WO2021168521A1 - Inhibiteurs de nécroptose - Google Patents

Inhibiteurs de nécroptose Download PDF

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Publication number
WO2021168521A1
WO2021168521A1 PCT/AU2021/050176 AU2021050176W WO2021168521A1 WO 2021168521 A1 WO2021168521 A1 WO 2021168521A1 AU 2021050176 W AU2021050176 W AU 2021050176W WO 2021168521 A1 WO2021168521 A1 WO 2021168521A1
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methyl
mmol
prodrug
stereoisomer
polymorph
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PCT/AU2021/050176
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English (en)
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Guillaume Laurent Lessene
Jean-Marc Daniel GARNIER
John Thomas Feutrill
Anthony Nicholas Cuzzupe
Peter Edward Czabotar
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Anaxis Pharma Pty Ltd
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Priority claimed from AU2020900562A external-priority patent/AU2020900562A0/en
Application filed by Anaxis Pharma Pty Ltd filed Critical Anaxis Pharma Pty Ltd
Publication of WO2021168521A1 publication Critical patent/WO2021168521A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents

Definitions

  • the present disclosure relates to novel heterocyclic compounds which inhibit necroptosis and methods for their use.
  • 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 eta!., Nat. Chem. Biol. 1 :112, 2005). This manner of cell death 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).
  • TNF-[alpha] and Fas ligand 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.
  • RIP1 is the switch by which cell death is either directed towards an apoptotic or necroptotic phenotype.
  • MLKL is the last known effector of the necroptotic cascade.
  • W is N or C-R, wherein R is selected from the group consisting of hydrogen, flouro, chloro, Ci- C2 alkyl, C1-C2 haloalkyl, methoxy, halomethoxy or cyano; and Ri is selected from the group consisting of hydrogen, C1 -C4 alkyl, deuterated C1 -C4 alkyl, and C1-C4 hydroxyalkyl, and 3-7 membered heterocyclyl;
  • J is selected selected from the group consisting of hydrogen, C1 -C4 alkyl, C1 -C4 hydroxyalkyl, and 3-7 membered heterocyclyl;
  • L is the linker -(CHR a ) n - wherein n is 0 or 1 and R a is selected from the group consisting of hydrogen, C1 -C4 alkyl, C1 -C4 hydroxyalkyl, C3-C7 cycloalkyl, and 3-7 membered heterocyclyl;
  • Xi, X 2 , X3, X4 and X 5 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, aryl, heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy, aryloxy, aralkoxy, halo, -CN, -NR'R', N(H)C(0)R", N(H)C(0)0R", N(H)C(0)NR'R', N(H)S(0) 2 R", OR", 0C(0)RR", C(0)R", SR", -S(0)R”', S(0) 2 R"', and S(0) 2 NR'R', wherein
  • R' is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, -OR 1 , -SR 1 , -S(0) 2 R 1 , -S(0)R 1 , and C(0)R 1 ; and
  • R" is selected from the group consisting of hydrogen, C1 -C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, -OR 1 , -NR 3 R 4 , -S(0) 2 R 1 , -S(0)R 1 and C(0)R 1 ; and
  • R' is selected from the group consisting of hydrogen, C1 -C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, -OR 1 and -NR 3 R 4 ;
  • A is selected from the group consisting of 5-6 membered heteroaryl and C& aryl;
  • Q is hydrogen or is one or more substituents, wherein one substituent is selected from a group consisting of:
  • Z is CH 2 and m is 0, 1 , 2, or 3;
  • Z 1 is C(O), and n is 0 or 1 ;
  • Z 2 is C1 -C4 alkyl, C1 -C4 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, NR 3 R 4 , aryl, arylamino, aralkyl, aralkoxy, or heteroaryl; wherein R 3 and R 4 are each independently selected from hydrogen, and C1-C6 alkyl; and optionally, the one or more substituents comprise a further substituent or substituents independently selected from the group consisting of halogen, C 1 -C 2 alkoxy, and C 1 -C 2 haloalkoxy; C 1 -C 3 alkyl, CrCs haloalkyl, and -OR 1 .
  • composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, and a pharmaceutically acceptable excipient.
  • a method for inhibiting necroptosis in a subject in need thereof comprising administering a therapeutically effective amount of a compound or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof of Formula (I) to a subject.
  • a method for inhibiting necroptosis in a subject in need thereof comprising administering a therapeutically effective amount of a composition containing a compound or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof of Formula (I) to a subject.
  • 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 salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • a method for inhibiting necroptosis in a subject in need thereof comprising administering a therapeutically effective amount of a composition comprising a compound according to Formula (I) a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • a composition comprising a compound according to Formula (I) a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • MLKL Mixed Lineage Kinase Domain-like
  • a compound of Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof in the preparation of a medicament for the inhibition of necroptosis in a subject.
  • composition comprising a compound of Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, in the preparation of a medicament for the inhibition of necroptosis in a subject.
  • a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof for inhibiting necroptosis.
  • composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, for inhibiting necroptosis.
  • composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, for use in inhibiting necroptosis.
  • composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, when used for inhibiting necroptosis.
  • 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.
  • the present invention provides a compound of Formula (I): Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer, polymorph and/or physiologically functional derivative thereof, wherein:
  • W is N or C-R, wherein R is selected from the group consisting of hydrogen, flouro, chloro, C1-C2 alkyl, C1-C2 haloalkyl, methoxy, halomethoxy or cyano; and
  • Ri is selected from the group consisting of hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, and C1-C4 hydroxyalkyl, and 3-7 membered heterocyclyl
  • J is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, and 3-7 membered heterocyclyl
  • L is the linker -(CHR a ) n - wherein n is 0 or 1 and R a is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C3-C7 cycloalkyl, and 3-7 membered heterocyclyl; and
  • Xi, X 2 , X3, X4 and X 5 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, aryl, heteroaryl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, hydroxy, aryloxy, aralkoxy, halo, -CN, -NR'R', N(H)C(0)R", N(H)C(0)0R", N(H)C(0)NR'R', N(H)S(0) R", OR", 0C(0)RR", C(0)R", SR", -S(0)R”', S(0) R'", and S(0) 2 NR'R', wherein
  • R' is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, -OR 1 , -SR 1 , -S(0) 2 R 1 , -S(0)R 1 , and C(0)R 1 ; and R" is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, -OR 1 , -NR 3 R 4 , -S(0) 2 R 1 , -S(0)R 1 and C(0)R 1 ; and
  • R'" is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocyclyl, -OR 1 and -NR 3 R 4 ;
  • A is selected from the group consisting of 5-6 membered heteroaryl and C& aryl;
  • Q is hydrogen or is one or more substituents, wherein one substituent of the one or more substituents is selected from a group consisting of:
  • Z is CH 2 and m is 0, 1 , 2, or 3; and Z 1 is C(O), and n is 0 or 1 ;
  • Z 2 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, 3-7 membered heterocyclyl, NR 3 R 4 , aryl, arylamino, aralkyl, aralkoxy, or heteroaryl; wherein R 3 , and R 4 are each independently selected from hydrogen, and C1-C6 alkyl; and optionally, the one or more substituents comprise a further substituent or substituents independently selected from the group consisting of hydrogen, halogen, C1-C2 alkoxy, and C1-C2 haloalkoxy; Ci -C 3 alkyl, CrCshaloalkyl, and -OR 1 .
  • Ri is methyl
  • Ri is 3-7 membered heterocyclyl wherein the heteroatom is oxygen.
  • R1 is oxetane.
  • X 2 and X 4 are each independently selected from -F, -Cl, -OCF 3 and -CF 3 and Xi, X 3 and X 5 are each hydrogen.
  • X 3 is other than hydrogen and Xi, X 2 , X 4 and X 5 are hydrogen.
  • X 3 is -OCF 3 .
  • J is methyl
  • W is CR and R is hydrogen, methyl, chloro, fluoro or trifluoromethyl. In a preferred embodiment, R is hydrogen.
  • A is 5 membered heteroaryl.
  • A is selected from the group consisting of pyrazole, imidazole, isoxazole or oxazole. More preferably, pyrazole.
  • Q is (Co-C 2 alkyl)3-7 membered heterocyclyl.
  • Q is a 4 membered heterocyclyl wherein the heteroatom is N. More preferably Q is: or
  • Q is (Cialkyl)C 6 heterocyclyl comprising two O heteroatoms.
  • Q is
  • L is absent, ie n is zero.
  • L is -CH2-.
  • the compound of formula (I) is selected from the group consisting of:
  • composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, and a pharmaceutically acceptable excipient.
  • alkyl refers to a straight or branched chain hydrocarbon radical having from one to twelve carbon atoms, or any range between, i.e. it contains 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the alkyl group may be unsubstituted or optionally substituted with one or more substituent(s), multiple degrees of substitution being allowed, for example 1 -6 substitutents.
  • substituent(s) include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
  • C1-C3 alkyl refers to an alkyl group, as defined above, containing at least 1 , and at most 3, 4 or 6 carbon atoms respectively, or any range in between (e.g. alkyl groups containing 2-5 carbon atoms are also within the range of Ci- Ce).
  • C0-C2 alkyl there may be no alkyl group, or an alkyl group containing 1 or 2 carbon atoms.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term “halo” refers to the halogen radicals fluoro (-F), chloro (-CI), bromo (-Br), and iodo (- I).
  • halo is fluoro or chloro.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring.
  • C3-C 7 cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to seven carbon atoms, or any range in between.
  • the C3-C 7 cycloalkyl group would also include cycloalkyl groups containing 4 to 6 carbon atoms.
  • the alkyl group is as defined above, and may be substituted.
  • C3-C 7 cycloalkyl groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • heterocyclic or “heterocyclyl” refer to a nonaromatic heterocyclic ring, being saturated or having one or more degrees of unsaturation, containing one or more heteroatom substitution selected from S, S(O), S(0) 2 , O, or N.
  • C3-C7 heterocyclyl refers to a non-aromatic cyclic hydrocarbon ring having from three to seven ring atoms containing one or more heteroatom substitutions as referred to herein. Accordingly, the term “C3-C 7 heterocyclyl” may alternatively be referred to as a 3-7 membered heterocyclyl.
  • the heterocyclic moiety may be unsubstituted or optionally substituted, multiple degrees of substitution being allowed.
  • C3-C 7 heterocyclyl also includes heterocyclyl groups containing C4-C5, C5-C 7 , C6-C 7 , C4-C 7 , C4-C6 and C5-C6 carbon atoms.
  • the term “3-7 membered heterocyclyl” also includes heterocyclyl groups containing 4-5 membered rings, 5-7 membered rings, 6-7 membered rings, 4-7 membered rings, 4-6 membered rings and 5-6 membered rings.
  • the heterocyclic ring contains four to six carbon atoms and one or two heteroatoms.
  • the heterocyclic ring contains five carbon atoms and one heteroatom, or four carbon atoms and two heteroatom substitutions, or five carbon atoms and one heteroatom.
  • Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s).
  • heterocyclic moieties include, but are not limited to, tetrahydrofuran, pyran, oxetane, 1 ,4- dioxane, 1 ,3-dioxane, piperidine, piperazine, /V-methylpiperazinyl, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • the term “(C 0 -C 2 alkyl)3-7 membered heterocyclyl” includes heterocyclyl groups containing either no alkyl group as a linker between the compound and the heterocycle, or an alkyl group containing 1 or 2 carbon atoms as a linker between the compound and the heterocycle (i.e. heterocycle, -CH 2 -heterocycle or -CH 2 CH 2 - heterocycle). These heterocycles may be further substituted.
  • Substituted cycloalkyl and heterocyclyl groups may be substituted with any suitable substituent as described below. They may be substituted at any of the carbons on the ring with another cycloalkyl or heterocyclic moiety to form a spiro compound.
  • aryl refers to an optionally substituted benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form, for example, anthracene, phenanthrene, or napthalene ring systems.
  • the aryl group may be unsubstituted or optionally substituted with one or more substituent(s), multiple degrees of substitution being allowed,
  • Examples of "aryl” groups include, but are not limited to, phenyl, 2- naphthyl, 1 -naphthyl, biphenyl, as well as substituted derivatives thereof.
  • Preferred aryl groups include arylamino, aralkyl, aralkoxy, heteroaryl groups.
  • heteroaryl refers to a monocyclic five, six or seven membered aromatic ring, or to a fused bicyclic or tricyclic aromatic ring system comprising at least one monocyclic five, six or seven membered aromatic ring.
  • These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxides are permissible heteroatom substitutions and may be optionally substituted with up to three members.
  • the heteroaryl moiety may be unsubstituted or optionally substituted, multiple degrees of substitution being allowed.
  • C 5 -C 6 heteroaryl or “5-6 membered heteroaryl” refers to an aromatic ring having 5 to 6 ring atoms, of which one or more of the ring atoms are heteroatom substitutions as referred to herein.
  • heteroaryl groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, and substituted versions thereof.
  • haloalkyl refers to refers to an alkyl group as defined above substituted with one or more halogens as defined above.
  • hydroxyalkyl refers to refers to an alkyl group as defined above bound to a hydroxyl group.
  • alkoxy refers to an alkyl group as defined above covalently bound via an O linkage.
  • haloakoxy refers to an alkyl group as defined above substituted with one or more halogens as defined above, wherein the alkyl group is covalently bound via an O linkage.
  • aryloxy refers to an aryl group as defined above covalently bound via an O linkage.
  • aralkoxy refers to refers to an aryl group as defined above covalently bound via an alkyl linkage as defined above, wherein the alkyl linkage is covalently bound via an O linkage.
  • arylamino refers to an aryl group as defined above covalently bound via an amino linkage.
  • a “ring substituent” may be a moiety such as a halogen, alkyl group, or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity.
  • substituents include but are not limited to:
  • substituents may be further substituted by any of the above- mentioned substituents, where appropriate.
  • substituents for example, alkylamino, or dialkylamino, C 1 -C 6 alkoxy, etc.
  • cyclic or heterocyclic substituents may form a spiro substituent with a carbon in the moiety from which the cyclic or heterocyclic group is substituted.
  • a method for inhibiting necroptosis in a subject in need thereof comprising administering a therapeutically effective amount of a compound or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof of Formula (I), Formula (II), Formula (III) and/or Formula (IV) to a subject.
  • a method for inhibiting necroptosis in a subject in need thereof comprising administering a therapeutically effective amount of a composition containing a compound or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof of Formula (I) to a subject.
  • 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 salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • a method for inhibiting necroptosis in a subject in need thereof comprising administering a therapeutically effective amount of a composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • a composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof, that binds to the ATP-binding site of the pseudokinase domain of Mixed Lineage Kinase Domain-like (MLKL) protein.
  • MLKL Mixed Lineage Kinase Domain-like
  • 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.
  • Some compounds of this invention may bind to RIP1 .
  • RIP1 kinase is the switch between apoptosis and necroptosis. It has already been shown that, in cases where apoptosis is inhibited (for example using a pan caspase inhibitor such as QVD-OPh), RIP1 mediates a necroptotic response. Moreover, it has also been shown that small molecule inhibitors of RIP1 can potently inhibit necroptosis (see for example Degterev et al, Nat Chem Biol, pp 112 - 119, 2005 and Harris, J Med Chem, 2016). Therefore compounds in this invention may inhibit necroptosis by inhibiting RIP1 .
  • MLKL is the last known effector of necroptosis (Murphy, Immunity, 39, pp 443 - 453, 2013). Without it, necroptosis cannot unfold properly. MLKL acts downstream of 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.
  • necroptotic stimulus e.g. using the combination of TNF, SMAC mimetic and QVD-OPh on suitable cell lines
  • RIP3 phosphorylates MLKL leading to a putative conformational change that triggers its necroptotic activity (Murphy, Immunity, 39, pp 443 -453, 2013).
  • Compounds of this invention may bind to MLKL and block this conformational change or any other key event in its activation.
  • Compounds that can simultaneously inhibit RIP1 auto-phosphorylation and MLKL activation may represent very powerful inhibitors of necroptosis due to the fact that they interfere with two key components of the pathway.
  • a compound of Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof in the preparation of a medicament for the inhibition of necroptosis in a subject.
  • composition comprising a compound of Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof in the preparation of a medicament for the inhibition of necroptosis in a subject.
  • composition comprising a compound of Formula (I) or a salt, solvate, prodrug tautomer, N-oxide, stereoisomer and/or polymorph thereof for inhibiting necroptosis.
  • a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof for use in inhibiting necroptosis.
  • composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof for use in inhibiting necroptosis.
  • composition comprising a compound according to Formula (I) or a salt, solvate, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof when used for inhibiting necroptosis.
  • the salts of the compounds of Formula (I) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable may be used to describe any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of Formula (I) or an active metabolite or residue thereof.
  • 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 forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • Amorphous solid forms of the compounds are also intended to be within the scope of the present invention and specified formulae.
  • the compound of Formula (I) or salts, tautomers, N-oxides, stereoisomers, solvates and/or prodrugs thereof that form crystalline solids may demonstrate polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides, stereoisomers, solvates and/or prodrugs are within the scope of this invention and may be used in the methods of the invention.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • Formula (I) includes compounds having the indicated structures, including the hydrated or solvated forms, as well as the non-hydrated and non-solvated forms.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula (I) or a salt, prodrug, tautomer, N-oxide, stereoisomer and/or polymorph thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower 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 within a compound of the invention may also be oxidised to form an N-oxide.
  • the compound of the invention may demonstrate tautomerism.
  • Tautomers are two interchangeable forms of a molecule that typically exist within an equilibrium. Any tautomers of the compounds described herein are to be understood as being within the scope of the invention and may be used in the methods of the invention.
  • the compound of the invention may contain one or more stereocentres. All stereoisomers of the compounds described herein 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. In some embodiments, the compound is a stereoisomerically enriched at any stereocentre. The compound may be enriched in one stereoisomer over another by about 60, 70, 80, 90, 95, 98 or 99%.
  • the compound of the invention or its salts, tautomers, solvates, N-oxides, polymorphs 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 0.
  • 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 (I) 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 (I).
  • 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 (I) through the carbonyl carbon prodrug sidechain.
  • the compounds of Formula (I) and prodrugs thereof may be covalent irreversible or covalent reversible inhibitors of the active site of a protein.
  • compositions may be formulated from compounds according to Formula (I) for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.
  • 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.
  • 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.
  • 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 Martin (ed.), Remington's Pharmaceutical Sciences.
  • administering and variations of that term including “administer” and “administration”, 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. Preferred doses range 5 from about 0.1 mg to about 140 mg per kilogram of body weight per day (e.g. about 0.5 mg to about 7 g per patient per day).
  • 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. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.
  • 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, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the subject), and the severity of the particular disorder undergoing therapy.
  • the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the compound of formula (I) to be administered may need to be optimized for each individual.
  • the pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 200 mg.
  • the daily dose can be administered in one to four doses per day.
  • 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.
  • therapeutically effective amount or “effective amount” refer to an amount of the compound of formula (I) that results in an improvement or remediation of the symptoms of necroptosis and/or associated diseases or their symptoms.
  • 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, including complete and partial inhibition.
  • the compounds of the present invention may be administered along with a pharmaceutical carrier, diluent or excipient as described above.
  • the methods of the present disclosure can be used to prevent or treat the following disease in a subject:
  • osteoporosis diseases of the bones, joints, connective tissue and of cartilage
  • osteomyelitis arthritises including for example osteoarthritis, rheumatoid arthritis and psoriatic arthritis, avascular necrosis, progressive fibrodysplasia ossificans, rickets, Cushing's syndrome
  • 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;
  • diseases of the skin such as dermatitis, eczema, psoriasis, aging or even alterations of scarring; • cardiovascular diseases such as cardiac and/or vascular ischemia, myocardium 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;
  • cardiovascular diseases such as cardiac and/or vascular ischemia, myocardium 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, cerebrovascular strokes, aneurisms;
  • haematological and vascular diseases such as: 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 bronchitis and emphysema;
  • 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, certain hereditary metabolic disorders, Wilson's disease, cirrhoses, non alcoholic hepatic steatosis, diseases of the liver due to toxins and to drugs such as drug- induced liver injury;
  • pancreatitis diseases of the pancreas such as for example acute or chronic pancreatitis
  • metabolic diseases such as diabetes mellitus and insipid diabetes, thyroiditis;
  • kidneys diseases of the kidneys such as for example acute renal disorders or glomerulonephritis;
  • 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;
  • mitochondria pathologies diseases associated with mitochondria (mitochondrial pathologies), 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; and
  • 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 myelogen
  • 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.
  • CDI 1,T-Carbonyldiimidazole CS2CO3 cesium carbonate DMSO-d 6 deuterated dimethylsulfoxide DCC dicyclohexylcarbodiimide DCM dichloromethane DIPEA diisopropylethylamine DMF A/,A/-dimethylformamide DMSO dimethylsulfoxide TEA triethylamine EtOAc ethylacetate EtOH ethanol hr hour(s)
  • Electrospray mass spectroscopy was carried out using the following method; Method B (5 min method): LC model: Agilent 1200 (Pump type: Binary Pump, Detector type: DAD) MS model: Agilent G6110A Quadrupole. Column: Xbridge-C18, 2.5 pm, 2.1x30 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.
  • VARIAN 940 LC VARIAN 940 LC.
  • Pump type Binary Pump.
  • Detector type PDA LC conditions:
  • Step 1 A/-methyl-3,5-dinitropyridin-2-amine
  • Step 3 3-methyl-6-nitro-N-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2- amine
  • Step 4 3-methyl-6-nitro-N-(4-(trifluoromethoxy)phenyl)-N-((2-(trimethylsilyl)ethoxy) methyl)-3H- imidazo[4,5-b]pyridin-2-amine
  • THF 20 ml_
  • NaH 310 mg, 15 mmol
  • SEMCI 852 mg, 5.1 mmol
  • Step 5 3-methyl-/ ⁇ /2-(4-(trifluoromethoxy)phenyl)-N2-((2-(trimethylsilyl)ethoxy) methyl)-3H- imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 6 A/6-(2-chloropyrimidin-4-yl)-3-methyl-N2-(4-(trifluoromethoxy)phenyl)-N2- ((2-chloropyrimidin-4-yl)-3-methyl-N2-(4-(trifluoromethoxy)phenyl)-N2- ((2-chloropyrimidin-4-yl)-3-methyl-N2-(4-(trifluoromethoxy)phenyl)-N2- ((2-
  • Step 7 (Intermediate A) A/6-(2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-(4-
  • Step 3 3-methyl-6-nitro-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
  • Step 4 2-chloro-3-methyl-6-nitro-3H-imidazo[4,5-b]pyridine
  • Intermediate B A solution of 3-methyl-6-nitro-1 H-imidazo[4,5-b]pyridin-2(3H)-one (2.0 g, 10.3 mmol) in POCI3 (30 ml.) was stirred at 120 °C for 8 hours, and then concentrated under reduced pressure. The residue was diluted with saturated NaHCC>3 solution (30 ml.) and ethyl acetate (50 ml_). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure.
  • Step 4 A/,2-dimethyl-5-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl) ((2-
  • Step 1 2-(4-nitro-1 /-/-pyrazol-1-yl)acetamide
  • Step 2 2-(4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl)amino)-3H- imidazo[4,5- b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl) acetamide
  • Step 2 A/-methyl-2-(4-nitro-1 H-pyrazol-1 -yl)acetamide
  • Step 1 tert-butyl 3-(4-nitro-1 H-pyrazol-1-yl)azetidine-1-carboxylate
  • Step 2 tert-butyl 3-(4-amino-1 H-pyrazol-1 -yl)azetidine-1 -carboxylate
  • Step 3 tert-butyl 3-(4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl) ((2- (trimethylsilyl)ethoxy)methyl)amino)-3H-imidazo[4,5-b]pyridin-6-yl)amino) pyrimidin-2-yl)amino)- 1 H-pyrazol-1 -yl)azetidine-1 -carboxylate
  • Step 4 N6-(2-((1-(azetidin-3-yl)-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)- N6,3-dimethyl-N2-(4- (trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 1 tert-butyl 2-(4-nitro-1 H-pyrazol-1 -yl)ethylcarbamate
  • Step 3 tert-butyl (2-(4-((4-(methyl(3-methyl-2-(1-(4-(trifluoromethoxy)phenyl)- 2-(2- (trimethylsilyl)ethoxy)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino) pyrimidin-2-yl)amino)-1 H- pyrazol-1 -yl)ethyl)carbamate
  • Step 4 N6-(2-((1-(2-aminoethyl)-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N6,3- dimethyl-N2-(4- (trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine-2,6- diamine
  • Step 1 A/,/V-dimethyl-2-(4-nitro-1 H-pyrazol-1 -yl)acetamide
  • Step 3 /V,/V-dimethyl-2-(4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl) amino)-3H- imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl) acetamide
  • Step 1 1-(azetidin-3-yl)-4-nitro-1 H-pyrazole
  • Step 4 N6,3-dimethyl-N6-(2-((1-(1-methylazetidin-3-yl)-1 H-pyrazol-4-yl) amino)pyrimidin-4-yl)- N2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b] pyridine-2, 6-diamine
  • Step 2 N6-(2-((1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N6,3-dimethyl-N2-(4- (trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 1 3,5-dinitro-N-(oxetan-3-yl)pyridin-2-amine
  • 2-chloro-3,5-dinitropyridine 4 g, 20 mmol
  • MeOH 30 ml_
  • oxetan- 3-amine 1.7 g, 20 mmol
  • a precipitated solid formed and was collected by filtration to give the desired product (3.9 g, 81%) as a white solid.
  • LCMS (acidic 5 min): 1.47 min [MH] + 241.1.
  • Step 4 6-nitro-3-(oxetan-3-yl)-N-(4-(trifluoromethoxy)phenyl)-N-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-amine
  • Step 6 N6-(2-chloropyrimidin-4-yl)-3-(oxetan-3-yl)-N2-(4-(trifluoromethoxy) phenyl)-N2-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2,6- diamine
  • Step 8 2-(4-((4-(methyl(3-(oxetan-3-yl)-2-((4-(trifluoromethoxy)phenyl) ((2- (trimethylsilyl)ethoxy)methyl)amino)-3H-imidazo[4,5-b]pyridin-6-yl)amino) pyrimidin-2-yl)amino)- 1 H-pyrazol-1 -yl)acetamide
  • Step 1 2-(1,3-dihydroxypropan-2-yl)isoindoline-1,3-dione 2-aminopropane-1,3-diol (5.0 g, 54.88 mml) and isobenzofuran-1,3-dione (8.13 g, 54.88 mmol) were dissolved in DMF (50 ml_). The resulting mixture was stirred at 95 °C for 5 h under N2. After cooling to RT, the mixture was diluted with H2O and extracted with EtOAc (2 x). The combined organic layers were washed with H2O, brine, dried over Na2SC>4 and concentrated under reduced pressure. The residue was washed with PE/EtOAc (2/1 v/v) to afford the title compound (4.2 g, 35%) as a white solid.
  • LCMS (acidic 5 min): 0.43 min [MH]+ 222.1.
  • Step 2 2-(2-(bromomethyl)-1 ,3-dioxan-5-yl)isoindoline-1 ,3-dione
  • Step 3 2-((2-((4-nitro-1 H-pyrazol-1-yl)methyl)-1,3-dioxan-5-yl)carbamoyl) benzoic acid
  • Step 4 2-(2-((4-nitro-1 H-pyrazol-1-yl)methyl)-1,3-dioxan-5-yl)isoindoline -1,3-dione
  • Step 5 2-(2-((4-amino-1 H-pyrazol-1-yl)methyl)-1 ,3-dioxan-5-yl)isoindoline -1 ,3-dione
  • Step 6 2-(2-((4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl)amino)- 3H-imidazo[4,5- b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl) methyl)-1 ,3-dioxan-5-yl)isoindoline- 1 ,3-dione
  • Step 7 N6-(2-((1-((5-amino-1 ,3-dioxan-2-yl)methyl)-1 H-pyrazol-4-yl)amino) pyrimidin-4-yl)-N6,3- dimethyl-N2-(4-(trifluoromethoxy)phenyl)-3H-imidazo [4, 5-b]pyridine-2, 6-diamine
  • Step 1 tert-butyl 2-(4-nitro-1 H-pyrazol-1-yl)ethylcarbamate
  • Step 2 tert-butyl methyl(2-(4-nitro-1 H-pyrazol-1-yl)ethyl)carbamate
  • Step 3 tert-butyl (2-(4-amino-1 H-pyrazol-1-yl)ethyl)(methyl)carbamate
  • Step 4 tert-butyl methyl(2-(4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy) phenyl)((2- (trimethylsilyl)ethoxy)methyl)amino)-3H-imidazo[4,5-b]pyridin-6-yl) amino)pyrimidin-2-yl)amino)- 1 H-pyrazol-1-yl)ethyl)carbamate
  • Step 1 N,N-dimethyl-2-(4-nitro-1 H-pyrazol-1 -yl)ethan-1-amine
  • 4-nitro-1 H- pyrazole 3 g, 26.5 mmol
  • 2-(dimethylamino)ethanol 2.36 g, 26.5 mmol
  • THF 40 ml.
  • triphenylphosphine 10.4 g, 39.8 mmol
  • DIAD 7.8 ml_, 39.8 mmol
  • Step 3 N6-(2-((1 -(2-(dimethylamino)ethyl)-1 H-pyrazol-4-yl)amino)pyrimidin- 4-yl)-N6,3-dimethyl- N2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 1 N-methyl-3,5-dinitropyridin-2-amine
  • 2-chloro-3,5-dinitropyridine 5 g, 24.6 mmol
  • MeOH 30 ml.
  • methylamine hydrochloride 1.6 g, 24.6 mmol
  • the precipitated solid was collected by filtration to give the desired product (4 g, 83%) as a yellow solid.
  • Step 4 3-methyl-6-nitro-N-phenyl-N-((2-(trimethylsilyl)ethoxy)methyl)-3H- imidazo[4,5-b]pyridin- 2-amine
  • Step 5 3-methyl-N2-phenyl-N2-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo [4,5-b]pyridine-2,6- diamine
  • To a solution of 3-methyl-6-nitro-N-phenyl-N-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- b]pyridin-2-amine (1.5 g, 3.8 mmol) in MeOH (10 ml.) were added zinc (1.5 g, 22.5mmol) and aqueous NhUCI (10 ml_). The reaction mixture was stirred at 60°C for 16 hours.
  • Step 6 N6-(2-chloropyrimidin-4-yl)-3-methyl-N2-phenyl-N2-((2-(trimethylsilyl) ethoxy)methyl)- 3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 7 N6-(2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-((2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-((2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-((2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-((2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-(2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-(2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-(2-chloropyrimidin-4-yl)-N6,3-dimethyl-N2-phenyl-N2-(2-chloro
  • Step 8 2-(4-((4-(methyl(3-methyl-2-(phenyl((2-(trimethylsilyl)ethoxy)methyl) amino)-3H- imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H- pyrazol-1 -yl)acetamide
  • Step 9 2-(4-((4-(methyl(3-methyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin- 6-yl) amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl)acetamide
  • Step 1 N,N-dimethyl-2-(5-methyl-4-nitro-1 H-pyrazol-1-yl)ethan-1 -amine and N,N-dimethyl-2-(3- methyl-4-nitro-1 H-pyrazol-1 -yl)ethan-1 -amine
  • 5-methyl-4-nitro-1 H-pyrazole 3 g, 23.6 mmol
  • 2-(dimethylamino)ethanol 2.1 g, 23.6 mmol
  • PPh 3 9.3 g, 35.4 mmol
  • DIAD 7.2 ml_, 35.4 mmol
  • Step 2 1 -(2-(dimethylamino)ethyl)-5-methyl-1 H-pyrazol-4-amine and 1-(2-(dimethylamino)ethyl)- 3-methyl-1 H-pyrazol-4-amine
  • N,N-dimethyl-2-(5-methyl-4-nitro-1 H-pyrazol-1 -yl)ethan-1 -amineand N,N- dimethyl-2-(3-methyl-4-nitro-1 H-pyrazol-1 -yl)ethan-1 -amine (2 g, 10.86 mmol) in methanol (20 mL) was added Pd/C (200 mg) and the mixture was stirred under H 2 at room temperature overnight.
  • the reaction mixture was filtered and filtrate was concentrated to give the mixture of desired products (1.8 g, 100%) as yellow oil.
  • LCMS (acidic 5 min): 0.25 min [MH] + 169.1.
  • Step 3 N6-(2-((1 -(2-(dimethylamino)ethyl)-5-methyl-1 H-pyrazol-4-yl)amino) pyrimidin-4-yl)-N6,3- dimethyl-N2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine and N6-(2-((1 - (2-(dimethylamino)ethyl)-3-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N6,3-dimethyl-N2-(4- (trifluoromethoxy) phenyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 2 N6-(2,5-dichloropyrimidin-4-yl)-N6,3-dimethyl-N2-(4-(trifluoromethoxy) phenyl)-N2-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2,6- diamine
  • Step 4 N-cyclopentyl-3-methyl-6-nitro-N-((2-(trimethylsilyl)ethoxy)methyl)-3H- imidazo[4,5- b]pyridin-2-amine
  • N-cyclopentyl-3-methyl-6-nitro-3H-imidazo[4,5-b] pyridin-2-amine 800 mg, 3 mmol
  • THF 20 ml.
  • SEMCI 750 mg, 4.5 mmol
  • the reaction mixture was stirred at rt for 3h.
  • the mixture was then concentrated under reduced pressure and the residue was diluted with ethyl acetate (25 ml_), and washed with H 2 0 (25 ml_).
  • the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure.
  • Step 5 N2-cyclopentyl-3-methyl-N2-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine- 2,6-diamine
  • Step 7 N6-(2-chloropyrimidin-4-yl)-N2-cyclopentyl-N6,3-dimethyl-N2-((2- (trimethylsilyl) ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 8 2-(4-((4-((2-(cyclopentylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl) (methyl) amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl)acetamide
  • 2-(4-((4-((2-(cyclopentylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl) (methyl) amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl)acetamide To a solution of N6-(2-chloropyrimidin-4-yl)-N2-cyclopentyl-N6,3-dimethyl-N2-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine (300 mg, 0.46 mmol) in 2- propanol (10 ml.) was added 2-(4
  • Step 3 2-(3-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl)amino)-3H- imidazo[4,5- b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl) acetamide
  • Step 2 N6-(2-chloro-5-methylpyrimidin-4-yl)-N6,3-dimethyl-N2-(4- (trifluoromethoxy) phenyl)-N2- ((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 1 N6-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-methyl-N2-(4- (trifluoromethoxy) phenyl)- N2-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo [4, 5-b]pyridine-2, 6-diamine
  • Step 2 N6-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-N6,3-dimethyl-N2-(4-(trifluoro methoxy)phenyl)-N2-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 3 2-(4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl)amino)-3H- imidazo[4,5- b]pyridin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1 H- pyrazol-1 -yl)acetamide
  • Step 1 4-methyl-3-nitro-1 H-pyrazole
  • Step 4 2-(4-methyl-3-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl) amino)-3H- imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H- pyrazol-1 -yl)acetamide
  • Step 1 2-(3,5-dimethyl-4-nitro-1 H-pyrazol-1 -yl)acetamide
  • Step 2 2-(4-amino-3,5-dimethyl-1 H-pyrazol-1 -yl)acetamide
  • a mixture of 2-(3,5-dimethyl-4-nitro-1 H-pyrazol-1 -yl)acetamide (100 mg, 0.505 mmol) and Pd/C (10 mg) in CH 3 OH (10 ml.) was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired compound (70 mg, 82%) as a brown solid.
  • LCMS (acidic 5 min): 0.30 min [MH] + 169.1 .
  • Step 3 2-(3,5-dimethyl-4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl) amino)-3H- imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl)acetamide
  • 2-(4-amino-3,5-dimethyl-1 H-pyrazol-1-yl)acetamide 70 mg, 0.41 mmol
  • intermediate A 242 mg, 0.417 mmol
  • Step 2 2-(4-((4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl)((2- (trimethylsilyl) ethoxy)methyl)amino)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1- yl)acetonitrile
  • Step 1 N6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-N2-(4-(trifluoromethoxy) phenyl)-N2-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 2 N6-(2-chloro-5-fluoropyrimidin-4-yl)-N6,3-dimethyl-N2-(4- (trifluoromethoxy) phenyl)-N2- ((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo [4, 5-b]pyridine-2, 6-diamine
  • Step 3 2-(4-((5-fluoro-4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl) amino)-3H- imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl)acetamide
  • Step 1 N-(methyl-d3)-3,5-dinitropyridin-2-amine
  • Step 3 3-(methyl-d3)-6-nitro-N-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b] pyridin-2-amine
  • Step 4 3-(methyl-d3)-6-nitro-N-(4-(trifluoromethoxy)phenyl)-N-((2-(trimethylsilyl)ethoxy) methyl)- 3H-imidazo[4,5-b]pyridin-2-amine
  • Step 6 N6-(2-chloropyrimidin-4-yl)-3-(methyl-d3)-N2-(4-(trifluoromethoxy) phenyl)-N2-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2,6- diamine
  • Step 8 2-(2-((4-((4-(methyl(3-(methyl-d3)-2-((4-(trifluoromethoxy)phenyl)amino)-3H-imidazo[4,5- b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1-yl)methyl)-1 ,3-dioxan-5-yl)isoindoline- 1 ,3-dione
  • Step 9 N6-(2-((1-((5-amino-1 ,3-dioxan-2-yl)methyl)-1 H-pyrazol-4-yl)amino) pyrimidin-4-yl)-N6- methyl-3-(methyl-d3)-N2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 3 3-methyl-N2-(4-(trifluoromethyl)phenyl)-N2-((2-(trimethylsilyl) ethoxy)methyl)-3H- imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 5 N-methyl-2-(4-((4-(methyl(3-methyl-2-((4-(trifluoromethyl)phenyl)((2-(trimethyl silyl)ethoxy)methyl)amino)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H- pyrazol-1 -yl)acetamide
  • Step 2 N 6 -(2-chloro-5-methoxypyrimidin-4-yl)-N 6 ,3-dimethyl-N 2 -(4-(trifluoromethoxy) phenyl)-N 2 - ((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2, 6-diamine
  • Step 3 2-(4-((5-methoxy-4-(methyl(3-methyl-2-((4-(trifluoromethoxy)phenyl) amino)-3H- imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-2-yl)amino)-1 H-pyrazol-1 -yl)-N-methyl acetamide
  • Assay Screening compounds for inhibition of TSQ induced necroptosis, 96 well plate format.
  • Cell Line ID U937 human histiocytic leukemia cell line.
  • Cell growth medium HT -RPMI + 7.4% FBS. Cells are cultured in Corning 150cm 2 tissue culture flasks with vented caps at 37°C/5% CO2.
  • hTNF-Fc (1 OOng/ml) - produced by standard procedures as shown in Bossen et al., J Biol Chem, 2006, 281 (20), 13964-13971.
  • the cellular assay was carried out according to the following steps:
  • DMSO control; columns 1 -2 and 23-24
  • compound in DMSO - addition was performed using acoustic transfer of nl volumes of stock compound to give final test concentrations of 36,12, 4, 1.3, 0.44, 0.148, 0.049, 0.016, 0.005 and 0.002 mM. All wells were backfilled with DMSO to a final total volume in the well of 10Onl.
  • DMSO control; columns 1 -2 and 23-24
  • compound in DMSO - addition was performed using acoustic transfer of nl volumes of stock compound to give final test concentrations of 36,12, 4, 1.3, 0.44, 0.148, 0.049, 0.016, 0.005 and 0.002 mM. All wells were backfilled with DMSO to a final total volume in the well of 10Onl.
  • b Following compound/DMSO addition in step (a), 40 mI_ of cell suspension (5x10 5 cells/mL) was added to provide a final cell concentration of 20,000 cells per
  • RawData is the readout of any cell containing a compound of the invention
  • Assay involving the TSQ cocktail (T: TNF; S: Smac mimetic; Q: Q-VD-OPh): TSQ treatment ensures that cells specifically undergo necroptotic cell death.
  • TNF activates the TNF receptor
  • Smac mimetic direct the signal away from proinflammatory signaling and toward the RIP1/RIP3- mediated cell death pathways
  • Q-VD-OPh ensures that the apoptotic response is blocked leaving only the programmed necrosis response.
  • the compounds’ activity (solution in DMSO) tested in this TSQ-induced assay is evaluated by determining the number of viable cells in culture by measuring the amount of ATP present as measured by CelltiterGlo.
  • Binding affinity for MLKL and RIP1 was determined using the KINOMEscanTM technology developed by DiscoverX (USA; http://www.discoverx.com). The assay was conducted according to manufacturer instructions.
  • Streptavid in -coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1 % BSA, 0.05 % Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific phage binding.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20 % SeaBlock, 0.17x PBS, 0.05 % Tween 20, 6 mM DTT).
  • Test compounds were prepared as 40x stocks in 100% DMSO and directly diluted into the assay. All reactions were performed in polypropylene 384-well plates in a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05 % Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05 % Tween 20, 0.5 pM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.
  • the Hill Slope was set to -1 .
  • Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.
  • Table 1 Table showing the results of cell based assays performed under assay 1 and binding data for compounds described above. A: IC 5 o ⁇ 100nM +++

Abstract

La présente invention concerne des composés représentés par la formule (I) et des sels, des solvates, des promédicaments, des tautomères, des N-oxydes, des stéréoisomères, des polymorphes et des dérivés physiologiquement fonctionnels de ceux-ci. L'invention concerne également des procédés d'utilisation des composés de formule (I), notamment dans l'inhibition de la nécroptose et le traitement de maladies, d'états et/ou de troubles associés.
PCT/AU2021/050176 2020-02-27 2021-03-01 Inhibiteurs de nécroptose WO2021168521A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015172203A1 (fr) * 2014-05-15 2015-11-19 Catalyst Therapeutics Pty Ltd Méthodes pour inhiber la nécroptose
WO2016127213A1 (fr) * 2015-02-10 2016-08-18 Catalyst Therapeutics Pty Ltd Inhibiteurs de nécroptose
WO2019089442A1 (fr) * 2017-10-30 2019-05-09 Bristol-Myers Squibb Company Aminoimidazopyridines utilisées en tant qu'inhibiteurs de kinase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015172203A1 (fr) * 2014-05-15 2015-11-19 Catalyst Therapeutics Pty Ltd Méthodes pour inhiber la nécroptose
WO2016127213A1 (fr) * 2015-02-10 2016-08-18 Catalyst Therapeutics Pty Ltd Inhibiteurs de nécroptose
WO2019089442A1 (fr) * 2017-10-30 2019-05-09 Bristol-Myers Squibb Company Aminoimidazopyridines utilisées en tant qu'inhibiteurs de kinase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIE YANGCHUN; ZHU SHAN; ZHONG MEIZUO; YANG MANHUA; SUN XIAOFAN; LIU JINBAO; KROEMER GUIDO; LOTZE MICHAEL; ZEH HERBERT J.; KANG RUI: "Inhibition of Aurora Kinase A Induces Necroptosis in Pancreatic Carcinoma", GASTROENTEROLOGY, ELSEVIER INC., US, vol. 153, no. 5, 1 January 1900 (1900-01-01), US, pages 1429, XP085279222, ISSN: 0016-5085, DOI: 10.1053/j.gastro.2017.07.036 *

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