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WO2025229029A1 - Conjugate of a senotherapeutic moiety and a lipid-targeting moiety - Google Patents

Conjugate of a senotherapeutic moiety and a lipid-targeting moiety

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Publication number
WO2025229029A1
WO2025229029A1 PCT/EP2025/061774 EP2025061774W WO2025229029A1 WO 2025229029 A1 WO2025229029 A1 WO 2025229029A1 EP 2025061774 W EP2025061774 W EP 2025061774W WO 2025229029 A1 WO2025229029 A1 WO 2025229029A1
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moiety
compound
group
salt
solvate
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PCT/EP2025/061774
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French (fr)
Inventor
Vassilis G GORGOULIS
Nicholaos KOTOPOULOS
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Priority claimed from GBGB2406749.8A external-priority patent/GB202406749D0/en
Priority claimed from GBGB2417102.7A external-priority patent/GB202417102D0/en
Application filed by Individual filed Critical Individual
Publication of WO2025229029A1 publication Critical patent/WO2025229029A1/en
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    • 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
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Described herein are compounds which are capable of selectively targeting senescent cells and modulating the activity of, or elimination of these cells. As such, these compounds are useful in treatment of diseases or conditions mediated by senescence, such as cancer.
  • Senescence is a fundamental stress response mechanism aiming to preserve tissue or organismal homeostasis [Gorgoulis & Halazonetis, Curr Opin Cell Biol 2010; Gorgoulis et al., J Pathol 2018; Gorgoulis et al., Cell 2019], Cells entering this state are characterized by prolonged and generally irreversible cell-cycle arrest, and resistance to apoptosis [Gorgoulis et al., Cell 2019; Childs et al., EMBO Rep 2014], They demonstrate also macromolecular damage, deregulated metabolism [Gorgoulis et al., Cell 2019; Myrianthopoulos et al., Pharmacol & Ther 2019], and exhibit secretory features, collectively described as senescence-associated secretory phenotype (SASP) [Gorgoulis et al., Cell 2019], SASP includes a variety of cytokines, chemokines, growth factors, proteases and other molecules, depending on the type of s
  • the senescent phenotype is highly diverse, as triggering stimuli and maintenance mechanisms involved are not pre-requisitely preserved among the senescence programs [Gorgoulis et al., Cell 2019],
  • Transient occurrence of this cellular state has beneficial roles in various physiological processes to ensure cellular and organism homeostasis.
  • senescence facilitates tissue development and morphogenesis, while in the adult life apart from promoting tissue repair [Gorgoulis & Halazonetis, Curr Opin Cell Biol 2010; Gorgoulis et al., J Pathol 2018; Gorgoulis et al., Cell 2019], It also restrains the expansion of damaged cells such as the case in the preneoplastic lesions where it serves as an anti-tumor barrier against the development of incipient cancerous cells [Halazonetis et al., Science 2008; Gorgoulis et al., J Pathol 2018],
  • the present invention provides new compounds comprising SBB analogues linked with senolytics, which allow for the selective targeting of senescent cells, followed by their modulation or elimination.
  • novel compounds have the ability to react with lipofuscin, in an analogous manner to the histochemical dye SBB and the ability to deliver specifically a senolytic drug to selectively modulate or eliminate senescent cells.
  • novel chemical compounds can be used for the modulation or elimination of senescent cells in subjects, animals, plants or live biological samples derived from them.
  • the present invention provides a compound of Formula I as defined herein, and/or a salt or solvate thereof.
  • the present invention provides a pharmaceutical composition which comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in treatment of a disease or condition mediated by senescence.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in treating a disease or a condition selected from a cancer, a fibrotic disorder, a neurodegenerative condition, a cardiovascular disease, a metabolic disease, a kidney disease, a liver disease and a degenerative disease.
  • the present invention provides a method of inducing death of a senescent cell in a subject or sample, comprising administering to said subject or sample an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of inhibiting senescence in a cell, comprising administering to said cell an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the present invention provides a combination comprising a compound of formula I, or a salt or solvate thereof as defined herein with another therapeutic agent.
  • a compound of formula I or a salt or solvate thereof as defined herein with another therapeutic agent.
  • Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.
  • Figure 1 provides the structures of some known senotherapeutic agents.
  • Figure 2 provides a schematic of GL392 synthesis, micelle encapsulation (A) and physicochemical characterization thereof (B, C)
  • Figure 3 provides data demonstrating validation of mGL392 and its lipofuscin binding properties (A-C).
  • Figure 4 provides data demonstrating that mGL392 promotes targeted senolysis in vitro in Li-Fraumeni-p21 WAF1/Cip1 Tet-ON cells.
  • Figure 5 provides data demonstrating that mGL392 promotes targeted senolysis in the HBEC-CDC6 Tet-ON cellular system.
  • Figure 6 provides data demonstrating that mGL392 promotes targeted senolysis in 3D lung organoids.
  • compositions and methods of treatment or diagnosis that employ or comprise one or more compounds of the Formula I, either by themselves or in combination with additional agents.
  • the various hydrocarbon-containing moieties provided herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, e.g. “(C a -b)” or “C a -Cb” or “(a-b)C”.
  • C a -b alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive.
  • Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure.
  • the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.
  • alkyl and alkyl group refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted.
  • alkoxy and alkoxy group refer to O-alkyl groups. Representative examples include, but are not limited to, -OMe, -OEt, -O-'Pr and O- f Bu. Alkoxy groups can be substituted or unsubstituted unless indicated otherwise.
  • heteroalkyl refers to a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • a heteroalkyl group is an uncyclized chain.
  • heteroalkyl moiety may include one or more heteroatoms which may be the same or different.
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like.
  • aromatic refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer.
  • Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”).
  • An aromatic ring system can be substituted or unsubstituted.
  • non-aromatic refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system.
  • non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S.
  • a non-aromatic ring system can be substituted or unsubstituted.
  • aryl and aryl group refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
  • Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e. , phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms.
  • Representative examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6, 7,8,9- tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl.
  • an aryl group is phenyl and naphthyl, suitably phenyl.
  • arylene and arylene group refer to a phenylene (-C6H4-) or to 7 to 15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
  • Arylene groups can be substituted or unsubstituted.
  • an arylene group may contain 6 (i.e., phenylene) ring atoms or be a ring system containing 9 to 15 atoms; such as 9 to 11 ring atoms; or 9 or 10 ring atoms.
  • Arylene groups can be substituted or unsubstituted.
  • arylalkyl and arylalkyl group refer to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as previously defined, such as, for example, benzyl (C6H5CH2-).
  • Arylalkyl groups can be substituted or unsubstituted.
  • Carbocyclic group and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation.
  • carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1 ,2,3,4-tetrahydro- naphthalenyl).
  • the terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.
  • cycloalkyl and cycloalkyl group refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused.
  • a cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms.
  • a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.).
  • Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane.
  • cycloalkylalkyl and “cycloalkylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as previously defined, such as, for example, cyclohexylmethyl (C6HnCH 2 -). Cycloalkylalkyl groups can be substituted or unsubstituted.
  • haloalkyl and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkyl groups can be substituted or unsubstituted.
  • a haloalkyl group is selected from CHF 2 and CF 3 , suitably CF 3 .
  • haloalkoxy and haloalkoxy group refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkoxy groups can be substituted or unsubstituted.
  • a haloalkyoxy group is selected from -OCHF2 and - OCF3, suitably -OCF3.
  • halo and halogen include fluorine, chlorine, bromine and iodine atoms and substituents.
  • heteroaryl and heteroaryl group refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic.
  • a heteroaryl group can contain two or more heteroatoms, which may be the same or different.
  • Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused.
  • a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms.
  • a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms.
  • Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1,2- dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2, 3, 4- tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl,
  • heteroarylalkyl and “heteroarylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heteroaryl group, wherein alkyl group and heteroaryl group are as previously defined. Heteroarylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heteroaryl(C n-m )alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
  • heterocyclic group and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation.
  • heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyrindinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1 , 2,3,6- tetrahydropyridinyl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrizinyl).
  • the terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.
  • heterocycloalkyl and “heterocycloalkyl group” refer to 3 to 15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted.
  • a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
  • Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl- S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridin
  • heterocycloalkylene and “heterocycloalkylene group” refer to 3 to 15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkylene groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused. Heterocycloalkylene groups can be substituted or unsubstituted.
  • a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. In other instances a heterocycloalkylene group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
  • heterocycloalkylalkyl and “heterocycloalkylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously defined, such as, for example, pyrrolidinylmethyl (C4H8NCH2-). Heteroycloalkylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heterocycloalkyl(C n -m)alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
  • “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.
  • composition refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.
  • stable and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity.
  • the present application is directed solely to the preparation of stable compounds.
  • substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, when considering the degree of optional substitution of a particular moiety, it should be understood that the number of substituents does not exceed the valency appropriate for that moiety.
  • substituted indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent”. It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).
  • terapéutica refers to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(b), either alone or in combination with any of the others (a)-(b).
  • a therapeutically effective amount in, for example, a human or other mammal, can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.
  • FDA United States Food and Drug Administration
  • treating refers to and include ameliorative, palliative, and curative uses and results.
  • the terms “treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein.
  • treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.
  • the terms “prevent”, “preventative” or “prevention”, refers to diminishing the likelihood, or delaying the onset, of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “prevent”, “preventative” or “prevention” are not necessarily used in an absolute sense, but also refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.
  • a ’’therapeutic agent or “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by Formula I. It should be understood that a therapeutic agent may or may not be approved by the FDA or an equivalent foreign regulatory body.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated.
  • the present invention relates to a compound, or a salt or solvate thereof, according to formula I:
  • X is a senotherapeutic moiety
  • L is a direct bond or a linking moiety
  • T is a lipid-targeting moiety of formula II or III: wherein
  • R 1 and R 2b are each independently selected from the group consisting of hydrogen; an optionally substituted (Ci- )alkyl group; an optionally substituted aryl group; and an optionally substituted aryl(Ci- )alkyl group; or R 1 and R 2b , together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring;
  • R 2a is selected from the group consisting of an optionally substituted (C1- w)alkylene group; an optionally substituted arylene group; and an optionally substituted aryl(Ci- )alkylene group; or
  • R 1 and R 2a together with the carbon to which they are attached form an optionally substituted C4 to C12 carbocyclic ring; each R 3 is independently hydrogen or a (Ci- )alkyl group;
  • R 4a is selected from the group consisting of hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1- 10 haloalkoxy, -OR A4 , -SR A4 , -NR A4 R B4 , -CN, -NO 2 , -N 3 , -NR A4 C(O)R B4 , -C(O)NR A4 R B4 , -NR A4 C(O)OR B4 , -OC(O)NR A4 R B4 , -NR A4 C(O)NR A4 R B4 , -NR A4 SO 2 R B4 , -SO 2 NR A4 R B4 , - SO 2 R A4 , -NR A4 C(S)R B4 , -C(S)NR A4 R B4 , -C(O)OR A4 , optional
  • R A4 , R B4 and R C4 are independently selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 heteroalkyl.
  • the lipid-targeting moiety, T is a lipofuscin targeting moiety.
  • T is of formula II. In another embodiment, T is of formula III.
  • R 1 is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted Ce-n aryl group; and an optionally substituted aryl(Ci- e)alkyl group.
  • R 1 is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci- e)alkyl group.
  • R 1 is selected from hydrogen, an optionally substituted phenyl and an optionally substituted (Ci-e)alkyl group.
  • R 1 is selected from hydrogen and an optionally substituted (Ci-4)alkyl group.
  • R 1 is selected from hydrogen and (Ci-4)alkyl group optionally substituted with a hydroxyl group. In another embodiment, R 1 is hydrogen or methyl.
  • R 2b is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted Ce-n aryl group; and an optionally substituted aryl(Ci- e)alkyl group.
  • R 2b is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci- e)alkyl group.
  • R 2b is selected from hydrogen, an optionally substituted phenyl group and an optionally substituted (Ci-e)alkyl group.
  • R 2b is selected from hydrogen and an optionally substituted (Ci-4)alkyl group.
  • R 2b is selected from hydrogen and an (Ci-4)alkyl group optionally substituted with a hydroxyl group. In another embodiment, R 2b is hydrogen or methyl.
  • R 1 and R 2b are independently selected from optionally substituted (Ci- )alkyl group, suitably an optionally substituted (Ci-e)alkyl group, suitably an optionally substituted (Ci-4)alkyl group.
  • R 1 and R 2b are independently selected from methyl, ethyl and propyl, suitably R 1 and R 2b are methyl.
  • R 1 and R 2b together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring, and thus a spirocyclic group.
  • R 1 and R 2b together with the carbon to which they are attached, form an optionally substituted C5 to C10 carbocyclic ring.
  • R 2a is selected from an optionally substituted (Ci-6)alkylene group; an optionally substituted Ce-n arylene group; and an optionally substituted aryl(Ci- e)alkylene group.
  • R 2a is selected from an optionally substituted (Ci-6)alkylene group; an optionally substituted phenylene group; and an optionally substituted aryl(Ci- e)alkylene group.
  • R 2a is selected from an optionally substituted (Ci-6)alkylene group.
  • R 2a is selected from an optionally substituted (Ci-4)alkylene group.
  • R 2a is a methylene, ethylene, propylene or butylene group, suitably methylene.
  • R 1 and R 2a together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring, and thus a spirocyclic group.
  • R 1 and R 2a together with the carbon to which they are attached, form an optionally substituted C5 to C10 carbocyclic ring.
  • each R 3 is independently hydrogen or a (Ci-e)alkyl group. In another embodiment, each R3 is independently hydrogen or a (Ci-s)alkyl group. In another embodiment, each R3 is independently hydrogen or methyl.
  • R 4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -OR A4 , -SR A4 , -NR A4 R B4 , -CN, -NO 2 , -N 3 , -NR A4 C(O)R B4 , -C(O)NR A4 R B4 , - NR A4 C(O)OR B4 , -OC(O)NR A4 R B4 , -NR A4 C(O)NR A4 R B4 , -NR A4 SO 2 R B4 , -SO 2 NR A4 R B4 , -SO 2 R A4 , optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group.
  • R 4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -OR A4 , -SR A4 , -NR A4 R B4 , -CN, -NO 2 , -N 3 , -NR A4 C(O)R B4 , -C(O)NR A4 R B4 , - NR A4 SC>2R B4 , -SC>2NR A4 R B4 , -SC>2R A4 , optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group.
  • R 4a is selected from hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1-10 haloalkoxy, -OR A4 , -CN, and -NO2.
  • R 4a is selected from hydrogen, halogen, C1-6 alkyl optionally substituted with a hydroxyl group, C1-6 haloalkyl, C-1-6 haloalkoxy, -OH, -NH2, -CN, C3-6 cycloalkyl and a 3-7 membered heterocycloalkyl group.
  • R 4a is selected from hydrogen, C1-6 alkyl optionally substituted with a hydroxyl group and -OH.
  • q is 0, 1 or 2. In another embodiment, q is 0 or 1.
  • R 4b is selected from direct bond, -O-, -S-, -NR C4 -, -
  • R 4b is selected from direct bond, -O-, -S-, -NR C4 -, an optionally substituted (Ci-e)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
  • R 4b is selected from direct bond, an optionally substituted (Ci-6)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
  • R 4b is selected from -CH2CH2- and -CH2CH2O-.
  • R A4 , R B4 and R C4 are independently selected hydrogen, C1-3 alkyl and C1-3 heteroalkyl. In another embodiment, R A4 , R B4 and R C4 , at each occurrence, are independently selected hydrogen, methyl and ethyl.
  • T is of sub-formula Ila where R 1 and R 4a are as defined in any of the above-mentioned embodiments.
  • T is T 1 :
  • T is of sub-formula Illa where R 1 and R 4b are as defined in any of the above-mentioned embodiments.
  • T is of sub-formula 11 lb: where R 1 and R 4b are as defined in any of the above-mentioned embodiments.
  • T is T 2 :
  • the linking moiety serves to connect the lipid-targeting moiety with the senotherapeutic moiety.
  • L may be a direct bond between the lipid-targeting moiety and the senotherapeutic moiety.
  • L comprises one or more atoms which covalently link the lipid-targeting moiety with the senotherapeutic moiety.
  • L is a linear moiety. In another embodiment, L is a branched moiety.
  • L comprises one or more functional groups, particularly at the end(s) of the moiety which may facilitate covalent bonding with the lipid-targeting moiety and/or the senotherapeutic moiety.
  • suitable functional groups include amino, amido, ester, ether, carbonyl, carboxyl, thioether, sulfonyl, and sulfonamido for instance.
  • Preferred linking groups are derived from groups which can react to form bonds with the lipid-targeting moiety and/or senotherapeutic moiety. Reactive groups may be selected from but not limited to a group that will react directly with other reactive groups on the lipid-targeting moiety or senotherapeutic moiety.
  • Reaction of the reactive groups with the reactive groups on precursor of the lipid-targeting moiety or the senotherapeutic moiety may result in a functional group in the linker adjacent to said lipid-targeting moiety or the senotherapeutic moiety, which may be referred to herein as a “bonding moiety”.
  • the linking moiety comprises two or more bonding moieties and one or more spacing moieties.
  • the spacing moiety can be varied in order to control the separation between the lipid-targeting moiety and the senotherapeutic moiety.
  • the spacing moiety may comprise or consist of aliphatic chains or polymeric chains, such as polyethylene glycol (PEG) chains. Functional groups may also be present within the spacing moiety, for instance to influence physical properties of the overall compounds, such as solubility.
  • the length of the linking moiety can be varied to avoid steric interaction of the lipid-targeting moiety and the senotherapeutic moiety and to allow efficient interaction of the lipid-targeting moiety with its lipid target.
  • the linking moiety is suitably such that it maintains the link between the lipid- targeting group and the senotherapeutic moiety under physiological conditions for an appropriate time. Nevertheless, the linking group may be cleavable.
  • the linking moiety comprises an ester bond.
  • the compound of formula I is cleaved by enzymes, such as an esterase, in order to release the senotherapeutic moiety in the presence of senescent cells.
  • the linking moiety may be a direct bond.
  • L is a direct bond.
  • L is a linking moiety of formula IV:
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • m is a number of value from 1 to 40, or 1 to 30, or 1 to 25, or 1 to 20, or 1 to 15, or 1 to 10, or 1 to 6.
  • m is a number of value from 3 to 40, or 3 to 30, or 3 to 25, or 3 to 20, or 3 to 15, or 3 to 10, or 3 to 6.
  • m is a number of value from 5 to 40, or 5 to 30, or 5 to 25, or 5 to 20, or 5 to 15, or 5 to 10.
  • L is a linking moiety of formula V: — [L 2 ]— [L 3 ]— [L 4 ]— [L 5 ]— [L 6 ]— [L 7 ]— [L 8 ]— [L 9 ]— (V) wherein
  • L 3 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 5 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] p -, where q and each p are independently a number of value 1 to 15;
  • L 7 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 9 is absent, -(CR 5 R 6 ) P -, -(CR 6 R 7 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;, where each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, CM alkyl, C1-4 alkenyl, C 2 -4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • L is a linking moiety of formula VI:
  • L 3 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] p -, where q and each p are independently a number of value 1 to 15;
  • L 5 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] p -, where q and each p are independently a number of value 1 to 15;
  • L 3 is absent or -(CR 5 R 6 ) P -.
  • L 3 is -(CH2) P -.
  • L 5 is absent or -(CR 5 R 6 ) P -.
  • L 5 is -(CH2) P -.
  • L 6 is absent, -NH-, -O-, phenylene and piperazinyl.
  • L 6 is attached to X.
  • L 7 is absent, -(CR 5 R 6 ) P - or (CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] p -.
  • L 7 is absent or -(CR 5 R 6 ) P -.
  • L 7 is -(CH2) P -.
  • L 8 is absent, -NH-, -O-, phenylene and piperazinyl.
  • L 8 is attached to X.
  • L 9 is absent or -(CR 5 R 6 ) P -.
  • L 9 is -(CH2) P -.
  • L is a linking moiety of formula VII:
  • L 3 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 2 , L 3 and L 4 are as defined in of the above-mentioned embodiments.
  • L 10 is absent, -(CH 2 ) P -, phenylene or piperazinyl. In one embodiment, L 10 is attached to X.
  • L 11 is absent, -O- or -NH-.
  • L 11 is attached to X.
  • q and p, at each occurrence are independently a number of value 1 to 12.
  • q and p, at each occurrence are independently a number of value 1 to 10, or 1 to 6, or 1 to 5.
  • q and p, at each occurrence are independently a number of value 3 to 10, or 3 to 6, or 3 to 5.
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C 2 -4 alkynyl, C1-4 haloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 haloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • R 5 and R 6 are independently selected from hydrogen or C1-4 alkyl.
  • R 5 and R 6 are independently selected from hydrogen, methyl and ethyl.
  • the lipid-targeting moiety and senotherapeutic moiety may be bonded to either end of the linking moiety, for instance either end of formulae IV, V, VI and VII. However, in one embodiment the lipid-targeting moiety is bonded to the left hand end of the linking moiety as depicted herein (e.g. formulae IV, V, VI and VII) and the senotherapeutic moiety is bonded to the right hand end of the linking moiety as depicted herein.
  • the Linking moiety L is of formula L1 : wherein
  • M is selected from the group consisting of -NH-, -C(O)O, -C(O)NH- and -C(O)- or is absent; and n is a number of value 1 to 10.
  • M is selected from the group consisting of -NH-, -C(O)O and -C(O)NH-.
  • n is a number of value 1 to 5, suitably 1 , 2 or 3.
  • the Linking moiety L is of formula L2: wherein M 1 and M 2 are independently selected from the group consisting of -NH-, -C(O)O, -C(O)NH- and -C(O)- or absent; and n1 and n2 are independently a number of value 1 to 10.
  • M 1 is selected from the group consisting of -NH-, -C(O)O and -C(O)NH-.
  • M 2 is selected from the group consisting of -NH-, - C(O)O and -C(O)NH-.
  • M 1 is -C(O)NH- and M 2 is selected from the group consisting of -NH-, -C(O)O and -C(O)NH-.
  • n1 and n2 are independently selected from a number of value 1 to 5, suitably 1, 2 or 3.
  • n1 is 2. In one embodiment, n1 is 2 and n2 is 1 , 2 or 3.
  • the Linking moiety L is selected from:
  • Linking moiety L is:
  • the wavy line indicates the point of attachment to
  • the dotted line indicates the point of attachment to X.
  • the lipid-targeting moiety and linking moiety, T-L- is selected from the following, wherein the dotted line indicates the point of attachment to X:
  • the lipid-targeting moiety is of formula Ila and the linking moiety, L is a direct bond, i.e. direct bond to X.
  • the lipid-targeting moiety is of formula T 1 and the linking moiety, L is a direct bond, i.e. direct bond to X.
  • X is a senolytic moiety.
  • a senolytic moiety refers to a senotherapeutic moiety which act directly on senescent cells to induce cell death of senescent cells.
  • Senolytic agents are known to the skilled person and the senolytic moiety may be derived from known senolytic agents, such as those described in Tables 1 and 2 of Rad et al, Mechanisms of Ageing and Development 217 (2024) 111888, and Table 1 of Zhang et al. The FEBS Journal 290 (2023) 1362-1383, each of which is incorporated herein by reference.
  • the senolytic moiety is selected from an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-2 inhibitor moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety, a HDAC inhibitor moiety, a Mcl-1 inhibitor moiety and a PI3K inhibitor moiety.
  • the senolytic agent is selected from an Eph receptor inhibitor moiety, a ABL inhibitor moiety or a flavonoid moiety.
  • the senolytic agent is selected from a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a curcumin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety, a fenofibrate moiety and a panobinostat moiety.
  • the senolytic agent is selected from a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, a fisetin moiety or a quercetin moiety.
  • the senolytic agent is selected from a dasatinib moiety or a quercetin moiety.
  • the dasatinib moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
  • A1331852 is BCI-XL inhibitor; of the following structure:
  • the A1331852 moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
  • A-1155463 is BCI-XL inhibitor, of the following structure: [00183] In one embodiment, the A1155463 moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
  • the fisetin moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
  • X is a senomorphic moiety.
  • a senomorphic moiety refers to a senotherapeutic moiety which can inhibit SASP and thus modulate senescence.
  • the senomorphic moiety is selected from a mTOR inhibitor moiety, a JAK inhibitor moiety and a glucocorticoid moiety.
  • the senomorphic moiety is selected from an apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety and a niguldipine moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety, a HDAC inhibitor moiety, a mTOR inhibitor moiety, a JAK inhibitor moiety and a glucocorticoid moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety and a HDAC inhibitor moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety and an alkaloid moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety and a flavonoid moiety.
  • senotherapeutic moiety X a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety, a panobinostat moiety, a apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety, a niguldipine moiety and a resveratrol moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety and a panobinostat moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, a quercetin moiety, a navitoclax moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety and a panobinostat moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety and a panobinostat moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a A1331852 moiety, a A1155463 moiety, a navitoclax moiety and a fisetin moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety and a fisetin moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, and a fisetin moiety.
  • senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety and a quercetin moiety.
  • senotherapeutic moiety X is (where the dotted line indicates the point of attachment to linker, L).
  • the moiety -L-X is
  • the compound of formula I is selected from the following, or a salt or solvate thereof:
  • L is a direct bond or a linking moiety
  • T is a lipid-targeting moiety of formula II or III (where the wavy line indicates the point of attachment to L): wherein
  • R 1 and R 2b are each independently selected from the group consisting of hydrogen; an optionally substituted (Ci- )alkyl group; an optionally substituted aryl group; and an optionally substituted aryl(Ci-io)alkyl group; or R 1 and R 2b , together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring;
  • R 1 and R 2a together with the carbon to which they are attached form an optionally substituted C4 to C12 carbocyclic ring; each R 3 is independently hydrogen or a (Ci- )alkyl group;
  • R 4a is selected from the group consisting of hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1-10 haloalkoxy, -OR A4 , - SR A4 , -NR A4 R B4 , -CN, -NO 2 , -N 3 , -NR A4 C(O)R B4 , -C(O)NR A4 R B4 , -NR A4 C(O)OR B4 , - OC(O)NR A4 R B4 , -NR A4 C(O)NR A4 R B4 , -NR A4 SO 2 R B4 , -SO 2 NR A4 R B4 , -SO 2 R A4 , -NR A4 C(S)R B4 , - C(S)NR A4 R B4 , -C(O)OR A4 ,
  • R 1 is selected from hydrogen; an optionally substituted (Ci-e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci-e)alkyl group.
  • R 1 is selected from hydrogen, an optionally substituted phenyl and an optionally substituted (C1- e)alkyl group.
  • R 1 is selected from hydrogen and an optionally substituted (Ci-4)alkyl group. 5. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R 1 is selected from hydrogen and (Ci-4)alkyl group optionally substituted with a hydroxyl group.
  • R 2a is selected from an optionally substituted (Ci-6)alkylene group; an optionally substituted phenylene group; and an optionally substituted aryl(Ci-6)alkylene group.
  • R 2a is selected from an optionally substituted (Ci-6)alkylene group.
  • R 2a is selected from an optionally substituted (Ci-4)alkylene group.
  • R 2a is a methylene, ethylene, propylene or butylene group.
  • R 4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -OR A4 , - SR A4 , -NR A4 R B4 , -CN, -NO 2 , -N 3 , -NR A4 C(O)R B4 , -C(O)NR A4 R B4 , -NR A4 C(O)OR B4 , - OC(O)NR A4 R B4 , -NR A4 C(O)NR A4 R B4 , -NR A4 SO 2 R B4 , -SO 2 NR A4 R B4 , -SO 2 R A4 , optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group
  • R 4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -OR A4 , - SR A4 , -NR A4 R B4 , -CN, -NO 2 , -N 3 , -NR A4 C(O)R B4 , -C(O)NR A4 R B4 , -NR A4 SO 2 R B4 , -SO 2 NR A4 R B4 , -SC>2R A4 , optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group.
  • R 4a is selected from hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1-10 haloalkoxy, -OR A4 , - CN, and -NO 2 .
  • R 4a is selected from hydrogen, halogen, C1-6 alkyl optionally substituted with a hydroxyl group, C1-6 haloalkyl, C-1-6 haloalkoxy, -OH, -NH2, -CN, C3-6 cycloalkyl and a 3-7 membered heterocycloalkyl group.
  • R 4a is selected from hydrogen, C1-6 alkyl optionally substituted with a hydroxyl group and -OH.
  • R 2b is selected from hydrogen; an optionally substituted (Ci-e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci-e)alkyl group.
  • R 2b is selected from hydrogen, an optionally substituted phenyl group and an optionally substituted (Ci-e)alkyl group.
  • R 2b is selected from hydrogen and an optionally substituted (Ci-4)alkyl group.
  • R 2b is selected from hydrogen and an (Ci-4)alkyl group optionally substituted with a hydroxyl group.
  • R 2b is selected from hydrogen and an (Ci-4)alkyl group optionally substituted with a hydroxyl group.
  • R 2b is hydrogen or methyl
  • R 4b is selected from direct bond, -O-, -S-, -NR C4 -, an optionally substituted (C1- e)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
  • R 4b is selected from direct bond, an optionally substituted (Ci-6)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
  • R 4b is selected from -CH2CH2- and -CH2CH2O-.
  • each R3 is independently hydrogen or a (Ci-e)alkyl group.
  • each R3 is independently hydrogen or a (Ci-s)alkyl group.
  • each R3 is independently hydrogen or methyl, suitably hydrogen.
  • T is T 1 , T 2 or T 3 :
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, CM alkyl, CM alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • m is a number of value from 1 to 10.
  • m is a number of value from 3 to 6.
  • L 3 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 5 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 7 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 9 is absent, -(CR 5 R 6 ) P -, -(CR 6 R 7 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;, where each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, CM alkyl, CM alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • L 3 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 3 is absent, -(CR 5 R 6 ) P -, -(CR 5 R 6 ) q [O(C(R 5 )(R 6 ))(C(R 5 )(R 6 ))] P -, where q and each p are independently a number of value 1 to 15;
  • L 5 is absent or -(CR 5 R 6 ) P -.
  • L 6 is absent, -NH-, -O-, phenylene and piperazinyl.
  • L 7 is absent or -(CR 5 R 6 ) P -.
  • L 7 is -(CH2) P -.
  • L 8 is absent, -NH-, -O-, phenylene and piperazinyl.
  • L 9 is absent or -(CR 5 R 6 ) P -.
  • L 9 is -(CH2) P -.
  • L 10 is absent, -(CH2) P -, phenylene or piperazinyl.
  • L 11 is absent, -O- or -NH-.
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, each of which may optionally be substituted with one or more groups selected from CM alkyl, CM alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 haloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
  • X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety, a HDAC inhibitor moiety, a mTOR inhibitor moiety, a JAK inhibitor moiety and a glucocorticoid moiety.
  • X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety, a panobinostat moiety, a apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety, a niguldipine moiety and a resveratrol moiety.
  • X is a moiety selected from the group consisting of a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, a quercetin moiety and a fisetin moiety.
  • a pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 85, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
  • amphiphilic polymer is a polyethylene glycol-polycaprolactone block copolymer (e.g. PEO-b-PCL).
  • a pharmaceutical composition according to any one of paragraphs 86 to 90 comprising an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e.g. salts of plasma cations with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (e.g. sorbitol or mannitol), glycols (e.g. glycerol), or other non-ionic polyol materials (e.g. polyethyleneglycols, propylene glycols and the like).
  • an injectable carrier liquid such as sterile, pyrogen-free water for injection
  • an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic)
  • a fibrotic condition affecting the lungs for example pulmonary fibrosis secondary to cystic fibrosis; idiopathic pulmonary fibrosis; coal worker’s progressive massive fibrosis; cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), or chronic asthma; or
  • a fibrotic condition affecting the liver for example cirrhosis, and associated conditions such as chronic viral hepatitis B or C, Wilson’s disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis or autoimmune hepatitis; or (iii) a fibrotic condition affecting the kidneys, for example diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangiocapillary glomerular nephritis;
  • a fibrotic condition affecting the heart or vascular system for example endomyocardial fibrosis; old myocardial infarction; atrial fibrosis; congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (for example pulmonary hypertension) and fibrosis associated with hypertension, atherosclerosis, restenosis (e.g. coronary, carotid, and cerebral lesions), and heart disease associated with cardiac ischemic events; or
  • HHD hypertensive heart disease
  • a fibrotic condition affecting the mediastinum for example mediastinal fibrosis
  • a fibrotic condition affecting bone for example myelofibrosis, including primary myelofibrosis, post polycythemia vera or post essential thrombocythemia myelofibrosis; or
  • a fibrotic condition affecting the retroperitoneum for example retroperitoneal fibrosis skin
  • a fibrotic condition affecting the skin for example nephrogenic systemic fibrosis, keloid formation and scarring, systemic sclerosis, scleroderma, hypertrophic scarring, scleredema (Buschke disease), systemic amyloidosis, lipodermatosclerosis, progeroid disorders, stiff skin syndrome, Dupuytren's contracture, nephrogenic fibrosing dermopathy (NFD), mixed connective tissue disease, scleromyxedema, graft-versus-host disease (GVHD), Peyronie’s disease and eosinophilic fasciitis; or
  • a fibrotic condition affecting the eye for example ocular scarring, ocular fibrosis following surgery or pseudoexfoliation syndrome glaucoma.
  • the cardiovascular condition is selected from pulmomary hypertension, heart failure, cardiac hypertrophy and atherosclerosis.
  • liver disease is non-alcoholic fatty liver disease or hepatic steatosis.
  • a method of inducing death of senescent cells in a subject or sample comprising administering to said subject or sample an effective amount of a compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85, or a pharmaceutical composition according to any one of paragraphs 86 to 91.
  • a method of inhibiting senescence in a cell comprising administering to said cell an effective amount of a compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85, or a pharmaceutical composition according to any one of paragraphs 86 to 91.
  • a combination comprising a compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85 with another therapeutic agent.
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts.
  • salt(s) and salt form(s) used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified.
  • industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use.
  • Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.
  • Pharmaceutically acceptable salts are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof.
  • Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.
  • the compounds of Formula I are isolated as pharmaceutically acceptable salts.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s).
  • Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge.
  • salts may be prepared and/or isolated using a single method or a combination of methods.
  • Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like.
  • salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
  • Certain compounds of the Formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
  • N-oxides Compounds of the Formula I containing an amine function may also form N-oxides.
  • a reference herein to a compound of the Formula I that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N- oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m- chloroperoxybenzoic acid
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. keto enol enolate
  • An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • Certain compounds of Formula I may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centres, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.
  • the compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of 12 C, 13 C, and 14 C; hydrogen atoms may be present in any ratio of 1 H, 2 H, and 3 H; etc.
  • the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.
  • a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is a polymeric micelle.
  • the pharmaceutically acceptable carrier is a nanoparticle, suitably a polymeric nano-micelle.
  • the polymeric micelle comprises an amphiphilic polymer.
  • the amphiphilic polymer is an amphiphilic polymer block copolymer, which is a block polymer composed of two or more polymers.
  • the hydrophilic part of the amphiphilic polymer is selected from polyethylene glycol (PEO), povidone and the like, and the hydrophobic part of the amphiphilic polymer is selected from polyoxypropylene, polylactic acid, polystyrene, polycaprolactone (PCL), polyamino acid, poly(lactic-co-glycolic acid), polyacrylic acid and the like.
  • the amphiphilic polymer is a combination of two or more of poloxamers (e.g. PEO-PPO-PEO), a polylactic acid-polyethylene glycol-polylactic acid triblock copolymer (PLA-PEO-PLA), a polyethylene glycol-polyacrylic acid block copolymer (PEO-PAA), a polyethylene glycol-polyaspartic acid block copolymer (PEO-PASP), a polyethylene glycol-poly(lactic-co-glycolic acid) block copolymer (PEO-PLAG), a polyethylene glycol-polycaprolactone block copolymer (PEO-PCL), a polyethylene glycolpolylactic acid block copolymer (PEO-PLA/PTX), or a polyethylene glycol-polystyrene block copolymer (PEO-b-PS), and the like.
  • poloxamers e.g. PEO-PPO-PEO
  • the amphiphilic polymer is a polyethylene glycol- polycaprolactone block copolymer (PEO-b-PCL).
  • the copolymer may have a numberaverage molecular weight of 500-50000 (specifically, such as 500, 1000, 2000, 3000, 4000, 5000, 6000, 8000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 24000, 26000, 28000, 30000, 32000, 34000, 36000, 38000, 40000, 42000, 44000, 46000, 48000 and 50000).
  • the polymeric micelle has a mean hydrodynamic diameter (Dh, nm; measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)) of about 1 to about 500 nm.
  • Dh mean hydrodynamic diameter
  • nm measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)
  • Dh mean hydrodynamic diameter
  • the polymeric micelle has a mean hydrodynamic diameter (Dh, nm; measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)) of about 1 to about 400 nm.
  • Dh mean hydrodynamic diameter
  • Zetasizer 3000 HSA Zetasizer 3000 HSA, Malvern, UK
  • CONTI N method MALVERN software
  • the polymeric micelle has a mean hydrodynamic diameter (Dh, nm; measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)) of about 75 to about 400 nm.
  • Dh mean hydrodynamic diameter
  • nm measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)
  • Dh mean hydrodynamic diameter
  • the pharmaceutical compositions described herein comprise a pharmaceutically acceptable excipient or carrier which is a fluid, especially a liquid, in which the compound of formula I is suspended or dissolved, such that the composition is physiologically tolerable, i.e. can be administered to the mammalian body without toxicity or undue discomfort.
  • the carrier medium is suitably an injectable carrier liquid such as sterile, pyrogen- free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e.g. salts of plasma cations with biocompatible counterions), sugars (e.g.
  • the carrier may also comprise biocompatible organic solvents such as ethanol. Such organic solvents are useful to solubilise more lipophilic compounds or formulations.
  • the carrier is pyrogen-free water for injection, isotonic saline or an aqueous ethanol solution.
  • the pH of the carrier for intravenous injection is suitably in the range 4.0 to 10.5.
  • compositions described herein may contain conventional pharmaceutical excipients, for example emulsifiers, fatty acid esters, gelling agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc., and may be in a form suitable for parenteral or enteral administration, for example injection or infusion or administration directly into a body cavity having an external escape duct, for example the gastrointestinal tract, the bladder or the uterus.
  • conventional pharmaceutical excipients for example emulsifiers, fatty acid esters, gelling agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc.
  • the compounds or compositions of the present invention may be in conventional pharmaceutical administration forms such as tablets, capsules, powders, solutions, suspensions, dispersions, syrups, suppositories etc.
  • the most preferred mode for administering contrast agents is parenteral, e.g., intravenous administration.
  • the compounds or compositions described herein are in a parenterally administrable forms, e.g. an intravenous solutions.
  • Said solution should be sterile and free from physiologically unacceptable agents, and should have low osmolality to minimize irritation or other adverse effects upon administration, and thus the composition should preferably be isotonic or slightly hypertonic.
  • suitable carriers for administering parenteral solutions such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection.
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical carriers and excipients, well known in the art.
  • the compounds of the present invention can be used in a method of treating a disease or medical condition exhibiting senescence.
  • the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in therapy.
  • the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in treating a disease or condition exhibiting or mediated by senescence.
  • the present invention provides the use of a compound of formula I, or a pharmaceutical composition, as described herein for treating a disease or condition exhibiting or mediated by senescence.
  • the present invention provides the use of a compound of formula I, or a pharmaceutical composition, as described herein in the manufacture of a medicament for treating a disease or condition exhibiting or mediated by senescence.
  • the present invention provides a method of treating a disease or condition exhibiting or mediated by senescence in a subject, or a biological sample obtained therefrom, comprising administering to said subject or sample an effective amount of a compound of formula I, or a pharmaceutical composition, as described herein.
  • the biological sample is selected from tissues of animal origin, ranging from invertebrates to mammals, including humans, in the live or preserved state; single animal cells either derived from the above tissues or in suspension, in the live or preserved state.
  • the subject is an animal. In one embodiment, the subject is a mammal, suitably a human.
  • the disease or condition exhibiting or mediated by senescence is selected from the group consisting of diabetes, obesity, age-related lipodystrophy, cardiac dysfunction, vascular hyporeactivity/calcification/arteriovenous fistulae, frailty, sarcopenia, muscular dystrophy, fibrodysplasia, age related diseases such as age-related impairment of muscle hypertrophy after resistance exercise and age-related cognitive impairment, Alzheimer’s disease, Parkinson’s disease, ALS, anxiety, response to and sequelae of chemotherapy/radiation, cancers, sequelae of organ transplantation, renal dysfunction, osteoporosis, osteoarthritis, rheumatoid arthritis, intervertebral disc disease, fracture healing, COPD, hyperoxic lung damage, pulmonary arterial hypertension, hepatic steatosis, cirrhosis, primary biliary cirrhosis, progerias, intestinal inflammation, preeclampsia, uterine fibrosis,
  • the disease or condition exhibiting or mediated by senescence is selected from the group consisting of a cancer, a fibrotic disorder, a neurodegenerative condition, a cardiovascular disease, a metabolic disease, a kidney disease, a liver disease and a degenerative disease.
  • the disease or condition exhibiting or mediated by senescence is selected from a cancer or a fibrotic disorder.
  • the disease or condition exhibiting or mediated by senescence is selected from cancer, chronic obstructive pulmonary disease (COPD), cystic fibrosis, osteoporosis, frailty, transplantation, opthalmic disorders, disc degeneration, osteoarthritis, renal diseases, neurodegenerative diseases, hepatic steatosis, metabolic dysfunction, fibrosis, neoplasias (pre- and neoplastic), diabetes, neuro-degenerative diseases, cardiovascular diseases, obesity, immune dysfunction, aging and age related functional decline.
  • COPD chronic obstructive pulmonary disease
  • cystic fibrosis cystic fibrosis
  • osteoporosis frailty
  • transplantation transplantation
  • opthalmic disorders disc degeneration
  • osteoarthritis renal diseases
  • neurodegenerative diseases hepatic steatosis
  • metabolic dysfunction fibrosis
  • fibrosis neoplasias (pre- and neoplastic)
  • diabetes neuro-degenerative diseases
  • the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in treating a fibrotic disorder.
  • the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein for treating a fibrotic disorder.
  • the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein in the manufacture of a medicament for treating a fibrotic disorder.
  • the present invention provides a method of treating a fibrotic disorder in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I, or a pharmaceutical composition, as described herein.
  • the fibrotic disorder may be a disorder characterised by excess fibrosis, e.g., an excess of fibrous connective tissue in a tissue or organ, e.g., triggered by a reparative or reactive process, e.g., in response to injury (e.g., scarring, healing, radiotherapy) or excess fibrotic tissue arising from a single cell line (e.g., fibroma).
  • excess fibrosis e.g., an excess of fibrous connective tissue in a tissue or organ, e.g., triggered by a reparative or reactive process, e.g., in response to injury (e.g., scarring, healing, radiotherapy) or excess fibrotic tissue arising from a single cell line (e.g., fibroma).
  • the fibrotic disorder is selected from:
  • a fibrotic disorder affecting the lungs for example pulmonary fibrosis secondary to cystic fibrosis; idiopathic pulmonary fibrosis; coal worker’s progressive massive fibrosis; cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), or chronic asthma; or
  • a fibrotic disorder affecting the liver for example cirrhosis, and associated conditions such as chronic viral hepatitis B or C, Wilson’s disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis or autoimmune hepatitis; or
  • a fibrotic disorder affecting the kidneys for example diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangiocapillary glomerular nephritis;
  • a fibrotic disorder affecting the heart or vascular system for example endomyocardial fibrosis; old myocardial infarction; atrial fibrosis; congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (for example pulmonary hypertension) and fibrosis associated with hypertension, atherosclerosis, restenosis (e.g. coronary, carotid, and cerebral lesions), and heart disease associated with cardiac ischemic events; or
  • a fibrotic disorder affecting the mediastinum for example mediastinal fibrosis
  • a fibrotic disorder affecting bone for example myelofibrosis, including primary myelofibrosis, post polycythemia vera or post essential thrombocythemia myelofibrosis; or
  • a fibrotic disorder affecting the retroperitoneum for example retroperitoneal fibrosis skin;
  • a fibrotic disorder affecting the skin for example nephrogenic systemic fibrosis, keloid formation and scarring, systemic sclerosis, scleroderma, hypertrophic scarring, scleredema (Buschke disease), systemic amyloidosis, lipodermatosclerosis, progeroid disorders, stiff skin syndrome, Dupuytren's contracture, nephrogenic fibrosing dermopathy (NFD), mixed connective tissue disease, scleromyxedema, graft-versus-host disease (GVHD), Peyronie’s disease and eosinophilic fasciitis; or
  • a fibrotic disorder affecting the Gl tract for example a fibrotic intestinal disorder, inflammatory bowel disease, ulcerative colitis or Crohn’s disease; or
  • a fibrotic disorder affecting connective tissue for example arthrofibrosis; or capsulitis; or
  • a fibrotic disorder affecting the eye for example ocular scarring, ocular fibrosis following surgery or pseudoexfoliation syndrome glaucoma.
  • a fibrotic disorder induced by radiation such as fibrosis following radiotherapy.
  • the fibrotic condition induced by radiation may occur in any tissue treated by radiotherapy, for instance, the skin and subcutaneous tissue, lungs, breast, gastrointestinal and genitourinary tracts, muscles, and other organs.
  • the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in treating a cancer.
  • the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein for treating a cancer.
  • the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein in the manufacture of a medicament for treating a cancer.
  • the present invention provides a method of treating a cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I, or a pharmaceutical composition, as described herein.
  • the cancer may be a solid tumour or a haematological (“liquid”) cancer.
  • the cancer is selected from:
  • Carcinoma including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas).
  • squamous cell carcinomas stratified squamous epithelia
  • adenocarcinomas derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands.
  • squamous cell carcinoma include breast, colon, lung, prostate, ovary, esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet
  • Sarcomas including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective
  • Hematopoietic tumours including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis.
  • myelogenous and granulocytic leukemia malignancy of the myeloid and granulocytic white blood cell series
  • lymphatic, lymphocytic, and lymphoblastic leukemia malignancy of the lymphoid and lymphocytic blood cell series
  • polycythemia vera and erythremia malignancy of various blood cell products, but with red cells predominating
  • Lymphomas including: Hodgkin and Non-Hodgkin lymphomas;
  • Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;
  • Mixed Types including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.
  • the cancer is selected from anus cancer, bile duct cancer, bladder cancer, blood cancer, brain cancer, breast cancer, uterine cervix cancer, colon cancer, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, head and neck cancer, hypopharyngeal cancer, pancreatic cancer, pharyngeal cancer, lip and oral cancer, liver cancer, lung cancer, melanoma, mesothelioma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
  • the cancer is selected from bladder cancer, blood cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, head and neck cancer, pancreatic cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
  • the cancer is selected from pancreatic cancer, colon cancer, breast cancer and lung cancer.
  • the present invention relates to a method of inducing death of a senescent cell in a subject or sample, comprising administering to said subject or sample an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the present invention relates to a method of inhibiting senescence in a cell, comprising administering to said cell an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the cell is present in a sample.
  • the sample is a fluid sample.
  • the sample may comprise a body fluid of a subject, such as urine, lymph, saliva, mucus, milk or amniotic fluid, blood, plasma or serum.
  • the sample is human in origin, but alternatively it may be from another mammal or animal such as from commercially farmed animals such as horses, cattle, sheep or pigs or may alternatively be pets such as cats or dogs.
  • the method is an in vivo method. In another, embodiment of each of the above aspects the method is an ex vivo or in vitro method.
  • the compounds of the invention may be used alone to provide a therapeutic effect.
  • the compounds of the invention may also be used in combination with one or more additional therapeutic agents or methods.
  • the present invention provides a compound of formula I as defined herein in combination with an anti-cancer agent and/or radiotherapy.
  • the anti-cancer agent may be selected from one or more of the following:
  • antiproliferative/antineoplastic drugs and combinations thereof such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin, temozolomide and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, leucovorin, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopur
  • cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafme and droloxafine; and abiraterone, Enzalutamide; analogues
  • anti-invasion agents for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, for example anti-erbB2 antibodies trastuzumab, margetuximab, the anti-HER2 antibody pertuzumab; the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family: gefitinib, erlotinib, , afatinib, vandetanib, osimertinib and rociletinib); erbB2 tyrosine kinase inhibitors such as lapatinib, neratinib, mobocertinib, tucatinib and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-1, or antibodies to cytokines (IL-IO, TGF-beta); inhibitors of the hetyrosine kinase
  • aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors or CDK4/CDK6 inhibitors such as palbociclib, abemaciclib, ribociclib; CCR2, CCR4 or CCR6 antagonists; mTOR kinase inhibitors such as Everolimus; Janus kinase family inhibitors such as ruxolitinib; Brunton’s tyrosine kinase inhibitors such as Ibrutinib, zanubrutinib; anaplastic lymphoma kinase - ALK - such as ceritinib, crizotinib, alectinib, lorlatinib, brigatinib; c-Met kinase inhibitors such as cabozantinib, tepotinib, cap
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2; oncolytic viruses such as talimogene laherparepvec; CAR-T cells based therapies such as ciltacabtagene autoleucel, brexucabtagene autoleucel
  • immunotherapy approaches including for example antibody therapy such as denosumab, obinutuzumab, blinatomumab, dinutuximab, idarucizumab, daratumumab, necitumumab, elotuzumab, olaratumab, alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), isatuximab, avelumab, tafasitamab, naxitamab and ofatumumab; interferons such as interferon a, peginterferon alpha-2b; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge);
  • cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM);
  • SMAC second mitochondria-derived activator of caspases
  • IAP Apoptosis Proteins
  • SMAC second mitochondria-derived activator of caspases
  • IAP Apoptosis Proteins
  • XIAP XIAP
  • clAP1 and clAP2 Birinapant
  • LCL161 Novartis
  • UPS ubiquitin proteasome system
  • bortezomib, ixazomib, carfilzomib and marizomib DNA repair inhibitors
  • DNA repair inhibitors such as Olaparib, rucaparib, niraparib
  • antiapoptotic BCL proteins family inhibitors such as venetoclax.
  • the present invention provides a compound of formula I as defined herein in combination with an anti-fibrotic agent.
  • the anti-fibrotic agent may be selected from one or more of the following:
  • Antifibrotic agents such as pirfenidone, nintedanib; CTFG antibody inhibitors such as pamrevlumab; recombinant human pentraxin-2 (PRM-151); anti-inflammatory agents such as corticosteroids, interferon-gamma; cardiovascular drugs such as pentoxifylline; ROS scavengers such as Vitamin E, superoxide dismutase.
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • the amount of the compound of the invention and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the patient.
  • the combined amounts are “therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse.
  • such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of the invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
  • a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore for the conjoint treatment of cancer.
  • a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-cancer agent as defined hereinbefore.
  • a compound of the invention or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-cancer agent as defined hereinbefore, in the treatment of a cancer.
  • the anti-cancer agent is selected from dasatinib and/or quercetin.
  • the compound of the invention may also be used be used in combination with radiotherapy.
  • Suitable radiotherapy treatments include, for example X-ray therapy, proton beam therapy or electron beam therapies.
  • Radiotherapy may also encompass the use of radionuclide agents, for example 131 1, 32 P, 90 Y, 89 Sr, 153 Sm or 223 Ra.
  • radionuclide therapies are well known and commercially available.
  • a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with radiotherapy.
  • a combination of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, an anti-fibrotic agent is provided.
  • a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-fibrotic agent as defined hereinbefore for the conjoint treatment of a fibrotic disorder.
  • a method of treatment of a human or animal subject suffering from a fibrotic disorder comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore.
  • a compound of the invention for use simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore, in the treatment of a fibrotic disorder.
  • the compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).
  • the purity of the target compound was determined on a Thermo Scientific® HPLC System (Accela Pump, Accela Autosampler, Accela PDA detector, 254 nm, XcaliburTM 2.2 Software); Waters ACQUITY UPLC® BEH C18-1.7 pm (2.1 x 150 mm); mobile phase: 1% acetic acid in Water / Acetonitrile; flowrate 0.2 mL/min; column temperature 25 °C; injection volume 5 pL.
  • the crude product was purified by flash column chromatography, using a mixture of dichloromethane/methanol (from 100/2 up to 100/10, v/v) as the eluent, to provide the pure hybrid derivative GL392 as a black solid, in 50% yield. M.p. 169-170 °C.
  • PEO-b-poly(s-caprolactone) (PEO-b- PCL(5K), 5K) copolymer purchased from BOC Sciences® (Lot No B23VO3091) was utilized.
  • Polymeric micelles were prepared by the thin-film hydration method. Briefly, an appropriate amount of PEO-b-PCL was dissolved in chloroform. An appropriate amount of GL392 (example 1) being dissolved in acetone was added. The mixture was then transferred into a round flask connected to a rotary evaporator (Hei-VAP series CORE-heidolph®). Vacuum was applied and the polymeric thin film was formed by slow removal of the solvent at 45°C. The film was subsequently hydrated in HPLC-grade water, by slowly stirring for 1 h, in a water bath at 45° C.
  • the concentration of PEO-b-PCL in the final micellar dispersion was 5mg/mL and the concentration of GL392 was 0.01mg/mL.
  • the resultant micelles were subjected to two, 5-minute long sonication cycles interrupted by a 5 minute resting period, using a probe sonicator (Bandelin sonopuls, homogenizer, HD3200). The resultant GL392 loaded micelles were allowed to anneal for 30 min at room temperature.
  • the physicochemical characteristics of the prepared nanosystems were evaluated by measuring their mean hydrodynamic diameter (Dh, nm) and size polydispersity index (PDI). These parameters were assessed for the physicochemical characterization of loaded micelles immediately after their preparation. 100 pL aliquots were 20-fold diluted in HPLC-grade water. For dynamic light scattering measurements, an AVL/CGS-3 Compact Goniometer System (ALV GmbH, Germany) was used, equipped with a cylindrical JDS Uniphase 22 mV He-Ne laser, operating at 632.8 nm/ and an Avalanche photodiode detector.
  • Dh, nm mean hydrodynamic diameter
  • PDI size polydispersity index
  • the system was interfaced with an ALV/LSE-5003 electronics unit, for stepper motor drive and limit switch control, and an ALV-5000/ EPP multi-tau digital correlator. Autocorrelation functions were analyzed by the cumulants method and the CONTI N software. All measurements were implemented at a fixed temperature (25 °C) and at a fixed scattering angle of 90° degrees.
  • the size (hydrodynamic diameter, Dh) of pure PEO-b-PCL micelles was found to be 85 nm; the addition of GL392 led to an increase in the Dh to 120 nm, indicating its successful incorporation into the micellar core (see Figure 2B).
  • the PDI value for mGL392 reveals a monodisperse particulate population.
  • the cryo-TEM image shows mGL392 with an irregular shape (but more or less spherical, Figure 2C, iv).
  • the size of the mGL392 is higher than the size of the sample obtained by TEM and DLS.
  • the phenomenon of secondary aggregation is probably responsible for this observation, caused by the low temperature conditions during the experiment and the different state of matter of the PEO-b-PCL block copolymer (Castillo and Muller, 2009). Additionally, the different contrast within the nanoparticles also indicates the successful incorporation of GL392 into the polymeric micelle.
  • mGL392 (example 2) was used to detect senescent cells in Li-Fraumeni- p2i AFi/ci Pi T e t-ON cells using fluorescence microscopy (Figure 3). Li-Fraumeni-p21 WAF1/Cip1 Tet-ON cells were maintained in DMEM, 10% tetracycline free fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • Senescence entry was accomplished upon addition of (50pg/ml) Doxycycline (Applichem, Darmstadt, Germany) replenishing every two days for 6 days [as described in Galanos et al, 2016; Zampetidis et al, 2021], [00303]
  • Fig 3A Proliferating (upper panel, Fig 3B) or senescent (lower panel, Fig 3B) Li-Fraumeni-p21 WAF1/Cip1 Tet-ON cells were treated with mGL392 (1.6 pg/ml) for 4 hours and subsequently observed under an EVOS microscope.
  • mGL392 treated senescent cells do not display lipofuscin autofluorescence since it is masked upon interaction with the compound. Untreated senescent cells display abundant autofluorescence, while corresponding non-senescent [(-) Doxycline] Li-Fraumeni- p2i AFi/ci Pi T e t-ON ce
  • Non-senescent and senescent Li-Fraumeni-p21 WAF1/Cip1 Tet-ON cells were treated with mGL392 (0,4 pg/ml), Dasatinib (D) (20mM), mGL392+Q, D+Q, Quercetin (Q) (10pM) or Vehicle. Cell viability was assessed by MTT assay. Results are presented as mean % of the vehicle ⁇ SD, from 2 independent experiments (Fig. 4A).
  • Apoptosis and senescence were estimated in cells treated with mGL392, mGL392+Q or Vehicle.
  • mGL392, mGL392+Q did not affect the viability of (-) Dox (noninduced) Li-Fraumeni-p21 WAF1/Cip1 Tet-ON cells as evaluated by the absence of Cl.
  • mGL392 and mGL392+Q treated (+)-Dox (senescence induced) Li-Fraumeni-p21 WAF1/Cip1 Tet-ON cells showed increased Cl.
  • Caspase-3 positivity Quantification of the immunofluorescence analysis is presented in pie charts as mean ⁇ SD. Results were from three independent experiments.
  • HBEC CDC6 Tet-ON were maintained in Keratinocyte Serum-Free Medium (#17005-075, Invitrogen) supplemented with 50 pg/ml Bovine Pituitary Extract and 5 ng/ml hEGF (#17005-075, Invitrogen).
  • Senescence entry was accomplished upon addition of (50
  • Senescent and non-senescent HBEC CDC6 Tet-ON cells were subsequently treated with mGL392 (0.4 pg/ml), Dasatinib (D) (20mM), mGL392+Q, D+Q, Quercetin (Q) (10pM) or Vehicle. Cell viability was assessed by MTT assay. Results are presented as mean % of vehicle ⁇ SD, from 2 independent experiments. Statistical significance: *p ⁇ 0.05 compared to respective vehicle by two-tailed Student’s t test (Fig. 5C).
  • 3D Airway Organoids (AO) were generated from lung tissue surgically resected from non-small cell lung cancer (NSCLC) patients, and cultured as described before [Sachs N, et al., EMBO (2019)]. Briefly, collection of tissues for the generation of airway organoids was carried out according to the European Network of Research Ethics Committees (ELIREC) guidelines and the local NKLIA Medical School Bioethics committee (Protocol number: 571). All organoid lines were generated from patients who signed informed consent forms and their personal information remained anonymous.
  • ELIREC European Network of Research Ethics Committees
  • Organoids were treated (or not) with 150 pM hydrogen peroxide (H2O2) for 72 h (replaced daily) to induce senescence, and then cultured for another 48h in H2O2-free medium. Organoids were then filtered using 70-pm strainers (Corning) to avoid formation of necrotic cores and subsequently treated with vehicle, mGL392 (500 nM), Dasatinib (500 nM), Quercetin (10 pM), Dasatinib and Quercetin or mGL392 and Quercetin for 4 days, in 5% BME/AO medium.
  • H2O2 hydrogen peroxide
  • senolysis was evaluated by cell viability measurements and quantification of senescent and apoptotic cells by immunofluorescence.
  • the experimental work flow is illustrated at Fig. 6a.
  • Cell viability was evaluated with the CellTiter-FluorTM Cell Viability Assay reagent (Promega #G6081), according to the manufacturer’s instructions.
  • Organoids (1/40, ab7481 , Abeam) in 1/40 dilution (in PBS) for 1h at RT.
  • Organoids were incubated with primary antibody (Cl. Caspase-3, 1/400, #9661, Cell Signaling) for 1h, and positive cells were visualized using secondary goat anti-rabbit IgG H&L antibody (Alexa Fluor® 488; 1/500, ab150077, polyclonal, Abeam) for 1h.
  • primary antibody Cl. Caspase-3, 1/400, #9661, Cell Signaling
  • secondary goat anti-rabbit IgG H&L antibody Alexa Fluor® 488; 1/500, ab150077, polyclonal, Abeam
  • organoids were stained for lipofuscin using GLF16 for 10 min (60 pg/ml) in the dark.
  • mGL392 was successfully delivered in the 3D setting and conferred a significant reduction of senescent cells, without affecting proliferating/non- senescent cells, as indicated by both organoid viability and immunofluorescence analyses (Fig. 6a-d).
  • Fig. 6a-d organoid viability and immunofluorescence analyses
  • mice were sex and age matched and melanoma tumors were generated upon subcutaneous injection of 5x10 5 cells/1 OOpI of PBS in the right flank of 8-10- week old C57BL/6 syngeneic mice. Once tumors became palpable (8-9 days post tumor cell inoculation), mice were randomly split into 6 groups receiving vehicle (normal saline), Palbociclib (CDK4/6 inhibitor, PD-0332991), Palbociclib and mGL392, Palbociclib and Dasatinib, Palbociclib and Dasatininib and Quercetin, Palbociclib and mGL392 and Quercetin.
  • vehicle normal saline
  • Palbociclib CDK4/6 inhibitor, PD-0332991
  • Palbociclib and mGL392 Palbociclib and Dasatinib
  • Palbociclib and Dasatininib and Quercetin Palbociclib and mGL392 and Quercetin.
  • Quercetin was not found to affect tumor size in vehicle- or Palbociclib-treated mice and was omitted from the experimental design.
  • Palbociclib was administered at 2.5 mg/mouse and mGL392 at 0.015 mg/mouse.
  • Dasatinib was administered at 0.125 mg/mouse and Quercetin at 1.25 mg/mouse.
  • the mGL392 dosage was selected based on the reported administered dose of free Dasatinib (5mg/kg b.w) in senolytic studies [Zhu Y, et al., 2015] and its bioavailability (approximately 14% [Korashy et al., 2014]).
  • Palbociclib and Quercetin were administered by oral gavage and mGL392 and Dasatinib intraperitoneally. Administration was performed daily, for 9 consecutive days. Tumors were monitored daily and measured every 2-3 days using a caliper. Tumor sizes were calculated using the formula: width 2 x length/2 and results were expressed in mm 3 . Mice were euthanized (humane end point was set for tumor volume below 2x10 3 mm 3 , or any sign of distress) by sevoflurane overdose and blood was collected, tumors, vital organs and hindlimb muscles were excised and fixed in formalin for subsequent analysis. Immunofluroresence analysis was performed similar to that described above.
  • Tissue sections were washed with PBS and incubated with the primary anticleaved Caspase-3 (1/400, #9661, Cell Signalling) antibody overnight at 4°C. Samples were washed with TBS and the positive signal was achieved utilizing the Dako REAL 140 EnVision Detection System, (Cat.no: K5007) according to the manufacturer’s instructions. Tissue Specimens were counterstained with Hematoxylin. Samples were observed under a ZEISS Axiolab5 microscope on the 10x and 20x Objectives and evaluated by two independent experienced pathologists. Variability was minimal among blinded observers (p ⁇ 0.005).
  • Fig 7h shows mGL392 enhances the melanoma-reducing action of Palbociclib. Tumor sizes were measured every three days.
  • Fig. 7i shows Representative tumors from (h), Scale bar: 5 mm.
  • Fig 7j shows Proposed model of mGL392 action.
  • Caspase-3 Cleaved Caspase-3.
  • Palbo Palbociclib.
  • mGL392 does not suppress proliferating B16 melanoma cells (Fig. 7f) nor tumors when senescence is absent (Fig. 7g), and a significant reduction of tumor sizes is seen in mice treated with both Palbociclib and mGL392 (Fig. 7h-i), the observed anti-tumor effects of mGL392 may only be attributed to selective senolysis.
  • micelle encapsulation facilitates GL392 cellular internalization and favors its selective release in senescent cells, as it preferably disintegrates upon exposure to the low cytosolic pH of senescent cells.
  • the discharged GL392 accumulates inside senescent cells due to its high affinity for lipofuscin and its ester linker is subsequently hydrolyzed by intracellular esterases to effectively release Dasatinib, overall promoting senolysis (Fig. 7j).
  • Gray-Schopfer VC et al., Br. J. Cancer 2006, 95: 496-505.
  • Halazonetis TD et al., Science 2008, 319: 1352-1355.
  • Prasanna PG et al., J Natl Cancer Inst. 2021 Oct 1;113(10):1285-1298.

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Abstract

A compound, or a salt or solvate thereof, according to formula (I) as defined herein and pharmaceutical composition comprising said compound. Compounds of formula (I) are capable of the selective elimination of senescent cells in a subject or biological sample. As such, these senolytic compounds can be useful in treatment of a disease or condition mediated by senescence.

Description

CONJUGATE OF A SENOTHERAPEUTIC MOIETY AND A LIPID-TARGETING MOIETY
INTRODUCTION
[001] Described herein are compounds which are capable of selectively targeting senescent cells and modulating the activity of, or elimination of these cells. As such, these compounds are useful in treatment of diseases or conditions mediated by senescence, such as cancer.
BACKGROUND OF THE INVENTION
[002] Senescence is a fundamental stress response mechanism aiming to preserve tissue or organismal homeostasis [Gorgoulis & Halazonetis, Curr Opin Cell Biol 2010; Gorgoulis et al., J Pathol 2018; Gorgoulis et al., Cell 2019], Cells entering this state are characterized by prolonged and generally irreversible cell-cycle arrest, and resistance to apoptosis [Gorgoulis et al., Cell 2019; Childs et al., EMBO Rep 2014], They demonstrate also macromolecular damage, deregulated metabolism [Gorgoulis et al., Cell 2019; Myrianthopoulos et al., Pharmacol & Ther 2019], and exhibit secretory features, collectively described as senescence-associated secretory phenotype (SASP) [Gorgoulis et al., Cell 2019], SASP includes a variety of cytokines, chemokines, growth factors, proteases and other molecules, depending on the type of senescence and the cells involved [Gorgoulis et al., Cell 2019; Myrianthopoulos et al., Pharmacol & Ther 2019],
[003] The senescent phenotype is highly diverse, as triggering stimuli and maintenance mechanisms involved are not pre-requisitely preserved among the senescence programs [Gorgoulis et al., Cell 2019],
[004] Transient occurrence of this cellular state has beneficial roles in various physiological processes to ensure cellular and organism homeostasis. For example, during embryogenesis, senescence facilitates tissue development and morphogenesis, while in the adult life apart from promoting tissue repair [Gorgoulis & Halazonetis, Curr Opin Cell Biol 2010; Gorgoulis et al., J Pathol 2018; Gorgoulis et al., Cell 2019], It also restrains the expansion of damaged cells such as the case in the preneoplastic lesions where it serves as an anti-tumor barrier against the development of incipient cancerous cells [Halazonetis et al., Science 2008; Gorgoulis et al., J Pathol 2018],
[005] In contrast, if senescent cells are not timely removed, resulting in their prolonged presence within tissues, they can exert detrimental effects leading to a variety of diseases, including cancer, and promotion of aging. An established harmful way is through that SASP factors that mediate pro-tumorigenic signaling, inducing chronic inflammation, sternness, angiogenesis or immune suppression [Schmitt et al, 2022], Recent evidence have demonstrated another way that is SASP-independent, through which persistent senescent cells can override the cell-cycle arrest condition, and re-enter the cell cycle, by breaching of anti-tumor barriers [Galanos et al., Nat Cell Biol 2016; Zampetidis et al., Mol Cell 2021], This “escape from senescence phenomenon” has been related to adverse properties and especially to tumor progression, tumor relapses and resistance to anti-tumor therapies [Galanos et al., Nat Cell Biol 2016; Myrianthopoulos et al., Pharmacol & Ther 2019; Zampetidis et al., Mol Cell 2021],
[006] Moreover, conventional chemotherapies, radiotherapy and several targeted therapies for cancer treatment bestow DNA damage and ROS production, leading to senescence induction in both malignant and non-malignant cells [Perez et al, 2016; Goel et al, 2016; Calcinotto et al, 2019; Mikula-Pietrasik et al, 2020], In turn, evidence supports that senescence may contribute to reduced patient resilience to cancer therapies and may be responsible for disease recurrence after cancer therapy [Prasanna et al, 2021], Therapy- Induced-Senescence (TIS) may also enhance the adverse effects from this treatment through SASP [Yao et al, 2020; Murali et al, 2018; Faccio et al, 2016; Baar et al, 2017; Demaria et al, 2017], Particularly, older patients are more vulnerable to developing severe side effects and develop resistance to therapy, or even secondary primary malignancies and non-cancer chronic diseases, as a result of impaired organ function [Bhakta et al, 2017; Zhu et al, 2020], Collectively, the above support the need for pharmacological elimination of senescence to reduce accompanying adverse effects and enhance the efficacy of non- and anti-cancer therapies.
[007] Development of senotherapeutics has been rapidly expanding since 2015 when the first senolytics were reported. Senolytics have shown potential promise in the selective removal of senescent cells when systematically administered in preclinical models, resulting in the alleviation of various pathologies and lifespan elongation [Xu et al, 2018; Yousefzadeh et al, 2018; Chaib et al, 2022], However, most senolytic drugs are derived from a drug repurposing procedure, thus they also harbor non-senescence related effects. As such, application of most of the currently available senolytics have been impeded by issues such as poor bioavailability, systemic toxicities and adverse side- and off-target effects, while evidence from clinical trials on their effectiveness, safety and interaction with other drugs is still poor [Wang et al, 2022; Schmitt et al, 2022; Raffaele and Vinciguerra, 2022; Romashkan et al, 2021 ; Steegmann et al, 2012], Bypass of the aforementioned obstacles by implementing targeted elimination of senescent cells emerges as an imperative demand and challenging task to improve senotherapeutic efficacy.
[008] The heterogeneous and dynamic nature of senescent cells renders their selective targeting a challenging task. Several markers, including the commonly used p2lWAF1/c'P1 or p16INKA4A QD inhibitors that are associated with the cell cycle arrest, are not universally expressed in senescent cells [Alcorta et al, 1996; Michaloglou et al, 2005; Gray-Schopfer et al, 2005], Within this context the only common denominator of senescent cells is lipofuscin: “the dark matter” of these cells [Georgakopoulou et al., 2013; Gorgoulis et al, 2019], Lipofuscin mainly consists of undegradable protein aggregates and lipids that accumulate due to deregulation of the translational process during senescence [Georgakopoulou et al., 2013; Papaspyropoulos et al, 2023], Lipofuscin is therefore a hallmark of senescent cells given that it is functionally associated with senescence [Gorgoulis et al, 2019; Kohli et al, 2021], Moreover, its detection has been adopted as a key step in a recently proposed methodology algorithm for senescence recognition [Gorgoulis et al, 2019; Kohli et al, 2021],
[009] Compounds that react with lipofuscin for senescence detection with high specificity have been developed [Georgakopoulou et al., 2013; Evangelou et al. 2017; Magkouta et al. 2023] exploiting innovative Sudan Black B (SBB) analogues. The uniqueness in their specificity has led to their adoption as the main tools in the aforementioned algorithm for lipofuscin reaction [Gorgoulis et al, 2019; Kohli et al, 2021],
[0010] However, there is a need in the art for compounds that can specifically target senescent cells and either modulate the activity thereof or eliminate senescent cells. Such compounds will facilitate the treatment of diseases or conditions mediated by senescence, advantageously with improved potency and/or reduced toxicity.
SUMMARY OF THE INVENTION
[0011] In view of the foregoing, the present invention provides new compounds comprising SBB analogues linked with senolytics, which allow for the selective targeting of senescent cells, followed by their modulation or elimination.
[0012] In particular, the novel compounds have the ability to react with lipofuscin, in an analogous manner to the histochemical dye SBB and the ability to deliver specifically a senolytic drug to selectively modulate or eliminate senescent cells. [0013] The novel chemical compounds can be used for the modulation or elimination of senescent cells in subjects, animals, plants or live biological samples derived from them.
[0014] In one aspect, the present invention provides a compound of Formula I as defined herein, and/or a salt or solvate thereof.
[0015] In another aspect, the present invention provides a pharmaceutical composition which comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
[0016] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
[0017] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in treatment of a disease or condition mediated by senescence.
[0018] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in treating a disease or a condition selected from a cancer, a fibrotic disorder, a neurodegenerative condition, a cardiovascular disease, a metabolic disease, a kidney disease, a liver disease and a degenerative disease.
[0019] In another aspect, the present invention provides a method of inducing death of a senescent cell in a subject or sample, comprising administering to said subject or sample an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[0020] In another aspect, the present invention provides a method of inhibiting senescence in a cell, comprising administering to said cell an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[0021] In another aspect, the present invention provides a combination comprising a compound of formula I, or a salt or solvate thereof as defined herein with another therapeutic agent. [0022] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.
BRIEF DESCRIPTION OF THE DRA WINGS
[0023] Figure 1 provides the structures of some known senotherapeutic agents.
[0024] Figure 2 provides a schematic of GL392 synthesis, micelle encapsulation (A) and physicochemical characterization thereof (B, C)
[0025] Figure 3 provides data demonstrating validation of mGL392 and its lipofuscin binding properties (A-C).
[0026] Figure 4 provides data demonstrating that mGL392 promotes targeted senolysis in vitro in Li-Fraumeni-p21WAF1/Cip1 Tet-ON cells.
[0027] Figure 5 provides data demonstrating that mGL392 promotes targeted senolysis in the HBEC-CDC6 Tet-ON cellular system.
[0028] Figure 6 provides data demonstrating that mGL392 promotes targeted senolysis in 3D lung organoids.
[0029] Figure 7 provides data demonstrating that mGL392 promotes targeted senolysis in an in vivo murine model.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0030] The compounds and intermediates described herein may be named according to either the IIIPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that unless expressly stated to the contrary, the terms “compounds of Formula I” and the more general term “compounds” refer to and include any and all compounds described by and/or with reference to Formula I. It should also be understood that these terms encompass all stereoisomers, i.e. cis and trans isomers, as well as optical isomers, i.e. R and S enantiomers, of such compounds and all salts thereof, in substantially pure form and/or any mixtures of the foregoing in any ratio. This understanding extends to pharmaceutical compositions and methods of treatment or diagnosis that employ or comprise one or more compounds of the Formula I, either by themselves or in combination with additional agents. [0031] The various hydrocarbon-containing moieties provided herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, e.g. “(Ca-b)” or “Ca-Cb” or “(a-b)C”. For example, Ca-b alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive. Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure. For example, the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.
[0032] "About" when used herein in conjunction with a measurable value such as, for example, an amount or a period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.
[0033] As used herein by themselves or in conjunction with another term or terms, "alkyl" and “alkyl group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.
[0034] As used herein by themselves or in conjunction with another term or terms, “alkoxy” and “alkoxy group” refer to O-alkyl groups. Representative examples include, but are not limited to, -OMe, -OEt, -O-'Pr and O-fBu. Alkoxy groups can be substituted or unsubstituted unless indicated otherwise.
[0035] As used herein by themselves or in conjunction with another term or terms, “alkylene” and “alkylene group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkylene groups typically contain 1-10 carbon atoms, such as 1- 6 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methylene (-CH2-), the ethylene isomers (-CH(CH3)- and -CH2CH2-), the propylene isomers (-CH(CH3)CH2-, - CH(CH2CH3)-, -C(CH3)3-, and -CH2CH2CH2-), etc.
[0036] As used herein by themselves or in conjunction with another term or terms, “alkenyl” and “alkenyl group” refer to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless specified otherwise, alkenyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.
[0037] As used herein by themselves or in conjunction with another term or terms, “alkynyl” and “alkynyl group” refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.
[0038] As used herein by themselves or in conjunction with another term or terms, “heteroalkyl,” refers to a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. A heteroalkyl group is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3 , -CH2-CH2-NH-CH3 , -CH2-CH2-N(CH3)-CH3 , -CH2-S-CH2-CH3 , -S(O)-CH3, -CH2-CH2-S(O)2-CH3 , -CH=CH-O-CH3 , -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH- N(CH3)-CH3, and polyethylenoxy chains such as -(O(CH2)2)n(OCH2CH3). Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O- Si(CH3)3. A heteroalkyl moiety may include one or more heteroatoms which may be the same or different.
[0039] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2 - and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like.
[0040] As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”). An aromatic ring system can be substituted or unsubstituted. [0041] As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S. A non-aromatic ring system can be substituted or unsubstituted.
[0042] As used herein by themselves or in conjunction with another term or terms, “aryl” and “aryl group” refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e. , phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms. Representative examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6, 7,8,9- tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl. Suitably an aryl group is phenyl and naphthyl, suitably phenyl.
[0043] As used herein by themselves or in conjunction with another term or terms, “arylene” and “arylene group” refer to a phenylene (-C6H4-) or to 7 to 15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Arylene groups can be substituted or unsubstituted. In some embodiments, an arylene group may contain 6 (i.e., phenylene) ring atoms or be a ring system containing 9 to 15 atoms; such as 9 to 11 ring atoms; or 9 or 10 ring atoms. Arylene groups can be substituted or unsubstituted.
[0044] As used herein by themselves or in conjunction with another term or terms, “arylalkyl” and “arylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as previously defined, such as, for example, benzyl (C6H5CH2-). Arylalkyl groups can be substituted or unsubstituted.
[0045] As used herein by themselves or in conjunction with another term or terms, “carbocyclic group” and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation. Thus, carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1 ,2,3,4-tetrahydro- naphthalenyl). The terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.
[0046] As used herein by themselves or in conjunction with another term or terms, “cycloalkyl” and “cycloalkyl group” refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused. A cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms. In some instances a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.). Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane. Suitably, cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
[0047] As used herein by themselves or in conjunction with another term or terms, “cycloalkylalkyl” and “cycloalkylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as previously defined, such as, for example, cyclohexylmethyl (C6HnCH2-). Cycloalkylalkyl groups can be substituted or unsubstituted.
[0048] As used herein by themselves or in conjunction with another term or terms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, - CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCI=CH2, -CBr=CH2, -CI=CH2, -C C-CF3, - CHFCH2CH3 and -CHFCH2CF3. Haloalkyl groups can be substituted or unsubstituted. Suitably, a haloalkyl group is selected from CHF2 and CF3, suitably CF3.
[0049] As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, -OCHFCF3, -OCH2CF3, -OCF2CH3, -OCHFCH3, -OCF2CF2CF3, -OCF2CH2CH3, -OCF=CF2, - OCCI=CH2, -OCBr=CH2, -OCHFCH2CH3 and -OCHFCH2CF3. Haloalkoxy groups can be substituted or unsubstituted. Suitably, a haloalkyoxy group is selected from -OCHF2 and - OCF3, suitably -OCF3.
[0050] As used herein by themselves or in conjunction with another term or terms, “halo” and “halogen” include fluorine, chlorine, bromine and iodine atoms and substituents.
[0051] As used herein by themselves or in conjunction with another term or terms, “heteroaryl” and “heteroaryl group” refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. In some instances, a heteroaryl group can contain two or more heteroatoms, which may be the same or different. Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused. In some instances, a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms. In other instances, a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms. Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1,2- dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2, 3, 4- tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl,
3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3- thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-,
4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, 10-aza- tricyclo[6.3.1.02J]dodeca-2(7), 3, 5-trienyl, 12-oxa-10-aza-tricyclo[6.3.1.02’7]dodeca-2(7), 3,5- trienyl, 12-aza-tricyclo[7.2.1.02’7]dodeca-2(7), 3, 5-trienyl, 10-aza-tricyclo[6.3.2.02’7]trideca- 2(7), 3, 5-trienyl, 2,3,4,5-tetrahydro-1 H-benzo[d]azepinyl, 1 ,3,4,5-tetrahydro-benzo[d]azepin- 2-onyl, 1,3,4,5-tetrahydro-benzo[b]azepin-2-onyl, 2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl, 1 ,2,3,4-tetrahydro-benzo[e][1 ,4]diazepin-5-onyl, 2,3,4,5-tetrahydro-1 H- benzo[e][1 ,4]diazepinyl , 5,6,8,9-tetrahydro-7-oxa-benzocycloheptenyl, 2,3,4,5-tetrahydro-1 H- benzo[b]azepinyl, 1 ,2,4,5-tetrahydro-benzo[e][1 ,3]diazepin-3-onyl, 3,4-dihydro-2H- benzo[b][1 ,4]dioxepinyl , 3,4-dihydro-2H-benzo[f][1 ,4]oxazepin-5-onyl, 6,7,8,9-tetrahydro-5- thia-8-aza-benzocycloheptenyl, 5,5-dioxo-6,7,8,9-tetrahydro-5-thia-8-aza- benzocycloheptenyl, and 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepinyl. Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
[0052] As used herein by themselves or in conjunction with another term or terms, “heteroarylalkyl” and “heteroarylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heteroaryl group, wherein alkyl group and heteroaryl group are as previously defined. Heteroarylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heteroaryl(Cn-m)alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
[0053] As used herein by themselves or in conjunction with another term or terms, “heterocyclic group” and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation. Thus, a heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyrindinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1 , 2,3,6- tetrahydropyridinyl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrizinyl). The terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.
[0054] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkyl” and “heterocycloalkyl group” refer to 3 to 15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted. In some instances a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl- S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8- diaza-bicyclo[3.2.1]octanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,9-diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl, [1,4]oxaphosphinanyl- 4- oxide, [1,4]azaphosphinanyl- 4-oxide, [1,2]oxaphospholanyl- 2-oxide, phosphinanyl-1 -oxide, [1,3]azaphospholidinynl- 3-oxide, [1,3]oxaphospholanyl- 3-oxide, 7- oxabicyclo[2.2.1]heptanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 6,8-dihydro-5H- imidazo[1 ,5-a]pyrazin-7-yl, 6,8-dihydro-5H-imidazo[1 ,2-a]pyrazin-7-yl, 5,6,8,9-tetrahydro- [1 ,2,4]triazolo[4, 3-d][1 ,4]diazepin-7-yl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl. Suitably, a heterocyclylalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.
[0055] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkylene” and “heterocycloalkylene group” refer to 3 to 15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkylene groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused. Heterocycloalkylene groups can be substituted or unsubstituted. In some instances, a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. In other instances a heterocycloalkylene group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
[0056] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkylalkyl” and “heterocycloalkylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously defined, such as, for example, pyrrolidinylmethyl (C4H8NCH2-). Heteroycloalkylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heterocycloalkyl(Cn-m)alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
[0057] As used herein, “oxo” refers to a double bond to oxygen, i.e. =0.
[0058] As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.
[0059] As used herein by itself or in conjunction with another term or terms, “pharmaceutical composition” refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.
[0060] As used herein by themselves or in conjunction with another term or terms, “stable” and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity. The present application is directed solely to the preparation of stable compounds. When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, when considering the degree of optional substitution of a particular moiety, it should be understood that the number of substituents does not exceed the valency appropriate for that moiety.
[0061] As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, suitably refer to mammals, in particular humans.
[0062] As used herein by itself or in conjunction with another term or terms, “substituted” indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent”. It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).
[0063] As used herein by themselves or in conjunction with another term or terms, “therapeutic” and “therapeutically effective amount” refer to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(b), either alone or in combination with any of the others (a)-(b). It should be understood that in, for example, a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.
[0064] As used herein whether by themselves or in conjunction with another term or terms, “treating”, “treated” and “treatment”, refer to and include ameliorative, palliative, and curative uses and results. In some embodiments, the terms “treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein. For example, treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.
[0065] As used herein, the terms “prevent”, “preventative” or “prevention”, refers to diminishing the likelihood, or delaying the onset, of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “prevent”, “preventative” or “prevention” are not necessarily used in an absolute sense, but also refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.
[0066] As used herein, a ’’therapeutic agent” or “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by Formula I. It should be understood that a therapeutic agent may or may not be approved by the FDA or an equivalent foreign regulatory body.
[0067] A “therapeutically effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated.
[0068] A bond terminating in a “ represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be variably connected to atoms in the ring structure where allowed by valency unless otherwise defined. [0069] As used herein, the term “moiety” refers a portion or functional group of a molecule. Chemical moieties are often recognized as chemical entities embedded in or appended to a molecule.
Compounds of Formula I
[0070] In one aspect the present invention relates to a compound, or a salt or solvate thereof, according to formula I:
T-L-X (I) wherein
X is a senotherapeutic moiety;
L is a direct bond or a linking moiety; and
T is a lipid-targeting moiety of formula II or III: wherein
R1 and R2b are each independently selected from the group consisting of hydrogen; an optionally substituted (Ci- )alkyl group; an optionally substituted aryl group; and an optionally substituted aryl(Ci- )alkyl group; or R1 and R2b, together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring;
R2a is selected from the group consisting of an optionally substituted (C1- w)alkylene group; an optionally substituted arylene group; and an optionally substituted aryl(Ci- )alkylene group; or
R1 and R2a together with the carbon to which they are attached form an optionally substituted C4 to C12 carbocyclic ring; each R3 is independently hydrogen or a (Ci- )alkyl group;
R4a is selected from the group consisting of hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1- 10 haloalkoxy, -ORA4, -SRA4, -NRA4RB4, -CN, -NO2, -N3, -NRA4C(O)RB4, -C(O)NRA4RB4, -NRA4C(O)ORB4, -OC(O)NRA4RB4, -NRA4C(O)NRA4RB4, -NRA4SO2RB4, -SO2NRA4RB4, - SO2RA4, -NRA4C(S)RB4, -C(S)NRA4RB4, -C(O)RA4, -C(O)ORA4, optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group; q is an integer of value 0, 1 , 2 or 3;
R4b is selected from the group consisting of a direct bond, -O-, -S-, -NRC4-, - NRC4C(=O)-, -C(=O)NRC4-, an optionally substituted (Ci-w)alkylene group; and an optionally substituted (Ci-w)heteroalkylene group; and
RA4, RB4 and RC4, at each occurrence, are independently selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 heteroalkyl.
Lipid Targeting Moiety
[0071] In one embodiment, the lipid-targeting moiety, T, is a lipofuscin targeting moiety.
[0072] In one embodiment, T is of formula II. In another embodiment, T is of formula III.
[0073] In one embodiment, R1 is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted Ce-n aryl group; and an optionally substituted aryl(Ci- e)alkyl group.
[0074] In another embodiment, R1 is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci- e)alkyl group. [0075] In another embodiment, R1 is selected from hydrogen, an optionally substituted phenyl and an optionally substituted (Ci-e)alkyl group.
[0076] In another embodiment, R1 is selected from hydrogen and an optionally substituted (Ci-4)alkyl group.
[0077] In another embodiment, R1 is selected from hydrogen and (Ci-4)alkyl group optionally substituted with a hydroxyl group. In another embodiment, R1 is hydrogen or methyl.
[0078] In one embodiment, R1 is optionally substituted by one or more substituents independently selected from halo, -CN, -NO2,-ORA1, -NRA1RB1, -SRA1, -C(O)RA1, -C(O)ORA1, -OC(O)RA1, -O(CRA1RB1)mORc1, -C(O)NRA1RB1, -NRA1C(O)RB1, -SO2RA1, -SO2NRA1RB1, - NRA1SO2RB1, CI-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, =0, =S, =NRA1, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA1, RB1 and RC1, at each occurrence, are independently selected hydrogen and Ci-6 alkyl and Ci-6 heteroalkyl.
[0079] In another embodiment, R1 is optionally substituted by one or more substituents independently selected from halo, -CN, -NO2,-ORA1, -NRA1RB1, -SRA1, -C(O)RA1, -C(O)ORA1, -OC(O)RA1, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, =S, =NRA1, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA1 and RB1, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[0080] In another embodiment, R1 is optionally substituted by one or more substituents independently selected from halo, -CN, -ORA1, -NRA1RB1, -SRA1, C1-6 alkyl, C1-6 haloalkyl, =0, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA1 and RB1, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[0081] In one embodiment, R2b is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted Ce-n aryl group; and an optionally substituted aryl(Ci- e)alkyl group.
[0082] In another embodiment, R2b is selected from hydrogen; an optionally substituted (C1- e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci- e)alkyl group. [0083] In another embodiment, R2b is selected from hydrogen, an optionally substituted phenyl group and an optionally substituted (Ci-e)alkyl group.
[0084] In another embodiment, R2b is selected from hydrogen and an optionally substituted (Ci-4)alkyl group.
[0085] In another embodiment, R2b is selected from hydrogen and an (Ci-4)alkyl group optionally substituted with a hydroxyl group. In another embodiment, R2b is hydrogen or methyl.
[0086] In one embodiment, R2b is optionally substituted by one or more substituents independently selected from halo, -CN, -NC>2,-ORA2b, -NRA2bRB2b, -SRA2b, -C(O)RA2b, - C(O)ORA2b, -OC(O)RA2b, -O(CRA2bRB2b)mORC2b, -C(O)NRA2bRB2b, -NRA2bC(O)RB2b, -SO2RA2b, -SO2NRA2bRB2b, -NRA2bSO2RB2b, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, =0, =S, =NRA2b, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA2b, RB2b and RC2b, at each occurrence, are independently selected hydrogen and C1-6 alkyl and C1-6 heteroalkyl.
[0087] In another embodiment, R2b is optionally substituted by one or more substituents independently selected from halo, -CN, -NO2,-ORA2b, -NRA2bRB2b, -SRA2b, -C(O)RA2b, - C(O)ORA2b, -OC(O)RA2b, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, =0, =S, =NRA2b, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA2b and RB2b, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[0088] In another embodiment, R2b is optionally substituted by one or more substituents independently selected from halo, -CN, -ORA2b, -NRA2bRB2b, -SRA2b, C1-6 alkyl, C1-6 haloalkyl, =0, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA2b and RB2b, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[0089] In one embodiment, at least one of R1 and R2b is not hydrogen. In another embodiment, R1 and R2b are independently selected from optionally substituted (Ci- )alkyl group, suitably an optionally substituted (Ci-e)alkyl group, suitably an optionally substituted (Ci-4)alkyl group. [0090] In another embodiment, in another embodiment, R1 and R2b are independently selected from methyl, ethyl and propyl, suitably R1 and R2b are methyl.
[0091] In one embodiment, R1 and R2b, together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring, and thus a spirocyclic group. In another embodiment, R1 and R2b, together with the carbon to which they are attached, form an optionally substituted C5 to C10 carbocyclic ring.
[0092] In one embodiment, R2a is selected from an optionally substituted (Ci-6)alkylene group; an optionally substituted Ce-n arylene group; and an optionally substituted aryl(Ci- e)alkylene group.
[0093] In another embodiment, R2a is selected from an optionally substituted (Ci-6)alkylene group; an optionally substituted phenylene group; and an optionally substituted aryl(Ci- e)alkylene group.
[0094] In another embodiment, R2a is selected from an optionally substituted (Ci-6)alkylene group.
[0095] In another embodiment, R2a is selected from an optionally substituted (Ci-4)alkylene group. In another embodiment, R2a is a methylene, ethylene, propylene or butylene group, suitably methylene.
[0096] In one embodiment, R2a is optionally substituted by one or more substituents independently selected from halo, -CN, -NC>2,-ORA2a, -NRAa2RB2a, -SRA2a, -C(O)RA2a, - C(O)ORA2a, -OC(O)RA2a, -O(CRA2aRB2a)mORC2a, -C(O)NRA2aRB2a, -NRA2aC(O)RB2a, -SO2RA2a, -SO2NRA2aRB2a -NRA2aSO2RB2a, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, =S, =NRA2a, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA2a, RB2a and RC2a, at each occurrence, are independently selected hydrogen and C1-6 alkyl and C1-6 heteroalkyl.
[0097] In another embodiment, R2a is optionally substituted by one or more substituents independently selected from halo, -CN, -NC>2,-ORA2a, -NRA2aRB2a, -SRA2a, -C(O)RA2a, - C(O)ORA2a, -OC(O)RA2a, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, =S, =NRA2a, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA2a and RB2a, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[0098] In another embodiment, R2a is optionally substituted by one or more substituents independently selected from halo, -CN, -ORA2a, -NRA2aRB2a, -SRA2a, C1-6 alkyl, C1-6 haloalkyl, =0, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA2a and RB2a, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[0099] In one embodiment, R1 and R2a, together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring, and thus a spirocyclic group. In another embodiment, R1 and R2a, together with the carbon to which they are attached, form an optionally substituted C5 to C10 carbocyclic ring.
[00100] In one embodiment, each R3 is independently hydrogen or a (Ci-e)alkyl group. In another embodiment, each R3 is independently hydrogen or a (Ci-s)alkyl group. In another embodiment, each R3 is independently hydrogen or methyl.
[00101] In one embodiment, R4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -ORA4, -SRA4, -NRA4RB4, -CN, -NO2, -N3, -NRA4C(O)RB4, -C(O)NRA4RB4, - NRA4C(O)ORB4, -OC(O)NRA4RB4, -NRA4C(O)NRA4RB4, -NRA4SO2RB4, -SO2NRA4RB4, -SO2RA4, optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group.
[00102] In another embodiment, R4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -ORA4, -SRA4, -NRA4RB4, -CN, -NO2, -N3, -NRA4C(O)RB4, -C(O)NRA4RB4, - NRA4SC>2RB4, -SC>2NRA4RB4, -SC>2RA4, optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group.
[00103] In another embodiment, R4a is selected from hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1-10 haloalkoxy, -ORA4, -CN, and -NO2.
[00104] In another embodiment, R4a is selected from hydrogen, halogen, C1-6 alkyl optionally substituted with a hydroxyl group, C1-6 haloalkyl, C-1-6 haloalkoxy, -OH, -NH2, -CN, C3-6 cycloalkyl and a 3-7 membered heterocycloalkyl group. [00105] In another embodiment, R4a is selected from hydrogen, C1-6 alkyl optionally substituted with a hydroxyl group and -OH.
[00106] In one embodiment, R4a is optionally substituted by one or more substituents independently selected from halo, -CN, -NO2,-ORA4a, -NRA4aRB4a, -SRA4a, -C(O)RA4a, - C(O)ORA4a, -OC(O)RA4a, -O(CRA4aRB4a)mORC4a, -C(O)NRA4aRB4a, -NRA4aC(O)RB4a, -SO2RA4a, -SO2NRA4aRB4a -NRA4aSO2RB4a, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, =0, =S, =NRA4a, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA4a, RB4a and RC4a, at each occurrence, are independently selected hydrogen and C1-6 alkyl and C1-6 heteroalkyl.
[00107] In another embodiment, R4a is optionally substituted by one or more substituents independently selected from halo, -CN, -NO2,-ORA4a, -NRA4aRB4a, -SRA4a, - C(O)RA4a, -C(O)ORA4a, -OC(O)RA4a, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, =0, =S, =NRA4a, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA4a and RB4a, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[00108] In another embodiment, R4a is optionally substituted by one or more substituents independently selected from halo, -CN, -ORA4a, -NRA4aRB4a, -SRA4a, C1-6 alkyl, C1-6 haloalkyl, =0, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA4a and RB4a, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[00109] In one embodiment, q is 0, 1 or 2. In another embodiment, q is 0 or 1.
[00110] In one embodiment, R4b is selected from direct bond, -O-, -S-, -NRC4-, -
NRC4C(=O)- , -C(=O)NRC4- , an optionally substituted (Ci-e)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
[00111] In another embodiment, R4b is selected from direct bond, -O-, -S-, -NRC4-, an optionally substituted (Ci-e)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group. [00112] In another embodiment, R4b is selected from direct bond, an optionally substituted (Ci-6)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
[00113] In another embodiment, R4b is selected from -CH2CH2- and -CH2CH2O-.
[00114] In one embodiment, R4b is optionally substituted by one or more substituents independently selected from halo, -CN, -NC>2,-ORA4b, -NRA4bRB4b, -SRA4b, -C(O)RA4b, - C(O)ORA4b, -OC(O)RA4b, -O(CRA4bRB4b)mORC4b, -C(O)NRA4bRB4b, -NRA4bC(O)RB4b, -SO2RA4b, -SO2NRA4bRB4b, -NRA4bSO2RB4b, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, =S, =NRA4b, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA4b, RB4b and RC4b, at each occurrence, are independently selected hydrogen and C1-6 alkyl and C1-6 heteroalkyl.
[00115] In another embodiment, R4b is optionally substituted by one or more substituents independently selected from halo, -CN, -NC>2,-ORA4b, -NRA4bRB4b, -SRA4b, - C(O)RA4b, -C(O)ORA4b, -OC(O)RA4b, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, =0, =S, =NRA4b, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA4b and RB4b, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[00116] In another embodiment, R4b is optionally substituted by one or more substituents independently selected from halo, -CN, -ORA4b, -NRA4bRB4b, -SRA4b, C1-6 alkyl, C1-6 haloalkyl, =0, C3-6 cycloalkyl, phenyl and 3- to 6- membered heterocyclyl including 1 , 2 or 3 heteroatoms selected from N, O and S; wherein RA4b and RB4b, at each occurrence, are independently selected hydrogen and C1-6 alkyl.
[00117] In one embodiment, RA4, RB4 and RC4, at each occurrence, are independently selected hydrogen, C1-3 alkyl and C1-3 heteroalkyl. In another embodiment, RA4, RB4 and RC4, at each occurrence, are independently selected hydrogen, methyl and ethyl.
[00118] In one embodiment, T is of sub-formula Ila where R1 and R4a are as defined in any of the above-mentioned embodiments.
[00119] In another embodiment, T is T1:
[00120] In one embodiment, T is of sub-formula Illa where R1 and R4b are as defined in any of the above-mentioned embodiments.
[00121] In another embodiment, T is of sub-formula 11 lb: where R1 and R4b are as defined in any of the above-mentioned embodiments.
[00122] In another embodiment, T is T2:
Linking Moiety, L
[00124] The linking moiety serves to connect the lipid-targeting moiety with the senotherapeutic moiety.
[00125] In one embodiment, L may be a direct bond between the lipid-targeting moiety and the senotherapeutic moiety. Alternatively, L comprises one or more atoms which covalently link the lipid-targeting moiety with the senotherapeutic moiety. In one embodiment, L is a linear moiety. In another embodiment, L is a branched moiety.
[00126] In one embodiment, L comprises one or more functional groups, particularly at the end(s) of the moiety which may facilitate covalent bonding with the lipid-targeting moiety and/or the senotherapeutic moiety. Examples of suitable functional groups include amino, amido, ester, ether, carbonyl, carboxyl, thioether, sulfonyl, and sulfonamido for instance. [00127] Preferred linking groups are derived from groups which can react to form bonds with the lipid-targeting moiety and/or senotherapeutic moiety. Reactive groups may be selected from but not limited to a group that will react directly with other reactive groups on the lipid-targeting moiety or senotherapeutic moiety. For example, the reactive groups may include carboxy, aldehyde, amines, alcohols, thiol groups, activated methylenes, alkynes, azides, active halogen containing groups including, for example, chloromethylphenyl groups and chloroacetyl [CICH2C(=O)-] groups, activated 2-(leaving group substituted)-ethylsulfonyl and ethylcarbonyl groups such as 2-chloroethylsulfonyl and 2-chloroethylcarbonyl; vinylsulfonyl; vinylcarbonyl; epoxy; isocyanato; isothiocyanato; aldehyde; aziridine; succinimidoxycarbonyl; activated acyl groups such as carboxylic acid halides; mixed anhydrides and the like.
[00128] Reaction of the reactive groups with the reactive groups on precursor of the lipid-targeting moiety or the senotherapeutic moiety may result in a functional group in the linker adjacent to said lipid-targeting moiety or the senotherapeutic moiety, which may be referred to herein as a “bonding moiety”.
[00129] Suitably, the linking moiety comprises two or more bonding moieties and one or more spacing moieties. The spacing moiety can be varied in order to control the separation between the lipid-targeting moiety and the senotherapeutic moiety. The spacing moiety may comprise or consist of aliphatic chains or polymeric chains, such as polyethylene glycol (PEG) chains. Functional groups may also be present within the spacing moiety, for instance to influence physical properties of the overall compounds, such as solubility.
[00130] The length of the linking moiety can be varied to avoid steric interaction of the lipid-targeting moiety and the senotherapeutic moiety and to allow efficient interaction of the lipid-targeting moiety with its lipid target.
[00131] The linking moiety is suitably such that it maintains the link between the lipid- targeting group and the senotherapeutic moiety under physiological conditions for an appropriate time. Nevertheless, the linking group may be cleavable.
[00132] In one embodiment, the linking moiety comprises an ester bond. In one embodiment, the compound of formula I is cleaved by enzymes, such as an esterase, in order to release the senotherapeutic moiety in the presence of senescent cells. [00133] In one embodiment, when steric hinderance between the lipid-targeting moiety and senotherapeutic moiety is low the linking moiety may be a direct bond. In one embodiment, L is a direct bond.
[00134] In one embodiment, L is a linking moiety of formula IV:
-[L1]m- (IV) where each occurrence of L1 is independently selected from -S-, -S(=O)-, -S(=O)2-, -O-, - C(=O)-, -C(=O)O-, -OC(=O)-, -CR5R6- , -CR5=CR6- , -C=C- , -NR5-, -NR5C(=O)- , -C(=O)NR5- , -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -NR5S(O)NR6-, -OC(R5)(R6)C(R5)(R6)-, - S(=O)2NR5-, -NR5S(=O)2-, phenylene, piperazinyl and 1 ,2,3-triazolyl; m is a number of value 1 to 50; and
R5 and R6, at each occurrence, are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
[00135] In one embodiment, L1 is independently selected from -S-, -S(=O)-, -S(=O)2-, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -CR5R6- , -NR5-, -NR5C(=O)- , -C(=O)NR5-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -NR5S(O)NR6-, -OC(R5)(R6)C(R5)(R6)-, -S(=O)2NR5-, -
NR5S(=O)2-, phenylene and piperazinyl.
[00136] In another embodiment, L1 is independently selected from -O-, -C(=O)-, - C(=O)O-, -OC(=O)-, -CR5R6- , -NR5-, -NR5C(=O)- , -C(=O)NR5-, phenylene and piperazinyl.
[00137] In one embodiment, m is a number of value from 1 to 40, or 1 to 30, or 1 to 25, or 1 to 20, or 1 to 15, or 1 to 10, or 1 to 6.
[00138] In another embodiment, m is a number of value from 3 to 40, or 3 to 30, or 3 to 25, or 3 to 20, or 3 to 15, or 3 to 10, or 3 to 6.
[00139] In another embodiment, m is a number of value from 5 to 40, or 5 to 30, or 5 to 25, or 5 to 20, or 5 to 15, or 5 to 10.
[00140] In another embodiment, L is a linking moiety of formula V: — [L2]— [L3]— [L4]— [L5]— [L6]— [L7]— [L8]— [L9]— (V) wherein
L2 is absent, -0-, -S-, -S(=0)-, -S(=0)2- , -NR5 -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L3 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;
L4 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L5 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, where q and each p are independently a number of value 1 to 15;
L6 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L7 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;
L8 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6; and
L9 is absent, -(CR5R6)P-, -(CR6R7)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;, where each occurrence of R5 and R6 is independently selected from the group consisting of hydrogen, CM alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
[00141] In another embodiment, L is a linking moiety of formula VI:
— [L2]— [L3]— [L4]— [L5]— [L6]— [L8]— (VI)
L2 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L3 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, where q and each p are independently a number of value 1 to 15;
L4 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L5 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, where q and each p are independently a number of value 1 to 15;
L6 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, - (CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6; and
L8 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6; where each occurrence of R5 and R6 is independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy. [00142] In one embodiment, L2 is selected from absent, -O-, -C(=O)-, -C(=O)O-, - OC(=O)- and -(CR5R6)P-. In another embodiment, L2 is selected from -O-, -C(=O)-, -C(=O)O-, -OC(=O)- and -(CR5R6)P-. In one embodiment, L2 is attached to T.
[00143] In one embodiment, L3 is absent or -(CR5R6)P-. Suitably, L3 is -(CH2)P-.
[00144] In one embodiment, L4 is absent, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -
C(=O)O-, -OC(=O)-, -(CR5R6)P-, phenylene and piperazinyl.
[00145] In another embodiment, L4 is absent, -C(=O)-, -C(=O)NR5-, -C(=O)O-, and - (CR5R6)P-. In one embodiment, L4 is attached to X.
[00146] In one embodiment, L5 is absent or -(CR5R6)P-. Suitably, L5 is -(CH2)P-.
[00147] In one embodiment, L6 is absent, -O-, -C(=O)NR5-, -NR5-, -NR5C(=O)-, phenylene and piperazinyl. Suitably, L6 is absent, -NH-, -O-, phenylene and piperazinyl. In one embodiment, L6 is attached to X.
[00148] In one embodiment, L7 is absent, -(CR5R6)P- or (CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-.
[00149] In one embodiment, L7 is absent or -(CR5R6)P-. Suitably, L7 is -(CH2)P-.
[00150] In one embodiment, L8 is absent, -O-, -C(=O)NR5-, -NR5C(=O)-, -NR5-, - (CR5R6)P-, phenylene and piperazinyl. Suitably, L8 is absent, -NH-, -O-, phenylene and piperazinyl. In one embodiment, L8 is attached to X.
[00151] In one embodiment, L9 is absent or -(CR5R6)P-. Suitably, L9 is -(CH2)P-.
[00152] In another embodiment, L is a linking moiety of formula VII:
-[L2]-[L3]-[L4]-[L10]-[L11]- (VI I)
L2 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L3 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15; L4 is absent, -0-, -S-, -S(=0)-, -S(=0)2- , -NR5 -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L10 is absent, -(CR5R6)P-, phenylene or piperazinyl, where p is a number of value 1 to 15; and
L11 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6- or -NR5C(=O)O-; where each occurrence of R5 and R6 is independently selected from the group consisting of hydrogen, CM alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
[00153] In one embodiment, L2, L3 and L4 are as defined in of the above-mentioned embodiments.
[00154] In one embodiment, L10 is absent, -(CH2)P-, phenylene or piperazinyl. In one embodiment, L10 is attached to X.
[00155] In one embodiment, L11 is absent, -O-, -NR5-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, or -OC(=O)-. In another embodiment, L11 is absent, -O- or -NH-. In one embodiment, L11 is attached to X.
[00156] In one embodiment, q and p, at each occurrence, are independently a number of value 1 to 12. Suitably, q and p, at each occurrence, are independently a number of value 1 to 10, or 1 to 6, or 1 to 5. Suitably, q and p, at each occurrence, are independently a number of value 3 to 10, or 3 to 6, or 3 to 5.
[00157] In one embodiment, R5 and R6, at each occurrence, are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
[00158] In one embodiment, R5 and R6, at each occurrence, are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 haloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
[00159] In one embodiment, R5 and R6, at each occurrence, are independently selected from hydrogen or C1-4 alkyl.
[00160] In one embodiment, R5 and R6, at each occurrence, are independently selected from hydrogen, methyl and ethyl.
[00161] The lipid-targeting moiety and senotherapeutic moiety may be bonded to either end of the linking moiety, for instance either end of formulae IV, V, VI and VII. However, in one embodiment the lipid-targeting moiety is bonded to the left hand end of the linking moiety as depicted herein (e.g. formulae IV, V, VI and VII) and the senotherapeutic moiety is bonded to the right hand end of the linking moiety as depicted herein.
[00162] In one embodiment, the Linking moiety L is of formula L1 : wherein
M is selected from the group consisting of -NH-, -C(O)O, -C(O)NH- and -C(O)- or is absent; and n is a number of value 1 to 10.
[00163] In one embodiment, M is selected from the group consisting of -NH-, -C(O)O and -C(O)NH-. In one embodiment, n is a number of value 1 to 5, suitably 1 , 2 or 3.
[00164] In one embodiment, the Linking moiety L is of formula L2: wherein M1 and M2 are independently selected from the group consisting of -NH-, -C(O)O, -C(O)NH- and -C(O)- or absent; and n1 and n2 are independently a number of value 1 to 10.
[00165] In one embodiment, M1 is selected from the group consisting of -NH-, -C(O)O and -C(O)NH-. In one embodiment, M2 is selected from the group consisting of -NH-, - C(O)O and -C(O)NH-.
[00166] In one embodiment M1 is -C(O)NH- and M2 is selected from the group consisting of -NH-, -C(O)O and -C(O)NH-.
[00167] In one embodiment, n1 and n2 are independently selected from a number of value 1 to 5, suitably 1, 2 or 3.
[00168] In one embodiment n1 is 2. In one embodiment, n1 is 2 and n2 is 1 , 2 or 3.
[00169] In one embodiment, the Linking moiety L is selected from:
[00170] In another embodiment, the Linking moiety L is:
[00171] In one embodiment, the wavy line indicates the point of attachment to
T. In another embodiment, the dotted line indicates the point of attachment to X.
[00172] In one embodiment, the lipid-targeting moiety and linking moiety, T-L-, is selected from the following, wherein the dotted line indicates the point of attachment to X:
[00173] In one embodiment, the lipid-targeting moiety is of formula Ila and the linking moiety, L is a direct bond, i.e. direct bond to X.
[00174] In one embodiment, the lipid-targeting moiety is of formula T1 and the linking moiety, L is a direct bond, i.e. direct bond to X.
Senotherapeutic Moiety, X [00175] In one embodiment, X is a senolytic moiety. As used herein, a senolytic moiety refers to a senotherapeutic moiety which act directly on senescent cells to induce cell death of senescent cells.
[00176] Senolytic agents are known to the skilled person and the senolytic moiety may be derived from known senolytic agents, such as those described in Tables 1 and 2 of Rad et al, Mechanisms of Ageing and Development 217 (2024) 111888, and Table 1 of Zhang et al. The FEBS Journal 290 (2023) 1362-1383, each of which is incorporated herein by reference.
[00177] In one embodiment, the senolytic moiety is selected from an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-2 inhibitor moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety, a HDAC inhibitor moiety, a Mcl-1 inhibitor moiety and a PI3K inhibitor moiety. Suitably, the senolytic agent is selected from an Eph receptor inhibitor moiety, a ABL inhibitor moiety or a flavonoid moiety.
[00178] In another embodiment, the senolytic agent is selected from a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a curcumin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety, a fenofibrate moiety and a panobinostat moiety. Suitably, the senolytic agent is selected from a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, a fisetin moiety or a quercetin moiety. Suitably, the senolytic agent is selected from a dasatinib moiety or a quercetin moiety.
[00179] In one embodiment, the dasatinib moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
[00180] A1331852, is BCI-XL inhibitor; of the following structure:
[00181] In one embodiment, the A1331852 moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
[00182] A-1155463, is BCI-XL inhibitor, of the following structure: [00183] In one embodiment, the A1155463 moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
[00184] In one embodiment, the fisetin moiety is as follows, where the dotted line indicates the point of attachment to linker, L:
[00185] In another embodiment, X is a senomorphic moiety. As used herein, a senomorphic moiety refers to a senotherapeutic moiety which can inhibit SASP and thus modulate senescence.
[00186] In one embodiment, the senomorphic moiety is selected from a mTOR inhibitor moiety, a JAK inhibitor moiety and a glucocorticoid moiety.
[00187] In another embodiment, the senomorphic moiety is selected from an apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety and a niguldipine moiety.
[00188] In one embodiment, senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety, a HDAC inhibitor moiety, a mTOR inhibitor moiety, a JAK inhibitor moiety and a glucocorticoid moiety.
[00189] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety and a HDAC inhibitor moiety.
[00190] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety and an alkaloid moiety.
[00191] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety and a flavonoid moiety.
[00192] Suitably, senotherapeutic moiety X a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety, a panobinostat moiety, a apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety, a niguldipine moiety and a resveratrol moiety.
[00193] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety and a panobinostat moiety.
[00194] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, a quercetin moiety, a navitoclax moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety and a panobinostat moiety.
[00195] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety and a panobinostat moiety. [00196] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a A1331852 moiety, a A1155463 moiety, a navitoclax moiety and a fisetin moiety.
[00197] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety and a fisetin moiety.
[00198] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, and a fisetin moiety.
[00199] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of a dasatinib moiety and a quercetin moiety.
[00200] Suitably, senotherapeutic moiety X is a moiety selected from the group consisting of an apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety, a niguldipine moiety and a resveratrol moiety.
[00201] In one embodiment, senotherapeutic moiety X is (where the dotted line indicates the point of attachment to linker, L).
[00202] In one embodiment, the moiety -L-X is
attachment to targeting moiety, T).
[00203] In one embodiment, the compound of formula I is selected from the following, or a salt or solvate thereof:
[00204] In another embodiment, the compound of formula I is selected from the following, or a salt or solvate thereof: [00205] The invention will now be further described by way of the following numbered paragraphs:
1. A compound, or a salt or solvate thereof, according to formula I:
T-L-X (I) wherein
X is a senotherapeutic moiety;
L is a direct bond or a linking moiety; and
T is a lipid-targeting moiety of formula II or III (where the wavy line indicates the point of attachment to L): wherein
R1 and R2b are each independently selected from the group consisting of hydrogen; an optionally substituted (Ci- )alkyl group; an optionally substituted aryl group; and an optionally substituted aryl(Ci-io)alkyl group; or R1 and R2b, together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring;
R2a is selected from the group consisting of an optionally substituted (Ci-w)alkylene group; an optionally substituted arylene group; and an optionally substituted aryl(Ci- )alkylene group; or
R1 and R2a together with the carbon to which they are attached form an optionally substituted C4 to C12 carbocyclic ring; each R3 is independently hydrogen or a (Ci- )alkyl group;
R4a is selected from the group consisting of hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1-10 haloalkoxy, -ORA4, - SRA4, -NRA4RB4, -CN, -NO2, -N3, -NRA4C(O)RB4, -C(O)NRA4RB4, -NRA4C(O)ORB4, - OC(O)NRA4RB4, -NRA4C(O)NRA4RB4, -NRA4SO2RB4, -SO2NRA4RB4, -SO2RA4, -NRA4C(S)RB4, - C(S)NRA4RB4, -C(O)RA4, -C(O)ORA4, optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group; q is an integer of value 0, 1 , 2 or 3;
R4b is selected from the group consisting of a direct bond, -O-, -S-, -NRC4-, -NRC4C(=O)- , - C(=O)NRC4- , an optionally substituted (Ci-w)alkylene group; and an optionally substituted (Ci-w)heteroalkylene group; and
RA4, RB4 and RC4, at each occurrence, are independently selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 heteroalkyl.
2. A compound, or a salt or solvate thereof, according to paragraph 1 , wherein R1 is selected from hydrogen; an optionally substituted (Ci-e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci-e)alkyl group.
3. A compound, or a salt or solvate thereof, according to paragraph 1 or 2, wherein R1 is selected from hydrogen, an optionally substituted phenyl and an optionally substituted (C1- e)alkyl group.
4. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R1 is selected from hydrogen and an optionally substituted (Ci-4)alkyl group. 5. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R1 is selected from hydrogen and (Ci-4)alkyl group optionally substituted with a hydroxyl group.
6. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R1 is hydrogen or methyl.
7. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein T is of formula II.
8. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R2a is selected from an optionally substituted (Ci-6)alkylene group; an optionally substituted phenylene group; and an optionally substituted aryl(Ci-6)alkylene group.
9. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R2a is selected from an optionally substituted (Ci-6)alkylene group.
10. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R2a is selected from an optionally substituted (Ci-4)alkylene group.
11. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R2a is a methylene, ethylene, propylene or butylene group.
12. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 7, wherein R1 and R2a, together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring.
13. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -ORA4, - SRA4, -NRA4RB4, -CN, -NO2, -N3, -NRA4C(O)RB4, -C(O)NRA4RB4, -NRA4C(O)ORB4, - OC(O)NRA4RB4, -NRA4C(O)NRA4RB4, -NRA4SO2RB4, -SO2NRA4RB4, -SO2RA4, optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group.
14. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R4a is selected from hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C-1-6 haloalkoxy, -ORA4, - SRA4, -NRA4RB4, -CN, -NO2, -N3, -NRA4C(O)RB4, -C(O)NRA4RB4, -NRA4SO2RB4, -SO2NRA4RB4, -SC>2RA4, optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group.
15. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R4a is selected from hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1-10 haloalkoxy, -ORA4, - CN, and -NO2.
16. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R4a is selected from hydrogen, halogen, C1-6 alkyl optionally substituted with a hydroxyl group, C1-6 haloalkyl, C-1-6 haloalkoxy, -OH, -NH2, -CN, C3-6 cycloalkyl and a 3-7 membered heterocycloalkyl group.
17. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R4a is selected from hydrogen, C1-6 alkyl optionally substituted with a hydroxyl group and -OH.
18. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein q is 0, 1 or 2.
19. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein , q is 0 or 1.
20. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 6, wherein T is of formula III.
21. A compound, or a salt or solvate thereof, according to paragraph 21 , wherein R2b is selected from hydrogen; an optionally substituted (Ci-e)alkyl group; an optionally substituted phenyl group; and an optionally substituted aryl(Ci-e)alkyl group.
22. A compound, or a salt or solvate thereof, according to paragraph 20 or 21 , wherein R2b is selected from hydrogen, an optionally substituted phenyl group and an optionally substituted (Ci-e)alkyl group.
23. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
22, wherein R2b is selected from hydrogen and an optionally substituted (Ci-4)alkyl group.
24. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
23, wherein R2b is selected from hydrogen and an (Ci-4)alkyl group optionally substituted with a hydroxyl group. 25. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
24, wherein R2b is hydrogen or methyl.
26. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
25, wherein R1 and R2b are methyl.
27. A compound, or a salt or solvate thereof, according to paragraph 1 , wherein R1 and R2b, together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring.
28. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
27, wherein R4b is selected from direct bond, -O-, -S-, -NRC4-, -NRC4C(=O)-, -C(=O)NRC4- , an optionally substituted (Ci-6)alkylene group; and an optionally substituted (C1- 6)heteroalkylene group.
29. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
28, wherein R4b is selected from direct bond, -O-, -S-, -NRC4-, an optionally substituted (C1- e)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
30. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
29, wherein R4b is selected from direct bond, an optionally substituted (Ci-6)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
31. A compound, or a salt or solvate thereof, according to any one of paragraphs 20 to
30, wherein R4b is selected from -CH2CH2- and -CH2CH2O-.
32. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein each R3 is independently hydrogen or a (Ci-e)alkyl group.
33. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein each R3 is independently hydrogen or a (Ci-s)alkyl group.
34. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein each R3 is independently hydrogen or methyl, suitably hydrogen.
35. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 7 and 13 to 17 of sub-formula Ila
36. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 6 and 28 to 31 of of sub-formula Illa
37. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 6 and 28 to 31 of of sub-formula formula 111 b:
38. A compound, or a salt or solvate thereof, according to paragraph 1 , wherein T is T1, T2 or T3:
39. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein L is a direct bond or a linking moiety of formula IV:
-[L1]m- (IV) where each occurrence of L1 is independently selected from -S-, -S(=O)-, -S(=O)2-, -O-, - C(=O)-, -C(=O)O-, -OC(=O)-, -CR5R6- , -CR5=CR6- , -C=C- , -NR5-, -NR5C(=O)- , -C(=O)NR5- , -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -NR5S(O)NR6-, -OC(R5)(R6)C(R5)(R6)-, - S(=O)2NR5-, -NR5S(=O)2-, phenylene, piperazinyl and 1 ,2,3-triazolyl; m is a number of value 1 to 50; and
R5 and R6, at each occurrence, are independently selected from the group consisting of hydrogen, CM alkyl, CM alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
40. A compound, or a salt or solvate thereof, according to paragraph 39, wherein L1 is independently selected from -S-, -S(=O)-, -S(=O)2-, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, - CR5R6- , -NR5-, -NR5C(=O)- , -C(=O)NR5-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, - NR5S(O)NR6-, -OC(R5)(R6)C(R5)(R6)-, -S(=O)2NR5-, -NR5S(=O)2-, phenylene and piperazinyl.
41 . A compound, or a salt or solvate thereof, according to paragraph 39 or 40, wherein L1 is independently selected from -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -CR5R6- , -NR5-, - NR5C(=O)- , -C(=O)NR5-, phenylene and piperazinyl.
42. A compound, or a salt or solvate thereof, according to any one of paragraphs 39 to
41 , wherein m is a number of value from 1 to 10.
43. A compound, or a salt or solvate thereof, according to any one of paragraphs 39 to
42, wherein m is a number of value from 3 to 6.
44. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 38, wherein L is a linking moiety of formula V:
— [L2]— [L3]— [L4]— [L5]— [L6]— [L7]— [L8]— [L9]— (V) wherein
L2 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L3 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;
L4 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L5 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;
L6 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L7 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;
L8 is absent, -0-, -S-, -S(=0)-, -S(=0)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6; and
L9 is absent, -(CR5R6)P-, -(CR6R7)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;, where each occurrence of R5 and R6 is independently selected from the group consisting of hydrogen, CM alkyl, CM alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
45. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 38, wherein L is a linking moiety of formula VI:
— [L2]— [L3]— [L4]— [L5]— [L6]— [L8]— (VI)
L2 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L3 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;
L4 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L5 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, where q and each p are independently a number of value 1 to 15; L6 is absent, -0-, -S-, -S(=0)-, -S(=0)2- , -NR5 -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, - (CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6; and
L8 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6; where each occurrence of R5 and R6 is independently selected from the group consisting of hydrogen, CM alkyl, CM alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
46. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 38, wherein L is a linking moiety of formula VII:
-[L2]-[L3]-[L4]-[L10]-[L11]- (VI I)
L2 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L3 is absent, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, where q and each p are independently a number of value 1 to 15;
L4 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L10 is absent, -(CR5R6)P-, phenylene or piperazinyl, where p is a number of value 1 to 15; and
L11 is absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, -CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, -NR5C(=O)NR6- or -NR5C(=O)O-; where each occurrence of R5 and R6 is independently selected from the group consisting of hydrogen, CM alkyl, CM alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
47. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
46, wherein L2 is selected from absent, -O-, -C(=O)-, -C(=O)O-, -OC(=O)- and -(CR5R6)P-.
48. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
47, wherein L2 is selected from -O-, -C(=O)-, -C(=O)O-, -OC(=O)- and -(CR5R6)P-.
49. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
48, wherein L3 is absent or -(CR5R6)P-.
50. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
49, wherein L3 is -(CH2)P-.
51. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
50, wherein L4 is absent, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, - (CR5R6)P-, phenylene and piperazinyl.
52. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
51 , wherein L4 is absent, -C(=O)-, -C(=O)NR5-, -C(=O)O-, and -(CR5R6)P-.
53. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
52, wherein L5 is absent or -(CR5R6)P-.
54. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
53, wherein L5 is -(CH2)P-.
55. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
54, wherein L6 is absent, -O-, -C(=O)NR5-, -NR5-, -NR5C(=O)-, phenylene and piperazinyl.
56. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
55, wherein L6 is absent, -NH-, -O-, phenylene and piperazinyl.
57. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
56, wherein L7 is absent, -(CR5R6)P- or -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-. 58. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
57, wherein L7 is absent or -(CR5R6)P-.
59. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
58, wherein L7 is -(CH2)P-.
60. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
59, wherein L8 is absent, -O-, -C(=O)NR5-, -NR5C(=O)-, -NR5-, -(CR5R6)P-, phenylene and piperazinyl.
61. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
60, wherein L8 is absent, -NH-, -O-, phenylene and piperazinyl.
62. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
61 , wherein L9 is absent or -(CR5R6)P-.
63. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
62, wherein L9 is -(CH2)P-.
64. A compound, or a salt or solvate thereof, according to any one of paragraphs 46 to
63, wherein L10 is absent, -(CH2)P-, phenylene or piperazinyl.
65. A compound, or a salt or solvate thereof, according to any one of paragraphs 46 to
64, wherein L11 is absent, -O-, -NR5-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, or - OC(=O)-.
66. A compound, or a salt or solvate thereof, according to any one of paragraphs 46 to
65, wherein L11 is absent, -O- or -NH-.
67. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
66, wherein q and p, at each occurrence, are independently a number of value 1 to 12.
68. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
67, wherein q and p, at each occurrence, are independently a number of value 3 to 6.
69. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to
68, wherein R5 and R6, at each occurrence, are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, each of which may optionally be substituted with one or more groups selected from CM alkyl, CM alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
70. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to 69, wherein R5 and R6, at each occurrence, are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 haloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
71. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to 70, wherein R5 and R6, at each occurrence, are independently selected from hydrogen or C1- 4 alkyl.
72. A compound, or a salt or solvate thereof, according to any one of paragraphs 44 to 70, wherein R5 and R6, at each occurrence, are independently selected from hydrogen, methyl and ethyl.
73. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 38, wherein the Linking moiety L is selected from a direct bond; or
74. A compound, or a salt or solvate thereof, according to paragraph 1, wherein the lipid- targeting moiety and linking moiety, T-L-, is selected from the following:
75. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is a senolytic moiety or a senomorphic moiety.
76. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety, a HDAC inhibitor moiety, a mTOR inhibitor moiety, a JAK inhibitor moiety and a glucocorticoid moiety.
77. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety and a flavonoid moiety.
78. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety, a panobinostat moiety, a apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety, a niguldipine moiety and a resveratrol moiety. 79. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is a moiety selected from the group consisting of a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, a quercetin moiety and a fisetin moiety.
80. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is a moiety selected from a dasatinib moiety or a quercetin moiety.
81. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is:
82. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein X is:
83. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 38, wherein the moiety -L-X is selected from:
84. A compound, or salt or solvate thereof, selected from:
85. A compound, or salt or solvate thereof, selected from:
86. A pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 85, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
87. A pharmaceutical composition according to paragraph 86, wherein the pharmaceutically acceptable carrier is a polymeric micelle.
88. A pharmaceutical composition according to paragraph 87, wherein the polymeric micelle comprises an amphiphilic polymer.
89. A pharmaceutical composition according to paragraph 88, wherein the amphiphilic polymer is a polyethylene glycol-polycaprolactone block copolymer (e.g. PEO-b-PCL).
90. A pharmaceutical composition according to any one of paragraphs 86 to 89, formulated for parenteral administration.
91. A pharmaceutical composition according to any one of paragraphs 86 to 90, comprising an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e.g. salts of plasma cations with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (e.g. sorbitol or mannitol), glycols (e.g. glycerol), or other non-ionic polyol materials (e.g. polyethyleneglycols, propylene glycols and the like).
92. A compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85, or a pharmaceutical composition according to any one of paragraphs 86 to 91, for use in therapy.
93. A compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85, or a pharmaceutical composition according to any one of paragraphs 86 to 91, for use in treatment of a disease or condition mediated by senescence.
94. A compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85, or a pharmaceutical composition according to any one of paragraphs 86 to 91, for use in treating a disease or a condition selected from a cancer, a fibrotic disorder, a neurodegenerative condition, a cardiovascular disease, a metabolic disease, a kidney disease, a liver disease and a degenerative disease.
95. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the cancer is selected from the cancer is selected from bladder cancer, blood cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, head and neck cancer, pancreatic cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
96. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the fibrotic disorder is selected from:
(i) a fibrotic condition affecting the lungs, for example pulmonary fibrosis secondary to cystic fibrosis; idiopathic pulmonary fibrosis; coal worker’s progressive massive fibrosis; cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), or chronic asthma; or
(ii) a fibrotic condition affecting the liver, for example cirrhosis, and associated conditions such as chronic viral hepatitis B or C, Wilson’s disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis or autoimmune hepatitis; or (iii) a fibrotic condition affecting the kidneys, for example diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangiocapillary glomerular nephritis;
(iv) a fibrotic condition affecting the heart or vascular system, for example endomyocardial fibrosis; old myocardial infarction; atrial fibrosis; congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (for example pulmonary hypertension) and fibrosis associated with hypertension, atherosclerosis, restenosis (e.g. coronary, carotid, and cerebral lesions), and heart disease associated with cardiac ischemic events; or
(v) a fibrotic condition affecting the mediastinum, for example mediastinal fibrosis; or
(vi) a fibrotic condition affecting bone, for example myelofibrosis, including primary myelofibrosis, post polycythemia vera or post essential thrombocythemia myelofibrosis; or
(vii) a fibrotic condition affecting the retroperitoneum, for example retroperitoneal fibrosis skin; or
(viii) a fibrotic condition affecting the skin, for example nephrogenic systemic fibrosis, keloid formation and scarring, systemic sclerosis, scleroderma, hypertrophic scarring, scleredema (Buschke disease), systemic amyloidosis, lipodermatosclerosis, progeroid disorders, stiff skin syndrome, Dupuytren's contracture, nephrogenic fibrosing dermopathy (NFD), mixed connective tissue disease, scleromyxedema, graft-versus-host disease (GVHD), Peyronie’s disease and eosinophilic fasciitis; or
(ix) a fibrotic condition affecting the Gl tract, for example a fibrotic intestinal disorder, inflammatory bowel disease, ulcerative colitis or Crohn’s disease; or
(x) a fibrotic condition affecting connective tissue, for example arthrofibrosis; or capsulitis; or
(xi) a fibrotic condition affecting the eye, for example ocular scarring, ocular fibrosis following surgery or pseudoexfoliation syndrome glaucoma.
(xii) a fibrotic condition induced by radiation, such as fibrosis following radiotherapy.
97. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the neurodegenerative condition is selected from Parkinson disease, Alzheimer’s disease and non-Alzheimer’s dementia. 98. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the cardiovascular condition is selected from pulmomary hypertension, heart failure, cardiac hypertrophy and atherosclerosis.
99. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the metabolic disease is selected from metabolic syndrome and diabetes.
100. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the kidney disease is selected from IgA nephropathy, diabetic nephropathy and glomerular disease.
101. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the liver disease is non-alcoholic fatty liver disease or hepatic steatosis.
102. A compound of formula I, or a salt or solvate thereof, for use according to claim 94, wherein the degenerative disease is osteoarthritis.
103. A method of inducing death of senescent cells in a subject or sample, comprising administering to said subject or sample an effective amount of a compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85, or a pharmaceutical composition according to any one of paragraphs 86 to 91.
104. A method of inhibiting senescence in a cell, comprising administering to said cell an effective amount of a compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85, or a pharmaceutical composition according to any one of paragraphs 86 to 91.
105. A combination comprising a compound of formula I, or a salt or solvate thereof according to any one of paragraphs 1 to 85 with another therapeutic agent.
106. A combination according to paragraph 105, wherein the therapeutic agent is an anticancer agent.
107. A combination according to paragraph 106, wherein the therapeutic agent is quercetin.
[00206] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
Salts and Solvates
[00207] The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.
[00208] Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.
[00209] In one embodiment, the compounds of Formula I are isolated as pharmaceutically acceptable salts.
[00210] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[00211] In general, salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and/or isolated using a single method or a combination of methods.
[00212] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
[00213] Certain compounds of the Formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
Polymorphs [00214] It is also to be understood that certain compounds of the Formula I may exhibit polymorphism, and that the invention encompasses all such forms.
N-oxides
[00215] Compounds of the Formula I containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N- oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
Tautomers
[00216] Compounds of the Formula I may exist in a number of different tautomeric forms and references to compounds of the Formula I include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. keto enol enolate
Isomers
[00217] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
[00218] Certain compounds of Formula I may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centres, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.
Isotopes
[00219] The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of 12C, 13C, and 14C; hydrogen atoms may be present in any ratio of 1H, 2H, and 3H; etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.
Pharmaceutical Compositions
[00220] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
[00221] In one embodiment, the pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable carrier. [00222] In one embodiment, the pharmaceutically acceptable carrier is a polymeric micelle. In one embodiment, the pharmaceutically acceptable carrier is a nanoparticle, suitably a polymeric nano-micelle.
[00223] In one embodiment, the polymeric micelle comprises an amphiphilic polymer.
[00224] In one embodiment, the amphiphilic polymer is an amphiphilic polymer block copolymer, which is a block polymer composed of two or more polymers. In one embodiment, the hydrophilic part of the amphiphilic polymer is selected from polyethylene glycol (PEO), povidone and the like, and the hydrophobic part of the amphiphilic polymer is selected from polyoxypropylene, polylactic acid, polystyrene, polycaprolactone (PCL), polyamino acid, poly(lactic-co-glycolic acid), polyacrylic acid and the like.
[00225] In one embodiment, the amphiphilic polymer is a combination of two or more of poloxamers (e.g. PEO-PPO-PEO), a polylactic acid-polyethylene glycol-polylactic acid triblock copolymer (PLA-PEO-PLA), a polyethylene glycol-polyacrylic acid block copolymer (PEO-PAA), a polyethylene glycol-polyaspartic acid block copolymer (PEO-PASP), a polyethylene glycol-poly(lactic-co-glycolic acid) block copolymer (PEO-PLAG), a polyethylene glycol-polycaprolactone block copolymer (PEO-PCL), a polyethylene glycolpolylactic acid block copolymer (PEO-PLA/PTX), or a polyethylene glycol-polystyrene block copolymer (PEO-b-PS), and the like.
[00226] In one embodiment, the amphiphilic polymer is a polyethylene glycol- polycaprolactone block copolymer (PEO-b-PCL). The copolymer may have a numberaverage molecular weight of 500-50000 (specifically, such as 500, 1000, 2000, 3000, 4000, 5000, 6000, 8000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 24000, 26000, 28000, 30000, 32000, 34000, 36000, 38000, 40000, 42000, 44000, 46000, 48000 and 50000).
[00227] In one embodiment, the polymeric micelle has a mean hydrodynamic diameter (Dh, nm; measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)) of about 1 to about 500 nm. Suitably about 50 to about 500 nm, suitably about 75 to 500 nm, suitably about 100 to 500nm, suitably about 100 to 150 nm.
[00228] In another embodiment, the polymeric micelle has a mean hydrodynamic diameter (Dh, nm; measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)) of about 1 to about 400 nm. Suitably about 1 to about 300 nm, suitably about 1 to 200 nm.
[00229] In another embodiment, the polymeric micelle has a mean hydrodynamic diameter (Dh, nm; measured at a detection angle of 90°, at 25 °C, in a photon correlation spectrometer (Zetasizer 3000 HSA, Malvern, UK) and analyzed by the CONTI N method (MALVERN software)) of about 75 to about 400 nm. Suitably about 75 to about 300 nm, suitably about 75 to 200 nm, suitably about 75 to 150 nm.
[00230] In one embodiment, the pharmaceutical compositions described herein comprise a pharmaceutically acceptable excipient or carrier which is a fluid, especially a liquid, in which the compound of formula I is suspended or dissolved, such that the composition is physiologically tolerable, i.e. can be administered to the mammalian body without toxicity or undue discomfort. The carrier medium is suitably an injectable carrier liquid such as sterile, pyrogen- free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e.g. salts of plasma cations with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (e.g. sorbitol or mannitol), glycols (e.g. glycerol), or other non-ionic polyol materials (e.g. polyethylene glycols, propylene glycols and the like). The carrier may also comprise biocompatible organic solvents such as ethanol. Such organic solvents are useful to solubilise more lipophilic compounds or formulations. Preferably the carrier is pyrogen-free water for injection, isotonic saline or an aqueous ethanol solution. The pH of the carrier for intravenous injection is suitably in the range 4.0 to 10.5.
[00231] The compositions described herein may contain conventional pharmaceutical excipients, for example emulsifiers, fatty acid esters, gelling agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc., and may be in a form suitable for parenteral or enteral administration, for example injection or infusion or administration directly into a body cavity having an external escape duct, for example the gastrointestinal tract, the bladder or the uterus.
[00232] The compounds or compositions of the present invention may be in conventional pharmaceutical administration forms such as tablets, capsules, powders, solutions, suspensions, dispersions, syrups, suppositories etc.
[00233] For imaging of some portions of the body the most preferred mode for administering contrast agents is parenteral, e.g., intravenous administration. [00234] In one embodiment, the compounds or compositions described herein are in a parenterally administrable forms, e.g. an intravenous solutions. Said solution should be sterile and free from physiologically unacceptable agents, and should have low osmolality to minimize irritation or other adverse effects upon administration, and thus the composition should preferably be isotonic or slightly hypertonic. The skilled person would be aware of suitable carriers for administering parenteral solutions such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection.
[00235] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical carriers and excipients, well known in the art.
Therapeutic Uses and Applications
[00236] The compounds of the present invention can be used in a method of treating a disease or medical condition exhibiting senescence.
[00237] Accordingly, in one aspect, the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in therapy.
[00238] In another aspect, the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in treating a disease or condition exhibiting or mediated by senescence.
[00239] In another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutical composition, as described herein for treating a disease or condition exhibiting or mediated by senescence.
[00240] In another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutical composition, as described herein in the manufacture of a medicament for treating a disease or condition exhibiting or mediated by senescence.
[00241] In another aspect, the present invention provides a method of treating a disease or condition exhibiting or mediated by senescence in a subject, or a biological sample obtained therefrom, comprising administering to said subject or sample an effective amount of a compound of formula I, or a pharmaceutical composition, as described herein.
[00242] In one embodiment, the biological sample is selected from tissues of animal origin, ranging from invertebrates to mammals, including humans, in the live or preserved state; single animal cells either derived from the above tissues or in suspension, in the live or preserved state.
[00243] In one embodiment, the subject is an animal. In one embodiment, the subject is a mammal, suitably a human.
[00244] In one embodiment, the disease or condition exhibiting or mediated by senescence is selected from the group consisting of diabetes, obesity, age-related lipodystrophy, cardiac dysfunction, vascular hyporeactivity/calcification/arteriovenous fistulae, frailty, sarcopenia, muscular dystrophy, fibrodysplasia, age related diseases such as age-related impairment of muscle hypertrophy after resistance exercise and age-related cognitive impairment, Alzheimer’s disease, Parkinson’s disease, ALS, anxiety, response to and sequelae of chemotherapy/radiation, cancers, sequelae of organ transplantation, renal dysfunction, osteoporosis, osteoarthritis, rheumatoid arthritis, intervertebral disc disease, fracture healing, COPD, hyperoxic lung damage, pulmonary arterial hypertension, hepatic steatosis, cirrhosis, primary biliary cirrhosis, progerias, intestinal inflammation, preeclampsia, uterine fibrosis, ovarian involution, vaginal dysplasia, cataracts, macular degeneration, glaucoma, ocular hypertension, diabetic retinopathy, progenitor growth, activation or differentiation, COVID-19, Down syndrome, skin disorders, chronic wound healing.
[00245] In one embodiment, the disease or condition exhibiting or mediated by senescence is selected from the group consisting of a cancer, a fibrotic disorder, a neurodegenerative condition, a cardiovascular disease, a metabolic disease, a kidney disease, a liver disease and a degenerative disease.
[00246] Suitably, the disease or condition exhibiting or mediated by senescence is selected from a cancer or a fibrotic disorder.
[00247] Suitably, the disease or condition exhibiting or mediated by senescence is selected from cancer, chronic obstructive pulmonary disease (COPD), cystic fibrosis, osteoporosis, frailty, transplantation, opthalmic disorders, disc degeneration, osteoarthritis, renal diseases, neurodegenerative diseases, hepatic steatosis, metabolic dysfunction, fibrosis, neoplasias (pre- and neoplastic), diabetes, neuro-degenerative diseases, cardiovascular diseases, obesity, immune dysfunction, aging and age related functional decline.
[00248] In another aspect, the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in treating a fibrotic disorder. [00249] In another aspect, the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein for treating a fibrotic disorder.
[00250] In another aspect, the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein in the manufacture of a medicament for treating a fibrotic disorder.
[00251] In another aspect, the present invention provides a method of treating a fibrotic disorder in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I, or a pharmaceutical composition, as described herein.
[00252] The fibrotic disorder may be a disorder characterised by excess fibrosis, e.g., an excess of fibrous connective tissue in a tissue or organ, e.g., triggered by a reparative or reactive process, e.g., in response to injury (e.g., scarring, healing, radiotherapy) or excess fibrotic tissue arising from a single cell line (e.g., fibroma).
[00253] In one embodiment, the fibrotic disorder is selected from:
(i) a fibrotic disorder affecting the lungs, for example pulmonary fibrosis secondary to cystic fibrosis; idiopathic pulmonary fibrosis; coal worker’s progressive massive fibrosis; cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), or chronic asthma; or
(ii) a fibrotic disorder affecting the liver, for example cirrhosis, and associated conditions such as chronic viral hepatitis B or C, Wilson’s disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis or autoimmune hepatitis; or
(iii) a fibrotic disorder affecting the kidneys, for example diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangiocapillary glomerular nephritis;
(iv) a fibrotic disorder affecting the heart or vascular system, for example endomyocardial fibrosis; old myocardial infarction; atrial fibrosis; congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (for example pulmonary hypertension) and fibrosis associated with hypertension, atherosclerosis, restenosis (e.g. coronary, carotid, and cerebral lesions), and heart disease associated with cardiac ischemic events; or
(v) a fibrotic disorder affecting the mediastinum, for example mediastinal fibrosis; or
(vi) a fibrotic disorder affecting bone, for example myelofibrosis, including primary myelofibrosis, post polycythemia vera or post essential thrombocythemia myelofibrosis; or
(vii) a fibrotic disorder affecting the retroperitoneum, for example retroperitoneal fibrosis skin; or
(viii) a fibrotic disorder affecting the skin, for example nephrogenic systemic fibrosis, keloid formation and scarring, systemic sclerosis, scleroderma, hypertrophic scarring, scleredema (Buschke disease), systemic amyloidosis, lipodermatosclerosis, progeroid disorders, stiff skin syndrome, Dupuytren's contracture, nephrogenic fibrosing dermopathy (NFD), mixed connective tissue disease, scleromyxedema, graft-versus-host disease (GVHD), Peyronie’s disease and eosinophilic fasciitis; or
(ix) a fibrotic disorder affecting the Gl tract, for example a fibrotic intestinal disorder, inflammatory bowel disease, ulcerative colitis or Crohn’s disease; or
(x) a fibrotic disorder affecting connective tissue, for example arthrofibrosis; or capsulitis; or
(xi) a fibrotic disorder affecting the eye, for example ocular scarring, ocular fibrosis following surgery or pseudoexfoliation syndrome glaucoma.
(xii) a fibrotic disorder induced by radiation, such as fibrosis following radiotherapy. The fibrotic condition induced by radiation may occur in any tissue treated by radiotherapy, for instance, the skin and subcutaneous tissue, lungs, breast, gastrointestinal and genitourinary tracts, muscles, and other organs.
[00254] In another aspect, the present invention provides a compound of formula I, or a pharmaceutical composition, as described herein for use in treating a cancer.
[00255] In another aspect, the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein for treating a cancer.
[00256] In another aspect, the present invention provides the use of compound of formula I, or a pharmaceutical composition, as described herein in the manufacture of a medicament for treating a cancer. [00257] In another aspect, the present invention provides a method of treating a cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I, or a pharmaceutical composition, as described herein.
[00258] The cancer may be a solid tumour or a haematological (“liquid”) cancer. In one embodiment, the cancer is selected from:
(1) Carcinoma, including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary, esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet ring cell carcinoma, bladder carcinoma (including transitional cell carcinoma (a malignant neoplasm of the bladder)), bronchogenic carcinoma, colorectal carcinoma (including, but not limited to, colon carcinoma and rectal carcinoma), anal carcinoma, gastric carcinoma, lung carcinoma (including but not limited to small cell carcinoma and non-small cell carcinoma of the lung, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and mesothelioma), neuroendocrine tumors (including but not limited to carcinoids of the gastrointestinal tract, breast, and other organs), adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma (including, but not limited to, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, acinar cell carcinoma, intraductal papillary mucinous neoplasm with invasive carcinoma, mucinous cystic neoplasm with invasive carcinoma, islet cell carcinoma and neuroendocrine tumors), breast carcinoma (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma), ovarian carcinoma (including, but not limited to, ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cystadenocarcinoma, sex-cord-stromal tumor), liver and bile duct carcinoma (including, but not limited to, hepatocellular carcinoma, cholangiocarcinoma and hemangioma), prostate carcinoma, adenocarcinoma, brain tumours (including, but not limited to glioma, glioblastoma and medulloblastoma), germ cell tumors, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney carcinoma (including, but not limited to, renal cell carcinoma, clear cell carcinoma and Wilm's tumor), medullary carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical carcinoma, uterine carcinoma (including, but not limited to, endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas, mixed mullerian tumors), testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma; oral and oropharyngeal squamous carcinoma;
(2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective tissue types) and other soft tissue sarcomas;
(3) Myeloma and multiple myeloma;
(4) Hematopoietic tumours, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis.
(5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas;
(6) Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;
(7) Melanoma, uveal melanoma and retinoblastoma; and
(8) Mixed Types, including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.
[00259] In one embodiment, the cancer is selected from anus cancer, bile duct cancer, bladder cancer, blood cancer, brain cancer, breast cancer, uterine cervix cancer, colon cancer, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, head and neck cancer, hypopharyngeal cancer, pancreatic cancer, pharyngeal cancer, lip and oral cancer, liver cancer, lung cancer, melanoma, mesothelioma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
[00260] In another embodiment, the cancer is selected from bladder cancer, blood cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, head and neck cancer, pancreatic cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
[00261] In another embodiment, the cancer is selected from pancreatic cancer, colon cancer, breast cancer and lung cancer.
[00262] In another aspect, the present invention relates to a method of inducing death of a senescent cell in a subject or sample, comprising administering to said subject or sample an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[00263] In another aspect, the present invention relates to a method of inhibiting senescence in a cell, comprising administering to said cell an effective amount of a compound of formula I, or a salt or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
[00264] In one embodiment, the cell is present in a sample. In one embodiment, the sample is a fluid sample. For instance, the sample may comprise a body fluid of a subject, such as urine, lymph, saliva, mucus, milk or amniotic fluid, blood, plasma or serum.
[00265] In one embodiment, the sample is human in origin, but alternatively it may be from another mammal or animal such as from commercially farmed animals such as horses, cattle, sheep or pigs or may alternatively be pets such as cats or dogs.
[00266] In one embodiment of each of the above aspects, the method is an in vivo method. In another, embodiment of each of the above aspects the method is an ex vivo or in vitro method.
Combinations [00267] The compounds of the invention may be used alone to provide a therapeutic effect. The compounds of the invention may also be used in combination with one or more additional therapeutic agents or methods.
[00268] In one embodiment, the present invention provides a compound of formula I as defined herein in combination with an anti-cancer agent and/or radiotherapy.
[00269] In one embodiment, the anti-cancer agent may be selected from one or more of the following:
(i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin, temozolomide and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, leucovorin, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine and hydroxyurea, and trifluridine with trifluracil); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors; eribulin); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, irinotecan, mitoxantrone and camptothecin); bleomcin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nabpaclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN- alpha), etoposide, teniposide, DNA-demethylating agents, (for example, azacitidine or decitabine); and histone de-acetylase (HDAC) inhibitors (for example vorinostat, MS-275, panobinostat, romidepsin, valproic acid, mocetinostat (MGCD0103) and pracinostat SB939; and belinostat, panobinostat); trabectedin; ivosidenib; belzutifan; lurbinectedin; tazemetostat; selinexor;
(ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafme and droloxafine; and abiraterone, Enzalutamide; analogues of somatostatin such as lanreotide; relugolix
(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example anti-erbB2 antibodies trastuzumab, margetuximab, the anti-HER2 antibody pertuzumab; the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family: gefitinib, erlotinib, , afatinib, vandetanib, osimertinib and rociletinib); erbB2 tyrosine kinase inhibitors such as lapatinib, neratinib, mobocertinib, tucatinib and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-1, or antibodies to cytokines (IL-IO, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib, nilotinib, ; inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, sorafenib, tipifarnib and lonafarnib, vemurafenib, dabrafenib, encorafenib, sotorasib), inhibitors of cell signalling through MEK (such as trametinib, cobimetinib, selumetinib) and/or AKT kinases, c-kit inhibitors, for example ripretinib, abl kinase inhibitors such as ponatinib, PI3 kinase inhibitors for example idelalisib, perifosine, alpelisib, umbralisib, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; FGFR inhibitors, e.g. erdafitinib, infigratinib, pemigatinib; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors or CDK4/CDK6 inhibitors such as palbociclib, abemaciclib, ribociclib; CCR2, CCR4 or CCR6 antagonists; mTOR kinase inhibitors such as Everolimus; Janus kinase family inhibitors such as ruxolitinib; Brunton’s tyrosine kinase inhibitors such as Ibrutinib, zanubrutinib; anaplastic lymphoma kinase - ALK - such as ceritinib, crizotinib, alectinib, lorlatinib, brigatinib; c-Met kinase inhibitors such as cabozantinib, tepotinib, capmatinib; RET kinase inhibitors such as pralsetinib; hedgehog signalling pathway inhibitors such as vismodegib, sonidegib; and RAF kinase inhibitors such as those described in WG2006043090, WG2009077766, WO2011092469 or WO2015075483; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example bevacizumab (Avastin™), anti-VEGF2 antibody ramucirumab; recombinant fusion protein ziv-aflibercept]; thalidomide; pomalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as regorafenib, vandetanib, vatalanib, sunitinib, axitinib, pazopanib, lenvatinib, tivozanib;
(vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2; oncolytic viruses such as talimogene laherparepvec; CAR-T cells based therapies such as ciltacabtagene autoleucel, brexucabtagene autoleucel
(vii) immunotherapy approaches, including for example antibody therapy such as denosumab, obinutuzumab, blinatomumab, dinutuximab, idarucizumab, daratumumab, necitumumab, elotuzumab, olaratumab, alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), isatuximab, avelumab, tafasitamab, naxitamab and ofatumumab; interferons such as interferon a, peginterferon alpha-2b; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); tolllike receptor modulators for example TLR-7 or TLR-9 agonists; PD-1, PD-L1 , PD-L2 and CTL4-A antibodies (for example Nivolumab, pembrolizumab, atezolizumab, ipilimumab, dostarlimab, cemiplimab), antibodies and vaccines; other IDO inhibitors (such as indoximod); LAG-3-blocking antibody such as relatlimab; antibody-drug conjugates such as Brentuximab vedotin, trastuzumab emtansine, fam-trastuzumab deruxtecan. tisotumab vedotin, sacituzumab govitecan; luspatercept;
(viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent™);
(ix) targeted therapies, for example; SMAC (second mitochondria-derived activator of caspases) mimetics, also known as Inhibitor of Apoptosis Proteins (IAP) antagonists (for example XIAP, clAP1 and clAP2), including Birinapant and LCL161 (Novartis), ; and agents which target ubiquitin proteasome system (UPS), for example, bortezomib, ixazomib, carfilzomib and marizomib; and DNA repair inhibitors such as Olaparib, rucaparib, niraparib; antiapoptotic BCL proteins family inhibitors such as venetoclax.
(xii) chimeric antigen receptors, anticancer vaccines and arginase inhibitors. [00270] In one embodiment, the present invention provides a compound of formula I as defined herein in combination with an anti-fibrotic agent.
[00271] In one embodiment, the anti-fibrotic agent may be selected from one or more of the following:
(i) Antifibrotic agents such as pirfenidone, nintedanib; CTFG antibody inhibitors such as pamrevlumab; recombinant human pentraxin-2 (PRM-151); anti-inflammatory agents such as corticosteroids, interferon-gamma; cardiovascular drugs such as pentoxifylline; ROS scavengers such as Vitamin E, superoxide dismutase.
[00272] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
[00273] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
[00274] In some embodiments in which a combination treatment is used, the amount of the compound of the invention and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the patient. In this context, the combined amounts are “therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of the invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s). [00275] According to a further aspect of the invention there is provided a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore, for use in the conjoint treatment of cancer.
[00276] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore for the conjoint treatment of cancer.
[00277] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-cancer agent as defined hereinbefore.
[00278] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-cancer agent as defined hereinbefore, in the treatment of a cancer.
[00279] In one embodiment, the anti-cancer agent is selected from dasatinib and/or quercetin.
[00280] The compound of the invention may also be used be used in combination with radiotherapy. Suitable radiotherapy treatments include, for example X-ray therapy, proton beam therapy or electron beam therapies. Radiotherapy may also encompass the use of radionuclide agents, for example 1311, 32P, 90Y, 89Sr, 153Sm or 223Ra. Such radionuclide therapies are well known and commercially available.
[00281] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in the treatment of cancer conjointly with radiotherapy.
[00282] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with radiotherapy. [00283] In another embodiment, there is provided a combination of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, an anti-fibrotic agent.
[00284] According to a further aspect of the invention there is provided a compound of the invention as defined hereinbefore and an additional anti-fibrotic agent as defined hereinbefore, for use in the conjoint treatment of a fibrotic disorder.
[00285] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-fibrotic agent as defined hereinbefore for the conjoint treatment of a fibrotic disorder.
[00286] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a fibrotic disorder comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore.
[00287] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore, in the treatment of a fibrotic disorder.
EXAMPLES
Chemistry
[00288] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
[00289] The compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).
[00290] Several methods for the chemical synthesis of the compounds of the present application are described herein. These and/or other well-known methods may be modified and/or adapted in various ways in order to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, it should be understood that the methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.
Synthesis and Characterisation
[00291] Melting points were determined on a Buchi apparatus and are uncorrected. 1H-NMR and 13C-NMR spectra were recorded on a Bruker Avance III 600 instrument, in deuterated solvents and were referenced to TMS (6 scale). Mass spectra were recorded with a LTQ Orbitrap Discovery instrument, possessing an lonmax ionization source. Flash chromatography was performed on Merck silica gel 60 (0.040-0.063 mm). Analytical thin layer chromatography (TLC) was carried out on precoated (0.25 mm) Merck silica gel F-254 plates. The purity of the target compound (>95%) was determined on a Thermo Scientific® HPLC System (Accela Pump, Accela Autosampler, Accela PDA detector, 254 nm, Xcalibur™ 2.2 Software); Waters ACQUITY UPLC® BEH C18-1.7 pm (2.1 x 150 mm); mobile phase: 1% acetic acid in Water / Acetonitrile; flowrate 0.2 mL/min; column temperature 25 °C; injection volume 5 pL.
[00292]
Example 1 :
[00293] Synthesis of 2-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2- yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethyl ((2-methyl-6-((E)-(4-((E)- phenyldiazenyl)naphthalen-1-yl)diazenyl)-2,3-dihydro-1H-perimidin-2-yl)methyl) succinate (GL392)
GL392 Step 1 : 4-((2-Methyl-6-((E)-(4-((E)-phenyldiazenyl)naphthalen-1 -yl)diazenyl)-2,3- dihydro-1 H-perimidin-2-yl)methoxy)-4-oxobutanoic acid (GL353)
[00294] DMAP (1.29 g, 10.56 mmol) and succinic anhydride (852 mg, 8.51 mmol) were added into a solution of the SBB derivative (2-methyl-6-((E)-(4-((E)- phenyldiazenyl)naphthalen-1-yl)diazenyl)-2,3-dihydro-1/7-perimidin-2-yl)methanol, 2 g, 4.24 mmol) (see Evangelou K et al., Aging Cell (2017), 16, 192-197) in dichloromethane (35 ml) and this mixture was stirred at room temperature for 2 hrs. Upon completion of the reaction, the solvent was evaporated under reduced pressure and in the residue an aqueous solution of HCI (0.1 N, 250 ml) was added until pH 3-4. The precipitate was filtered under vacuum and air-dried. The crude solid product was collected and purified by flash column chromatography, using ethyl acetate as the eluent, to provide the pure carboxylic acid GL353 as a black solid, in 87% yield. M.p. 110°C. 1H-NMR (600 MHz, acetone-d6) 5 1.63 (s, 3H), 2.59-2.61 (m, 4H), 4.22 (d, 1 H, J=10.7 Hz), 4.29 (d, 1 H, J=10.7 Hz), 6.19 (brs, 1 H, D2O exch.), 6.67 (d, 1 H, J=7.4 Hz), 6.71 (d, 1 H, J=8.4 Hz), 7.07 (brs, 1 H, D2O exch.), 7.44 (t, 1 H, J=8.2 Hz), 7.59 (t, 1 H, J=7.3 Hz), 7.65 (t, 2H, J=7.3 Hz), 7.77-7.82 (m, 2H), 8.06 (d, 1 H, J=8.3 Hz), 8.09-8.12 (m, 3H), 8.21 (d, 1 H, J=8.4 Hz), 8.35 (d, 1 H, J=8.4 Hz), 9.09 (d, 1 H, J=7.7 Hz), 9.17 (d, 1 H, J=7.7 Hz), 10.77 (brs, 1 H, D2O exch.). 13C-NMR (151 MHz, acetonede) 5 25.25, 29.28, 29.35, 66.90, 68.29, 106.33, 107.00, 112.07, 112.47, 112.60, 113.56, 118.65, 124.05, 124.25, 124.98, 127.79, 128.30, 130.37, 130.67, 132.26, 132.86, 133.59, 134.85, 140.77, 142.00, 147.42, 148.06, 151.55, 154.50, 172.51 , 174.10. HRMS (ESI) m/z: calcd for C33H29N6O4, [M+H]+ = 573.2245, found 573.2245.
Step 2: Synthesis of title compound
DCC (80 mg, 0.39 mmol) and DMAP (40 mg, 0.33 mmol) were added under argon, into a suspension of GL353 (200 mg, 0.35 mmol) in anhydrous /V,/V-dimethylformamide (4 mL), and this mixture was stirred at room temperature for 15 minutes, followed by the addition of Dasatinb (172 mg, 0.35 mmol). The reaction was then stirred for additional 72 hrs, at room temperature, under argon. Upon completion of the reaction, brine (80 ml) was added in the flask, followed by extraction with ethyl acetate (3 x 100 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated to dryness. The crude product was purified by flash column chromatography, using a mixture of dichloromethane/methanol (from 100/2 up to 100/10, v/v) as the eluent, to provide the pure hybrid derivative GL392 as a black solid, in 50% yield. M.p. 169-170 °C. 1H-NMR (600 MHz, acetone-d6) 5 1.63 (s, 3H), 2.33 (s, 3H), 2.42 (s, 3H), 2.49-2.51 (m, 4H), 2.57-2.61 (m, 6H), 3.53-3.55 (m, 4H), 4.19-4.23 (m, 3H), 4.30 (d, 1 H, J=10.7 Hz), 6.09 (s, 1 H), 6.23 (brs, 1 H, D2O exch.), 6.66 (d, 1 H, J=7.4 Hz), 6.70 (d, 1 H, J=8.4 Hz), 7.12 (brs, 1 H, D2O exch.), 7.21- 7.27 (m, 2H), 7.34 (d, 1 H, J=7.7 Hz), 7.45 (t, 1 H, J=8.2 Hz), 7.58 (t, 1 H, J=7.3 Hz), 7.64 (t, 2H, J=7.3 Hz), 7.76-7.80 (m, 2H), 8.05 (d, 1 H, J=8.3 Hz), 8.09-8.12 (m, 3H), 8.19-8.23 (m, 2H), 8.35 (d, 1 H, J=8.4 Hz), 9.03 (brs, 1 H, D2O exch.), 9.08 (d, 1 H, J=7.7 Hz), 9.16 (d, 1 H, J=7.7 Hz), 10.25 (brs, 1 H, D2O exch.). 13C-NMR (151 MHz, acetone-cfe) 5 18.93, 25.19, 25.22, 25.85, 44.76, 53.62, 57.24, 62.64, 66.76, 66.83, 68.61 , 83.39, 106.17, 106.23,
106.77, 106.81 , 111.92, 112.30, 112.46, 113.42, 118.52, 123.96, 124.13, 124.85, 127.42,
127.68, 128.18, 128.88, 129.85, 130.26, 130.58, 132.15, 132.74, 133.49, 134.53, 134.64,
134.76, 140.12, 140.58, 141.39, 141.96, 142.00, 147.37, 147.44, 147.87, 151.35, 154.33,
158.11 , 160.93, 163.90, 166.62, 172.35, 172.86. HRMS (ESI) m/z: calcd for C55H51CIN13O5S, [M-H]- = 1040.3550, found 1040.3563. HPLC analysis: tR = 13.35 min, purity 95.34%.
Example 2:
Preparation of polymeric micelle comprising a compound of formula I (mGL392)
[00295] For the micelle preparation, poly(ethylene oxide)-b-poly(s-caprolactone) (PEO-b- PCL(5K), 5K) copolymer purchased from BOC Sciences® (Lot No B23VO3091) was utilized.
[00296] Polymeric micelles were prepared by the thin-film hydration method. Briefly, an appropriate amount of PEO-b-PCL was dissolved in chloroform. An appropriate amount of GL392 (example 1) being dissolved in acetone was added. The mixture was then transferred into a round flask connected to a rotary evaporator (Hei-VAP series CORE-heidolph®). Vacuum was applied and the polymeric thin film was formed by slow removal of the solvent at 45°C. The film was subsequently hydrated in HPLC-grade water, by slowly stirring for 1 h, in a water bath at 45° C. The concentration of PEO-b-PCL in the final micellar dispersion was 5mg/mL and the concentration of GL392 was 0.01mg/mL. The resultant micelles were subjected to two, 5-minute long sonication cycles interrupted by a 5 minute resting period, using a probe sonicator (Bandelin sonopuls, homogenizer, HD3200). The resultant GL392 loaded micelles were allowed to anneal for 30 min at room temperature.
Physicochemical characterization of micelles - Dynamic Light Scattering (DLS)
[00297] The physicochemical characteristics of the prepared nanosystems were evaluated by measuring their mean hydrodynamic diameter (Dh, nm) and size polydispersity index (PDI). These parameters were assessed for the physicochemical characterization of loaded micelles immediately after their preparation. 100 pL aliquots were 20-fold diluted in HPLC-grade water. For dynamic light scattering measurements, an AVL/CGS-3 Compact Goniometer System (ALV GmbH, Germany) was used, equipped with a cylindrical JDS Uniphase 22 mV He-Ne laser, operating at 632.8 nm/ and an Avalanche photodiode detector. The system was interfaced with an ALV/LSE-5003 electronics unit, for stepper motor drive and limit switch control, and an ALV-5000/ EPP multi-tau digital correlator. Autocorrelation functions were analyzed by the cumulants method and the CONTI N software. All measurements were implemented at a fixed temperature (25 °C) and at a fixed scattering angle of 90° degrees.
[00298] The size (hydrodynamic diameter, Dh) of pure PEO-b-PCL micelles was found to be 85 nm; the addition of GL392 led to an increase in the Dh to 120 nm, indicating its successful incorporation into the micellar core (see Figure 2B). The PDI value for mGL392 reveals a monodisperse particulate population..
Physicochemical characterization of micelles - Transmision Electron Microscopy (TEM)
[00299] The structure and the shape of the micelles of example 2 (m-GL392) are visualized in Figure 2C through TEM image acquisition (i-iii) (TEM, CM20, Philips, Amsterdam, The Netherlands) and cryo-TEM (iv).
[00300] The TEM images showed that the size of the mGL392 is higher in comparison to the size observed with DLS. In TEM images, the diameter values are around 120-150 nm (Figure 2C). According to the size distribution obtained by TEM, the majority of mGL392 exhibits a mean diameter below 100 nm (Figure 20). This last observation is in line with the results obtained by DLS. The mGL392 exhibited an irregular, but close to spherical, shape. These differences in the obtained results in the size/size distribution are expected and are associated with the different state of matter of the sample during the experiments contacted by the two methods. Namely, solution and solid are the states of matter for the mGL392 for DLS and TEM measurements, respectively. In the images obtained two different phases can are observed within the micelles. A bright inner phase which is expected to primarily consist of drug and an outer phase that is expected to primarily consist of the amphiphilic block copolymer material.
Physicochemical characterization of micelles - cryo TEM
[00301] 4 pl of the sample were applied to glow-discharged Quantifoil holey Au grids
(R2/2, Quantifoil Micro Tools GmbH, Germany), which were loaded on Leica GP2 plunge freezer. Each grid was blotted with filter paper for 1.5 seconds and immediately frozen by plunging into liquid ethane cooled by liquid nitrogen. The vitrified samples were then stored in cryo grid box in liquid nitrogen until observed in transmission electron microscope Jeol 2100Plus operated at 200 keV and equipped with LaB6 filament. Cryo-samples were transferred into the microscope with an Elsa cryo-holder, model 698 (Gatan Inc., USA), which was kept a -175°C and observed under low-dose conditions (30e/A2) using the SerialEM software. Images were acquired using the Gatan One View camera, at original magnification 100.000x. Using Fiji software, the brightness of the captured images was adjusted to cover the complete range of the histogram and the Gaussian Blur filter was applied to reduce the image noise.
The cryo-TEM image shows mGL392 with an irregular shape (but more or less spherical, Figure 2C, iv). The size of the mGL392 is higher than the size of the sample obtained by TEM and DLS. The phenomenon of secondary aggregation is probably responsible for this observation, caused by the low temperature conditions during the experiment and the different state of matter of the PEO-b-PCL block copolymer (Castillo and Muller, 2009). Additionally, the different contrast within the nanoparticles also indicates the successful incorporation of GL392 into the polymeric micelle.
Biology
Detection of senescent in cell cultures
[00302] mGL392 (example 2) was used to detect senescent cells in Li-Fraumeni- p2i AFi/ciPi Tet-ON cells using fluorescence microscopy (Figure 3). Li-Fraumeni-p21WAF1/Cip1 Tet-ON cells were maintained in DMEM, 10% tetracycline free fetal bovine serum (FBS). Senescence entry was accomplished upon addition of (50pg/ml) Doxycycline (Applichem, Darmstadt, Germany) replenishing every two days for 6 days [as described in Galanos et al, 2016; Zampetidis et al, 2021], [00303] Schematic representation of the masking of lipofuscin autofluorescence upon mGL392 binding is provided in Fig 3A. Proliferating (upper panel, Fig 3B) or senescent (lower panel, Fig 3B) Li-Fraumeni-p21WAF1/Cip1 Tet-ON cells were treated with mGL392 (1.6 pg/ml) for 4 hours and subsequently observed under an EVOS microscope. mGL392 treated senescent cells do not display lipofuscin autofluorescence since it is masked upon interaction with the compound. Untreated senescent cells display abundant autofluorescence, while corresponding non-senescent [(-) Doxycline] Li-Fraumeni- p2i AFi/ciPi Tet-ON ce||S d0 not, since they do not accumulate lipofuscin.
[00304] In each case, quantification of the lipofuscin autofluorescence signal was performed using Image J and is presented as means ± SD from three independent experiments. Objective x20. Scale bar: 10 pm (Fig 3C). Notably, the strong affinity of the compound for lipofuscin was not affected by its conjugation with Dasatinib as GL392 successfully masked lipofuscin autofluorescence.
Targeted senolysis in vitro in Li-Fraumeni-p21WAF1/Cip1 Tet-ON cells
[00305] Non-senescent and senescent Li-Fraumeni-p21WAF1/Cip1 Tet-ON cells were treated with mGL392 (0,4 pg/ml), Dasatinib (D) (20mM), mGL392+Q, D+Q, Quercetin (Q) (10pM) or Vehicle. Cell viability was assessed by MTT assay. Results are presented as mean % of the vehicle ± SD, from 2 independent experiments (Fig. 4A).
[00306] Cells treated with Vehicle, mGL392, Dasatinib, mGL392+Q, D+Q, or Quercetin were co-stained for (cleaved) Cl. Caspase-3 (depicted in red), and GLF16 (depicted in green) for identification of apoptotic and senescent cells, respectively (Fig. 4B).
(GLF16)
[00307] Apoptosis and senescence were estimated in cells treated with mGL392, mGL392+Q or Vehicle. mGL392, mGL392+Q did not affect the viability of (-) Dox (noninduced) Li-Fraumeni-p21WAF1/Cip1 Tet-ON cells as evaluated by the absence of Cl. Caspase- 3. mGL392 and mGL392+Q treated (+)-Dox (senescence induced) Li-Fraumeni-p21WAF1/Cip1 Tet-ON cells showed increased Cl. Caspase-3 positivity. Quantification of the immunofluorescence analysis is presented in pie charts as mean ± SD. Results were from three independent experiments. Statistical significance: p < 0.05 compared to respective vehicle by two-tailed Student’s t test. Objective x20. Scale bar: 10 pm. (Fig. 4C). mGL392 significantly impeded viability of senescent cells either alone or even more when combined with Quercetin.
Validation of the senolytic properties of mGL392 in the HBEC CDC6-Tet-ON cellular system
[00308] HBEC CDC6 Tet-ON were maintained in Keratinocyte Serum-Free Medium (#17005-075, Invitrogen) supplemented with 50 pg/ml Bovine Pituitary Extract and 5 ng/ml hEGF (#17005-075, Invitrogen). Senescence entry was accomplished upon addition of (50|jg/ml) Doxycycline (Applichem, Darmstadt, Germany) replenishing every two days for 6 days [as described in Galanos et al, 2016; Zampetidis et al, 2021], [00309] mGL392 treatment significantly decreased lipofuscin autofluorescence in senescent HBEC CDC6-Tet-ON cells compared to their non senescent counterparts. Quantification of the lipofuscin autofluorescence signal was evaluated using Image J and is presented as mean ± SD from three independent experiments (Fig 5A, B).
[00310] Senescent and non-senescent HBEC CDC6 Tet-ON cells were subsequently treated with mGL392 (0.4 pg/ml), Dasatinib (D) (20mM), mGL392+Q, D+Q, Quercetin (Q) (10pM) or Vehicle. Cell viability was assessed by MTT assay. Results are presented as mean % of vehicle ± SD, from 2 independent experiments. Statistical significance: *p < 0.05 compared to respective vehicle by two-tailed Student’s t test (Fig. 5C).
[00311] Apoptosis and senescence estimation in cells treated with mGL392, mGL392+Q or vehicle and co-stained for Cl. Caspase-3 and GLF16, respectively. mGL392, mGL392+Q did not affect the viability of (-) dox HBEC CDC6 Tet-ON cells as evaluated by the absence of Cl. Caspase-3. mGL392, mGL392+Q treated (+)-Dox (senescence induced) HBEC CDC6 Tet-ON cells showed a few single GLF16-positive cells and increased Cl. Caspase-3 positivity (Fig. 5D).
[00312] Quantification of the immunofluorescence analysis is presented in pie charts as mean ± SD, from 3 independent experiments. Statistical significance^ < 0.05 compared to respective vehicle by two-tailed Student’s t test. Objective x20. Scale bar: 10 pm. (Fig. 5E). mGL392 significantly impeded viability of senescent cells either alone or more so when combined with Quercetin. ex vivo 3D lung organoid cultures
[00313] 3D: Airway Organoids (AO) were generated from lung tissue surgically resected from non-small cell lung cancer (NSCLC) patients, and cultured as described before [Sachs N, et al., EMBO (2019)]. Briefly, collection of tissues for the generation of airway organoids was carried out according to the European Network of Research Ethics Committees (ELIREC) guidelines and the local NKLIA Medical School Bioethics committee (Protocol number: 571). All organoid lines were generated from patients who signed informed consent forms and their personal information remained anonymous.
[00314] Organoids were treated (or not) with 150 pM hydrogen peroxide (H2O2) for 72 h (replaced daily) to induce senescence, and then cultured for another 48h in H2O2-free medium. Organoids were then filtered using 70-pm strainers (Corning) to avoid formation of necrotic cores and subsequently treated with vehicle, mGL392 (500 nM), Dasatinib (500 nM), Quercetin (10 pM), Dasatinib and Quercetin or mGL392 and Quercetin for 4 days, in 5% BME/AO medium. Selective senolysis was evaluated by cell viability measurements and quantification of senescent and apoptotic cells by immunofluorescence. The experimental work flow is illustrated at Fig. 6a. Cell viability was evaluated with the CellTiter-Fluor™ Cell Viability Assay reagent (Promega #G6081), according to the manufacturer’s instructions.
[00315] Blocking of non-specific epitopes was performed using normal goat serum
(1/40, ab7481 , Abeam) in 1/40 dilution (in PBS) for 1h at RT. Organoids were incubated with primary antibody (Cl. Caspase-3, 1/400, #9661, Cell Signaling) for 1h, and positive cells were visualized using secondary goat anti-rabbit IgG H&L antibody (Alexa Fluor® 488; 1/500, ab150077, polyclonal, Abeam) for 1h. Upon staining with primary and secondary antibodies, organoids were stained for lipofuscin using GLF16 for 10 min (60 pg/ml) in the dark. Excess compound was removed by washing thrice with the GLF16 diluent (2.5% DMSO/2.5% Tween- 20/PBS). Nuclei were finally visualized by DAPI staining. Organoids were washed (30 sec with dH2O) and coverslips were mounted onto slides for microscopy. Samples were imaged on a Leica TCS-SP8 confocal microscope.
[00316] The senolytic ability in 3D organoid cultures is shown in Fig. 6b-d. Results are presented as % of vehicle. Blue and red stars in each condition represent statistical significance compared to (-) and (+) H2O2 vehicles, respectively (n=3, biological replicates), (c, d) Apoptosis (Cl. Caspase-3 immunoreactivity, red) and senescence (GLF16 staining, green) assessment was performed to verify the selective senolytic activity of mGL392. (c) Representative images of confocal microscopy. Objective 20x. Scale bar: 10 pm. (d) Quantification of immunofluorescence analysis in (c). Results are expressed as % positive (senescent or apoptotic) cells counted against DAPI-stained nuclei inspected from at least ten optical fields per sample (n=3, biological replicates). Blue, red and green stars in each condition represent statistical significance compared to respective (-) and (+) H2O2 vehicles. ** p : 0.001 - 0.01, **** p < 0.0001, two-way ANOVA test. Error bars indicate S.D. n.s.; nonsignificant. Data are presented as mean values +/-SD from 3 independent biological replicates. Cl. Caspase: Cleaved Caspase-3.
[00317] In summary, mGL392 was successfully delivered in the 3D setting and conferred a significant reduction of senescent cells, without affecting proliferating/non- senescent cells, as indicated by both organoid viability and immunofluorescence analyses (Fig. 6a-d). Taken together, these data showcase a selective and highly potent senolytic profile of mGL392 in a 3D environment, at concentrations that its respective free counterpart (Dasatinib) is accompanied by significant off-target and deleterious effects. Palbociclib-induced senescence murine melanoma model
[00318] C57BL/6 male and female mice (6-8 weeks old) were purchased from BSRC
Alexander Fleming Institute and housed at the Animal Model Research Unit of Evangelismos Hospital and housed under a 12-h light/dark cycle, at 22.5°C temperature and 55% humidity, receiving food and water ad libitum. Animals were acclimatized for 10 days before experiments. Mouse experiments were approved by the Veterinary Administration Bureau, Prefecture of Athens, Greece (Decision No: 854066, 15/07/2023) under compliance to the national law and the EU Directives. Sample size was determined upon power analysis using GPower software [Faul F, et al., (2007)] (setting significance 0.05, effect size f 0.89 and power 0.80). In brief, mice were sex and age matched and melanoma tumors were generated upon subcutaneous injection of 5x105 cells/1 OOpI of PBS in the right flank of 8-10- week old C57BL/6 syngeneic mice. Once tumors became palpable (8-9 days post tumor cell inoculation), mice were randomly split into 6 groups receiving vehicle (normal saline), Palbociclib (CDK4/6 inhibitor, PD-0332991), Palbociclib and mGL392, Palbociclib and Dasatinib, Palbociclib and Dasatininib and Quercetin, Palbociclib and mGL392 and Quercetin. Quercetin was not found to affect tumor size in vehicle- or Palbociclib-treated mice and was omitted from the experimental design. Palbociclib was administered at 2.5 mg/mouse and mGL392 at 0.015 mg/mouse. Dasatinib was administered at 0.125 mg/mouse and Quercetin at 1.25 mg/mouse. The mGL392 dosage was selected based on the reported administered dose of free Dasatinib (5mg/kg b.w) in senolytic studies [Zhu Y, et al., 2015] and its bioavailability (approximately 14% [Korashy et al., 2014]). Palbociclib and Quercetin were administered by oral gavage and mGL392 and Dasatinib intraperitoneally. Administration was performed daily, for 9 consecutive days. Tumors were monitored daily and measured every 2-3 days using a caliper. Tumor sizes were calculated using the formula: width2 x length/2 and results were expressed in mm3. Mice were euthanized (humane end point was set for tumor volume below 2x103 mm3, or any sign of distress) by sevoflurane overdose and blood was collected, tumors, vital organs and hindlimb muscles were excised and fixed in formalin for subsequent analysis. Immunofluroresence analysis was performed similar to that described above.
[00319] Formalin fixed B16 melanoma tumors were embedded in paraffin and 4pm sections were analyzed for the presence of apoptotic cells via cleaved (Cl.) Caspase-3 staining. In brief, sections were de-paraffinized and hydrated. Antigens were retrieved using pre-heated citric acid buffer (pH=6) for 18 minutes. Samples were cooled down into an icebath for 20 minutes, washed with TBS and treated with 3% H2O2 (Cat.no: K5007) for blocking of endogenous peroxidase for 18 minutes in RT. Non-specific binding sites of the primary antibody were blocked applying normal goat serum (1/40, ab7481, Abeam) for 1 hour at RT. Tissue sections were washed with PBS and incubated with the primary anticleaved Caspase-3 (1/400, #9661, Cell Signalling) antibody overnight at 4°C. Samples were washed with TBS and the positive signal was achieved utilizing the Dako REAL 140 EnVision Detection System, (Cat.no: K5007) according to the manufacturer’s instructions. Tissue Specimens were counterstained with Hematoxylin. Samples were observed under a ZEISS Axiolab5 microscope on the 10x and 20x Objectives and evaluated by two independent experienced pathologists. Variability was minimal among blinded observers (p < 0.005).
[00320] For the assessment of organ histopathological features, muscle, lung, heart, spleen, liver and kidneys from all groups were fixed and embedded in paraffin and 4 pm sections were stained by hematoxylin-eosin for visualization of organ microanatomy. Histopathological evaluation was performed by two independent experienced pathologists.
The timeline of the in vivo study is shown in Fig. 7a. Representative immunofluorescence images displaying senescent cells is shown in Fig. 7b (GLF16+, green); and quantification of senescent cell populations in the tumors is shown in Fig. 7c. Results are expressed as % positive senescent cells counted against DAPI-stained nuclei from at least ten inspected optical fields per sample. Data are presented as mean values ±SD of total cells, n=5 (biological replicates), *p < 0.05 compared to vehicle, #p < 0.05 compared to the Palbociclib group by one-way ANOVA. Objective 20x. Scale bar: 10 pm. As shown is Figs. 7d and 7e, effective mGL392-mediated senolysis leads to enhanced tumor cell apoptosis, (d) Representative images of Cl. Caspase-3 staining (cells depicted by red arrows) and (e) quantification of analysis. Results expressed as % mean ±SD of total cells, n=5 (biological replicates), *p < 0.05 compared to vehicle, #p < 0.05 compared to the Palbociclib group by one-way ANOVA. Data are presented as mean values ±SD. Objective 20x. Scale bar: 10 pm. As shown in Figs, 7f and 7g, mGL392 does not affect non-senescent B16 melanoma growth in vitro (n=4, biological replicates) (f) or in vivo (n=6, biological replicates) (g), as assessed by MTT cell-viability and tumor size measurements, respectively. Results are expressed as mean ±SD, *p < 0.05 compared to vehicle by one-way ANOVA. Data expressed are presented as mean values ±SD. Fig 7h shows mGL392 enhances the melanoma-reducing action of Palbociclib. Tumor sizes were measured every three days. Data are presented as mean values ±SEM, n=8 (biological replicates), *p < 0.05 compared to vehicle, #p < 0.05 compared to Dasatinib, $p < 0.05 compared to Palbociclib by one-way ANOVA. Fig 7i shows Representative tumors from (h), Scale bar: 5 mm. Fig 7j shows Proposed model of mGL392 action. Cl. Caspase-3: Cleaved Caspase-3. Palbo: Palbociclib. [00321] In summary, mGL392 administration substantially eliminated senescent cells robustly induced in melanomas by Palbociclib treatment (Fig. 7b-c), accompanied by elevated apoptosis (evaluated by cleaved caspase-3 levels in tumor sections) (Fig. 7d-e). Given that mGL392 does not suppress proliferating B16 melanoma cells (Fig. 7f) nor tumors when senescence is absent (Fig. 7g), and a significant reduction of tumor sizes is seen in mice treated with both Palbociclib and mGL392 (Fig. 7h-i), the observed anti-tumor effects of mGL392 may only be attributed to selective senolysis.
[00322] On the contrary, free Dasatinib administration resulted in reduced cell viability even in the absence of senescence (Fig. 7f). Of note, tumors formed in mGL392 (+ Palbociclib)-treated mice were significantly smaller than those treated with Dasatinib (+ Palbociclib) or combined Dasatinib and Quercetin (+ Palbociclib) (Fig. 7h). Quercetin administration did not improve the efficacy of Dasatinib or mGL392 (Fig. 7b-e, h).
[00323] In conclusion, we present a delivery platform allowing targeted in vitro and in vivo selective senolysis, whose mode of action can be summarized as follows: micelle encapsulation facilitates GL392 cellular internalization and favors its selective release in senescent cells, as it preferably disintegrates upon exposure to the low cytosolic pH of senescent cells. The discharged GL392 accumulates inside senescent cells due to its high affinity for lipofuscin and its ester linker is subsequently hydrolyzed by intracellular esterases to effectively release Dasatinib, overall promoting senolysis (Fig. 7j).
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[00324] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).
[00325] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
[00326] The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise paragraphed. No language in the specification should be construed as indicating any non-paragraphed element as essential to the practice of the invention.
[00327] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.
[00328] This invention includes all modifications and equivalents of the subject matter recited in the paragraphs appended hereto as permitted by applicable law.

Claims

1. A compound, or a salt or solvate thereof, according to formula I:
T-L-X (I) wherein
X is a senotherapeutic moiety;
L is a direct bond or a linking moiety; and
T is a lipid-targeting moiety of formula II or III: wherein
R1 and R2b are each independently selected from the group consisting of hydrogen; an optionally substituted (Ci- )alkyl group; an optionally substituted aryl group; and an optionally substituted aryl(Ci- )alkyl group; or
R1 and R2b, together with the carbon to which they are attached, form an optionally substituted C4 to C12 carbocyclic ring; R2a is selected from the group consisting of an optionally substituted (Ci- w)alkylene group; an optionally substituted arylene group; an optionally substituted aryl(Ci- )alkylene group; or
R1 and R2a together with the carbon to which they are attached form an optionally substituted C4 to C12 carbocyclic ring; each R3 is independently hydrogen or a (Ci- )alkyl group;
R4a is selected from the group consisting of hydrogen, halogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 haloalkyl, optionally substituted C-1- 10 haloalkoxy, -ORA4, -SRA4, -NRA4RB4, -CN, -NO2, -N3, -NRA4C(O)RB4, -C(O)NRA4RB4, -NRA4C(O)ORB4, -OC(O)NRA4RB4, -NRA4C(O)NRA4RB4, -NRA4SO2RB4, -SO2NRA4RB4, - SO2RA4, -NRA4C(S)RB4, -C(S)NRA4RB4, -C(O)RA4, -C(O)ORA4, optionally substituted C3-6 cycloalkyl and an optionally substituted 3-7 membered heterocycloalkyl group; q is an integer of value 0, 1 , 2 or 3;
R4b is selected from the group consisting of a direct bond, -O-, -S-, -NRC4-, - NRC4C(=O)-, -C(=O)NRC4-, an optionally substituted (Ci-w)alkylene group; and an optionally substituted (Ci-w)heteroalkylene group; and
RA4, RB4 and RC4, at each occurrence, are independently selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 heteroalkyl.
2. A compound, or a salt or solvate thereof, according to claim 1 , wherein R1 is selected from the group consisting of hydrogen, an optionally substituted phenyl and an optionally substituted (Ci-e)alkyl group.
3. A compound, or a salt or solvate thereof, according to claim 1 or 2, wherein R1 is hydrogen or methyl.
4. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R2a is selected from an optionally substituted (Ci-4)alkylene group.
5. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R4a is selected from the group consisting of hydrogen, C1-6 alkyl optionally substituted with a hydroxyl group and -OH.
6. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R2b is hydrogen or methyl.
7. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R1 and R2b are methyl.
8. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R4b is selected from the group consisting of direct bond, an optionally substituted (Ci-6)alkylene group; and an optionally substituted (Ci-6)heteroalkylene group.
9. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein each R3 is hydrogen.
10. A compound, or a salt or solvate thereof, according to claim 1, wherein T is selected from T1, T2 and T3:
11. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein L is a direct bond or a linking moiety of formula IV:
-[L1]m- (IV) where each occurrence of L1 is independently selected from the group consisting of -S-, - S(=O)-, -S(=O)2-, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -CR5R6- , -CR5=CR6- , -C=C- , -NR5-, - NR5C(=O)- , -C(=O)NR5-, -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -NR5S(O)NR6-, - OC(R5)(R6)C(R5)(R6)-, -S(=O)2NR5-, -NR5S(=O)2-, phenylene, piperazinyl and 1 ,2,3-triazolyl; m is a number of value 1 to 50; and
R5 and R6, at each occurrence, are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
12. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein L is a linking moiety of formula VII:
-[L2]-[L3]-[L4]-[L10]-[L11]- (VI I) wherein
L2 is selected from the group consisting of absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR5 -, - CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, - NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6; L3 is selected from the group consisting of absent, -(CR5R6)P-, (CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]p-, where q and each p are independently a number of value 1 to 15;
L4 is selected from the group consisting of absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, - CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, - NR5C(=O)NR6-, -NR5C(=O)O-, -(CR5R6)P-, -(CR5R6)q[O(C(R5)(R6))(C(R5)(R6))]P-, phenylene, piperazinyl and 1 ,2,3-triazolyl, where q and each p are independently a number of value 1 , 2, 3, 4, 5, or 6;
L10 is absent, -(CR5R6)P-, phenylene or piperazinyl, where p is a number of value 1 to 15; and
L11 is selected from the group consisting of absent, -O-, -S-, -S(=O)-, -S(=O)2- , -NR5 -, - CH(OH)-, -C(=O)-, -C(=O)NR5-, - NR5C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR5-, - NR5C(=O)NR6- and -NR5C(=O)O-; where each occurrence of R5 and R6 is independently selected from the group consisting of hydrogen, CM alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, phenyl, and hydroxy.
13. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein the Linking moiety L is selected from a direct bond, or:
14. A compound, or a salt or solvate thereof, according to claim 1, wherein the lipid- targeting moiety and linking moiety, T-L-, is selected from the following:
15. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein X is a senolytic moiety or a senomorphic moiety.
16. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein X is a moiety selected from the group consisting of an Eph receptor inhibitor moiety, a ABL inhibitor moiety, a flavonoid moiety, a Bcl-XL inhibitor moiety, a Bcl-w inhibitor moiety, an alkaloid moiety, a HSP90 inhibitor moiety, a HDAC inhibitor moiety, a mTOR inhibitor moiety, a JAK inhibitor moiety and a glucocorticoid moiety.
17. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein X is a moiety selected from the group consisting of a dasatinib moiety, a quercetin moiety, a navitoclax moiety, a A1331852 moiety, a A1155463 moiety, a ABT-737 moiety, a fisetin moiety, a piperlongumine moiety, a geldanamycin moiety, a tanespimycin moiety, a panobinostat moiety, an apigenin moiety, a kaempferol moiety, a rapamycin moiety, a ruxolitinib moiety, a metformin moiety, a corticosterone moiety, a cortisol moiety, a loperamide moiety, a niguldipine moiety and a resveratrol moiety.
18. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein X is a moiety selected from the group consisting of a dasatinib moiety, a A1331852 moiety, a A1155463 moiety, a quercetin moiety and a fisetin moiety.
19. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein X is a moiety selected from a dasatinib moiety or a quercetin moiety.
20. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein X is:
21. A compound, or a salt or solvate thereof, according to any one of claims 1 to 10, wherein the moiety -L-X is selected from:
22. A compound, or salt or solvate thereof, selected from:
23. A compound, or salt or solvate thereof, according to claim 22 which is:
24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
25. A pharmaceutical composition according to claim 24, wherein the pharmaceutically acceptable carrier is a polymeric micelle.
26. A pharmaceutical composition according to claim 25, wherein the polymeric micelle comprises an amphiphilic polymer.
27. A compound of formula I, or a salt or solvate thereof according to any one of claims 1 to 23, or a pharmaceutical composition according to any one of claims 24 to 26, for use in therapy.
28. A compound of formula I, or a salt or solvate thereof according to any one of claims 1 to 23, or a pharmaceutical composition according to any one of claims 24 to 26, for use in treatment of a disease or condition mediated by senescence.
29. A compound of formula I, or a salt or solvate thereof according to any one of claims 1 to 23, or a pharmaceutical composition according to any one of claims 24 to 26, for use in treating a disease or a condition selected from a cancer, a fibrotic disorder, a neurodegenerative condition, a cardiovascular disease, a metabolic disease, a kidney disease, a liver disease and a degenerative disease.
30. A method of inducing death of senescent cells in a subject or sample, comprising administering to said subject or sample an effective amount of a compound of formula I, or a salt or solvate thereof according to any one of claims 1 to 23, or a pharmaceutical composition according to any one of claims 24 to 26.
31. A method of inhibiting senescence in a cell, comprising administering to said cell an effective amount of a compound of formula I, or a salt or solvate thereof according to any one of claims 1 to 23, or a pharmaceutical composition according to any one of claims 24 to 26.
32. A combination comprising a compound of formula I, or a salt or solvate thereof according to any one of claims 1 to 23 with another therapeutic agent.
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