl.
  • X is an optionally substituted amino preferably disubstituted amino, such as -N(C 1-4 alkyl) 2 . In some embodiments, X is -N(CH 3 ) 2 .
  • X is selected from any one of the following groups: methyl, ethyl, isopropyl, tert-butyl, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 N(CH 3 ) 2 , cyclohexyl, cyclopropyl, -N(CH 3 ) 2
  • X is selected from any one of the following groups: ethyl, difluoromethyl, trifluoroethyl and cyclopropyl.
  • X is difluoromethyl
  • X is a group that has a longest linear chain extending from the sulfur atom depicted in formula (I) by not more than 6, 5, 4, 3 or 2 atoms, preferably 3-6 atoms.
  • longest linear chain it is meant the number of atoms from the point of attachment not including any branching or rings.
  • X is benzyl
  • the longest linear chain is 6 atoms which includes the methylene carbon atom, four ring atoms and the hydrogen atom attached to the carbon at the 4-position of the benzyl
  • X is -CH 2 CF 3
  • the longest linear chain in each of these exemplary X-substituents is numbered in the partial formulas shown below:
  • Y and Z are independently selected from H, R 4 , -OR 4 and -NR 4 R 4 ; wherein at least one of Y and Z is H.
  • Y and Z are independently selected from H, R 4 , -OR 4 and halo; wherein at least one of Y and Z is H.
  • Y and Z are independently selected from H, R 4 , -OR 4 , -NR 4 R 4 and halo; wherein at least one of Y and Z is H and the remaining one of Y and Z is selected from R 4 , - OR 4 , -NR 4 R 4 and halo.
  • Y and Z are independently selected from H, R 4 , -OR 4 and halo; wherein at least one of Y and Z is H and the remaining one of Y and Z is selected from R 4 , - OR 4 and halo.
  • Y and Z are independently selected from H, R 4 , -OR 4 ; wherein at least one of Y and Z is H.
  • Y and Z are independently selected from H, -OR 4 ; and halo; wherein at least one of Y and Z is H.
  • Y and Z are independently selected from H and -OR 4 ; wherein at least one of Y and Z is H.
  • the compound of formula (I) may be provided as a compound of formula (la): wherein J, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , n, R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined for formula (I) or any embodiment thereof.
  • the compound of formula (I) may be provided as a compound of formula (lb): wherein J, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , n, R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined for formula (I) or any embodiment thereof.
  • Y when Y is halo; Z is H. In some embodiments, both of Y and Z are H.
  • Y and Z are independently selected from H, R 4 , -OR 4 and halo; wherein at least one of Y and Z is H and the remaining one of Y and Z is selected from R 4 , - OR 4 and halo.
  • Y and Z are independently selected from H, R 4 and -OR 4 ; wherein at least one of Y and Z is H and the remaining one of Y and Z is selected from R 4 , and -OR 4 .
  • Y and Z are independently selected from H, -OR 4 and halo; wherein at least one of Y and Z is H and the remaining one of Y and Z is selected from -OR 4 and halo.
  • the halo at Y or Z is fluoro.
  • R 4 is H. In some embodiments, R 4 is C 1-6 alkyl.
  • R 4 is selected from C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, C 1-6 alkylcycloalkyl, C 1-6 alkylaryl and C 1-6 alkylheterocyclyl, wherein each alkyl (including when present as an optional substituent) is optionally substituted with one or more groups independently selected from halo, C 1-4 alkoxy, hydroxy, nitrile, amino, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, aryl, cycloalkyl and heterocyclyl; wherein each aryl (including when present as an optional substituent) is optionally substituted with one or more groups independently selected from halo, hydroxy, nitrile, amino, C 1- 4 alkylamino and (C 1-4 alkyl) 2 amino, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, aryl, cycl
  • R 4 is selected from C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, C 1- 6 alkylcycloalkyl, C 1-6 alkylaryl, C 1-6 alkylheterocyclyl, C 3-10 cycloalkylaryl, C 3-10 cycloalkylheterocyclyl, C 3-10 cycloalkylC 3-10 cycloalkyl, 3-6 membered non-aromatic heterocyclyl-aryl, 3-6 membered non-aromatic heterocyclyl-C 3-10 cycloalkyl and 3-6 membered non-aromatic heterocyclyl-3-10 membered heterocyclyl and wherein each cycloalkyl, aryl and heterocyclyl are optionally substituted with one or more groups independently selected from halo, hydroxy, nitrile, amino, C 1-4 alkylamino and (C 1-4 alkyl) 2 amino, C 1-4 alkyl, C 1-4 al
  • R 4 is selected from C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl and -(CH 2 ) m R 9 ,
  • R 9 is selected from C 3-10 cycloalkyl, aryl, heterocyclyl, and m is an integer selected from 1 to 6; wherein each cycloalkyl, aryl and heterocyclyl are optionally substituted with one or more groups independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • R 4 is selected from C 1-4 alkyl, cycloalkyl, haloaryl, -C 1-2 alkylaryl, -C 1- 2 alkylarylhalo, -C 1-2 alkylC 3-6 cycloalkyl, -C 1-2 alkylheterocyclyl, -C 1-2 alkylarylCialkylhalo, -C 1-2 alkylarylhaloCialkyl, -C 1-2 alkylaralkylhalo, -C 1-2 alkylarylhaloalkoxy, cycloalkylaryl, cycloalkylheterocyclyl, cycloalkylcycloalkyl, 3-6 membered non-aromatic heterocyclyl-aryl, 3- 6 membered non-aromatic heterocyclylcycloalkyl and 3-6 membered non-aromatic heterocyclyl-3-10 membered heterocyclyl wherein each alkyl, cycloalkyl, cyclo
  • R 4 is an optionally substituted CialkylC 6 aryl.
  • the Cialkyl moiety is substituted.
  • the aryl moiety is substituted.
  • the CialkylC 6 aryl moiety may be represented by the following partial formula: wherein
  • R a and R b are independently selected from H, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 1-4 alkylhydroxy, optionally substituted C 1- 4 alkylnitrile, optionally substituted amino, optionally substituted C 1-4 alkylamino and optionally substituted (C 1-4 alkyl) 2 amino, or
  • R a and R b together with the carbon atom to which they are attached form an optionally substituted C 3-6 cycloalkyl or a 3-6 membered non-aromatic heterocyclyl;
  • R c is selected from halo and an optionally substituted C 1-4 alkyl; and m is 0, 1 or 2.
  • R a and R b are independently selected from H, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 1-4 alkylhydroxy, optionally substituted C 1-4 alkylnitrile, optionally substituted C 1-4 alkylamino and optionally substituted (C 1-4 alkyl)2amino.
  • R a and/or R b are an optionally substituted C 1-4 alkylamino, either the C 1-4 alkyl or amino moiety may be optionally substituted.
  • R a and R b together with the carbon atom to which they are attached form an optionally substituted C 3-6 cycloalkyl or a 3-6 membered non-aromatic heterocyclyl selected from an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted oxetane and an optionally substituted azetidine.
  • R 5 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl and aryl. In some embodiments, R 5 is selected from H and optionally substituted C 1-6 alkyl. In some embodiments, R 5 is selected from H and optionally substituted aryl. In some embodiments, R 5 is selected from H, optionally substituted methyl and optionally substituted phenyl. In some embodiments, R 5 is H.
  • m is 0 or 1 .
  • m is 1 or 2.
  • At least one R c is in the para position relative to the benzyl carbon atom.
  • R c is selected from methyl, fluoro and chloro.
  • R a is selected from H and methyl, and R b is H.
  • R a and R b together with the carbon atom to which they are attached are cyclopropyl.
  • R 4 has partial structure (A): wherein
  • R d is selected from H, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 1-4 alkoxyC 1-4 alkyl, optionally substituted C 1-4 alkylhydroxy, optionally substituted C 1-4 alkylnitrile, optionally substituted C 1-4 alkylamino and optionally substituted (C 1-4 alkyl) 2 amino, optionally substituted cycloalkyl and optionally substituted C 1- 4 alkylcycloalkyl; and
  • R e is selected from optionally substituted aryl, optionally substituted C 1-5 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1-5 alkylheterocyclyl, optionally substituted cycloalkyl, and optionally substituted C 1-5 alkyl C 3-10 cycloalkyl.
  • the compound of formula (I) may be provided as a compound of formula (IV):
  • R d is methyl
  • R e is selected from optionally substituted aryl, optionally substituted C 1-5 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1-4 alkylheterocyclyl, optionally substituted cycloalkyl, and optionally substituted C 1-4 alkylC 3-10 cycloalkyl.
  • R e is selected from optionally substituted aryl, optionally substituted cycloalkyl and optionally substituted heterocyclyl.
  • R e is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R d is selected from optionally substituted C 1-4 alkyl, optionally substituted cycloalkyl and optionally substituted C 1-4 alkylcycloalkyl.
  • the partial structure (A) may contain a chiral centre at the carbon to which R d and R e are attached. Therefore, the carbon atom to which R d and R e are attached may be enantiomerically enriched.
  • the carbon atom to which R d and R e is attached is enriched as the (S) stereoisomer, for example when R e has a higher ranking than R d in the Cahn-lngold-Prelog rules for stereochemical assignment.
  • the carbon atom to which R d and R e is attached is enriched as the (R) stereoisomer, for example when R e has a lower ranking than R d the Cahn-lngold-Prelog rules for stereochemical assignment.
  • R d is selected from optionally substituted C 1-4 alkyl, and the carbon atom to which R d and R e are attached is enriched in the (S) stereoisomer.
  • partial structure (A) may have the stereochemical configuration shown in by partial structure (A1): wherein R e has a higher ranking than R d in the Cahn-lngold-Prelog rules for stereochemical assignment.
  • R e has a higher ranking than R d in the Cahn-lngold-Prelog rules for stereochemical assignment
  • MLKL activity may be greater than 2-fold more active than the other corresponding stereoisomer, and in some embodiments, may be at least about 5-fold or about 10-fold more active than other corresponding stereoisomer(s) for MLKL inhibition.
  • the compound is provided as a compound of formula (S): wherein X, J and R 3 are as defined for formula (I) and R e and R d are as defined for partial formula (A).
  • R 4 is selected from any one of the following groups:
  • R 4 is selected from any one of the following groups:
  • R 4 is selected from any one of the following groups:
  • R 4 is: R 1 and R 3
  • R 1 and R 3 are H. In some embodiments, R 3 is H and R 1 is selected from H, methyl and isopropyl, preferably methyl.
  • R 1 is selected from H, methyl and isopropyl. In some embodiments, R 1 is methyl. J1
  • J is J1.
  • the compound of formula (I) may be provided as a compound of formula (II) wherein X, R 2 , R 3 , R 4 , A 1 , A 2 , A 3 and A 4 are as defined for formula (I) or any embodiment thereof.
  • the compound of formula (I) may also be provided as a compound of formula (lie) wherein X, R 2 , R 3 , R 4 , A 1 , A 2 , A 3 and A 4 are as defined for formula (I) or any embodiment thereof.
  • the J1 structure as shown below (and equivalent structures within other formulas), indicates a conjugated fused aromatic ring system:
  • J1 may have the following substitution pattern:
  • J1 may have the following substitution pattern:
  • At least one of A 1 , A 2 , A 3 and A 4 is selected from N, NR 1 , O and S.
  • a 3 is selected from N, NR 1 , O and S.
  • a 1 is C or N.
  • a 1 is C.
  • a 2 is selected from N and CH.
  • a 4 is selected from C and N.
  • a 1 , A 2 , A 3 and A 4 are selected from the following embodiments:
  • any one of embodiment nos. 1-4 are preferred.
  • embodiment no. 2 is preferred.
  • R 2 is selected from:
  • R 2 is selected from:
  • R 2 is selected from optionally substituted C 2-4 alkynyl and optionally substituted 5- or 6-membered heterocyclyl. In some embodiments, R 2 is selected from optionally substituted C 2-4 alkynyl and optionally substituted 5- or 6-membered aromatic heterocyclyl. In some embodiments, R 2 is selected from optionally substituted C 2-4 alkynyl and optionally substituted 5-membered aromatic heterocyclyl. In some embodiments, R 2 is selected from optionally substituted C 2-4 alkynyl and optionally substituted 5- or 6-membered heterocyclyl, wherein the ring heteroatom(s) of the heterocyclyl are N. In some embodiments, R 2 is selected from optionally substituted C 2-4 alkynyl and optionally substituted 5- or 6- membered aromatic heterocyclyl, wherein the ring heteroatom(s) of the heterocyclyl are N.
  • R 2 is optionally substituted with one or more group(s) (preferably 1-3 groups) selected from: halo, an optionally substituted C 1-6 alkyl, an optionally substituted C 3- scycloalkyl, an optionally substituted C 1-6 alkyl-N(R 11 ) 2 , -N(R 11 ) 2 , an optionally substituted (C 1-
  • R 2 is a 5- or 6-membered heterocyclyl optionally substituted with one or more group(s) selected from: halo, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 1-6 alkyl-N(R 11 ) 2 , -N(R 11 ) 2 , an optionally substituted (C 1-6 alkyl) 2 amino, an optionally substituted aryl, an optionally substituted heterocyclyl, an optionally substituted haloheterocyclyl, an optionally substituted C 1- 6 alkylheterocyclyl, an optionally substituted halo C 1-6 alkylheterocyclyl, an optionally substituted C 1-4 alkoxyheterocyclyl, an optionally substituted acylheterocyclyl, an optionally substituted C 1- 4 alkoxy, an optionally substituted C 1-4 alkyl-OH, an optionally substituted C 1-4 al
  • R 2 is a 5- or 6-membered heterocyclyl optionally substituted with one or more group(s) selected from: halo, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, an optionally substituted C 1-4 alkoxy, an optionally substituted C 1-4 alkyl-OH, an optionally substituted C 1-4 alkylhalo, an optionally substituted C 1-4 alkylheterocyclyl, an optionally substituted C 1-4 alkylC 3-8 cycloalkyl, an optionally substituted C 1-4 alkylaryl;
  • R 2 is H.
  • R 2 is cyano
  • R 2 is H or cyano. In some embodiments, R 2 is optionally substituted C 1-4 alkylamido or optionally substituted C 2- 4alkynyl.
  • R 2 is selected from optionally substituted C 1-4 alkylaryl, optionally substituted aryl, and optionally substituted 5- or 6-membered heterocyclyl.
  • R 2 is selected from:
  • a 5- or 6-membered heterocyclyl optionally substituted with one or more group(s) selected from: halo, an optionally substituted C 1-6 alkyl, an optionally substituted C 3 . scycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, an optionally substituted C 1-4 alkoxy, an optionally substituted C 1-4 alkyl-OH, an optionally substituted C 1-4 alkylhalo, an optionally substituted C 1-4 alkylheterocyclyl, an optionally substituted C 1-4 alkylC 3-8 cycloalkyl, an optionally substituted C 1-4 alkylaryl;
  • R 2 is a 5- or 6-membered heterocylyl selected from: pyrazolyl, pyridyl, tetrahydropyridyl, isozazolyl, pyrimidinyl, piperidinyl and tetrahydropyranyl, and wherein the 5- or 6-membered heterocyclyl is optionally substituted with one or more group(s) selected from: halo, an optionally substituted C 1-8 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 1-6 alkyl-N(R 11 ) 2 , -N(R 11 ) 2 , an optionally substituted (C 1-6 alkyl) 2 amino, an optionally substituted aryl, an optionally substituted heterocyclyl, an optionally substituted haloheterocyclyl, an optionally substituted C 1- 6 alkylheterocyclyl, an optionally substituted haloC 1-6 alkylheter
  • R 2 is a 5- or 6-membered heterocyclyl optionally substituted with one or more substituent(s) selected from: halo, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkylamido, optionally substituted C 3-8 cycloalkyl, optionally substituted C 1- 8 alkylC 3-8 cycloalkyl, optionally substituted halo C 1-6 alkylC 3-8 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkyl-OH and optionally substituted C 1- 6 alkylhalo.
  • the optionally substituted C 1-6 alkylamido is provided by - C 1-
  • any heterocyclyl group of these optional substituents may be a 4-7 membered heterocyclyl (including nonaromatic heterocyclyl and heteroaryl groups).
  • R 2 is a 5- or 6-membered heterocyclyl optionally substituted with one, two or three of any of the optional substituent(s) of R 2 described herein.
  • R 2 is a 5- or 6-membered heterocyclyl optionally substituted with one, two or three groups, preferably one or two groups, selected from: methyl, methoxy, methoxyethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, isopropyl, tert-butyl, 2-hydroxyethyl, dimethylamino, cyclopentyl, oxetanyl, tetrahydrofuranyl, piperidinyl, N-methyl-piperidinyl, tetrahydropyranyl and N-methyl-piperazinyl-2-ethyl.
  • R 2 is an optionally substituted 5- or 6-membered heterocyclyl selected from 4-pyridyl, 3-pyridyl, 4-piperidinyl, 1 ,4-piperazinyl, 4-tetrahydropyranyl, 2H, 4H, 5H-3- piperidinyl, 3,4-pyrazolyl, 3H,5H,6H-4-tetrahydropyranyl, 2,4-pyrimidinyl and 3,4-isoxazolyl.
  • R 2 is an optionally substituted pyrazolyl, preferably a substituted pyrazolyl, more preferably a mono-substituted pyrazolyl.
  • the mono-substituted pyrazolyl is substituted at N.
  • R 2 is a 5- or 6-membered heterocyclyl optionally substituted with one or more group(s) selected from: optionally substituted C 1-4 alkylhalo, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl and optionally substituted haloC 1- 6 alkylheterocyclyl.
  • the 5- or 6-membered heterocyclyl is preferably selected from pyrazolyl, pyridyl, tetrahydropyridyl, isozazolyl, pyrimidinyl, piperidinyl and tetrahydropyranyl, more preferably pyrazolyl, most preferably N-substituted-pyrazolyl.
  • R 2 is a 5- or 6-membered heterocyclyl optionally substituted with one or more group(s) selected from: optionally substituted C 1-4 alkylhalo, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl and optionally substituted haloC 1- 6 alkylheterocyclyl; wherein the optionally substituted C 1-4 alkylhalo, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl and optionally substituted haloC 1- 6 alkylheterocyclyl; are optionally substituted with one or more substituent(s) selected from C 1- 4 alkyl and C 3-4 cycloalkyl.
  • the 5- or 6-membered heterocyclyl is preferably selected from pyrazolyl, pyridyl, tetrahydropyridyl, isozazolyl, pyrimidinyl, piperidinyl and tetrahydropyranyl, more preferably pyrazolyl, most preferably N-substituted-pyrazolyl.
  • R 2 is an optionally substituted 6-membered non-aromatic heterocyclyl.
  • R 2 is a 5- or 6-membered heterocyclyl comprising at least 1 nitrogen heteroatom. In some embodiments, R 2 is a 5- or 6-membered heterocyclyl comprising at least 1 oxygen heteroatom. In some embodiments, R 2 is a 5- or 6-membered heterocyclyl comprising at least 1 nitrogen and at least 1 oxygen heteroatom. In some embodiments, R 2 is a 5- or 6-membered heterocyclyl comprising 2 nitrogen heteroatoms.
  • R 2 is an optionally substituted fused heterocyclyl.
  • R 2 is an optionally substituted 5- or 6-membered heteroaryl.
  • R 2 is an optionally substituted pyridyl.
  • R 2 is an optionally substituted isoxazolyl.
  • R 2 is an optionally substituted morpholinyl.
  • R 2 is an optionally substituted pyrimidinyl.
  • R 2 is an optionally substituted pyrrolyl.
  • R 2 is an optionally substituted 1 ,3-dihydro-2H-benzo[cf]imidazol-2-one, preferably including methyl substitution.
  • R 2 is an optionally substituted 1-methylindolinyl-2-one.
  • R 2 is an optionally substituted 1-methyl-1 H-indazolyl.
  • R 2 is enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C, 14 C, 15 N and/or 17 O, preferably 2 H.
  • R 2 is an optionally substituted C 2-4 alkynyl.
  • the C 2-4 alkynyl may optionally be substituted with one or more groups (preferably 1 group) selected from optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, optionally substituted (C 1- 6 alkyl)i. 3 C 3 .8cycloalkyl, optionally substituted heterocyclyl, optionally substituted halo heterocyclyl, optionally substituted (C 1-6 alkyl)i. 3 heterocyclyl and optionally substituted (C 1- 6 alkylhalo)i. 3 heterocyclyl.
  • R 2 is an optionally substituted C 2-4 alkynyl.
  • the C 2-4 alkynyl may optionally be substituted with one or more groups (preferably 1 group) selected from optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, optionally substituted (C 1-6 alkyl)i. 3 C 3 .8cycloalkyl, optionally substituted heterocyclyl, optionally substituted halo heterocyclyl and optionally substituted (C 1-6 alkyl)i. 3 heterocyclyl.
  • groups preferably 1 group selected from optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, optionally substituted (C 1-6 alkyl)i. 3 C 3 .8cycloalkyl, optionally substituted heterocyclyl, optionally substituted halo heterocyclyl and optionally substituted (C 1-6 alkyl)i. 3 heterocyclyl.
  • R 2 is selected from: H, cyano, methyl, 3-pyridyl, 4-pyridyl, benzyl, In some embodiments, R 2 is selected from: H, methyl, 3-pyridyl, 4-pyridyl, benzyl,
  • R 2 comprises a basic moiety (such as an optionally substituted amine including an optionally substituted cyclic amine).
  • R 2 comprises a nitrogen-containing heterocyclyl and the nitrogen atom of these cyclic amines may be optionally substituted with a group selected from C 1-
  • R 2 is represented by the following partial formula:
  • G is selected from:
  • each R 10 is independently selected from: halo, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, an optionally substituted C 1-4 alkoxy, an optionally substituted C 1-4 alkyl-OH, an optionally substituted C 1-4 alkylhalo, an optionally substituted C 1-4 alkylheterocyclyl, an optionally substituted C 1-4 alkylC 3 .8cycloalkyl, an optionally substituted C 1-4 alkylaryl; and w is an integer from 0-3.
  • thecompound isprovidedasacompoundofformula(IIA)or(IIB): whereinA 1 ,A 2 ,A 3 ,A 4 , R 3 , R 4 , R d , R e ,G,wand R 10 areasdefined herein.
  • G isaC 2-4 alkynyl.
  • Insomeembodiments,G isethynylandwis 1.
  • Insomeembodiments,G isa6-membered heterocyclyl. Intheseembodiments, Gmaybea6-membered non-aromaticheterocyclylora6-membered heteroaryl.
  • each R 10 maybeindependentlyselectedfromhalo,anoptionallysubstitutedC 1-6 alkyl, anoptionallysubstitutedC 1-4 alkoxy,anoptionallysubstitutedC 1-4 alkylhaloandanoptionallysubstituted (C 1-6 alkyl) 2 amine.
  • G isa6-membered non-aromaticheterocyclylcomprisingaheteroatomselectedfromNandO.WhentheheteroatomisN, R 10 ispreferablybondedtoan N ringatom.
  • Insomeembodiments,G isa5-membered heterocyclyl.
  • G is a 5- or6-membered heterocyclyl comprising at least 1 oxygenheteroatom. Insomeembodiments,Gisa5-or6-memberedheterocyclylcomprisingatleast 1 nitrogen and at least 1 oxygen heteroatom. In some embodiments, G is a 5- or 6-membered heterocyclyl comprising 2 nitrogen heteroatoms.
  • G is an optionally substituted fused heterocyclyl.
  • G is selected from morpholinyl, pyrimidinyl, pyrrolyl, 1 ,3-dihydro-2H- benzo[d]imidazol-2-one, 1 -methylindolinyl-2-one, 1-methyl-1 H-indazolyl, pyrazolyl and isoxazolyl.
  • G is selected from pyrazolyl and isoxazolyl.
  • G is pyrazolyl.
  • R 10 may be bonded to a nitrogen ring atom.
  • R 2 may be represented by the following partial formula:
  • the compound may be provided as a compound of formula (HO) or (HD):
  • a 1 , A 2 , A 3 , A 4 , R 3 , R 4 , R d , R e and R 10 are as defined herein.
  • R 10 is selected from C 1-6 alkyl, heterocyclyl, C 1-6 alkyl-OH, C 1-6 alkyl- NH 2 , C 1-6 alkoxyC 1-6 alkyl, C 3-8 cycloalkyl, wherein the heterocyclyl and C 3-8 cycloalkyl may be further substituted with one or more groups (preferably 1-3 groups, most preferably 1 group) selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-OH, C 1-6 alkoxyC 1-6 alkyl, halo, C 1-6 alkyl-NH 2 , C 1-6 alkylketone (eg acyl) and -NH 2 .
  • groups preferably 1-3 groups, most preferably 1 group
  • R 10 is heterocyclyl or alkylheterocyclyl optionally substituted with one or more groups (preferably 1-3 groups, most preferably 1 group) selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-OH, C 1-6 alkoxyC 1-6 alkyl, halo, C 1-6 alkyl-NH 2 , C 1- 6 alkylketone (eg acyl) and -NH 2 .
  • groups preferably 1-3 groups, most preferably 1 group
  • groups preferably 1-3 groups, most preferably 1 group
  • the heterocyclyl may preferably be a 4-8 membered heterocyclyl, preferably comprising one heteroatom selected from N and O, preferably N.
  • R 10 is an optionally substituted heterocyclyl selected from an optionally substituted spirocyclic heterocyclyl, optionally substituted fused heterocyclyl or an optionally substituted bridged heterocyclyl.
  • R 10 is an optionally substituted heterocyclyl selected from an optionally substituted spirocyclic heterocyclyl or an optionally substituted bridged heterocyclyl.
  • Preferred optional substituents of the spirocyclic, fused and bridged heterocyclyl groups include C 1-6 alkyl and haloC 1-6 alkyl.
  • R 10 is enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C, 14 C, 15 N and/or 17 O, preferably 2 H
  • R 10 is selected from: methyl, difluoromethyl, trifluoromethyl, methoxy, tert-butyl, phenyl, acyl, dimethylamino, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, hydroxyethyl, methoxyethyl, isopropyl, cyclopentyl, difluorocyclopenyl, piperidinyl, N- methylpiperidinyl, N-acetylpiperidine, azetidinyl,
  • R 10 is selected from: methyl, difluoromethyl, trifluoromethyl, methoxy, tert-butyl, phenyl, acyl, dimethylamino, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, hydroxyethyl, methoxyethyl, isopropyl, cyclopentyl, difluorocyclopenyl, piperidinyl, N- methylpiperidinyl, N-acetylpiperidine, azetidinyl,
  • R 10 is selected from C 3-8 cycloalkyl, aryl and 4-8 membered heterocyclyl, each of which may be optionally substituted with 1-3 groups selected from C 1- 4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-NR’R”, wherein R’ and R” are independently selected from H and C 1-4 alkyl, haloC 1-4 alkyl, halo, C 1-4 alkoxy, and C 1-4 alkoxyC 1-4 alkyl.
  • w is 0 or 1 .
  • w is selected from 0, 1 and 3.
  • the compound may be provided as a compound of formula (HF) or (IIG):
  • a 1 , A 2 , A 3 , A 4 , R 3 , R 4 , R d and R e are as defined herein;
  • R 12 is one or more groups independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxyl, oxo, C 1-6 alkoxy, aryloxy, C 1-6 alkoxyaryl, halo, C 1-6 alkylhalo, C 1- 6 alkoxyhalo and amino; and
  • R 13 is selected from H, Cialkyl and haloC 1-6 alkyl.
  • R 12 is one or more groups independently selected from H, Cialkyl and C 3-8 cycloalkyl. In some embodiments, R 12 is one or more groups independently selected from H, C 1-3 alkyl and C 3-4 cycloalkyl; preferably Cialkyl and C 3 cycloalkyl. In some embodiments, R 12 substitutes the carbon alpha to the piperidyl nitrogen.
  • R 13 is selected from H, Cialkyl and haloC 1-3 alkyl; preferably C 1-3 alkyl; more preferably Cialkyl.
  • J is J2.
  • the compound of formula (I) may be provided as a compound of formula (III)
  • a 5 is CH.
  • a 5 is N.
  • a 6 is N.
  • a 6 is CR 2 .
  • a 5 is N and A 6 is N.
  • a 5 is CH and A 6 is N.
  • a 5 is N and A 6 is CR 2 .
  • At least one of A 5 and A 6 is N.
  • R 5 is H.
  • the compound of the invention is selected from any of compounds 1001 to 1031 , 1037 and 1039 to 1145 described herein, preferably from any of compounds 1001 to 1031 , 1037 and 1039 to 1137.
  • the compound of the invention is selected from any of compounds 1001 to 1031 described herein, preferably from any of compounds 1001 to 1023 and 1029 to 1031 , more preferably from any of compounds 1003, 1005, 1006, 1008 to 1012, 1014, 1015, 1017 and 1022.
  • the compound comprises a radical of a compound selected from compounds 1-173 described herein. In some embodiments, the compound of the invention comprises a radical of a compound selected from compounds 1-125 described herein.
  • the compound of the invention comprises a radical of a compound selected from compounds 113, 116, 145, 154, 155, 170 and 171 described herein.
  • MLKLi is a compound of formula (X) comprising a radical at: i) R 2 when J is J1 so that R 2 and L are covalently bound; or ii) R 5 when J is J2 so that R 5 and L are covalently bound.
  • the compound of formula (X) may be provided as a compound of formula (XX): wherein A 1 , A 2 , A 3 , A 4 , n, R 1 , R 2 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein.
  • the compound of formula (X) may be provided as a compound of formula (XXI): wherein A 1 , A 2 , A 3 , A 4 , n, R 1 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein;
  • a 7 , A 8 , A 9 and A 10 are independently selected from C(R 12 ) q , O, S, N, NR 13 , C(R 12 )-L-E3L, C- L-E3L and N-L-E3L; one of A 7 , A 8 , A 9 and A 10 is selected from C(R 12 )-L-E3L, C-L-E3L and N-L-E3L; at least one of A 7 , A 8 , A 9 and A 10 is selected from C(R 12 ) 2 , O, S, NR 13 , C(R 12 )-L-E3L; each R 12 is independently selected from H and R 14 ; each R 14 is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -OC 1-6 alkylC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, nitrile, amid
  • iocycloalkyl C 1-6 alkylC 3-10 cycloalkyl, C 1-6 alkoxyC 3-10 cycloalkyl, haloC 1-6 alkylC 3-10 cycloalkyl, haloC 1-6 alkoxyC 3-10 cycloalkyl, C 1-6 alkylheterocyclyl, C 1-6 alkoxyheterocyclyl, haloC 1-
  • each R 13 is independently selected from H, C 1-6 alkyl, haloC 1-4 alkyl, C 1-6 alkylacyl and haloC 1-6 alkylacyl; or when two adjacent groups selected from A 7 , A 8 , A 9 and A 10 are selected from CR 12 , C(R 12 )-L-E3L and NR 13 , two R 12 , two R 13 or one R 12 and one R 13 may together form an optionally substituted 5-10 membered ring selected from cycloalkyl, aryl and heterocyclyl; q is 1 or 2.
  • a 9 is N
  • a 8 is N-L-E3L
  • a 7 is CR 12
  • a 10 is CR 12 .
  • the compound of formula (X) may be provided as a compound of formula (XXII):
  • a 1 , A 2 , A 3 , A 4 , n, R 1 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein.
  • the compound of formula (X) may be provided as a compound of formula (XXIII): wherein A 1 , A 2 , A 3 , A 4 , n, R 1 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein.
  • the compound of formula (X) may be provided as a compound of formula (XXIV):
  • a 1 , A 2 , A 3 , A 4 , n, R 1 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein; wherein A 11 -A 15 are independently selected from N, CR 12 and C-L-E3L, one of A 11 -A 15 is C-L-E3L wherein not more than 2 of A 11 , A 12 , A 13 , A 14 and A 15 are N; each R 12 is independently selected from H and R 14 ; each R 14 is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl,
  • a 11 -A 15 may be defined as any one of embodiments 1 -4:
  • the compound of formula (X) may be provided as a compound of formula (XXa): wherein A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4 , R 5 , X, Y, Z, L and E3L are as defined herein.
  • the compound of formula (X) may be provided as a compound of formula (XXIa):
  • a 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein;
  • a 7 , A 8 , A 9 and A 10 are independently selected from C(R 12 ) q , O, S, N, NR 13 , C(R 12 )-L-E3L, C- L-E3L and N-L-E3L; one of A 7 , A 8 , A 9 and A 10 is selected from C(R 12 )-L-E3L, C-L-E3L and N-L-E3L; at least one of A 7 , A 8 , A 9 and A 10 is selected from C(R 12 ) 2 , O, S, NR 13 , C(R 12 )-L-E3L; each R 12 is independently selected from H and R 14 ; each R 14 is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -OC 1-6 alkylC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, nitrile, amid
  • each R 13 is independently selected from H, C 1-6 alkyl, haloC 1-4 alkyl, C 1-6 alkylacyl and haloC 1-6 alkylacyl; or when two adjacent groups selected from A 7 , A 8 , A 9 and A 10 are selected from CR 12 , C(R 12 )-L-E3L and NR 13 , two R 12 , two R 13 or one R 12 and one R 13 may together form an optionally substituted 5-10 membered ring selected from cycloalkyl, aryl and heterocyclyl; q is 1 or 2.
  • a 9 is N
  • a 8 is N-L-E3L
  • a 7 is CR 12
  • a 10 is CR 12 .
  • the compound of formula (X) may be provided as a compound of formula (XXIIa): wherein A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein.
  • the compound of formula (X) may be provided as a compound of formula (XXIIIa): wherein A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein.
  • the compound of formula (X) may be provided as a compound of formula (XXIVa):
  • a 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4 , X, Y, Z, L and E3L are as defined herein; wherein A 11 -A 15 are independently selected from N, CR 12 and C-L-E3L, one of A 11 -A 15 is C-L-E3L wherein not more than 2 of A 11 , A 12 , A 13 , A 14 and A 15 are N; each R 12 is independently selected from H and R 14 ; each R 14 is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl,
  • a 11 -A 15 may be defined as any one of embodiments 1 -4:
  • E3L denotes an E3 ligase binding moiety. Any suitable E3 ligase binding moiety may be included in the compounds of the invention. Suitable E3 ligase binding moieties include different suitable linker attachment points and/or different suitable stereochemistries of E3 ligase binding moieties. E3 ligase binding moieties have been reviewed in Bricelj et al, Front. Chem., 2021 , 9, 707317, Schapira et al, Nat Rev Drug Discovery, 2019, 18, 949, Bricelj, A. et al., Front. Chem. 2021 , 9, 707317, Maple, H. J. et al., Med. Chem.
  • E3 ligase binding moiety includes the E3 ligase binding structures depicted in Bricelj et al, Front. Chem., 2021 , 9, 707317, Schapira et al, Nat Rev Drug Discovery, 2019, 18, 949, Bricelj, A. et al., Front. Chem. 2021 , 9, 707317, Maple, H. J. et al., Med. Chem. Commun., 2019, 10, 1755, and Ishida, T. and Ciulli, A. SLAS Discovery, 2021 , 26(4), 484; as well as E3 ligase binding structures that features different suitable linker attachment points and/or different suitable stereochemistries.
  • the human genome includes more than 600 E3 ligases (or E3 ubiquitin ligases).
  • E3 ligases are involved in the protein ubiquitination cascade, whereby one or more molecules of ubiquitin are linked to a substrate protein, marking those proteins for degradation via the ubiquitin-proteasome pathway.
  • the E3 ligases are categorised into 3 broad classes: Really Interesting New Gene (RING), Homologous to E6AP C-terminus (HECT) and RING- between-RING (RBR). Of these, RING E3 ligases are the most common.
  • the E3 ligase binding moiety may bind a RING, HECT or RBR E3 ligase, with E3L typically representing a RING E3 ligase binding moiety.
  • E3L typically representing a RING E3 ligase binding moiety.
  • MDM2 mouse double minute 2 homologue
  • IAP inhibitor of apoptosis
  • E3L may also be a moiety capable of binding any of these E3 ligases. Binders of the following E3 ligases have been described: RING-type zinc-finger protein 114 (RNF114), damage-specific DNA binding protein 1 (DDB1)-CUL4 associated factor 16 (DCAF16), Kelchlike ECH-associated protein 1 (KEAP1), cereblon (CRBL or CRBN) and von Hippel- Landau (VHL) tumor suppressor protein.
  • RNF114 RING-type zinc-finger protein 114
  • DDB1-CUL4 associated factor 16 DCAF16
  • KEAP1 Kelchlike ECH-associated protein 1
  • cereblon CRBL or CRBN
  • VHL von Hippel- Landau tumor suppressor protein.
  • E3L is a moiety capable of binding CRBL and/or VHL.
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from:
  • the arrow denotes the covalent bond to L or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is: wherein the arrow denotes the covalent bond to L or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is: wherein the arrow denotes the covalent bond to L or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from a radical of:
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L, the portion of L not depicted in the structure, or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L, the portion of L not depicted in the structure, or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L, the portion of L not depicted in the structure, or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L, the portion of L not depicted in the structure, or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L, the portion of L not depicted in the structure, or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from:
  • the E3 ligase binding moiety is selected from: wherein the arrow denotes the covalent bond to L or an E3 ligase binding derivative thereof.
  • the E3 ligase binding moiety is selected from:
  • the arrow denotes the covalent bond to L or an E3 ligase binding derivative thereof.
  • the E3 ligase binding derivative is an optionally substituted derivative of any of the E3 ligase binding moieties described herein.
  • L denotes a linker covalently linking MLKLi and E3L.
  • Any suitable linking group may be used that it is compatible with MLKLi and E3L, does not interfere with the binding of MLKLi and E3L to their respective protein targets, and allows ubiquitin transfer from the E3 ligase to MLKL.
  • the linker has a shortest linear chain length of 1 to 50 atoms.
  • shortest linear chain length defines the number of atoms in a chain defining the shortest path from MLKLi to E3L in a compound of the invention.
  • shortest linear chain length in each of the following structures is 7 atoms (shortest chain length is numbered in each structure):
  • the linker has a minimum shortest linear chain length of at least 1 , 2, 3, 4, 5, 6, or 7 atoms.
  • the linker may have a maximum shortest linear chain length of not more than 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8 or 7 atoms.
  • the linker may be characterised by a shortest linear chain length from any of these minimum lengths to any of these maximum lengths provided the minimum is less than the maximum.
  • the linker may be characterised by a shortest linear chain length of 1 to 35 atoms, 1-25 atoms, 1-20 atoms, 1 - 10 atoms, 2-10 atoms, 3-10 atoms or 5-9 atoms.
  • the linker is a Ci soalkyl optionally interrupted by one or more groups selected from: a. -O-, b. -NR Z -, c. C 3-8 cycloalkyl, d. aryl, e. C 1-4 alkaryl, f. heteroaryl, g. (C 1-4 alkoxy)i-4aryl, h. haloaryl, i. 4-8-membered non-aromatic heterocyclyl, j. -C(O)NR Z -, k. alkenyl, l.
  • each R z is independently selected from H and C 1-4 alkyl
  • each of the one or more groups a-l may be further optionally substituted with a group selected from: C 3-6 cycloalkyl, halo, -OH, -CN, -NR Z 2 , C 1-4 alkyl, C 1-4 alkoxy, oxo, C 1- 4 alkylketone, -COOH, -C(O)N(R Z ) 2 , and -NR Z C(O)R Z .
  • the one or more groups a-l may be optionally substituted with one or more groups selected from oxo, - C(O)N(R Z ) 2 , and -NR Z C(O)R Z .
  • each of the one or more groups a-l. may be further optionally substituted with a group selected from: halo, -OH, -CN, -NR Z 2 , C 1-4 alkyl, C 1-4 alkoxy, oxo, C 1- 4 alkylketone, -COOH, -C(O)N(R Z ) 2 , and -NR Z C(O)R Z .
  • the one or more groups a-l. may be optionally substituted with one or more groups selected from oxo, - C(O)N(R Z ) 2 , and -NR Z C(O)R Z .
  • C 1-50 alkyl may be optionally interrupted by any number of groups a-l provided the stability of the linker is sufficient to maintain the covalent connection between MLKLi and E3L under physiological conditions. Typically no more than 2 optional interrupting groups are included at consecutive positions along the C 1-50 alkyl chain. In some embodiments, the C 1-50 alkyl linker may be optionally interrupted by any number of groups a-l and optionally substituted.
  • the C 1-50 aIky I linker may comprise 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 of the one or more groups a-l.
  • the C 1- 50 alkyl linker may comprise any number of groups a-l from any of these numbers to any other of these numbers, for example, from 1 to 20 or from 4-12 groups.
  • the heteroaryl comprises at least one N heteroatom, such as triazolyl or pyrazolyl, preferably pyrazolyl.
  • the linker may comprise the moiety -(OCH 2 CH 2 )v-, wherein v is an integer from 1 to 15. Inclusion of the repeating ethylene oxide moiety may assist to control the hydrophilicity (and hence solubility) of the compounds of the invention.
  • the linker may comprise 1 -6 ethylene glycol units, preferably 2-5 ethylene glycol units.
  • the linker may comprises at least one coupling moiety selected from: -C(O)O-, -C(O)NR Z -, - OC(O)O-, -NR Z C(O)NR Z -, -OC(O)NR Z -, triazolyl, aryl, a,p-unsubstituted ketone, p-hydroxy- ketone, 4-8-membered heteroaryl, unsaturated C 6 -cycloalkyl and optionally substituted C 2 alkenyl, wherein each R z is independently selected from H and C 1-4 alkyl.
  • the coupling moiety is typically the product of the reaction used to couple MLKLi with E3L. In some embodiments the coupling moiety is selected from: -C(O)O, C(O)NR Z -, triazolyl, aryl, 4-8 membered heteroaryl (such as pyrazolyl) and aryl.
  • the linker is a C 1-50 alkyl optionally substituted by one or more groups selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxyl, oxo, C 1-6 alkoxy, aryloxy, C 1-6 alkoxyaryl, halo, C 1-6 alkylhalo, C 1-6 alkoxyhalo, carboxyl, ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, substituted ketone, amide, aminoacyl, substituted amide, disubstituted amide, thiol, alkylthio, thioxo, sulfate, sulfonate, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamide, substituted
  • the linker is a C 1-50 alkyl optionally substituted by one or more groups selected from: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-4 cycloalkyl, hydroxyl, oxo, C 1-4 alkoxy, C 1- 4 alkoxyaryl, halo, C 1-4 alkylhalo, C 1-4 alkoxyhalo, carboxyl, ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, substituted ketone, amide, thiol, alkylthio, thioxo, sulfate, sulfonate, sulfinyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted.
  • the C 1-50 alkyl may be optionally substituted by any number of groups provided the stability of the linker is sufficient to maintain the covalent connection between MLKLi and E3L under physiological conditions. Typically no more than 2 optional substituting groups are included at consecutive positions along the C 1-50 alkyl chain.
  • the compounds of the invention may be prepared by techniques known in the art.
  • a process for preparing a compound of formula (I) or a salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof comprises any of the following 4 steps:
  • LG is a leaving group, such as halo.
  • the leaving group may be any that is capable of activating the sulphonyl moiety of the compound of formula (VI) as an electrophile capable of reacting under appropriate conditions with the free aniline nitrogen of the compound of formula (V).
  • E 1 and E 2 are an electrophilic pair suitable to direct a palladium catalysed cross- coupling reaction.
  • E 1 and E 2 are selected from halo, a boronic acid, a boronic ester and triflate, or a group capable of conversion to any of these moieties, such as hydroxyl, a mixed anhydride, tetrafluorophenyl ether, etc.
  • E 1 is halo
  • E 2 is selected from a boronic acid, a boronic ester and triflate.
  • E 2 is halo, and E 1 is selected from a boronic acid, a boronic ester and triflate;
  • E 3 and E 4 are an electrophilic pair suitable to direct a palladium catalysed cross- coupling reaction.
  • E 3 and E 4 are selected from halo, a boronic acid, a boronic ester and triflate, or a group capable of conversion to any of these moieties, such as hydroxyl, a mixed anhydride, tetrafluorophenyl ether, etc.
  • E 3 is halo
  • E 4 is selected from a boronic acid, a boronic ester and triflate.
  • E 4 is halo, and E 3 is selected from a boronic acid, a boronic ester and triflate;
  • the process comprises a reaction with one or more of formula (XIII), formula (XIV) and formula (XV)
  • L’ is a linker moiety or a protected form of a linker moiety
  • E3L is an E3 ligase binding moiety or a protected form of an E3 ligase binding moiety
  • LG V is a group cleavable in the reaction with its coupling partner, wherein the coupling partner is selected from a compound of formula (I), formula (1A), formula (1 B), formula (1A’), formula (1 B’), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) and formula (VIII); and
  • LG A is H or a group cleavable in a subsequent step reacting moiety L’ with E3L’.
  • the process comprises reacting a compound of formula (I) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (1A) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (1 B) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (1A’) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV). In some embodiments, the process comprises reacting a compound of formula (1 B’) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (II) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (III) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (IV) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (V) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (VI) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (VII) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • the process comprises reacting a compound of formula (VIII) with a compound selected from the group consisting of formula (XIII), formula (XIV) and formula (XV).
  • L’ may be deprotected before deprotection of E3L’. In some embodiments, L’ may be deprotected subsequent to deprotection of E3L’.
  • L’ may be deprotected before coupling with the coupling partner. In some embodiments, L’ may be deprotected subsequent to coupling with the coupling partner. In some embodiments, L’ may be deprotected before cleavage of LG A . In some embodiments, L’ may be deprotected subsequent to cleavage of LGA.
  • E3L’ may be deprotected before coupling with the coupling partner. In some embodiments, E3L’ may be deprotected subsequent to coupling with the coupling partner.
  • E3L’ may be deprotected before cleavage of LG A . In some embodiments, E3L’ may be deprotected subsequent to cleavage of LG A .
  • LG A is cleaved prior to coupling with the coupling partner.
  • the process comprises reacting a compound of formula (XIII) with a compound of formula (XIV), thereby forming a compound of formula (XV).
  • LG A is cleaved subsequent to coupling with the coupling partner.
  • the process involving a reaction with one or more of formula (XIII), formula (XIV) and formula (XV) comprises a palladium mediated cross-coupling reaction.
  • the process involving a reaction with one or more of formula (XIII), formula (XIV) and formula (XV) comprises deprotection of an amino protein group.
  • the process further comprises a deprotection step.
  • a method for inhibiting necroptosis in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof.
  • the compounds of the invention treat necroptosis by binding to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein and triggering its ubiquitination and protein degradation via the ubiquitin-proteasome pathway.
  • MLKL Mixed Lineage Kinase Domain-like
  • MLKL mixed lineage kinase domain-like protein
  • the terms “degrading” and “degradation” would be understood by the person skilled in the art to mean partial or complete proteolysis of the protein via the ubiquitin-proteasome pathway.
  • the E3 ubiquitin ligase prompts transfer of ubiquitin from an E2 ubiquitin conjugating enzyme, leading to ubiquitination of the target protein and degradation by the proteasomes.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • administration of a compound according to Formula (I) inhibits a conformational change of MLKL.
  • the conformational change of MLKL involves release of the four-helix bundle (4HB) domain of MLKL.
  • administration of the compound inhibits oligomerisation of MLKL.
  • administration of the compound inhibits translocation of MLKL to the cell membrane.
  • administration of the compound inhibits a conformational change of MLKL, inhibits oligomerisation of MLKL and inhibits translocation of MLKL to the cell membrane.
  • pseudokinase domain as understood by a person skilled in the art, means a protein containing a catalytically-inactive or catalytically-defective kinase domain. “Pseudokinase domains” are often referred to as “protein kinase-like domains” as these domains lack conserved residues known to catalyse phosphoryl transfer. It would be understood by a person skilled in the art that although pseudokinase domains are predicted to function principally as catalysis independent protein-interaction modules, several pseudokinase domains have been attributed unexpected catalytic functions.
  • pseudokinase domain includes “pseudokinase domains” which lack kinase activity and “pseudokinase domains” which possess weak kinase activity.
  • ATP-binding site means a specific sequence of protein subunits that promotes the attachment of ATP to a target protein.
  • An ATP binding site is a protein micro-environment where ATP is captured and hydrolyzed to ADP, thereby releasing energy that is utilized by the protein to work by changing the protein shape and/or making the enzyme catalytically active.
  • the “ATP-binding site” is often referred to as the “pseudoactive site”.
  • the term “ATP-binding site” may also be referred to as a “nucleotide-binding site” as binding at this site includes the binding of nucleotides other than ATP.
  • nucleotide includes any nucleotide.
  • exemplary nucleotides include, but are not limited to, AMP, ADP, ATP, AMPPNP, GTP, CTP and UTP.
  • inhibition of necroptosis includes both complete and partial inhibition of necroptosis. In one embodiment, inhibition of necroptosis is complete inhibition. In another embodiment, inhibition of necroptosis is partial inhibition.
  • Binding of the compound to the ATP-binding site of the pseudokinase domain of MLKL may inhibit phosphorylation of MLKL by an effector kinase or binding of the compound to the ATP-binding site of the pseudokinase domain of MLKL may not inhibit phosphorylation of MLKL by an effector kinase.
  • the present disclosure demonstrates that compounds that bind to the ATP-binding site of the pseudokinase domain of the MLKL protein, as described herein, can inhibit necroptosis without inhibiting phosphorylation of MLKL by an effector kinase.
  • binding of the compound to the ATP-binding site of the pseudokinase domain of MLKL does not inhibit phosphorylation of MLKL by an effector kinase. In another embodiment, binding of the compound to the ATP-binding site of the pseudokinase domain of MLKL inhibits phosphorylation of MLKL by an effector kinase.
  • RIP1 , RIP3 and MLKL are three proteins implicated in the necroptotic pathway.
  • necroptotic stimulus e.g. using the combination of TNF, SMAC mimetic and QVD-OPh on suitable cell lines
  • RIP1 Upon necroptotic stimulus (e.g. using the combination of TNF, SMAC mimetic and QVD-OPh on suitable cell lines), RIP1 is auto-phosphorylated leading to association with RIP3, which in turn auto-phosphorylates itself.
  • Activated RIP3 phosphorylates MLKL leading to a putative conformational change that triggers its necroptotic activity (Murphy, Immunity, 39, pp 443 - 453, 2013).
  • MLKL acts downstream of RIP1 and RIP3, and is therefore understood to be a key effector of necroptosis.
  • Compounds of this invention may bind to MLKL and block this conformational change or any other key event in its activation.
  • the compounds of the invention may be selective for MLKL. In some embodiments, the compounds of the invention are selective for MLKL over RIP1 . In some embodiments, the compounds of the invention are selective for MLKL over RIP3. In some embodiments, the compounds of the invention are selective for MLKL over RIP1 and RIP3.
  • a selective compound may have 5-fold, 10-fold, 50-fold, 100-fold, 500-fold, 1000-fold or greater selectivity for MLKL compared to RIP1 and/or RIP3. Typically, the relative selectivity may be assessed by comparing K D values for each respective compound binding to the relevant protein (ie MLKL and either or both of RIP1 and RIP3). Suitable assay conditions are described in the Examples below. Compounds selective for MLKL may avoid undesired side- effects associated with RIP1 and/or RIP3 loss of function.
  • a compound of Formula (X) a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof in the preparation of a medicament for the inhibition of necroptosis in a subject.
  • composition comprising a compound of Formula (X) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof for the inhibition of necroptosis in a subject.
  • composition comprising a compound of Formula (X) or a salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof for inhibiting necroptosis.
  • composition comprising a compound according to Formula (X) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof for use in inhibiting necroptosis.
  • the composition is a pharmaceutical composition.
  • composition comprising a compound according to Formula (X) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof when used for inhibiting necroptosis.
  • a method of inhibiting MLKL comprising contacting a cell with an effective amount of a compound of formula (X) or a salt, solvate, tautomer, N- oxide, stereoisomer and/or prodrug thereof.
  • salts of the compounds of Formula (X) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, for example, as these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or in methods not requiring administration to a subject.
  • pharmaceutically acceptable may be used to describe any salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of Formula (X) or an active metabolite or residue thereof and typically that is not deleterious to the subject.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • the invention includes all crystalline forms of a compound of Formula (X) including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms demonstrates polymorphism, all polymorphs are within the scope of this invention.
  • Formula (X) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • Formula (X) includes compounds having the indicated structures, including the hydrated or solvated forms, as well as the non-hydrated and non-solvated forms.
  • the compounds of Formula (X) or salts, tautomers, N-oxides, polymorphs or prodrugs thereof may be provided in the form of solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF), acetic acid, and the like with the solvate forming part of the crystal lattice by either non- covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol.
  • Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the invention.
  • Basic nitrogen-containing groups may be quarternised with such agents as C 1-6 alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • C 1-6 alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • Nitrogen containing groups may also be oxidised to form an N-oxide.
  • the compound of Formula (X) or salts, tautomers, N-oxides, solvates and/or prodrugs thereof that form crystalline solids may demonstrate polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides, solvates and/or prodrugs are within the scope of the invention.
  • the compound of Formula (I) (and therefore also the compound of formula (X)) may demonstrate tautomerism.
  • Tautomers are two interchangeable forms of a molecule that typically exist within an equilibrium. Any tautomers of the compounds of Formula (I) are to be understood as being within the scope of the invention when included in a compound of the invention as moiety MLKLi.
  • R 1 is H
  • the compounds of formula (1 A) and (1 B) may exist as tautomers, eg in equilibrium with each other.
  • the compounds of formula (1A) and (1 B) wherein R 1 is H are depicted below as compounds of formulas (1A’) and (1 B’).
  • the proportion of compounds of formula (1A’) to (1 B’) in equilibrium may depend on the specific compound and conditions, such as solvent, temperature, concentration, etc. This equilibrium may be described as follows:
  • the compound of Formula (X) may contain one or more stereocentres. All stereoisomers of the compounds of formula (X) are within the scope of the invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olephinic forms and cis and trans substitution patterns) and atropisomers.
  • the compound is a stereoisomerically enriched form of the compound of formula (X) at any stereocentre. The compound may be enriched in one stereoisomer over another by at least about 60, 70, 80, 90, 95, 98 or 99%.
  • the compound of Formula (X) or its salts, tautomers, solvates, N-oxides, and/or stereoisomers may be isotopically enriched with one or more of the isotopes of the atoms present in the compound.
  • the compound may be enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C, 14 C, 15 N and/or 17 O, preferably 2 H.
  • An isotope may be considered enriched when its abundance is greater than its natural abundance.
  • a “prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (X) provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, and amido groups of compounds of Formula (X).
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of Formula (X) through the carbonyl carbon prodrug sidechain.
  • compositions may be formulated from compounds according to Formula (X) for any appropriate route of administration including, for example, oral, rectal, nasal, vaginal, topical (including transdermal, buccal, ocular and sublingual), parenteral (including subcutaneous, intraperitoneal, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracisternal injection as well as any other similar injection or infusion techniques), inhalation, insufflation, infusion or implantation techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • parenteral including subcutaneous, intraperitoneal, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracister
  • compositions in a form suitable for oral use or parenteral use are preferred.
  • suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • aqueous or oily suspensions dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride or glycine, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
  • physiologically compatible substances such as sodium chloride or glycine
  • the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials. Examples of components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993), and Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins. All methods include the step of bringing the active ingredient, for example a compound defined by Formula (X), or a pharmaceutically acceptable salt or prodrug thereof, into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient, for example a compound defined by Formula (X), or a pharmaceutically acceptable salt or prodrug thereof, into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect.
  • the method of the invention comprises administering a pharmaceutical comprising a compound of Formula (X) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • administering includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means.
  • the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements.
  • Active compounds according to the present invention are generally administered in a therapeutically effective amount.
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the subject, time of administration, route of administration, and rate of excretion, drug combination (i.e.
  • An effective amount of an agent is that amount which causes a statistically significant decrease in necroptosis.
  • necroptosis inhibition may be determined by assays used to measure TSQ-induced necroptosis, as described in the biological tests defined herein.
  • treating encompasses curing, ameliorating or tempering the severity of necroptosis and/or associated diseases or their symptoms.
  • Preventing means preventing the occurrence of the necroptosis or tempering the severity of the necroptosis if it develops subsequent to the administration of the compounds or pharmaceutical compositions of the present invention.
  • Subject includes any human or non-human animal.
  • the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
  • inhibitor is used to describe any form of inhibition that results in prevention, reduction or otherwise amelioration of necroptosis and/or MLKL function, including complete and partial inhibition.
  • a compound of the invention trigger substantially complete degradation of the target MLKL protein to which it binds. Accordingly, also described herein are methods of degrading MLKL in a subject, comprising administering to the subject a compound of the invention.
  • compounds of the invention include both an MLKL binding moiety - MLKLi - that is based on a series of MLKL inhibitors described in AU 2021904206 (entirely incorporated herein by reference), compounds of the invention may both inhibit and degrade MLKL, which may enhance the amelioration of necroptosis in a subject.
  • the compounds of the present invention may be administered along with a pharmaceutical carrier, diluent and/or excipient as described above.
  • the methods of the present disclosure can be used to prevent or treat the following disease(s), condition(s) and/or disorder(s) in a subject:
  • osteoporosis diseases of the bones, joints, connective tissue and of cartilage
  • osteomyelitis including chronic recurrent multifocal osteomyelitis
  • arthritises including for example osteoarthritis, rheumatoid arthritis and psoriatic arthritis, avascular necrosis, progressive fibrodysplasia ossificans, rickets, Cushing's syndrome
  • osteoarthritis for example osteoarthritis, rheumatoid arthritis and psoriatic arthritis
  • avascular necrosis progressive fibrodysplasia ossificans, rickets, Cushing's syndrome
  • muscular diseases such as muscular dystrophy, such as for example Duchenne's muscular dystrophy, myotonic dystrophies, myopathies and myasthenias;
  • cardiovascular diseases such as cardiac and/or vascular ischemia, myocardial infarction, ischemic cardiopathy, chronic or acute congestive heart failure, cardiac dysrythmia, atrial fibrillation, ventricular fibrillation, paroxystic tachycardia, congestive heart failure, hypertrophic cardiopathy, anoxia, hypoxia, secondary effects due to therapies with anti-cancer agents;
  • circulatory diseases such as atherosclerosis, arterial scleroses and peripheral vascular diseases, strokes including cerebrovascular strokes, aneurisms;
  • haematological and vascular diseases such as: anemia, aplastic anemia, vascular amyloidosis, haemorrhages, drepanocytosis, red cell fragmentation syndrome, neutropenia, leukopenia, medullar aplasia, pantocytopenia, thrombocytopenia, haemophilia; • lung diseases including pneumonia, asthma; obstructive chronic diseases of the lungs such as for example chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema;
  • COPD chronic obstructive pulmonary disease
  • diseases of the liver such as for example hepatitis particularly hepatitis of viral origin or having as causative agent other infectious agents, auto-immune hepatitis, fulminating hepatitis, inflammatory hepatitis, certain hereditary metabolic disorders, Wilson's disease, cirrhoses, non-alcoholic fatty liver disease (NAFLD) including non- alcoholic hepatic steatosis and/or non-alcoholic steatohepatitis (NASH), diseases of the liver due to toxins and to drugs such as drug-induced liver injury, ethanol (or alcohol)-induced liver disease;
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic fatty liver disease
  • diseases of the liver due to toxins and to drugs such as drug-induced liver injury, ethanol (or alcohol)-induced liver disease
  • pancreatitis diseases of the pancreas such as for example acute or chronic pancreatitis
  • metabolic diseases such as diabetes, including diabetes mellitus, pre-diabetes and insipid diabetes; thyroiditis;
  • kidneys diseases of the kidneys such as acute renal disorders (such as acute kidney injury (AKI), including ischaemic reperfusion injury (IRI)) or glomerulonephritis;
  • AKI acute kidney injury
  • IRI ischaemic reperfusion injury
  • inflammatory diseases such as Terminal ileitis including Crohn's disease, rheumatoid polyarthritis, TNF-induced systemic inflammatory syndrome;
  • auto-immune diseases such as erythematous lupus (including systemic lupus erythematosus), cleavage-resistant RIPK1 -induced autoinflammatory (CRIA) syndrome; • dental disorders such as those resulting in degradation of tissues such as for example periodontitis;
  • ophthalmic diseases or disorders including diabetic retinopathies, glaucoma, macular degenerations, retinal degeneration, retinitis pigmentosa, retinal holes or tears, retinal detachment, retinal ischemia, acute retinopathies associated with trauma, inflammatory degenerations, post-surgical complications, medicinal retinopathies, cataract, cone cell degeneration;
  • Ischemic reperfusion injury including retinal ischaemic reperfusion injury
  • Neuronal loss including Alzheimer’s disease and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS; also referred to as motor neuron disease (MND) and Charcot disease);
  • ALS amyotrophic lateral sclerosis
  • MND motor neuron disease
  • Charcot disease Charcot disease
  • mitochondria pathologies diseases associated with mitochondria
  • diseases associated with mitochondria such as Friedrich's ataxia, congenital muscular dystrophy with structural mitochondrial abnormality, certain myopathies (MELAS syndrome, MERFF syndrome, Pearson's syndrome), MIDD (mitochondrial diabetes and deafness) syndrome, Wolfram's syndrome, dystonia;
  • cancer and metastasis including but not limited to cancers of the lung and bronchus, including non-small cell lung cancer (NSCLC), squamous lung cancer, brochioloalveolar carcinoma (BAC), adenocarcinoma of the lung, and small cell lung cancer (SCLC); prostate cancer, including androgen-dependent and androgen- independent prostate cancer; breast cancer, including metastatic breast cancer; pancreatic cancer; cancers of the colon and rectum; thyroid cancer; cancers of the liver and intrahepatic bile duct; hepatocellular cancer; gastric cancer; endometrial cancer; melanoma; cancers of the kidney, renal pelvis, urinary bladder, uterine corpus and uterine cervix; ovarian cancer, including progressive epithelial or primary peritoneal cancer; multiple myeloma; oesophageal cancer, including squamous cell carcinoma and adenocarcinoma of the oesophagus; acute myelogenous
  • the methods of the present disclosure may be for treating and/or preventing any one or more of the diseases, conditions and/or disorders disclosed herein.
  • the methods can also be used for protecting cells, tissues and/or transplanted organs, whether before, during (removal, transport and/or re-implantation) or after transplantation.
  • the compound of the invention may be administered in combination with a further active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the API may be any that is suitable for treating any of the diseases, conditions and/or disorders associated with necroptosis, such as those described herein.
  • the compound of the invention may be co-formulated with the further API in any of the pharmaceutical compositions described herein, or the compound of the invention may be administered in a concurrent, sequential or separate manner.
  • Concurrent administration includes administering the compound of the invention at the same time as the other API, whether coformulated or in separate dosage forms administered through the same or different route.
  • Sequential administration includes administering, by the same or different route, the compound of the invention and the other API according to a resolved dosage regimen, such as within about 0.5, 1 , 2, 3, 4, 5, or 6 hours of the other.
  • the compound of the invention may be administered before or after administration of the other API.
  • Separate administration includes administering the compound of the invention and the other API according to regimens that are independent of each other and by any route suitable for either active, which may be the same or different.
  • the methods may comprise administering the compound of Formula (X) in any pharmaceutically acceptable form.
  • the compound of Formula (X) is provided in the form of a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer or prodrug thereof, or a combination of these forms in any ratio.
  • the methods may also comprise administering a pharmaceutical composition comprising the compound of formula (X) or a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer or prodrug thereof to the subject in need thereof.
  • the pharmaceutical composition may comprise any pharmaceutically acceptable carrier, diluent and/or excipient described herein.
  • the compounds of Formula (X), or a pharmaceutically acceptable salt or prodrug thereof, as defined herein, may be administered by any suitable means, for example, orally, rectally, nasally, vaginally, topically (including buccal and sub-lingual), parenterally, such as by subcutaneous, intraperitoneal, intravenous, intramuscular, or intracisternal injection, inhalation, insufflation, infusion or implantation techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • suitable means for example, orally, rectally, nasally, vaginally, topically (including buccal and sub-lingual), parenterally, such as by subcutaneous, intraperitoneal, intravenous, intramuscular, or intracisternal injection, inhalation, insufflation, infusion or implantation techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • the compounds of the invention may be provided as pharmaceutical compositions including those for oral, rectal, nasal, topical (including buccal and sub-lingual), parenteral administration (including intramuscular, intraperitoneal, sub-cutaneous and intravenous), or in a form suitable for administration by inhalation or insufflation.
  • the compounds of Formula (X), or a pharmaceutically acceptable salt or prodrug thereof, together with a conventional adjuvant, carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • kits of parts comprising in separate parts: • a compound of Formula (X) or a pharmaceutically acceptable salt, solvate, N- oxide, polymorph, tautomer or prodrug thereof; and
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography.
  • ambient temperature e.g. a reaction temperature
  • room temperature e.g. a temperature that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
  • B 2 pin 2 (bis(pinacolato)diboron
  • BOC 2 Q (di-te/Y-butyl dicarbonate); c-Hex (cyclohexane);
  • CDCI 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • CsF cesium fluoride
  • cone. Concentrated
  • d day
  • DAST diethylaminosulphur trifluoride
  • dba dibenzylideneacetone
  • DIAD diisopropyl azodicarboxylate
  • DIPEA N,N-diisopropylethylamine
  • Et 2 O diethyl ether
  • EtOAc ethyl acetate
  • EtOH ethanol
  • EtSO 2 CI ethanesulfonyl chloride
  • HCI hydrochloric acid/hydrogen chloride
  • HOBt hydroxybenzotriazole
  • 1 H NMR proton nuclear magnetic resonance
  • Hz Hertz
  • /-PrOH /so-propanol
  • KF potassium fluoride
  • MsCI methanesulfonyl chloride
  • n-BuLi n-butyllithium
  • NaH sodium hydride
  • NaHCO 3 sodium bicarbonate
  • NaOEt sodium ethoxide
  • NaOH sodium hydroxide
  • NaOMe sodium methoxide
  • Na 2 SO 4 sodium sulphate
  • NBS N-bromosuccinimide
  • NIS N-lodosuccinimide
  • NH 4 CI ammonium chloride
  • NMP N-methyl-2-pyrrolidone
  • Pd/C palladium on activated charcoal
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(O)
  • Pd(dppf)CI 2 [1 ,1 ’-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll));
  • Pd(OH) 2 palladium ⁇ I hydroxide on carbon - Pearlman’s catalyst
  • PE Petroleum Ether
  • prep-HPLC preparative high-performance liquid chromatography
  • prep-TLC preparative thin layer chromatography
  • PPm parts per million
  • psi poundss per square inch
  • p-TSA p-toluenesulfonic acid
  • RT room temperature
  • SEMCI (2-(trimethylsilyl)ethoxymethyl chloride); SPhos (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl); TBAF (tetra-n-butylammonium fluoride); f-BuNHNH 2 .HCI (te/Y-butylhydrazine hydrochloride); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); v/v (volume/volume); Xantphos (9,9-Dimethyl-4,5-bis(di-tert-butylphosphino)xanthene);
  • Electrospray mass spectroscopy was carried out using the following method.
  • Method A (5 minutes): LC model: Method A 1200 (Pump type: Binary Pump, Detector type: DAD) MS model: Method A G6110A Quadrupole. Column: Xbridge-C18, 2.5 ⁇ m, 2.1 x30 mm. Column temperature: 30 °C. Acquisition of wavelength: 214 nm, 254 nm. Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH. Run time: 5 min. MS: Ion source: ES+ (or ES-). MS range: 50 ⁇ 900 m/z. Fragmentor: 60. Drying gas flow: 10 L/min. Nebulizer pressure: 35 psi. Drying gas temperature: 350 °C. Vcap: 3.5 kV.
  • Method B (3.5 minutes): LC model: Method A 1200 (Pump type: Binary Pump, Detector type: DAD) MS model: Method A G6110A Quadrupole. Column: Xbridge-C18, 2.5 ⁇ m, 2.1 x30 mm. Column temperature: 30 °C. Acquisition of wavelength: 214 nm, 254 nm. Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH. Run time: 5 min. MS: Ion source: ES+ (or ES-). MS range: 50 ⁇ 900 m/z. Fragmentor: 60. Drying gas flow: 10 L/min. Nebulizer pressure: 35 psi. Drying gas temperature: 350 °C. Vcap: 3.5 kV.
  • LC model Waters 2695 alliance (Pump: Quaternary Pump, Detector: 2996 Photodiode Array Detector) MS model: Micromass ZQ LC: Column: Xbridge-C18, 3.5 ⁇ m, 2.1 x50 mm Column temperature: 20 °C.
  • Method D Mass detector: Agilent G6120B MSD Pump: 1260 Infinity G1312B Binary pump Autosampler: 1260 Infinity G1367E HiPALS Detector: 1260 Infinity G4212B DAD
  • Solvent A Water 0.1 % Formic Acid Solvent B: Acetonitrile 0.1 % Formic Acid Gradient: 5-100% B over 3.8 min Acquisition time: 4.1 min Detection: 254 nm and 254 nm
  • Ion source Single Quadrupole Ion Mode: API-ES Drying gas temperature: 350 °C
  • Method E Mass detector: Agilent G6120B MSD Pump: 1260 Infinity G1312B Binary pump Autosampler: 1260 Infinity G1367E HiPALS Detector: 1260 Infinity G4212B DAD Column: Atlantis T3, 3uM, 100A, 3.0 x 50mm Column temperature: 30 °C Injection volume: 1 ⁇ L Flowrate: 1.0 ml/min Solvent A: Water 0.1 % Formic Acid Solvent B: Acetonitrile 0.1 % Formic Acid Gradient: 5-50% B over 3.0 min Acquisition time: 4.1 min Detection: 214 and 254nm Ion source: Single Quadrupole Ion Mode: API-ES Drying gas temperature: 350 °C Capillary voltage (V): 4000 (positive) Capillary voltage (V): 4000 (negative) Scan Range: 100-1000 Step size: 0.1 sec
  • Method F Agilent: Mass detector: Agilent G6120B MSD, Pump: 1260 Infinity G1312B Binary pump, Autosampler: 1260 Infinity G1367E HiPALS, Detector: 1260 Infinity G4212B DAD.
  • LC conditions Column: Poroshell 120 EC-C18, 2.1 x 30mm 2.7 Micron, Column temperature: 30 °C, Injection volume: 1 uL, Flowrate: 1.0 ml/min, Solvent A: Water 0.1 % Formic Acid, Solvent B: Acetonitrile 0.1 % Formic Acid, Gradient: 5-100% B over 3.8 min, Acquisition time: 4.1 min, Detection: 214 and 254 nm.
  • Method G Agilent High MW: Mass detector: Agilent G6120B MSD, Pump: 1260 Infinity G1312B Binary pump, Autosampler: 1260 Infinity G1367E HiPALS, Detector: 1260 Infinity G4212B DAD.
  • LC conditions Column: Poroshell 120 EC-C18, 2.1 x30mm 2.7 Micron, Column temperature: 30 °C, Injection volume: 1 uL, Flowrate: 1.0 ml/min, Solvent A: Water 0.1 % Formic Acid, Solvent B: Acetonitrile 0.1 % Formic Acid, Gradient: 5-100% B over 3.8 min, Acquisition time: 4.1 min, Detection: 214 and 254 nm.
  • Method H Waters: Waters ZQ 3100 -Mass Detector, Waters 2545-Pump, Waters SFO System Fluidics Organizer, Waters 2996 Diode Array Detector, Waters 2767 Sample Manager.
  • LC conditions Reverse Phase HPLC analysis, Column: Xbridge TM C18 5 ⁇ m 4.6 x 100mm, Injection Volume 10 ⁇ L, Solvent A: Water 0.1 % Formic Acid, Solvent B: Acetonitrile 0.1 % Formic Acid, Gradient: 10-100% B over 8min, Flow rate: 1 .5 ml/min, Detection: 100-600 nm.
  • Method A Instrument type: VARIAN 940 LC. Pump type: Binary Pump. Detector type: PDA. LC conditions: Column: Waters SunFire prep C18 OBD, 5 ⁇ m, 19x100 mm. Acquisition wavelength: 214 nm, 254 nm. Mobile Phase: A: 0.07% TFA aqueous solution (or 0.1 % HCOOH aqueous solution), B: MeOH (or CH 3 CN).
  • Method B Waters ZQ 3100 -Mass Detector, Waters 2545-Pump, Waters SFO System Fluidics Organizer, Waters 2996 Diode Array Detector, Waters 2767 Sample Manager.
  • LC conditions Column: Xbridge TM prep C18 OBD 5 ⁇ m 19 x 100mm, Solvent A: Water 0.1 % Formic Acid, Solvent B: Acetonitrile 0.1 % Formic Acid, Gradient: variable, Flow rate: 20 ml/min, Detection: 100-600 nm MS conditions: Ion Source: Single-quadrupole, Ion Mode: ES positive, Source Temp: 150°C, Desolvation Temp: 350 °C, Detection: Ion counting, Capillary (KV)-3.00, Cone (V): 30, Extractor (V):3, RF Lens (V): 0.1 , Scan Range: 100-1000 Amu, Scan Time: 0.5 sec, Acquisition time: 20min Gas Flow: Desolvation L
  • Method C Waters ZQ 3100 -Mass Detector, Waters 2545-Pump, Waters SFO System Fluidics Organizer, Waters 2996 Diode Array Detector, Waters 2767 Sample Manager.
  • LC conditions Column: Xbridge TM prep C18 OBD 5 ⁇ m 19 x 100mm, Solvent A: Water, Solvent
  • Nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz or 300 MHz for 1 H nuclei as specified. Samples were recorded in deuterated solvent as specified, and data acquired at 25 °C. Chemical shifts are reported in p ⁇ m on the 6 scale and referenced to the appropriate solvent peak.-ln reporting spectral data, the following abbreviations have been used: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
  • Step 1 4-chloro-3-iodo-1 H-pyrazolo[4,3-c]pyridine
  • Step 1 4-chloro-3-iodo-1 H-pyrazolo[4,3-c]pyridine
  • Step 1 4-chloro-3-iodo-1 -isopropyl-1 H-pyrazolo[4,3-c]pyridine
  • Step 2 3-iodo-1-isopropyl-N-(4-methoxybenzyl)-1 H-pyrazolo[4,3-c]pyridin-4-amine
  • Step 1 N-(2,2-dimethoxyethyl)-1 H-pyrazole-5-carboxamide
  • Step 2 7-hydroxy-6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one
  • Step 3 pyrazolo[1 ,5-a]pyrazin-4(5H)-one
  • Step 4 4-chloropyrazolo[1 ,5-a]pyrazine
  • Step 5 4-chloro-3-iodopyrazolo[1 ,5-a]pyrazine
  • Step 1 (S)-4-bromo-2-(1 -(4-fluorophenyl)ethoxy)-1 -nitrobenzene
  • Step 4 (S)-1 ,1 -difluoro-N-(2-(1-(4-fluorophenyl)ethoxy)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl) methanesulfonamide
  • intermediates B were similarly prepared from the appropriate benzyl alcohol (step 1) according to the preparation of (S)-1 ,1-difluoro-N-(2-(1-(4-fluorophenyl)ethoxy)-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (intermediate B1)
  • Step 2 N-[4-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)phenyl]ethane-1 -sulfonamide
  • Step 1 1 ,1 -difluoro-N-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl] methanesulfonamide
  • Step 1 4-bromo-2-((4-fluorobenzyl)oxy)-1 -nitrobenzene
  • Step 4 N-(2-((4-fluorobenzyl)oxy)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2- yl)phenyl)ethanesulfonamide
  • Step 1 4-bromo-2-fluoroaniline To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (5 g, 22.7 mmol) in MeOH (12 mL) and sat. aq. NH4CI (4 mL) was added Zn (7.39 g, 113 mmol), And the reaction was stirred at 60 °C for 6 h. The mixture was concentrated, and the residue was diluted with water (150 mL) and extracted with EtOAc (150 mL x 3). The combined organic phases were washed with water and brine, dried (Na2SC>4) and concentrated. The residue was purified by column chromatography to afford the title product (2.5 g, 58%) as a brown oil. LCMS (method A): 3.39 min, m/z: 189.9,191 ,9[M+H] + .
  • Step 3 N-[2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]ethane-1- sulfonamide
  • Step 1 N- ⁇ 4-bromo-2-[(4-fluorophenyl)methoxy]phenyl ⁇ -1 ,1-difluoromethanesulfonamide
  • pyridine 6.54 g, 82.8 mmol
  • difluoromethanesulfonyl chloride 4.98 g, 33.1 mmol
  • Step 2 1 ,1 -difluoro-N- ⁇ 2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl ⁇ methanesulfonamide
  • Step 1 N-(4- ⁇ 4-amino-1 -methyl-1 Hpyrazolo[4,3-c]pyridin-3-yl ⁇ -2-[(1 S)-1 -(4-fluorophenyl) ethoxy]phenyl)-1 ,1-difluoromethanesulfonamide (Compound 17)
  • Step 1 N-(4- ⁇ 4-amino-1-methyl-1 H-pyrazolo[4,3-c]pyridin-3-yl ⁇ -2-[(4-fluorophenyl)methoxy] phenyl)ethane-1 -sulfonamide
  • Step 2 N-(4-(4-amino-7-iodo-1-methyl-1 H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl) oxy)phenyl)ethanesulfonamide
  • Step 1 N-(4- ⁇ 4-amino-1-methyl-1 H-pyrazolo[4,3-c]pyridin-3-yl ⁇ -2-[(4-fluorophenyl)methoxy] phenyl)-1,1 -difluoromethanesulfonamide (Compound 10)
  • Step 2 N-(4-(4-amino-7-iodo-1-methyl-1 H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl) oxy)phenyl)-1 ,1 -difluoro methanesulfonamide
  • Step 1 (S)-N-(4-(4-amino-1 -isopropyl-1 H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1 -(4- fluorophenyl)ethoxy)phenyl)-1 ,1 -difluoromethanesulfonamide (Compound 53)
  • Step 2 (S)-N-(4-(4-amino-7-iodo-1 -isopropyl-1 H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1 -(4- fluorophenyl)ethoxy)phenyl)-1 ,1 -difluoromethanesulfonamide
  • Step 1 (S)-N-(4-(4-aminopyrazolo[1 ,5-a]pyrazin-3-yl)-2-(1 -(4-fluorophenyl)ethoxy)phenyl)- 1,1 -difluoromethanesulfonamide (Compound 22)
  • Step 2 (S)-N-(4-(4-amino-7-bromopyrazolo[1 ,5-a]pyrazin-3-yl)-2-(1-(4-fluorophenyl)ethoxy) phenyl)-1 ,1 -difluoro methanesulfonamide
  • Step 1 tert-butyl 4-(benzyloxy)piperidine-1 -carboxylate
  • Step 3 4-(benzyloxy)-1 -(2,2,2-trifluoroethyl)piperidine
  • Step 5 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl)-1 -(2,2,2- trifluoroethyl)piperidine
  • Step 1 1 -(2-bromoethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
  • Step 2 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1- yl)ethyl)piperazine
  • Step 1 N-methyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl)ethan-1 - amine
  • Step 1 N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1- yl)ethan-1 -amine
  • Step 1 8-methyl-8-azabicyclo[3.2.1]octan-3-yl methanesulfonate
  • Step 2 8-methyl-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl]-8- azabicyclo[3.2.1]octane
  • 8-methyl-8-azabicyclo[3.2.1]octan-3-yl methanesulfonate 500 mg, 2.27 mmol
  • 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole 440 mg, 2.27 mmol
  • K 2 CO 3 941 mg, 6.81 mmol
  • Step 1 4-bromo-1-methyl-1 H-pyrrole-2-carbonitrile
  • Step 2 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-2-carbonitrile
  • Step 1 2- ⁇ 3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl]oxetan-3- yljacetonitrile
  • Step 3 2-(4-bromo-1 H-pyrazol-1 -yl)-N-isopropyl-N-methylpropan-1 -amine
  • Step 4 methyl(propan-2-yl) ⁇ 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 - yl]propyl ⁇ amine
  • Step 1 2-(4-iodo-1 H-pyrazol-1 -yl)acetonitrile To a solution of 4-iodo-1 H-pyrazole (1 g, 5.15 mmol) in DMF (10 mL) were added K 2 CO 3 (1 .42 g, 10.3 mmol) and 2-bromoacetonitrile (678 mg, 5.66 mmol) at RT. The reaction mixture was stirred at 50 °C overnight. The reaction mixture was extracted with EtOAc (2 x 30mL) and the combined rganics were washed with water and brine, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 2 1-(4-iodo-1 H-pyrazol-1 -yl)cyclopropane-1 -carbonitrile
  • Step 3 1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 -yl)cyclopropane-1 - carbonitrile
  • Step 1 4-(4-(4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl)piperidine
  • Step 2 1-(methyl-d3)-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 - yl)piperidine
  • Step 1 tert-butyl 3-methyl-5-(tosyloxy)piperidine-1-carboxylate
  • Step 2 tert-butyl 3-(4-bromo-1 H-pyrazol-1-yl)-5-methylpiperidine-1 -carboxylate
  • Step 3 tert-butyl 3-methyl-5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1- y I) pipe rid i ne- 1 -carboxylate
  • Step 1 tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate
  • Step 2 tert-butyl 2- ⁇ [(4-methylbenzenesulfonyl)oxy]methyl ⁇ pyrrolidine-1 -carboxylate
  • Step 3 tert-butyl 2-[(4-bromo-1 H-pyrazol-1-yl)methyl]pyrrolidine-1 -carboxylate
  • Step 4 tert-butyl 2-((4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1- yl)methyl)pyrrolidine-1 -carboxylate
  • Step 1 tert-butyl 6-[(4-methylbenzenesulfonyl)oxy]-2-azaspiro[3.3]heptane-2-carboxylate
  • Step 2 tert-butyl 6-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl)-2- azaspiro[3.3]heptane-2-carboxylate
  • Step 1 tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate
  • Step 2 tert-butyl 4-(4-bromo-1 H-pyrazol-1 -yl)azepane-1 -carboxylate
  • Step 3 tert-butyl 4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl]azepane- 1 -carboxylate
  • Step 1 1 -(1 -methylpyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole
  • Step 1 tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate
  • Step 2 tert-butyl 3-(4-bromo-1 H-pyrazol-1 -yl)azetidine-1 -carboxylate
  • Step 3 tert-butyl 3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl)azetidine -1 -carboxylate
  • Pd(dppf)Cl2 (1.86 g, 2.55 mmol
  • AcOK 7.49 g, 76.44 mmol
  • B 2 (pin) 2 9.71 g, 38.22 mmol
  • Step 4 1 -(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole hydrochloride
  • Step 5 1-(1-isopropylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyraz ole
  • Step 1 tert-butyl 3-oxoazetidine-1 -carboxylate
  • Step 2 tert-butyl 3-hydroxyazetidine-1 -carboxylate
  • Step 3 tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1 -carboxylate
  • Step 4 tert-butyl 3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 -yl]azetidine-1 - carboxylate
  • Step 5 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
  • Step 6 1-(1 -methylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
  • Step 1 tert-butyl 3-(benzyloxy)azetidine-1 -carboxylate
  • Step 5 1-(2,2,2-trifluoroethyl)azetidin-3-yl methanesulfonate
  • DCM DCM
  • Et 3 N 103 mg, 1 .02 mmol
  • MsCI 70.7 mg, 618 ⁇ mol
  • the solution was stirred at RT for 1 h, then poured into water (10 mL) and extracted with DCM (2 x 20mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to give the title product (100 mg, 83%) as a light yellow oil.
  • Step 6 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-[1-(2,2,2--trifluoroethyl)azetidin-3- yl]-1 H-pyrazole
  • Step 1 give 2-chloro-N-methyl-N-(propan-2-yl)propanamide
  • Step 2 N-methyl-N-(propan-2-yl)-2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazol-1 -yl]propanamide
  • 2-chloro-N-methyl-N-(propan-2-yl)propanamide (1.45 g, 8.86 mmol) in DMF (25 mL) were added K2CO3 (3.05 g, 22.1 mmol) and 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 Hpyrazole (1 .43 g, 7.38 mmol).
  • Step 1 tert-butyl 2, 2-dimethyl-5-((methylsulfonyl)oxy)piperidine-1 -carboxylate
  • Step 2 tert-butyl 2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol- 1 -y I) pi pe rid i n e- 1 -carboxylate
  • Step 1 3-hydroxycyclopentyl 4-methylbenzene-1 -sulfonate
  • Step 3 3-(4-bromo-1 H-pyrazol-1-yl)cyclopentyl 4- methylbenzene-1 -sulfonate
  • Step 4 3-(4-bromo-1 H-pyrazol-1-yl)-N,N-dimethylcyclopentan-1 -amine
  • Step 5 N,N-dimethyl-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1- yl]cyclopentan-1 -amine

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WO2024137742A1 (en) * 2022-12-20 2024-06-27 Blueprint Medicines Corporation Compounds and compositions as fgfr3 degraders and uses thereof
WO2025051160A1 (zh) * 2023-09-08 2025-03-13 北京华益健康药物研究中心 用于治疗或预防冠状病毒感染的3cl蛋白酶抑制剂及其用途
EP4452977A4 (en) * 2021-12-22 2025-12-17 Anaxis Pharma Pty Ltd ARYLSULFONAMIDE COMPOUNDS

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WO2007144202A1 (en) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Substituted aminopyrazolopyridines and salts thereof, their preparations and pharmaceutical compositions comprising them
WO2021053495A1 (en) * 2019-09-16 2021-03-25 Novartis Ag Bifunctional degraders and their methods of use
WO2021253095A1 (en) * 2020-06-19 2021-12-23 Anaxis Pharma Pty Ltd Sulphonamide compounds

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WO2018192416A1 (en) * 2017-04-17 2018-10-25 National Institute Of Biological Sciences, Beijing Treating Male Senescence
MX2024007885A (es) * 2021-12-22 2024-09-23 Anaxis Pharma Pty Ltd Compuestos de arilsulfonamida.

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WO2007144202A1 (en) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Substituted aminopyrazolopyridines and salts thereof, their preparations and pharmaceutical compositions comprising them
WO2021053495A1 (en) * 2019-09-16 2021-03-25 Novartis Ag Bifunctional degraders and their methods of use
WO2021253095A1 (en) * 2020-06-19 2021-12-23 Anaxis Pharma Pty Ltd Sulphonamide compounds

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Cited By (3)

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EP4452977A4 (en) * 2021-12-22 2025-12-17 Anaxis Pharma Pty Ltd ARYLSULFONAMIDE COMPOUNDS
WO2024137742A1 (en) * 2022-12-20 2024-06-27 Blueprint Medicines Corporation Compounds and compositions as fgfr3 degraders and uses thereof
WO2025051160A1 (zh) * 2023-09-08 2025-03-13 北京华益健康药物研究中心 用于治疗或预防冠状病毒感染的3cl蛋白酶抑制剂及其用途

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