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WO2025054665A1 - Polythérapie - Google Patents

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Publication number
WO2025054665A1
WO2025054665A1 PCT/AU2024/050979 AU2024050979W WO2025054665A1 WO 2025054665 A1 WO2025054665 A1 WO 2025054665A1 AU 2024050979 W AU2024050979 W AU 2024050979W WO 2025054665 A1 WO2025054665 A1 WO 2025054665A1
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Prior art keywords
formula
alkyl
compound
halogen
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/AU2024/050979
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English (en)
Inventor
Lenka Munoz
Michael Kassiou
George JOUN
Brianna CHEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Sydney
QIMR Berghofer Medical Research Institute
Original Assignee
Queensland Institute of Medical Research QIMR
University of Sydney
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Priority claimed from AU2023902987A external-priority patent/AU2023902987A0/en
Application filed by Queensland Institute of Medical Research QIMR, University of Sydney filed Critical Queensland Institute of Medical Research QIMR
Publication of WO2025054665A1 publication Critical patent/WO2025054665A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to therapy for proliferative diseases involving combinations of tubulin polymerisation inhibitors and cholesterol homeostasis disrupting agents.
  • Intra-tumour heterogeneity characterized by distinct cell subpopulations within the same tumour, significantly contributes to therapy failure and tumour recurrence.
  • R 1 may be an aryl group.
  • the aryl group may be monocyclic or bicyclic.
  • the aryl group may be phenyl or naphthyl.
  • the aryl group may be substituted.
  • the substituent may be selected from a halo group and a heteroalkyl group.
  • the halo group may be F
  • the heteroalkyl group may be O-alkyl (eg OCH3 or OCH2CH3) or aminoalkyl (eg - CH2NH2 or -CH2CH2NH2).
  • R 1 may be a heterocycloalkyl group.
  • the heterocycloalkyl group may include one or more nitrogen atoms.
  • the heterocycloalkyl group may be piperazine.
  • the heterocycloalkyl group may include one or more oxygen atoms.
  • the heterocycloalkyl group may be morpholine.
  • the heterocycloalkyl group may be substituted by, for example, a halo group (eg F) or a heteroalkyl group (eg O-alkyl, such as -OCH3 or OCH2CH3, or aminoalkyl, such as e.g. -CH2NH2 or -CH2CH2NH2).
  • Ar may be an aryl group.
  • the aryl group may be phenyl.
  • Ar may be a heteroaryl group.
  • the heteroaryl group may include one or more nitrogen atoms.
  • the heteroaryl group may have 4 or 5 ring carbon atoms.
  • the heteroaryl group may be pyridine or pyrimidine.
  • Z may be an aryl group.
  • the aryl group may be monocyclic or bicyclic.
  • the aryl group may be phenyl.
  • the aryl group may be substituted.
  • the substituent may be an alkyl group, and alkene group or a heteroalkyl group.
  • the heteroalkyl group may include one or more oxygen atoms, one or more amino groups, and/or one or more N- alkyl groups.
  • the heteroalkyl group may form a ring with the aryl group.
  • Z may be a heteroaryl group.
  • the heteroaryl group may be monocyclic or bicyclic.
  • the heteroaryl group may include one or more nitrogen atoms.
  • the heteroaryl group may be pyrazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, quinoline, benzimidazole or indole.
  • the heteroaryl group may include one or more oxygen atoms (in addition to, or as an alternative to, one or more nitrogen atoms).
  • the heteroaryl may be furan.
  • the heteroatom may be at one or more positions on the ring or rings.
  • Z is a pyridine group
  • the nitrogen may be at the meta position.
  • the nitrogen may be at the ortho position and/or at one or more of the meta and/or para positions.
  • the heteroaryl group may be substituted.
  • the substituent may be a hydroxyl, a halo group (eg F) or a heteroalkyl group (eg O-alkyl, such as -OCH3, or aminoalkyl, such as -CH2NH2).
  • Z may be a heterocycloalkyl group.
  • the heterocycloalkyl group may include one or more nitrogen atoms.
  • the heterocycloalkyl group may be piperazine.
  • the heterocycloalkyl group may include one or more oxygen atoms (in addition to, or as an alternative to, one or more nitrogen atoms).
  • the heterocycloalkyl group may be morpholine.
  • the heterocycloalkyl group may be partially unsaturated.
  • the heterocycloalkyl group may be substituted by, for example, a hydroxyl, a halo group (eg F) or a heteroalkyl group (eg O-alkyl, such as -OCH3, or aminoalkyl, such as -CH2NH2.
  • R 2 may be H, alkyl or alkenyl.
  • R 2 may be H.
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-
  • the tubulin polymerisation inhibitor is a compound of Formula (III): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • Ring A is heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n is 1 -4; m is 1 -4; p is 1 -4; and q is 1 -5.
  • Ring A is heteroaryl
  • Ring A is a 6-membered heteroaryl.
  • Ring A is pyridyl
  • Ring A is pyrimidinyl
  • Ring A is pyrazinyl
  • Ring A is a 5-membered heteroaryl.
  • Ring A is tetrazolyl.
  • Ring A is thiazolyl
  • Ring A is furanyl
  • Ring A is thiophenyl.
  • Ring A is oxazolyl.
  • Ring A is oxadiazolyl.
  • Ring A is thiadiazolyl.
  • Ring A is pyrazolyl
  • Ring A is imidazolyl
  • Ring A is triazolyl
  • Ring A is pyrrolidinyl
  • Ring A is piperazinyl
  • Ring A is cyclopentyl
  • Ring B is heteroaryl
  • Ring B is thiophenyl.
  • Ring B is furanyl
  • Ring B is pyrrolyl
  • Ring B is thiazolyl
  • Ring B is oxazolyl
  • Ring B is isoxazolyl.
  • Ring B is imidazolyl.
  • Ring B is pyrazolyl
  • Ring B is thiadiazolyl.
  • Ring B is oxadiazolyl.
  • each R 3 is independently hydrogen.
  • each R 3 is independently halogen.
  • each R 3 is independently Ci-Ce alkyl.
  • each R 3 is independently Ci-Ce haloalkyl.
  • each R 3 is independently fluoro.
  • n 1 .
  • n is 2.
  • n 3.
  • n is 4.
  • each R 4 is independently halogen.
  • each R 4 is independently Ci-Ce alkyl.
  • each R 4 is independently Ci-Ce haloalkyl.
  • each R 4 is hydrogen.
  • m is 1 .
  • m is 2.
  • m is 3.
  • m is 4.
  • each R 5 is independently halogen.
  • each R 5 is independently Ci-Ce alkyl.
  • each R 5 is independently Ci-Ce haloalkyl.
  • each R 5 is hydrogen.
  • p is 1 .
  • p is 2.
  • p is 3.
  • p is 4.
  • R 6 is hydrogen or Ci-Ce alkyl.
  • R 6 is Ci-Ce alkyl
  • R 6 is hydrogen
  • each R 7 is independently hydrogen.
  • each R 7 is independently halogen.
  • each R 7 is independently -OH.
  • q is 1 .
  • q is 4.
  • q is 5.
  • tubulin polymerisation inhibitor is a compound of Formula (Ila): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • Ring A is heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
  • L 3 is a bond or -CR 9 R 10 -;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n is 1 -4; m is 1 -4; p is 1 -4; and q is 1 -5.
  • Ring A is pyrazinyl
  • Ring A is tetrazolyl.
  • Ring A is thiazolyl
  • Ring A is furanyl
  • Ring A is thiophenyl.
  • Ring A is oxazolyl
  • Ring A is oxadiazolyl.
  • Ring A is thiadiazolyl.
  • Ring A is pyrazolyl
  • Ring A is imidazolyl.
  • Ring A is triazolyl.
  • Ring A is C2-C8 heterocycloalkyl.
  • Ring A is pyrrolidinyl.
  • Ring A is piperidinyl.
  • Ring A is piperazinyl
  • Ring A is pyranyl
  • Ring A1 is tetrahydrofuranyl.
  • Ring A is morpholinyl
  • Ring A is cyclopropyl.
  • Ring A is cyclobutyl
  • Ring A is cyclohexyl.
  • Ring A is cyclopentyl.
  • Ring B is aryl.
  • Ring B is phenyl
  • Ring B is naphthyl
  • Ring B is heteroaryl
  • Ring B is fused heteroaryl.
  • Ring B is 6-membered heteroaryl.
  • Ring B is pyridyl
  • Ring B is pyrimidinyl.
  • Ring B is pyrazinyl.
  • Ring B is a 5- membered heteroaryl.
  • Ring B is thiophenyl.
  • Ring B is furanyl
  • Ring B is pyrrolyl
  • Ring B is thiazolyl.
  • Ring B is oxazolyl
  • Ring B is isoxazolyl.
  • Ring B is imidazolyl.
  • Ring B is pyrazolyl
  • Ring B is thiadiazolyl.
  • Ring B is oxadiazolyl.
  • each R 3 is independently hydrogen.
  • each R 3 is independently halogen.
  • each R 3 is independently Ci-Ce alkyl.
  • each R 3 is independently Ci-Ce haloalkyl.
  • each R 3 is independently fluoro.
  • n is 1 .
  • n is 2.
  • n 3.
  • n 4.
  • each R 4 is independently halogen.
  • each R 4 is independently Ci-Ce alkyl.
  • each R 4 is independently Ci-Ce haloalkyl.
  • each R 4 is hydrogen.
  • m is 1 .
  • m is 2.
  • m is 3.
  • m is 4.
  • each R 5 is independently halogen.
  • each R 5 is independently Ci-Ce alkyl.
  • each R 5 is independently Ci-Ce haloalkyl.
  • each R 5 is hydrogen.
  • p is 1 .
  • p is 2.
  • p is 3.
  • p is 4.
  • R 6 is hydrogen or Ci-
  • R 6 is Ci-Ce alkyl.
  • R 6 is hydrogen
  • each R 7 is independently halogen.
  • each R 7 is independently -OH.
  • each R 7 is independently Ci-Ce alkyl.
  • each R 7 is independently Ci-Ce haloalkyl.
  • each R 7 is methyl.
  • q is 1 .
  • q is 2.
  • q is 3.
  • q is 4.
  • q is 5.
  • tubulin polymerisation inhibitor is a compound of Formula (III): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 1 is -CR 16 R 17 and L 2 is a bond, or
  • L 1 is a bond and L 2 is -CR 18 R 19 , provide that L 1 and L 2 are not on the same carbon;
  • Ring A1 is aryl, heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • the tubulin polymerisation inhibitor is a compound of Formula (III): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 1 is -CR 16 R 17 and L 2 is a bond, or
  • L 1 is a bond and L 2 is -CR 18 R 19 , provide that L 1 and L 2 are not on the same carbon;
  • Ring A1 is aryl, heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n1 is 1 -4; ml is 1 -4; p1 is 1 -4; and q1 is 1 -5.
  • L 1 is a bond and L 2 is a bond. In some embodiments of a compound of Formula (III), one of L 1 or L 2 is not a bond.
  • L 1 is a bond and L 2 is - CR 18 R 19 .
  • R 18 and R 19 are hydrogen.
  • L1 is -CR 16 R 17 - and L 2 is a bond.
  • R 16 and R 17 are hydrogen.
  • Ring A1 is heteroaryl
  • Ring A1 is a 6- membered heteroaryl.
  • Ring A1 is pyrimidinyl.
  • Ring A1 is pyrazinyl
  • Ring A1 is pyridyl
  • Ring A1 is a 5- membered heteroaryl.
  • Ring A1 is thiophenyl.
  • Ring A1 is furanyl
  • Ring A1 is pyrrolyl
  • Ring A1 is thiazolyl
  • Ring A1 is oxazolyl.
  • Ring A1 is isoxazolyl.
  • Ring A1 is imidazolyl.
  • Ring A1 is pyrazolyl
  • Ring A1 is thiadiazolyl.
  • Ring A1 is oxadiazolyl.
  • Ring A1 is C2-C8 heterocycloalkyl.
  • Ring A1 is pyrrolidinyl
  • Ring A1 is piperidinyl
  • Ring A1 is piperazinyl
  • Ring A1 is pyranyl
  • Ring A1 is tetrahydrofuranyl.
  • Ring A1 is morpholinyl
  • Ring A1 is C3-C8 cycloalkyl.
  • Ring A1 is cyclopropyl.
  • Ring A1 is cyclobutyl
  • Ring A1 is cyclohexyl.
  • Ring A1 is cyclopentyl
  • Ring B1 is aryl.
  • Ring B1 is phenyl
  • Ring B1 is biphenyl.
  • Ring B1 is heteroaryl.
  • Ring B1 is fused bicyclic heteroaryl.
  • Ring B1 is a 6- membered heteroaryl.
  • Ring B1 is pyrimidinyl.
  • Ring B1 is pyrazinyl.
  • Ring B1 is pyridyl
  • Ring B1 is a 5- membered heteroaryl.
  • Ring B1 is thiophenyl.
  • Ring B1 is furanyl
  • Ring B1 is pyrrolyl
  • Ring B1 is thiazolyl.
  • Ring B1 is oxazolyl
  • Ring B1 is isoxazolyl.
  • Ring B1 is imidazolyl.
  • Ring B1 is thiadiazolyl.
  • Ring B1 is oxadiazolyl.
  • Ring B1 is pyrazolyl
  • each R 11 is independently halogen.
  • each R 11 is independently Ci-Ce alkyl.
  • each R 11 is independently Ci-Ce haloalkyl.
  • each R 11 is hydrogen.
  • n1 is 1 .
  • n1 is 2.
  • n1 is 3.
  • n1 is 4.
  • each R 12 is independently halogen.
  • each R 12 is independently Ci-Ce alkyl.
  • each R 12 is independently Ci-Ce haloalkyl.
  • each R 12 is hydrogen.
  • ml is 1 .
  • ml is 2.
  • ml is 3.
  • ml is 4.
  • each R 13 is independently halogen.
  • each R 13 is independently Ci-Ce alkyl.
  • each R 13 is independently Ci-Ce haloalkyl.
  • each R 13 is hydrogen.
  • p1 is 1 .
  • p1 is 2.
  • p1 is 3.
  • p1 is 4.
  • R 14 is hydrogen or Ci- Ce alkyl.
  • R 14 is Ci-Ce alkyl.
  • R 14 is hydrogen
  • each R 15 is independently hydrogen.
  • each R 15 is independently halogen.
  • each R 15 is independently -OH.
  • each R 15 is independently Ci-Ce alkyl.
  • each R 15 is independently Ci-Ce haloalkyl.
  • each R 15 is methyl
  • q1 is 1 .
  • q1 is 2.
  • q1 is 3.
  • q1 is 4.
  • q1 is 5.
  • tubulin polymerisation inhibitor is a compound of Formula (IV): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • Ring A2 is heteroaryl
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-
  • Ring A2 is heteroaryl
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • Ring A2 is a 6- membered heteroaryl.
  • Ring A2 is pyrimidinyl.
  • Ring A2 is pyrazinyl.
  • Ring A2 is pyridyl
  • Ring A2 is a 5- membered heteroaryl.
  • Ring A2 is thiophenyl.
  • Ring A2 is furanyl
  • Ring A2 is pyrrolyl
  • Ring A2 is thiazolyl. In some embodiments of a compound of Formula (IV), Ring A2 is oxazolyl.
  • Ring A2 is isoxazolyl.
  • Ring A2 is imidazolyl.
  • Ring A2 is pyrazolyl. In some embodiments of a compound of Formula (IV), Ring A2 is thiadiazolyl. [0349] In some embodiments of a compound of Formula (IV), Ring A2 is oxadiazolyl.
  • Ring B2 is aryl
  • Ring B2 is phenyl
  • Ring B2 is biphenyl
  • Ring B2 is heteroaryl.
  • Ring B2 is a 6- membered heteroaryl.
  • Ring B2 is pyrimidinyl.
  • Ring B2 is pyrazinyl.
  • Ring B2 is pyridyl
  • Ring B2 is a 5- membered heteroaryl.
  • Ring B2 is thiophenyl.
  • Ring B2 is furanyl
  • Ring B2 is pyrrolyl
  • Ring B2 is thiazolyl.
  • Ring B2 is oxazolyl
  • Ring B2 is isoxazolyl.
  • Ring B2 is imidazolyl.
  • Ring B2 is thiadiazolyl.
  • Ring B2 oxadiazolyl.
  • Ring B2 is pyrazolyl.
  • each R 21 is independently halogen.
  • each R 21 is independently Ci-Ce alkyl.
  • each R 21 is independently Ci-Ce haloalkyl.
  • each R 21 is hydrogen.
  • n2 is 1 .
  • n2 is 2.
  • n2 is 3.
  • n2 is 4.
  • each R 22 is independently halogen.
  • each R 22 is independently Ci-Ce alkyl.
  • each R2 2 is independently Ci-Ce haloalkyl.
  • each R 22 is hydrogen.
  • m2 is 1 .
  • m2 is 2.
  • m2 is 3.
  • m2 is 4.
  • each R 23 is independently Ci-Ce haloalkyl.
  • each R 23 is hydrogen.
  • p2 is 1 .
  • p2 is 2.
  • p2 is 3.
  • p2 is 4.
  • each R 25 is independently hydrogen.
  • each R 25 is independently halogen.
  • each R 25 is independently -OH.
  • each R 25 is independently Ci-Ce alkyl.
  • each R 25 is independently Ci-Ce haloalkyl.
  • each R 25 is methyl
  • q2 is 1 .
  • q2 is 2.
  • q2 is 3.
  • q2 is 4.
  • q2 is 5.
  • tubulin polymerisation inhibitor is a compound of Formula (V): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R a is hydrogen, Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n3 is 1 -4; m3 is 1 -4; and q3 is 1 -5
  • Ring B3 is aryl
  • Ring B3 is phenyl
  • Ring B3 is naphthyl
  • Ring B3 is heteroaryl.
  • Ring B3 is a 6- membered heteroaryl.
  • Ring B3 is pyrimidinyl.
  • Ring B3 is pyrazinyl.
  • Ring B3 is pyridyl
  • Ring B3 is a 5- membered heteroaryl.
  • Ring B3 is thiophenyl.
  • Ring B3 is furanyl.
  • Ring B3 is pyrrolyl.
  • Ring B3 is thiazolyl.
  • Ring B3 is oxazolyl
  • Ring B3 is isoxazolyl.
  • Ring B3 is imidazolyl.
  • Ring B3 is thiadiazolyl.
  • Ring B3 is oxadiazolyl.
  • Ring B3 is pyrazolyl
  • each R 31 is independently hydrogen.
  • each R 31 is independently Ci-Ce alkyl.
  • each R 3 is independently Ci-Ce haloalkyl.
  • n3 is 1 .
  • n3 is 2.
  • n3 is 3.
  • n3 is 4.
  • each R 32 is independently halogen.
  • each R 32 is independently Ci-Ce alkyl.
  • each R 32 is independently Ci-Ce haloalkyl.
  • each R 32 is hydrogen.
  • m3 is 1 .
  • m3 is 2.
  • m3 is 3.
  • m3 is 4.
  • each R 34 is hydrogen or Ci-C 6 alkyl.
  • each R 34 is Ci-Ce alkyl.
  • each R 34 is hydrogen.
  • each R 35 is independently hydrogen.
  • each R 35 is independently halogen.
  • each R 35 is independently -OH.
  • each R 35 is independently Ci-Ce alkyl.
  • each R 35 is independently Ci-Ce haloalkyl.
  • each R 35 is methyl.
  • q3 is 1 .
  • q3 is 2. [0450] In some embodiments of a compound of Formula (V), q3 is 3.
  • q3 is 4.
  • q3 is 5.
  • each R 36 and R 37 is hydrogen, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.
  • each R 36 and R 37 are hydrogen.
  • tubulin polymerisation inhibitor is a compound of Formula (VI): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 43 is -C(R 43 ) 2 C(R 43 )2 C(R 43 ) 2 -;
  • L 43 is a bond or -CR 46 R 47 -;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
  • tubulin polymerisation inhibitor is a compound of Formula (VI): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 43 is -C(R 43 ) 2 C(R 43 )2 C(R 43 ) 2 -;
  • L 43 is a bond or -CR 46 R 47 -;
  • R a is hydrogen, Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; each R c and R d are independently hydrogen, Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH 2 ; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
  • L 44 is a bond.
  • L 44 is -CR 46 R 47 -.
  • R 46 and R 47 are independently hydrogen.
  • R 46 and R 47 are independently halogen.
  • R4 6 and R 47 are independently fluoro.
  • R 46 and R 47 are independently aryl.
  • R 46 and R 47 are independently heteroaryl.
  • R 46 and R 47 are independently C3-C8 cycloalkyl, C2-C8 heterocycloalkyl; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OR a or -NR c R d .
  • Ring B4 is heterocycloalkyl.
  • Ring B4 is C2-C8 heterocycloalkyl.
  • Ring B4 is pyrrolidinyl.
  • Ring B4 is piperidinyl.
  • Ring B4 is piperazinyl.
  • Ring B4 is pyranyl.
  • Ring B4 is tetrahydrofuranyl.
  • Ring B4 is morpholinyl.
  • Ring B4 is heteroaryl.
  • Ring B4 is 6-membered heteroaryl.
  • Ring B4 is pyrimidinyl.
  • Ring B4 is pyrazinyl.
  • Ring B4 is pyridyl.
  • Ring B4 is a 5- membered heteroaryl.
  • Ring B4 is thiophenyl.
  • Ring B4 is furanyl
  • Ring B4 is pyrrolyl
  • Ring B4 is thiazolyl.
  • Ring B4 is oxazolyl.
  • Ring B4 is isoxazolyl.
  • Ring B4 is imidazolyl.
  • Ring B4 is pyrazolyl
  • Ring B4 is thiadiazolyl.
  • Ring B4 is oxadiazolyl.
  • Ring B4 is C7-C9 heteroaryl.
  • Ring B4 is indolyl.
  • Ring B4 is indazolyl.
  • Ring B4 is benzofuranyl.
  • Ring B4 is a fused bicyclic ring.
  • the tubulin polymerisation inhibitor is a compound of Formula (Via): pharmaceutically acceptable salt or prodrug thereof, wherein;
  • L 43 is -C(R 43 ) 2 C(R 43 )2 C(R 43 ) 2 -;
  • R a is hydrogen, Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; each R c and R d are independently hydrogen, Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH 2 ; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
  • the compound has the Formula (Via): pharmaceutically acceptable salt or prodrug thereof, wherein;
  • L 43 is -C(R 43 ) 2 C(R 43 )2 C(R 43 ) 2 -;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
  • each R 41 is independently halogen.
  • each R 41 is independently fluoro.
  • each R 41 is independently Ci-Ce alkyl.
  • each R 41 is independently Ci-Ce haloalkyl.
  • n4 is 1 .
  • n4 is 2.
  • n4 is 3.
  • n4 is 4.
  • n4 is 4.
  • n4 is 5.
  • R 42 is independently halogen.
  • each R 42 is independently Ci-Ce alkyl.
  • each R 42 is independently Ci-Ce haloalkyl.
  • each R 42 is hydrogen.
  • m4 is
  • m4 is
  • m4 is
  • m4 is 4.
  • each R 43 is independently halogen.
  • each R 43 is independently Ci-Ce alkyl.
  • each R 43 is independently Ci-Ce haloalkyl.
  • each R 43 is hydrogen.
  • each R 44 is Ci-C 6 alkyl.
  • each R 44 is hydrogen.
  • each R 44 is methyl.
  • q4 is 1 .
  • q4 is 2.
  • q4 is 3.
  • q4 is 4.
  • q4 is 5.
  • Ring B4 is fused bicyclic heteroaryl comprising at least two nitrogen atoms in the rings.
  • Ring B4 is cinnolinyl.
  • Ring B4 is quinazolinyl.
  • Ring B4 is quinoxalinyl.
  • Ring B4 is indazolyl.
  • Ring B4 is benzoimidazolyl.
  • each R 45 is independently C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OR a or -NR c R d .
  • R 45 is hydrogen or C1-C5 alkyl.
  • each R 48 is independently hydrogen.
  • each R 48 is independently halogen.
  • each R 48 is independently taken together to form an oxo.
  • each R 48 is independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OR a , or -NR c R d .
  • each R 48 is independently Ci-Ce heterocyclyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -OR a , or -NR c R d .
  • tubulin polymerisation inhibitor is a compound of Formula (VII): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 53 is -C(R 53 ) 2 C(R 53 )2 C(R 53 ) 2 -;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cyclo
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n5 is 1 -5; m5 is 1 -4; and
  • the tubulin polymerisation inhibitor is a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ; wherein:
  • L 53 is -C(R 53 ) 2 C(R 53 )2 C(R 53 )2-;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n5 is 1 -5; m5 is 1 -4; and q5 is 1 -5.
  • Ring B5 is aryl.
  • Ring B5 is phenyl
  • Ring B5 is naphthyl
  • Ring B5 is heterocycloalkyl.
  • Ring B5 is C2-C8 heterocycloalkyl.
  • Ring B5 is pyrrolidinyl.
  • Ring B5 is piperidinyl.
  • Ring B5 is piperazinyl
  • Ring B5 is pyranyl
  • Ring B5 is tetrahydrofuranyl.
  • Ring B5 is morpholinyl.
  • Ring B5 is a 6- membered heteroaryl.
  • Ring B5 is pyrimidinyl.
  • Ring B5 is pyrazinyl.
  • Ring B5 is pyridyl
  • Ring B5 is a 5- membered heteroaryl.
  • Ring B5 is thiophenyl.
  • Ring B5 is furanyl.
  • Ring B5 is pyrrolyl.
  • Ring B5 is thiazolyl.
  • Ring B5 is oxazolyl.
  • Ring B5 is isoxazolyl.
  • Ring B5 is imidazolyl.
  • Ring B5 is thiadiazolyl.
  • Ring B5 is oxadiazolyl.
  • Ring B5 is pyrazolyl
  • each R 51 is independently halogen.
  • each R 51 is independently Ci-Ce alkyl.
  • each R 51 is independently Ci-Ce haloalkyl.
  • each R 51 is independently fluoro.
  • n5 is 1 .
  • n5 is 2.
  • n5 is 3.
  • n5 is 4.
  • n5 is 5.
  • each R 52 is independently halogen.
  • each R 52 is independently Ci-Ce alkyl.
  • each R 52 is independently Ci-Ce haloalkyl.
  • each R 52 is independently hydrogen.
  • m5 is 1 .
  • m5 is 2.
  • m5 is 3.
  • m5 is 4.
  • each R 53 is independently halogen.
  • each R 53 is independently Ci-Ce alkyl.
  • each R 53 is independently Ci-Ce haloalkyl.
  • each R 53 is independently hydrogen.
  • each R 54 is hydrogen or Ci-C 6 alkyl.
  • each R 54 is Ci-Ce alkyl.
  • each R 54 is hydrogen.
  • each R 55 is independently hydrogen.
  • each R 55 is independently halogen.
  • each R 55 is independently -OH.
  • each R 55 is independently Ci-Ce alkyl.
  • each R 55 is independently Ci-Ce haloalkyl.
  • each R 55 is methyl.
  • q5 is 1 .
  • q5 is 2.
  • q5 is 3.
  • q5 is 4.
  • q5 is 5.
  • tubulin polymerisation inhibitor is a compound of Formula (VIII): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 63 is -C(R 63 ) 2 C(R 63 )2-;
  • L 66 is O, NR 66 , S, SO, or SO2;
  • Ring B6 is aryl, heteroaryl, or C2-C8 heterocyclyl; each R 61 is independently hydrogen, fluoro, chloro, bromo, iodo, -CN, -OR a , -SR a , -
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n6 is 1 -5; m6 is 1 -4; and q6 is 1 -5.
  • the tubulin polymerisation inhibitor is a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein:
  • L 63 is -C(R 63 ) 2 C(R 63 )2-;
  • L 66 is O, NR 66 , S, SO, or SO2;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n6 is 1 -5; m6 is 1 -4; and q6 is 1 -5
  • L 66 is O, NR 66 , or S.
  • L 66 is O or NR 66 .
  • L 66 is O.
  • Formula (Villa) (Villa), or a pharmaceutically acceptable salt or prodrug thereof, wherein: L 63 is -C(R 63 ) 2 C(R 63 )2-;
  • L 66 is O, NR 66 , S, SO, or SO2;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • the compound has the Formula (Villa): (Villa), or a pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 63 is -C(R 63 ) 2 C(R 63 )2-;
  • L 66 is O, NR 66 , S, SO, or SO2;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n6 is 1 -5; m6 is 1 -4; and q6 is 1 -5
  • L 67 is NR 66 , or S.
  • L 66 is NR 66 .
  • Ring B6 is aryl. [0628] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is phenyl.
  • Ring B6 is napthyl.
  • Ring B6 is heterocycloalkyl.
  • Ring B6 is C2-C8 heterocycloalkyl.
  • Ring B6 is pyrrolidinyl.
  • Ring B6 is piperidinyl.
  • Ring B6 is piperazinyl.
  • Ring B6 is pyranyl.
  • Ring B6 is tetrahydrofuranyl.
  • Ring B6 is morpholinyl.
  • Ring B6 is heteroaryl.
  • Ring B6 is a 6-membered heteroaryl.
  • Ring B6 is pyrimidinyl.
  • Ring B6 is pyrazinyl.
  • Ring B6 is pyridyl.
  • Ring B6 is a 5-membered heteroaryl.
  • Ring B6 is thiophenyl.
  • Ring B6 is furanyl.
  • Ring B6 is pyrrolyl
  • Ring B6 is thiazolyl.
  • Ring B6 is oxazolyl.
  • Ring B6 is isoxazolyl.
  • Ring B6 is imidazolyl.
  • Ring B6 is thiadiazolyl.
  • Ring B6 is oxadiazolyl.
  • Ring B6 is pyrazolyl.
  • each R 61 is independently halogen.
  • each R 61 is independently Ci-Ce alkyl.
  • each R 61 is independently Ci-Ce haloalkyl.
  • each R 61 is independently fluoro.
  • n6 is 1 .
  • n6 is 2.
  • n6 is 3.
  • n6 is 4.
  • each R 63 is independently halogen.
  • each R 63 is independently Ci-Ce alkyl.
  • each R 63 is independently Ci-Ce haloalkyl.
  • each R 63 is hydrogen.
  • each R 64 is hydrogen or Ci-Ce alkyl.
  • R 64 is independently Ci-Ce alkyl.
  • R 64 is hydrogen
  • each R 65 is independently hydrogen.
  • each R 65 is independently halogen.
  • each R 65 is independently -OH.
  • each R 65 is independently Ci-Ce alkyl.
  • each R 65 is independently hydrogen or Ci-Ce haloalkyl.
  • each R 65 is independently methyl.
  • q6 is 1 .
  • q6 is 2.
  • q6 is 3.
  • q6 is 4.
  • tubulin polymerisation inhibitor is a compound of Formula (IV): pharmaceutically acceptable salt or prodrug thereof, wherein:
  • L 83 is -C(R 83 )2C(R 83 ) 2 C(R 83 )2-, -C(R 83 ) 2 C(R 83 )2-, -OC(R 83 ) 2 C(R 83 )-, or -SC(R 83 ) 2 C(R 83 )- ;
  • L 84 is a bond or -CR 86 R 87 -;
  • R a is hydrogen, Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n8 is 1 -5; m8 is 1 -4; and q8 is 1 -5.
  • L 83 is -C(R 83 )2C(R 83 ) 2 C(R 83 )2-, -C(R 83 ) 2 C(R 83 )2-, -OC(R 83 ) 2 C(R 83 )-, or -SC(R 83 ) 2 C(R 83 )- ;
  • L 84 is a bond or -CR 86 R 87 -;
  • R a is hydrogen, Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
  • L 83 is a bond.
  • L 83 is -CR 83 R 83 -.
  • L 83 is -
  • L 83 is -OC(R 83 )2C(R 83 )-.
  • L 83 is -SC(R 83 )2C(R 83 )-.
  • R 83 is independently hydrogen.
  • R 83 is independently halogen.
  • R 83 is independently fluoro.
  • R 83 is independently aryl.
  • R 83 is independently heteroaryl.
  • R 83 is independently Ca-Cs cycloalkyl, C 2 -Cs heterocycloalkyl; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OR a or -NR c R d .
  • L 83 is a bond.
  • L 83 is -CR 83 R 83 -.
  • L 83 is -
  • D8 is aryl and B8 is heterocyclyl.
  • D8 is aryl and B8 is heteroaryl.
  • D8 is heteroaryl and B8 is heterocyclyl.
  • D8 is heteroaryl and B8 is aryl.
  • D8 is aryl and B8 is aryl.
  • D8 is heteroaryl and B8 is heteroaryl.
  • R 81 is halogen.
  • R 84 is hydrogen or Ci-
  • L 84 is a bond.
  • L 84 is -CR 86 R 87 -.
  • R 86 and R 87 are hydrogen or Ci-Ce alkyl.
  • L 84 is a bond.
  • R 86 and R 87 are independently hydrogen.
  • R 86 and R 87 are independently halogen.
  • R 86 and R 87 are independently fluoro.
  • R 86 and R 87 are independently aryl.
  • R 86 and R 87 are independently heteroaryl.
  • Rings D8 and B8 are independently heterocycloalkyl.
  • Rings D8 and B8 are independently C2-C8 heterocycloalkyl.
  • Rings D8 and B8 are independently pyrrolidinyl.
  • Rings D8 and B8 are independently piperidinyl.
  • Rings D8 and B8 are independently piperazinyl.
  • Rings D8 and B8 are independently pyranyl.
  • Rings D8 and B8 are ndependently tetrahydrofuranyl.
  • Rings D8 and B8 are independently morpholinyl.
  • Rings D8 and B8 are independently phenyl.
  • Rings D8 and B8 are independently heteroaryl.
  • Rings D8 and B8 are independently a 6-membered heteroaryl.
  • Rings D8 and B8 are independently pyridyl.
  • Rings D8 and B8 are independently a 5-membered heteroaryl.
  • Rings D8 and B8 are independently thiophenyl.
  • Rings D8 and B8 are independently furanyl.
  • Rings D8 and B8 are independently pyrrolyl.
  • Rings D8 and B8 are independently thiazolyl.
  • Rings D8 and B8 are independently oxazolyl.
  • Rings D8 and B8 are independently isoxazolyl.
  • Rings D8 and B8 are independently imidazolyl.
  • Rings D8 and B8 are independently pyrazolyl.
  • Rings D8 and B8 are independently thiadiazolyl.
  • Rings D8 and B8 are independently oxadiazolyl.
  • Rings D8 and B8 are independently C7-C9 heteroaryl.
  • Rings D8 and B8 are independently indolyl.
  • Rings D8 and B8 are independently indazolyl.
  • Rings D8 and B8 are independently benzofuranyl.
  • Rings D8 and B8 are independently a fused bicyclic ring.
  • L 83 is -C(R 83 )2C(R 83 ) 2 C(R 83 )2-,
  • L 84 is a bond or -CR 86 R 87 -;
  • R a is hydrogen, Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; each R c and R d are independently hydrogen, Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Ci
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n8 is 1 -5; m8 is 1 -4; and q8 is 1 -5.
  • L 83 is -C(R 83 )2C(R 83 ) 2 C(R 83 )2-,
  • L 84 is a bond or -CR 86 R 87 -;
  • R a is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n8 is 1 -5; m8 is 1 -4; q8 is 1 -5; and provided that when D8 is heteroaryl and L 84 is a bond, then B8 is heteroaryl or C2-C8 heterocyclyl; or when D8 is phenyl, n is 1 , R 81 is fluoro at the ortho position of the phenyl ring, and L 84 is a bond, then B8 is C2-C8 heterocyclyl.
  • Formula (VI I Ic ) pharmaceutically acceptable salt or prodrug thereof , wherein:
  • L 83 is -C(R 83 )2C(R 83 )2C(R 83 ) 2 -
  • L 84 is a bond or -CR 86 R 87 -;
  • Ring B8 is selected from the group consisting of: bicyclic ring comprising at least one nitrogen atom; a 5-membered ring comprising at least one nitrogen atom; cycloalkyl; a monocyclic heteroaryl or monocyclic C 2 -C 8 heterocyclyl ring, wherein at least one R 85 is selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, amino, hydroxy, Ci- Ce A/-acylamino, acyl, Ci-Ce alkoxy, and aryl,; and monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclyl ring, provided that L 84 is not a bond.
  • R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; each R c and R d are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n8 is 1 -5; m8 is 1 -4; and q8 is 1 -5.
  • the tubulin polymerisation inhibitor is a compound of Formula (X):
  • L 93 is -C(R 93 )2C(R 93 )2C(R 93 ) 2 -, -C(R 93 ) 2 C(R 93 )2-, -OC(R 93 ) 2 C(R 93 )-, or -SC(R 93 ) 2 C(R 93 )- ;
  • L 94 is a bond or -CR 96 R 87 -;
  • R a is hydrogen, Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C 2 -Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; R b is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH 2 ; n9 is 1 -5; m9 is 1 -4; and q9 is 1 -5.
  • L 93 is -C(R 93 )2C(R 93 ) 2 C(R 93 )2-.
  • L 93 is -C(R 93 )2C(R 93 )2-.
  • L 93 is -OC(R 93 )2C(R 93 )-.
  • L 93 is -SC(R 93 )2C(R 93 )-.
  • E is oxadiazole.
  • E is thiadiazole.
  • E is sulfonamide.
  • L 94 is -CR 96 R 97 -.
  • L 94 is a bond.
  • tubulin polymerisation inhibitor examples include tubulin polymerisation inhibitor, and
  • the compounds of the present invention can be synthesised by any suitable method known to a person skilled in the art.
  • suitable methods for the preparing of these compounds have been disclosed in WO/2017/119017
  • the tubulin polymerisation inhibitors preferably exhibit high anti-proliferative activity and in particular, high efficacy against brain cancers - see, for example US11 ,472,774 where specific compounds are shown to induce apoptosis and are also able to cross the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • the invention may rely on any suitable cholesterol homeostasis disrupting agent.
  • a cholesterol homeostasis disrupting agent may be any agent capable of disrupting cholesterol homeostasis.
  • Cholesterol plays a critical role in cell proliferation and survival. Intracellular cholesterol levels are maintained by the dynamic equilibrium between biosynthesis, uptake, esterification, and export. The transcriptional regulation of cholesterol metabolism is governed by sterol regulatory element-binding proteins (SREBPs) and Liver X Receptors (LXRs). SREBPs primarily promote the transcription of genes involved in cholesterol biosynthesis and uptake from the extracellular microenvironment. LXRs respond to excessive intracellular cholesterol or oxidized cholesterols (oxysterols) by inducing the expression of ABCA1 , ABCG1 , and ApoE, which are responsible for cholesterol efflux. While disrupted cholesterol metabolism is a well-established hallmark of cancer, its role in drug tolerance and regulation in persisters remains unclear.
  • SREBPs sterol regulatory element-binding proteins
  • LXRs Liver X Receptors
  • the cholesterol homeostasis disrupting agent may be any agent capable of inducing expression of one or more of ABCA1 , ABCG1 , and ApoE.
  • the cholesterol homeostasis disrupting agent is not a statin or HMG-CoA antagonist.
  • Statins typically do not cross the blood-brain barrier, and therefore may not be useful in the treatment of brain cancers.
  • the cholesterol homeostasis disrupting agent is selected from an LXR agonist, a PRDM7/9 inhibitor, a DHCR inhibitor or a combination thereof.
  • the cholesterol homeostasis disrupting agent is selected from LXR-623, GW3965, T0901317, MRK-740, AY-9944 and SH-42.
  • the cholesterol homeostasis disrupting agent is an LXR agonist.
  • LXR agonists increase cholesterol efflux from cells, which in turn disrupts cholesterol homeostasis to reduce the available intracellular cholesterol.
  • Any suitable LXR agonist may be used in the combinations of the present invention.
  • Preferred LXR agonists include LXR-623, GW3965 and T0901317.
  • the cholesterol homeostasis disrupting agent is a PRDM7/9 inhibitor.
  • PRDM7/9 inhibitors target the histone-3 arginine-4 (H3K4) methyltransferases PRDM7/9.
  • PRDM7/9 inhibitors antagonise cholesterol biosynthesis, which in turn disrupts cholesterol homeostasis to reduce the available intracellular cholesterol.
  • Any suitable PRDM7/9 inhibitor may be used in the combinations of the present invention.
  • Preferred PRDM7/9 inhibitors include MRK-740.
  • the cholesterol homeostasis disrupting agent is a DHCR inhibitor.
  • the DHCR inhibitor may be an inhibitor of DHCR7 and/or DHCR24.
  • DHCR inhibitors antagonise cholesterol biosynthesis by inhibiting the last enzyme in the biosynthetic cascade, which in turn disrupts cholesterol homeostasis to reduce the available intracellular cholesterol.
  • Any suitable DHCR inhibitor may be used in the combinations of the present invention.
  • Preferred DHCR inhibitors include AY-9944 and SH-42.
  • the combination of an tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent may be provided as a pharmaceutical composition optionally further comprising a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention also relates to pharmaceutical compositions including a therapeutically effective amount of the combination of an tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent, and optionally one or more pharmaceutically acceptable excipients.
  • a "pharmaceutical carrier, diluent or excipient” includes, but is not limited to, any physiological buffered (i.e., about pH 7.0 to 7.4) medium including a suitable water soluble carrier, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
  • suitable water soluble carriers include, but are not limited to saline, dextrose, corn oil, dimethylsulfoxide, and gelatin capsules.
  • lactose lactose
  • mannitol corn starch
  • potato starch binders such as crystalline cellulose, cellulose derivatives, acacia, gelatins, disintegrators such as sodium carboxymethyl-cellulose, and lubricants such as talc or magnesium stearate.
  • binders such as crystalline cellulose, cellulose derivatives, acacia, gelatins
  • disintegrators such as sodium carboxymethyl-cellulose
  • lubricants such as talc or magnesium stearate.
  • compositions may be formulated for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.
  • compositions in a form suitable for oral use or parenteral use are preferred.
  • Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride or glycine, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
  • the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials.
  • suitable components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.
  • the dose of the tubulin polymerisation inhibitor may vary within wide limits and may be adjusted to individual requirements.
  • the tubulin polymerisation inhibitors may therefore be administered in any therapeutically effective amount.
  • Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day (e.g. about 0.5 mg to about 7 g per patient per day).
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.
  • the dose of the cholesterol homeostasis disrupting agent may vary within wide limits and may be adjusted to individual requirements.
  • the cholesterol homeostasis disrupting agents may therefore be administered in any therapeutically effective amount.
  • the skilled person will be able to determine the effective amount based on the cholesterol homeostasis disrupting agent selected and the tubulin polymerisation inhibitor included in the combination.
  • the cholesterol homeostasis disrupting agent is administered at a dose lower than the agent’s effective dose when used to treat high cholesterol.
  • preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day (e.g. about 0.5 mg to about 7 g per patient per day).
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg to about 2000 mg of an active ingredient.
  • the specific dose level of either or both members of the combination for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient), the severity of the particular disorder undergoing therapy, and the location of the unwanted proliferating cells.
  • the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the combination to be administered may need to be optimized for each individual.
  • Neoplastic disorders responsive to the agents of the present invention include, but are not limited to, brain cancer, including glioblastoma.
  • terapéuticaally effective amount refers to an amount of the compound of formula (I) that results in prevention, an improvement or remediation of the symptoms of a proliferative disorder.
  • dosage form and amount of the compounds or pharmaceutical compositions of the present invention can be readily established by reference to known treatment or prophylactic regimens.
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability and BBB permeability, such that the preferred dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.
  • the compounds of the present invention are preferably administered to a patient (for example, a human) orally or parenterally, and are present within at least one body fluid or tissue of the patient. Accordingly, the present invention further provides methods for treating patients suffering from proliferative disorders (including cancer, such as brain cancer).
  • proliferative disorders including cancer, such as brain cancer.
  • treating encompasses curing and ameliorating the severity of cancer or its associated symptoms.
  • Preventing means preventing the occurrence of the cancer or tempering the severity of the cancer if it develops subsequent to the administration of the compounds or pharmaceutical compositions of the present invention. This prevents the onset of clinically evident unwanted cell proliferation altogether or the onset of a preclinically evident stage of unwanted rapid cell proliferation in individuals at risk.
  • Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs and sheep.
  • Compounds of the present invention may be useful for the treatment and/or prevention of conditions and disorders associated with cell proliferation.
  • the cellular proliferation may be any that is ameliorated by tubulin polymerisation inhibition and/or cholesterol homeostasis disruption.
  • the cellular proliferation is a cancer, such as a brain cancer, for example glioblastoma.
  • the present invention also relates to a method of treating or preventing a proliferative disorder in a patient including administration to the patient of a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective amount of a cholesterol homeostasis disrupting agent, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
  • the present invention also relates to the use of the combination for treating or preventing a proliferative disorder.
  • the present invention also provides a pharmaceutical composition for use in treating or preventing a proliferative disorder, in any of the embodiments described in the specification.
  • the present invention also relates to the use of a therapeutically effective amount of the combination, the tubulin polymerisation inhibitor alone or cholesterol homeostasis disrupting agent alone in the manufacture of a medicament comprising the combination for treating or preventing a proliferative disorder.
  • the present invention also relates to the combination when used in a method of treating or preventing a proliferative disorder.
  • the present invention also relates to a composition having an active ingredient for use in treating or preventing a proliferative disorder, wherein the active ingredient is one or both of an tubulin polymerisation inhibitor or a cholesterol homeostasis modifying agent.
  • the present invention also relates to the use of a pharmaceutical composition containing the combination in treating or preventing a proliferative disorder, such as described above.
  • the proliferative disorder is a cancer.
  • the cancer is a brain cancer (eg a solid tumour).
  • the combinations according to the present invention, and pharmaceutical compositions thereof, may be used in the treatment or prevention of proliferative diseases, preferably cancer.
  • the compounds and compositions of the invention may be useful for the treatment of a wide variety of cancers (tumours), including but not limited to, solid tumours, such as for example, brain cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, uterine cancer brain cancer, skin cancer, colon cancer and bladder cancer.
  • the type of cancer or tumor cells that may be amenable to treatment according to the invention include, for example, breast, colon, lung, and prostate cancers, gastrointestinal cancers including esophageal cancer, stomach cancer, colorectal cancer, polyps associated with colorectal neoplasms, pancreatic cancer and gallbladder cancer, cancer of the adrenal cortex, ACTH-producing tumor, bladder cancer, brain cancer (including those discussed below), Ewing's sarcoma, head and neck cancer including mouth cancer and larynx cancer, kidney cancer including renal cell carcinoma, liver cancer, lung cancer including small and non-small cell lung cancers, malignant peritoneal effusion, malignant pleural effusion, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, and hemangiopericytoma, mesothelioma, Kaposi's sarcoma, bone cancer including osteomas and sarcomas such as
  • the cancer is primary.
  • the cancer is metastatic.
  • the cancer is benign.
  • the cancer is malignant
  • the proliferative disorder to be treated and/or prevented is brain cancer.
  • the brain cancer may be selected from anaplastic astrocytoma, astrocytoma, central neurocytoma, choroid plexus carcinoma, choroid plexus papilloma, choroid plexus tumour, diffuse intrinsic pontine glioma, dysembryoplastic neuroepithelial tumour, ependymal tumour, fibrillary astrocytoma, giant-cell glioblastoma, glioblastoma multiforme, gliomatosis cerebri, gliosarcoma, hemangiopericytoma, medulloblastoma, medulloepithelioma, meningeal carcinomatosis, neuroblastoma, neurocytoma, oligoastrocytoma, oligodendroglioma, optic nerve sheath meningioma, paediatric ependymoma
  • the brain cancer is a tumour (preferably, a solid tumour).
  • the brain cancer may be a primary cancer (eg a glioma, a meningioma, a pituitary adenoma or a nerve sheath tumour) or a metastatic cancer (ie a brain cancer that has arisen as a result of cancer in other parts of the body, such as melanoma or lung cancer).
  • the cancer is a recurring cancer. Accordingly, the subject may be a subject who has previously been treated for the same cancer, and may have been in remission for a period of time, for example a period of less than 5 years.
  • the compounds may be administered in further combination with other agents, for example, chemotherapeutic or immune-stimulating drugs or therapeutic agents.
  • ком ⁇ онент therapy in defining use of a compound of the present invention and one or more other pharmaceutical agents, are intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of these active agents, or in multiple, separate formulations of each agent.
  • the combinations may be formulated or administered in combination with one or more further therapeutic agents. Therefore, in accordance with various embodiments of the present invention, the combinations described herein may be included in combination treatment regimens with surgery and/or other known treatments or therapeutic agents, such as other anticancer agents, in particular, chemotherapeutic agents, radiotherapeutic agents, and/or adjuvant or prophylactic agents.
  • antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of cancers or other neoplasias by combination drug chemotherapy.
  • Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
  • other anti-neoplastic agents such as metallomatrix proteases inhibitors may be used.
  • Suitable agents which may be used in combination therapy will be recognized by those of skill in the art. Suitable agents are listed, for example, in the Merck Index, An Encyclopaedia of Chemicals, Drugs and Biologicals, 12th Ed., 1996.
  • the methods described herein may comprise administering the active agents of the combinations simultaneously, separately or consecutively.
  • simultaneously it is meant that each of the active ingredients are administered at the same time in the same composition (or administered together).
  • separately it is meant that each of the active ingredients are administered at the same time in different compositions and optionally by different routes of administration.
  • consecutively it is meant that each of the composition and the further active ingredient are administered separately optionally by different administration routes and may be at different times.
  • the active ingredients are administered consecutively they are administered within 24 hours, or within 12, 8, 6, 5, 4, 3, 2, or 1 hour(s) of each other.
  • the tubulin polymerisation inhibitor may be administered before or after the cholesterol homeostasis disrupting agent.
  • the tubulin polymerisation inhibitor is administered after or concurrently with the cholesterol homeostasis disrupting agent.
  • the cholesterol homeostasis disrupting agent results in the cancer cells (including the persisters) being more susceptible to tubulin polymerisation inhibitor activity.

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Abstract

La présente divulgation concerne des combinaisons d'inhibiteurs de polymérisation de tubuline et d'agents de perturbation de l'homéostasie du cholestérol qui sont utiles dans le traitement de maladies prolifératives, telles que le cancer. Des combinaisons préférées sont présentées comme efficaces contre divers types de cellules cancéreuses, y compris les cancers du cerveau tels que les glioblastomes.
PCT/AU2024/050979 2023-09-15 2024-09-13 Polythérapie Pending WO2025054665A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016119017A1 (fr) * 2015-01-30 2016-08-04 The University Of Sydney Composés anti-cancereux
WO2019148244A1 (fr) * 2018-02-01 2019-08-08 The University Of Sydney Composés anticancéreux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016119017A1 (fr) * 2015-01-30 2016-08-04 The University Of Sydney Composés anti-cancereux
WO2019148244A1 (fr) * 2018-02-01 2019-08-08 The University Of Sydney Composés anticancéreux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GROSSI PAOLETTI E, ET AL.: "EFFECT OF HYPOCHOLESTEREMIC AGENTS ON AN EXPERIMENTAL BRAIN TUMOR IN MICE", RETINAL DEGENERATIVE DISEASES: ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, SPRINGER, US, vol. 04, 22 April 1969 (1969-04-22), US , pages 457 - 471, XP001029663, ISBN: 978-3-319-72798-1 *
GUO D ET AL.: "An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway", CANCER DISCOV., vol. 1, no. 5, 2011, pages 442 - 456, XP055227662, DOI: 10.1158/2159-8290.CD-11-0102 *

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