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WO2025054665A1 - Combination therapy - Google Patents

Combination therapy Download PDF

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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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WIPO (PCT)
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
Application number
PCT/AU2024/050979
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French (fr)
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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Filing date
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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/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • A61K9/10—Dispersions; Emulsions
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    • 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

This disclosure relates to combinations of tubulin polymerisation inhibitors and cholesterol homeostasis disrupting agents that are useful in the treatment of proliferative diseases, such as cancer. Preferred combinations are shown as effective against various cancer cell types, including brain cancers such as glioblastomas.

Description

Combination therapy
[0001] The present application claims priority to Australian provisional patent application no. 2023902987, filed on 15 September 2024, the entire contents of which are incorporated herein by reference.
Field of the invention
[0002] The present invention relates to therapy for proliferative diseases involving combinations of tubulin polymerisation inhibitors and cholesterol homeostasis disrupting agents.
Background of the invention
[0003] Intra-tumour heterogeneity, characterized by distinct cell subpopulations within the same tumour, significantly contributes to therapy failure and tumour recurrence.
Tumour recurrence is, in part, attributed to a specific cancer cell subpopulation known as drug-tolerant persister cells. Unlike resistant cells, persister cells do not possess permanent resistance-conferring genetic mutations but instead enter a reversible drug- tolerant state. Upon cessation of therapy or in periods between therapy cycles (drug holidays), persister cells give rise to a new population of cells that are often as sensitive to the drug as the original drug-naive population. Alternatively, persister cells may acquire genetic mutations that confer irreversible drug resistance.
[0004] Glioblastoma, the most prevalent and aggressive brain tumour, is primarily sustained by stem-like cancer cells. The unpredictable transition of glioblastoma stem cells between chemotherapy-sensitive and chemotherapy-tolerant persister phenotypes is a crucial factor contributing to treatment failures. This phenotypic plasticity allows glioblastoma stem cells to evade the cytotoxic effects of drugs while maintaining the potential to re-establish drug sensitivity upon treatment withdrawal or during drug holidays.
[0005] Persisters demonstrate a transient nature of drug-tolerant states, with reversible drug sensitivity upon treatment withdrawal. Persister cells emerge through various mechanisms, including epigenetic reprogramming, metabolic adaptations, and activation of survival signalling pathways. [0006] There is therefore a continuing need to provide alternative treatment options effective in the treatment of proliferative disease, particularly treatments that are effective against a higher proportion or cancer persister cells. Further, it is also desirable for treatments capable of penetrating the blood-brain barrier to improve treatments for brain cancers, such as glioblastoma.
[0007] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art.
Summary of the invention
[0008] Surprisingly, the inventors found that combinations of a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent demonstrated enhanced potency against glioblastoma cells over either agent independently. Also surprising was that preferred combinations substantially eradicated persister cells present in the glioblastoma whereas either agent alone did not.
[0009] Accordingly, in a first aspect, the invention provides a method for treating a proliferative disease, the method comprising administering to a subject in need thereof an effective amount of a combination of a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent.
[0010] As the combinations of the present invention are surprisingly more effective against persister cancer cells, the methods described herein may be useful in the treatment of primary cancers, but also recurring cancers. Recurring cancers may recur as not all persister cells are effected by traditional chemotherapies.
[0011] In another aspect, the invention provides a pharmaceutical composition comprising a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent.
[0012] In a further aspect, the invention provides use of a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent in the manufacture of a medicament for treating a proliferative disease. [0013] In yet another aspect, the invention provides use of a tubulin polymerisation inhibitor in the manufacture of a medicament for treating a proliferative disease in combination with a cholesterol homeostasis disrupting agent.
[0014] In a still further aspect, the invention provides use of a cholesterol homeostasis disrupting agent in the manufacture of a medicament for treating a proliferative disease in combination with a tubulin polymerisation inhibitor.
[0015] In another aspect, the invention provides a tubulin polymerisation inhibitor for use in treating a proliferative disease in combination with a cholesterol homeostasis disrupting agent.
[0016] In a further aspect, the invention provides a cholesterol homeostasis disrupting agent for use in treating a proliferative disease in combination with a tubulin polymerisation inhibitor.
[0017] In some embodiments, the proliferative disease is cancer.
[0018] The present methods find particular efficacy in the treatment of brain cancers, such as glioblastoma. In such embodiments, the preferred combinations comprising brain penetrant tubulin polymerisation inhibitors and brain penetrant cholesterol homeostasis disrupting agents. Preferred brain penetrating tubulin polymerisation inhibitors include CMPD1 and WJA88.
[0019] In another aspect, there is provided a kit comprising:
- a tubulin polymerisation inhibitor; and
- instructions for its use to treat cancer in combination with a cholesterol homeostasis disrupting agent.
[0020] In a further aspect, there is provided a kit comprising:
- a cholesterol homeostasis disrupting agent; and
- instructions for its use to treat cancer in combination with a tubulin polymerisation inhibitor. [0021] In a yet further aspect, there is provided use of a tubulin polymerisation inhibitor in the manufacture of a medicament for treating a proliferative disorder in combination with a cholesterol homeostasis disrupting agent.
[0022] In another aspect, there is provided use of a cholesterol homeostasis disrupting agent in the manufacture of a medicament for treating a proliferative disorder in combination with a tubulin polymerisation inhibitor.
[0023] In a further aspect, there is provided a combination comprising a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent for use in treating a proliferative disorder.
[0024] In a still further aspect, there is provided a tubulin polymerisation inhibitor for use in treating a proliferative disorder in combination with a cholesterol homeostasis disrupting agent.
[0025] In another aspect, there is provided a cholesterol homeostasis disrupting agent for use in treating a proliferative disorder in combination with a tubulin polymerisation inhibitor.
[0026] In a further aspect, the present invention relates to a method of completely or partially preventing the recurrence of a solid tumour in a subject, the method comprising administering to the subject an effective amount of a combination of a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent.
[0027] In another aspect the invention relates to the use of a tubulin polymerisation inhibitor and/or a cholesterol homeostasis disrupting agent in the manufacture of a medicament for completely or partially preventing the recurrence of a solid tumour.
[0028] In a still further aspect, the invention relates to a tubulin polymerisation inhibitor and/or a cholesterol homeostasis disrupting agent for use in completely or partially preventing the recurrence of a solid tumour.
[0029] The solid tumour may be a brain cancer (eg glioblastoma, astrocytoma, or glioma). The brain cancer may be a primary cancer. The brain cancer may be a metastatic cancer. [0030] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.
[0031] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.
Brief description of the drawings
[0032] The invention may be further described with reference to the following nonlimiting drawings, in which:
Figure 1. RKI1 glioblastoma stem cells were treated with CMPD1 (25 pM) in combination with MRK-740 (3 pM) for 14 days. Untreated (Day 0) and drug-tolerant persisters (DTPs, Day 14) were stained with Nuclear-ID. Representative images and quantification of DTPs are presented, data represent the mean ± SD (n = 3, unpaired t- test). A - representative images; and B - quatification of DTPs. Data represent the mean ± SD (n = 3, unpaired t-test).
Figure 2. Glioblastoma stem cell lines were treated with MRK-740 (3 pM) or MRK-740- NC (3 pM) for 7 days, then cultured in drug-free media for additional 7-21 days and colonies stained. Representative images of three independent experiments are shown.
Figure 3. Glioblastoma stem cell lines were treated with CMPD1 (25 pM) in combination with MRK-740 (3 pM) or MRK-740-NC (3 pM) for 7 days. Surviving cells (DTPs) were then left to recover in drug-free media for additional 7-21 days and colonies stained. A - Representative images, B - quatification of DTP-derived colonies for RKI1 cells, C - quantification of DTP-derived colonies for FPW1 cells, D - quantification of DTP-derived colonies for HW1 cells, E - quantification of DTP-derived colonies for SB2b cells, and F - quantification of DTP-derived colonies for RN1 cells. Data represent the mean ± SD (n = 3, one-way ANOVA).
Figure 4. RKI1 and FPW1 glioblastoma stem cells were treated with CMPD1 (25 pM) in combination with LXR agonists LXR-623 (1 pM), T0901317 (1 pM), GW3965 (1 pM) or LXR inverse agonist SR9243 (1 pM) for 14 days. Untreated (Day 0) and DTPs (Day 14) were stained with Nuclear-ID. A - representative images, B - quantification of DTPs for RK11 cells and C - quantification of DTPs for FPW1 cells. Data represent the mean ± SD (n = 3, one-way ANOVA).
Figure 5. RK11 and FPW1 glioblastoma stem cell lines were treated with with LXR agonists LXR-623 (1 pM), T0901317 (1 pM), GW3965 (1 pM) or LXR inverse agonist SR9243 (1 pM) for 7 days, then cultured in drug-free media for additional 7-21 days and colonies stained. Representative images of 3 independent experiments are shown.
Figure 6. RKI1 and FPW1 glioblastoma stem cell lines were treated with CMPD1 (25 pM) in combination with with LXR agonists LXR-623 (1 pM), T0901317 (1 pM), GW3965 (1 pM) or LXR inverse agonist SR9243 (1 pM) for 7 days. Surviving cells (DTPs) were then left to recover in drug-free media for additional 7-21 days and colonies stained. A - representative images, B - quantification of DTP-derived colonies for RKI1 cells, and C - quantification of DTP-derived colonies for FPW1 cells. Data represent the mean ± SD (n = 3, one-way ANOVA).
Figure 7. RKI1 glioblastoma stem cells were treated with CMPD1 (25 pM) in combination with DHCR7 inhibitor AY-9944 (0.5 pM) and DHCR24 inhibitor SH-42 (0.5 pM) for 14 days. DTPs (Day 14) were stained with Nuclear-ID. A - representative images and B - quantification of DTPs are presented. Data represent the mean ± SD (n = 3, one-way ANOVA).
Figure 8. Glioblastoma stem cell lines were treated with CMPD1 (25 pM) and AY-9944 (1 pM) as single agents and in combination for 7 days. Surviving cells (DTPs) were then left to recover in drug-free media for additional 7 - 21 days and colonies stained. A - representative images, B - quantification of DTP-derived colonies for RKI1 cells, C - quantification of DTP-derived colonies for HW1 cells, and D - quantification of DTP- derived colonies for RN1 cells. Data represent the mean ± SD (n = 3, unpaired t-test).
Figure 9. Glioblastoma stem cell lines were treated with CMPD1 (25 pM) and SH-42 (1 pM) as single agents and in combination for 7 days. Surviving cells (DTPs) were then left to recover in drug-free media for additional 7 - 21 days and colonies stained. A - representative images and B - quantification of DTP-derived colonies are presented. Data represent the mean ± SD (n = 3, unpaired t-test). Figure 10. RK11 and FPW1 glioblastoma stem cells were treated with WJA88 (25 pM) in combination with MRK-740 (3 pM), LXR-623 (1 pM) or T0901317 (1 pM) for 14 days. Untreated (Day 0) and drug-tolerant persisters (DTPs, Day 14) were stained with Nuclear-ID. A - representative images, B - quantification of DTPs for RKI1 cells, and C - quantification of DTPs for FPW1 cells. Data represent the mean ± SD (n = 4-5, one-way ANOVA).
Figure 11. RKI1 and FPW1 glioblastoma stem cell lines were treated with with MRK- 740 (3 pM), LXR-623 (1 pM) or T0901317 (1 pM) for 7 days, then cultured in drug-free media for additional 7-21 days and colonies stained. Representative images of 2-3 independent experiments are shown.
Figure 12. RKI1 and FPW1 glioblastoma stem cell lines were treated with WJA88 (25 pM) in combination with MRK-740 (3 pM), LXR-623 (1 pM) or T0901317 (1 pM) for 7 days. Surviving cells (DTPs) were then left to recover in drug-free media for additional 7-21 days and colonies stained. A - representative images, B - quantification of DTP- derived colonies from RKI1 cells, and C - quantification of DTP-derived colonies from FPW1 cells. Data represent the mean ± SD (n = 2-3, one-way ANOVA).
Figure 13. In vivo efficacy of tubulin polymerisation inhibitor WJA88 (50 mg/kg), LXR agonist LXR-623 (100 mg/kg), and combination treatment of GBM6 xenografts (n = 8 per treatment arm). A - Tumour responses measured before (Day 5), during (Day 12) and after treatment (Day 21). B - Kaplan-Meier survival curves of GBM6 xenografts, comparison of survival curves was performed with Mantel-Cox test.
Detailed description of the embodiments
[0033] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.
[0034] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.
[0035] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Therefore, as used herein, the singular forms "a", "an" and "the" include plural aspects, and vice versa, unless the context clearly dictates otherwise. For example, reference to "a" includes a single as well as two or more; reference to "an" includes a single as well as two or more; reference to "the" includes a single as well as two or more and so forth.
[0036] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centres, it will be understood that, unless otherwise specified, all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may occur in Z and E forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, ie, an atom having the same atomic number but a different mass number. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C, and 14C.
[0037] Compounds according to any of formulas (l)-(X) provided herein, which have one or more stereogenic centres, may have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors, biosynthesis or by resolution of the racemates, for example, enzymatic resolution or resolution by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.
[0038] Certain compounds are described herein using a general formula that includes variables such as R1, R2, Ar, W, X, Y, Z, R3, R4 R5, R6, R7, R8, R9, R10, A, B, Ra, Rb, Rc, Rd, L3, L1 , L2, A1 , B1 , R11 , R12, R13, R14, R15, R16, R17, R18, R19, R21, R22, R23, R25, A2, B2, B3, R31 , R32, R34, R35, R36, R37, L43, R41, R42, R43 R44, R45, R46, R47, R48, B4, R51 , R52, R53 R54 R55 |_53 |_55 g4 R61 R62 p63 R64 p65 R66 |_63 |_66 g g81 g82 g83 g84 g85 R86, R87, L83, L84, E, B8, D8, R91 , R92, R93, R94, R95, R96, R97, L93, L94, B9, D9, m, n, p, q, ml , n1 , p1 , q1 , m2, n2, p2, q2, m3, n3, q3, m4, n4, q4, m5, n5, q6, m6, n6, q6, m8, n8, q8, m8, n9 and q9. Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Therefore, for example, if a group is shown to be substituted with 0, 1 or 2 R*, the group may be unsubstituted or substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, ie, compounds that can be isolated, characterized and tested for biological activity.
[0039] A "pharmaceutically acceptable salt" of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. In particular, pharmaceutically acceptable salts in accordance with the present invention are those that do not adversely affect the ability of the compound to cross the BBB. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
[0040] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic (such as acetic, HOOC-(CH2)n-COOH where n is any integer from 0 to 6, i.e. 0, 1 , 2, 3, 4, 5 or 6), and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. A person skilled in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent (such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile), or in a mixture of the two.
[0041] It will be apparent that each compound of formulas (l)-(X) may, but need not, be present as a hydrate, solvate or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds provided herein.
[0042] A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce the active compound provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
[0043] A "substituent" as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, heteroalkyl group, haloalkyl group or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity. When a substituent is oxo, ie, =0, then two hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to -C(=0)- and a loss of aromaticity. For example a pyridyl group substituted by oxo is a pyridone. Examples of suitable substituents are alkyl (including haloalkyl e.g. CF3), heteroalkyl (eg -OCH3, -CH2NHCH3, -CH2NH2), halogen (for example, fluorine, chlorine, bromine or iodine atoms), OH, =0, SH, SO3H, NH2, =NH, N3 and NO2 groups.
[0044] The term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group. Preferred alkyl groups are Ci ealkyl, Ci-4alkyl, Ci salkyl, Ci-2alkyl, C2-4alkyl, C2- ealkyl and C2-3alkyl groups, where the “Cx-y” notation defines that the alkyl group includes from ‘x’ to ‘y’ carbon atoms covalently bonded into a straight or branched saturated hydrocarbon chain. Specific examples of alkyl groups are methyl, ethyl, propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, tert-butyl, n-pentyl, /so-pentyl, n-hexyl and 2,2-dimethylbutyl.
[0045] The term "heteroalkyl" refers to an alkyl group as defined above that contains one or more heteroatoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen). Specific examples of heteroalkyl groups are O-alkyl groups, such as methoxy, trifluoromethoxy, ethoxy, n-propyloxy, /so-propyloxy, butoxy and tertbutyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, methoxyethyl, 1 - methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, aminoalkyl (such as - CH2NH2, -CH2CH2NH2, etc) methylamino, ethylamino, propylamino, iso-propylamino, dimethylamino, diethylamino, iso-propylethylamino, methylamino methyl, ethylamino methyl, di-zso-propylamino ethyl, methylthio, ethylthio, /so-propylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino, propionylamino, carboxymethyl, carboxyethyl, carboxypropyl, A/-ethyl-A/-methylcarbamoyl and N- methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, /so-nitrile, cyanate, thiocyanate, /so-cyanate, /so-thiocyanate and alkylnitrile groups.
[0046] The term "alkenyl" refers to an at least partially unsaturated, straight-chain or branched hydrocarbon group that contains at least two carbon atoms (ie C2 alkenyl). Specific examples of alkenyl groups are ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, /so-prenyl and hex-2-enyl group. Preferably, alkenyl groups have one or two double bond(s). [0047] The term "cycloalkyl" refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 ( especially 3, 4, 5, 6 or 7) ring carbon atoms. Specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, adamantane (ie tricycle[3.3.1 .13, 7]decane ), cyclopentylcyclohexyl and cyclohex-2-enyl.
[0048] The term "heterocycloalkyl" refers to a cycloalkyl group as defined above in which one or more (preferably 1 , 2 or 3) ring carbon atoms, each independently, have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom). This includes groups containing these atoms, such as NH. A heterocycloalkyl group has preferably 1 or 2 rings containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). Specific examples are piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl and 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.
[0049] The term "aryl" refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Examples are phenyl, naphthyl and biphenyl groups.
[0050] The term "heteroaryl" refers to an aromatic group that contains one or more rings, wherein the heteroaryl typically contains from 5 to 14 ring atoms, preferably from 5 to 10 ( especially 5 or 6) ring atoms, and contains one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N) with the rest being carbon ring atoms. This includes O, S or N-containing groups, such as NH. Examples are pyridyl (for example, 4-pyridyl), imidazolyl (for example, 2- imidazolyl), phenylpyrrolyl (for example, 3-phenylpyrrolyl), thiazolyl, iso-thiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, iso-quinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl and pyrazolyl (for example, 3-pyrazolyl) groups. [0051] In some embodiments, the term “heteroaryl” includes polycyclic (eg bicyclic) moieties that include at least one aromatic ring, while not all rings within the moiety must be aromatic. The aromatic ring of such a mixed aromatic/non-aromatic system may include one or more heteroatoms, but such heteroaryl groups may include a carbocyclic aryl and a non-aromatic heterocycloalkyl ring, typically fused, provided all other conditions are met.
[0052] The expression "halogen" or "halogen atom" as used herein means fluorine, chlorine, bromine, or iodine.
[0053] The term "optionally substituted" refers to a group in which one, two, three or more hydrogen atoms have been replaced independently of each other by halogen (for example, fluorine, chlorine, bromine or iodine atoms) and/or by, for example, OH, =0, SH, SO3H, NH2, A/-alkyl, NH-alkyl, N3 or NO2 groups. This expression also refers to a group that is substituted by one, two, three or more alkyl, alkenyl or heteroalkyl (eg - OCH3, -OCH2CH3, -CH2NHCH3 and -CH2NH2) groups. These groups may themselves be substituted. For example, an alkyl group substituent may be substituted by one or more halogen atoms (ie may be a haloalkyl group). The term "haloalkyl" refers to an alkyl group (as defined above) that is substituted by one or more halogen atoms (as also defined above). Specific examples of haloalkyl groups are trifluoromethyl, dichloroethyl, dichloromethyl and iodoethyl.
[0054] As used herein a wording defining the limits of a range of length such as, for example, “C1-5” or "from 1 to 5" means any integer from 1 to 5, ie 1 , 2, 3, 4 and 5. In other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
[0055] Described herein are new combinations of tubulin polymerisation inhibitors and cholesterol homeostasis disrupting agents. These combinations are shown in the data included in this specification to be surprisingly effective at treating cancer cells, including persistor cells. The combinations are more effective at treating persistor cells than either member alone. Further, the combinations are effective against traditionally hard to treat cancers, including brain cancers such as glioblastoma. Tubulin polymerisation inhibitors
[0056] The invention may rely on any suitable tubulin polymerisation inhibitor. Tubulin polymerisation inhibitors may alternatively be referred to as microtubule-destabilising agents.
[0057] Tubulin polymerisation inhibitors are a class of microtubule-targeting agents. Microtubule-targeting agents can be divided into three classes: i. tubulin depolymerisation (eg taxane, epothiliones) ii. tubulin polymerisation inhibitors (eg vinca alkaloids, colchicine) iii. degraders (eg tubulin-targeting proteolysis targeting chimeras (e.g. PROTACs))
[0058] Tubulin polymerisation inhibitors exert their therapeutic efficacy by disrupting microtubules, which regulate fundamental cell functions such as mitosis, migration, and vesicle transport. As cancer cells, by definition, divide at faster rates than non-cancer cells, tubulin polymerisation inhibitors may therefore be effective at treating any cancertype.
[0059] In embodiments when the combinations are for treating brain cancers, the tubulin polymerisation inhibitor is brain penetrant. In these embodiments, the combinations may therefore comprise a brain penetrating tubulin polymerisation inhibitor.
[0060] Suitable tubulin polymerisation inhibitors are described in US10,745,355, US1 1 ,472,774, AU 2019200683, and US2019/0169127, the entire disclosure of each of these is incorporated herein by reference, including the formulas of the various tubulin polymerisation inhibitors described along with their embodiments. The compounds described in US10,745,355, US11 ,472,774, AU 2019200683 and US2019/0169127 may be brain pentrant.
[0061] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (I):
Figure imgf000015_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is Ci-Ce alkyl or C2-C6 alkenyl;
Figure imgf000016_0001
W is O or S;
R2 is H, alkyl or alkenyl;
Z is selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl group, which may be optionally substituted;
R1 is a halo, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which heterocycloalkyl group is optionally substituted;
Ar is an aryl or heteroaryl group.
[0062] In some embodiments, the tubulin polymerisation inhibitor is a compound of
Formula (la): zAr ZY\
R1 x z (la), or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is C1-C6 alkyl or C2-C6 alkenyl;
Figure imgf000016_0002
W is O or S;
R2 is H, alkyl or alkenyl;
Z is heterocycloalkyl or heteroaryl group, which heterocycloalkyl group is optionally substituted;
R1 is a halo, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which heterocycloalkyl group is optionally substituted; Ar is an aryl or heteroaryl group.
X may be C3 alkyl or C3 alkenyl.
W may be O.
Preferred compounds of formula (I) are those where X is Ci, C2 or C3 alkyl, or C2 or C3 alkenyl (eg C3 alkyl or C3 alkenyl).
R1 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, and the heteroalkyl group may be O-alkyl (eg OCH3 or OCH2CH3) or aminoalkyl (eg - CH2NH2 or -CH2CH2NH2).
R1 may be a heteroaryl group. The heteroaryl group may be monocyclic or bicyclic. The heteroaryl group may include one or more nitrogen atoms. For example, the heteroaryl group may be pyrazole, isoxazole, triazole, pyridine, pyrimidine, quinoline, benzimidazole or indole. The heteroaryl group may be substituted. For example, the substituent may be a halo group (eg F) or a heteroalkyl group (eg O- alkyl, such as - OCH3 or OCH2CH3, or aminoalkyl, such as -CH2NH2 or -CH2CH2NH2).
R1 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. For example, 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. For example, 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). For example, the heteroaryl may be furan. The heteroatom may be at one or more positions on the ring or rings. For example, when 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. For example, 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.
R2 may be H, alkyl or alkenyl.
R2 may be H.
[0063] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (II):
Figure imgf000018_0001
pharmaceutically acceptable salt or prodrug thereof, wherein: Ring A is aryl, partially unsaturated cycloalkyl or heterocycloalkyl, heteroaryl, C2-C10 heterocycloalkyl, or C3-C8 cycloalkyl;
Ring B is aryl or heteroaryl; each R3 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R4 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R5 is independently hydrogen, halogen, -CN, -ORa, -SRa, two R5 on the same carbon are taken together to form an oxo, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa -NRaC(=O)NRcRd, Ci-C6 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, -ORa, or -NRcRd and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa, or -NRcRd; each R6 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -S(=O)2Rd , -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n is 1 -4; m is 1 -4; p is 1 -4; and q is 1 -5. [0064] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (III):
Figure imgf000021_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
Ring A is heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
Ring B is aryl or heteroaryl; each R3 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb,-NC>2, -NRcRd, -S(=O)2Rd, NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R4 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R5 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa or -NRcRd;
R6 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb -CO2Ra, -C(=O)NRcRd, 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R7 is independently hydrogen, halogen, -CN, -ORa, -SRa -S(=O)Rb -NO2, -NRcRd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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; or
Rc and Rd, 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 -NH2; n is 1 -4; m is 1 -4; p is 1 -4; and q is 1 -5.
[0065] In some embodiments of a compound of Formula (II), Ring A is heteroaryl.
[0066] In some embodiments of a compound of Formula (II), Ring A is a 6-membered heteroaryl.
[0067] In some embodiments of a compound of Formula (II), Ring A is pyridyl.
[0068] In some embodiments of a compound of Formula (II), Ring A is pyrimidinyl.
[0069] In some embodiments of a compound of Formula (II), Ring A is pyrazinyl.
[0070] In some embodiments of a compound of Formula (II), Ring A is a 5-membered heteroaryl.
[0071] In some embodiments of a compound of Formula (II), Ring A is tetrazolyl.
[0072] In some embodiments of a compound of Formula (II), Ring A is thiazolyl.
[0073] In some embodiments of a compound of Formula (II), Ring A is furanyl.
[0074] In some embodiments of a compound of Formula (II), Ring A is thiophenyl. [0075] In some embodiments of a compound of Formula (II), Ring A is oxazolyl.
[0076] In some embodiments of a compound of Formula (II), Ring A is oxadiazolyl.
[0077] In some embodiments of a compound of Formula (II), Ring A is thiadiazolyl.
[0078] In some embodiments of a compound of Formula (II), Ring A is pyrazolyl.
[0079] In some embodiments of a compound of Formula (II), Ring A is imidazolyl.
[0080] In some embodiments of a compound of Formula (II), Ring A is triazolyl.
[0081] In some embodiments of a compound of Formula (II), Ring A is C2-C8 heterocycloalkyl.
[0082] In some embodiments of a compound of Formula (II), Ring A is pyrrolidinyl.
[0083] In some embodiments of a compound of Formula (II), Ring A is piperidinyl.
[0084] In some embodiments of a compound of Formula (II), Ring A is piperazinyl.
[0085] In some embodiments of a compound of Formula (II), Ring A is pyranyl.
[0086] In some embodiments of a compound of Formula (II), Ring A is tetrahydrofuranyl.
[0087] In some embodiments of a compound of Formula (II), Ring A is morpholinyl.
[0088] In some embodiments of a compound of Formula (II), Ring A is azetidinyl.
[0089] In some embodiments of a compound of Formula (II), Ring A is C3-C8 cycloalkyl.
[0090] In some embodiments of a compound of Formula (II), Ring A is cyclopropyl.
[0091] In some embodiments of a compound of Formula (II), Ring A is cyclobutyl.
[0092] In some embodiments of a compound of Formula (II), Ring A is cyclohexyl.
[0093] In some embodiments of a compound of Formula (II), Ring A is cyclopentyl.
[0094] In some embodiments of a compound of Formula (II), Ring B is aryl. [0095] In some embodiments of a compound of Formula (II), Ring B is phenyl.
[0096] In some embodiments of a compound of Formula (II), Ring B is naphthyl.
[0097] In some embodiments of a compound of Formula (II), Ring B is heteroaryl.
[0098] In some embodiments of a compound of Formula (II), Ring B is fused heteroaryl.
[0099] In some embodiments of a compound of Formula (II), Ring B is 6-membered heteroaryl.
[0100] In some embodiments of a compound of Formula (II), Ring B is pyridyl.
[0101] In some embodiments of a compound of Formula (II), Ring B is pyrimidinyl.
[0102] In some embodiments of a compound of Formula (II), Ring B is pyrazinyl.
[0103] In some embodiments of a compound of Formula (II), Ring B is a 5-membered heteroaryl.
[0104] In some embodiments of a compound of Formula (II), Ring B is thiophenyl.
[0105] In some embodiments of a compound of Formula (II), Ring B is furanyl.
[0106] In some embodiments of a compound of Formula (II), Ring B is pyrrolyl.
[0107] In some embodiments of a compound of Formula (II), Ring B is thiazolyl.
[0108] In some embodiments of a compound of Formula (II), Ring B is oxazolyl.
[0109] In some embodiments of a compound of Formula (II), Ring B is isoxazolyl.
[0110] In some embodiments of a compound of Formula (II), Ring B is imidazolyl.
[0111] In some embodiments of a compound of Formula (II), Ring B is pyrazolyl.
[0112] In some embodiments of a compound of Formula (II), Ring B is thiadiazolyl.
[0113] In some embodiments of a compound of Formula (II), Ring B is oxadiazolyl. [0114] In some embodiments of a compound of Formula (II), each R3 is independently hydrogen.
[0115] In some embodiments of a compound of Formula (II), each R3 is independently halogen.
[0116] In some embodiments of a compound of Formula (II), each R3 is independently Ci-Ce alkyl.
[0117] In some embodiments of a compound of Formula (II), each R3 is independently Ci-Ce haloalkyl.
[0118] In some embodiments of a compound of Formula (II), each R3 is independently fluoro.
[0119] In some embodiments of a compound of Formula (II), n is 1 .
[0120] In some embodiments of a compound of Formula (II), n is 2.
[0121] In some embodiments of a compound of Formula (II), n is 3.
[0122] In some embodiments of a compound of Formula (II), n is 4.
[0123] In some embodiments of a compound of Formula (II), each R4 is independently halogen.
[0124] In some embodiments of a compound of Formula (II), each R4 is independently Ci-Ce alkyl.
[0125] In some embodiments of a compound of Formula (II), each R4 is independently Ci-Ce haloalkyl.
[0126] In some embodiments of a compound of Formula (II), each R4 is hydrogen.
[0127] In some embodiments of a compound of Formula (II), m is 1 .
[0128] In some embodiments of a compound of Formula (II), m is 2.
[0129] In some embodiments of a compound of Formula (II), m is 3.
[0130] In some embodiments of a compound of Formula (II), m is 4. [0131] In some embodiments of a compound of Formula (II), each R5 is independently halogen.
[0132] In some embodiments of a compound of Formula (II), each R5 is independently Ci-Ce alkyl.
[0133] In some embodiments of a compound of Formula (II), each R5 is independently Ci-Ce haloalkyl.
[0134] In some embodiments of a compound of Formula (II), each R5 is hydrogen.
[0135] In some embodiments of a compound of Formula (II), p is 1 .
[0136] In some embodiments of a compound of Formula (II), p is 2.
[0137] In some embodiments of a compound of Formula (II), p is 3.
[0138] In some embodiments of a compound of Formula (II), p is 4.
[0139] In some embodiments of a compound of Formula (II), R6 is hydrogen or Ci-Ce alkyl.
[0140] In some embodiments of a compound of Formula (II), R6 is Ci-Ce alkyl.
[0141] In some embodiments of a compound of Formula (II), R6 is hydrogen.
[0142] In some embodiments of a compound of Formula (II), each R7 is independently hydrogen.
[0143] In some embodiments of a compound of Formula (II), each R7 is independently halogen.
[0144] In some embodiments of a compound of Formula (II), each R7 is independently -OH.
[0145] In some embodiments of a compound of Formula (II), each R7 is independently Ci-Ce alkyl.
[0146] In some embodiments of a compound of Formula (II), each R7 is independently Ci-Ce haloalkyl. [0147] In some embodiments of a compound of Formula (II), each R7 is methyl.
[0148] In some embodiments of a compound of Formula (II), q is 1 .
[0149] In some embodiments of a compound of Formula (II), q is 2.
[0150] In some embodiments of a compound of Formula (II), q is 3.
[0151] In some embodiments of a compound of Formula (II), q is 4.
[0152] In some embodiments of a compound of Formula (II), q is 5.
[0153] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (Ila):
Figure imgf000028_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
Ring A is heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
E is -C(=O)NR8- or -NR8C(=O)-;
L3 is a bond or -CR9R10-;
Ring B is aryl or heteroaryl; each R3 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R4 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb,-OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb,-NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R5 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb,-NO2, -NRcRd, -S(=O)2Rd, NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa or -NRcRd;
R6 is is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R7 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb,-NO2, -NRcRd, -NRaS(=O)Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)RcRd, NRaC(=O)ORb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa or -NRcRd;
R9 and R10 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb,-NO2, NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n is 1 -4; m is 1 -4; p is 1 -4; and q is 1 -5.
[0154] In some embodiments of a compound of Formula (Ila), E is -NR8C(=O)-.
[0155] In some embodiments of a compound of Formula (Ila), E is -C(=O)NR8-.
[0156] In some embodiments of a compound of Formula (Ila), L3 is a bond. In some embodiments of a compound of Formula (Ila), L3 is -CR9R10-.
[0157] In some embodiments of a compound of Formula (Ila), Ring A is pyridyl.
[0158] In some embodiments of a compound of Formula (Ila), Ring A is pyrimidinyl.
[0159] In some embodiments of a compound of Formula (Ila), Ring A is pyrazinyl.
[0160] In some embodiments of a compound of Formula (Ila), Ring A is a 5- membered heteroaryl.
[0161] In some embodiments of a compound of Formula (Ila), Ring A is tetrazolyl.
[0162] In some embodiments of a compound of Formula (Ila), Ring A is thiazolyl.
[0163] In some embodiments of a compound of Formula (Ila), Ring A is furanyl.
[0164] In some embodiments of a compound of Formula (Ila), Ring A is thiophenyl.
[0165] In some embodiments of a compound of Formula (Ila), Ring A is oxazolyl.
[0166] In some embodiments of a compound of Formula (Ila), Ring A is oxadiazolyl.
[0167] In some embodiments of a compound of Formula (Ila), Ring A is thiadiazolyl.
[0168] In some embodiments of a compound of Formula (Ila), Ring A is pyrazolyl.
[0169] In some embodiments of a compound of Formula (Ila), Ring A is imidazolyl.
[0170] In some embodiments of a compound of Formula (Ila), Ring A is triazolyl.
[0171] In some embodiments of a compound of Formula (Ila), Ring A is C2-C8 heterocycloalkyl.
[0172] In some embodiments of a compound of Formula (Ila), Ring A is pyrrolidinyl. [0173] In some embodiments of a compound of Formula (Ila), Ring A is piperidinyl.
[0174] In some embodiments of a compound of Formula (Ila), Ring A is piperazinyl.
[0175] In some embodiments of a compound of Formula (Ila), Ring A is pyranyl.
[0176] In some embodiments of a compound of Formula (Ila), Ring A1 is tetrahydrofuranyl.
[0177] In some embodiments of a compound of Formula (Ila), Ring A is morpholinyl.
[0178] In some embodiments of a compound of Formula (Ila), Ring A is azetidinyl.
[0179] In some embodiments of a compound of Formula (Ila), Ring A is C3-C8 cycloalkyl.
[0180] In some embodiments of a compound of Formula (Ila), Ring A is cyclopropyl.
[0181] In some embodiments of a compound of Formula (Ila), Ring A is cyclobutyl.
[0182] In some embodiments of a compound of Formula (Ila), Ring A is cyclohexyl.
[0183] In some embodiments of a compound of Formula (Ila), Ring A is cyclopentyl.
[0184] In some embodiments of a compound of Formula (Ila), Ring B is aryl.
[0185] In some embodiments of a compound of Formula (Ila), Ring B is phenyl.
[0186] In some embodiments of a compound of Formula (Ila), Ring B is naphthyl.
[0187] In some embodiments of a compound of Formula (Ila), Ring B is heteroaryl.
[0188] In some embodiments of a compound of Formula (Ila), Ring B is fused heteroaryl.
[0189] In some embodiments of a compound of Formula (Ila), Ring B is 6-membered heteroaryl.
[0190] In some embodiments of a compound of Formula (Ila), Ring B is pyridyl.
[0191] In some embodiments of a compound of Formula (Ila), Ring B is pyrimidinyl. [0192] In some embodiments of a compound of Formula (Ila), Ring B is pyrazinyl.
[0193] In some embodiments of a compound of Formula (Ila), Ring B is a 5- membered heteroaryl.
[0194] In some embodiments of a compound of Formula (Ila), Ring B is thiophenyl.
[0195] In some embodiments of a compound of Formula (Ila), Ring B is furanyl.
[0196] In some embodiments of a compound of Formula (Ila), Ring B is pyrrolyl.
[0197] In some embodiments of a compound of Formula (Ila), Ring B is thiazolyl.
[0198] In some embodiments of a compound of Formula (Ila), Ring B is oxazolyl.
[0199] In some embodiments of a compound of Formula (Ila), Ring B is isoxazolyl.
[0200] In some embodiments of a compound of Formula (Ila), Ring B is imidazolyl.
[0201] In some embodiments of a compound of Formula (Ila), Ring B is pyrazolyl.
[0202] In some embodiments of a compound of Formula (Ila), Ring B is thiadiazolyl.
[0203] In some embodiments of a compound of Formula (Ila), Ring B is oxadiazolyl.
[0204] In some embodiments of a compound of Formula (Ila), each R3 is independently hydrogen.
[0205] In some embodiments of a compound of Formula (Ila), each R3 is independently halogen.
[0206] In some embodiments of a compound of Formula (Ila), each R3 is independently Ci-Ce alkyl.
[0207] In some embodiments of a compound of Formula (Ila), each R3 is independently Ci-Ce haloalkyl.
[0208] In some embodiments of a compound of Formula (Ila), each R3 is independently fluoro.
[0209] In some embodiments of a compound of Formula (Ila), n is 1 . [0210] In some embodiments of a compound of Formula (Ila), n is 2.
[0211] In some embodiments of a compound of Formula (Ila), n is 3.
[0212] In some embodiments of a compound of Formula (Ila), n is 4.
[0213] In some embodiments of a compound of Formula (Ila), each R4 is independently halogen.
[0214] In some embodiments of a compound of Formula (Ila), each R4 is independently Ci-Ce alkyl.
[0215] In some embodiments of a compound of Formula (Ila), each R4 is independently Ci-Ce haloalkyl.
[0216] In some embodiments of a compound of Formula (Ila), each R4 is hydrogen.
[0217] In some embodiments of a compound of Formula (Ila), m is 1 .
[0218] In some embodiments of a compound of Formula (Ila), m is 2.
[0219] In some embodiments of a compound of Formula (Ila), m is 3.
[0220] In some embodiments of a compound of Formula (Ila), m is 4.
[0221] In some embodiments of a compound of Formula (Ila), each R5 is independently halogen.
[0222] In some embodiments of a compound of Formula (Ila), each R5 is independently Ci-Ce alkyl.
[0223] In some embodiments of a compound of Formula (Ila), each R5 is independently Ci-Ce haloalkyl.
[0224] In some embodiments of a compound of Formula (Ila), each R5 is hydrogen.
[0225] In some embodiments of a compound of Formula (Ila), p is 1 .
[0226] In some embodiments of a compound of Formula (Ila), p is 2.
[0227] In some embodiments of a compound of Formula (Ila), p is 3. [0228] In some embodiments of a compound of Formula (Ila), p is 4.
[0229] In some embodiments of a compound of Formula (Ila), R6 is hydrogen or Ci-
Ce alkyl.
[0230] In some embodiments of a compound of Formula (Ila), R6 is Ci-Ce alkyl.
[0231] In some embodiments of a compound of Formula (Ila), R6 is hydrogen.
[0232] In some embodiments of a compound of Formula (Ila), each R7 is independently halogen.
[0233] In some embodiments of a compound of Formula (Ila), each R7 is independently -OH.
[0234] In some embodiments of a compound of Formula (Ila), each R7 is independently Ci-Ce alkyl.
[0235] In some embodiments of a compound of Formula (Ila), each R7 is independently Ci-Ce haloalkyl.
[0236] In some embodiments of a compound of Formula (Ila), each R7 is methyl.
[0237] In some embodiments of a compound of Formula (Ila), q is 1 .
[0238] In some embodiments of a compound of Formula (Ila), q is 2.
[0239] In some embodiments of a compound of Formula (Ila), q is 3.
[0240] In some embodiments of a compound of Formula (Ila), q is 4.
[0241] In some embodiments of a compound of Formula (Ila), q is 5.
[0242] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (III):
Figure imgf000036_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L1 is -CR16R17 and L2 is a bond, or
L1 is a bond and L2 is -CR18R19, provide that L1 and L2 are not on the same carbon;
Ring A1 is aryl, heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
Ring B1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each R11 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R12 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb -NO2, - NRcRd, -S(=O)2Rd, NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd, each R13 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb -NO2, - NRcRd, -S(=O)2Rd, NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - 0C02Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd,
R14 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb -CO2Ra, -C(=O)NRcRd, 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R15 is independently hydrogen, halogen, -CN, -ORa, -SRa -S(=O)Rb -NO2, -NRcRd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R16 and R17 are independently hydrogen, taken together to form an oxo, halogen, -CN, - ORa, SRa, -S(=O)Rb, -NO2, -NRcRd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, - OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, - NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, - ORa, or -NRcRd;
R18 and R19 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -S(=O)2Rd , -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n1 is 1 -4; ml is 1 -4; p1 is 1 -4; and q1 is 1 -5. [0243] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (III):
Figure imgf000039_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L1 is -CR16R17 and L2 is a bond, or
L1 is a bond and L2 is -CR18R19, provide that L1 and L2 are not on the same carbon;
Ring A1 is aryl, heteroaryl, C2-C8 heterocycloalkyl, or C3-C8 cycloalkyl;
Ring B1 is aryl or heteroaryl; each R11 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R12 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb -NO2, - NRcRd, -S(=O)2Rd, NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd, each R13 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb -NO2, - NRcRd, -S(=O)2Rd, NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd,
R14 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb -CO2Ra, -C(=O)NRcRd, 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R15 is independently hydrogen, halogen, -CN, -ORa, -SRa -S(=O)Rb -NO2, -NRcRd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R16 and R17 are independently hydrogen, halogen, -CN, -ORa, SRa, -S(=O)Rb, -NO2, - NRcRd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R18 and R19 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -S(=O)2Rd , -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n1 is 1 -4; ml is 1 -4; p1 is 1 -4; and q1 is 1 -5.
[0244] In some embodiments of a compound of Formula (III), L1 is a bond and L2 is a bond. In some embodiments of a compound of Formula (III), one of L1 or L2 is not a bond.
[0245] In some embodiments of a compound of Formula (III), L1 is a bond and L2 is - CR18R19.
[0246] In some embodiments of a compound of Formula (III), R18 and R19 are hydrogen.
[0247] In some embodiments of a compound of Formula (III), L1 is -CR16R17- and L2 is a bond.
[0248] In some embodiments of a compound of Formula (III), R16 and R17 are hydrogen.
[0249] In some embodiments of a compound of Formula (III), Ring A1 is heteroaryl.
[0250] In some embodiments of a compound of Formula (III), Ring A1 is a 6- membered heteroaryl.
[0251] In some embodiments of a compound of Formula (III), Ring A1 is pyrimidinyl.
[0252] In some embodiments of a compound of Formula (III), Ring A1 is pyrazinyl
[0253] In some embodiments of a compound of Formula (III), Ring A1 is pyridyl.
[0254] In some embodiments of a compound of Formula (III), Ring A1 is a 5- membered heteroaryl.
[0255] In some embodiments of a compound of Formula (III), Ring A1 is thiophenyl.
[0256] In some embodiments of a compound of Formula (III), Ring A1 is furanyl.
[0257] In some embodiments of a compound of Formula (III), Ring A1 is pyrrolyl.
[0258] In some embodiments of a compound of Formula (III), Ring A1 is thiazolyl.
[0259] In some embodiments of a compound of Formula (III), Ring A1 is oxazolyl. [0260] In some embodiments of a compound of Formula (III), Ring A1 is isoxazolyl.
[0261] In some embodiments of a compound of Formula (III), Ring A1 is imidazolyl.
[0262] In some embodiments of a compound of Formula (III), Ring A1 is pyrazolyl.
[0263] In some embodiments of a compound of Formula (III), Ring A1 is thiadiazolyl.
[0264] In some embodiments of a compound of Formula (III), Ring A1 is oxadiazolyl.
[0265] In some embodiments of a compound of Formula (III), Ring A1 is C2-C8 heterocycloalkyl.
[0266] In some embodiments of a compound of Formula (III), Ring A1 is pyrrolidinyl.
[0267] In some embodiments of a compound of Formula (III), Ring A1 is piperidinyl.
[0268] In some embodiments of a compound of Formula (III), Ring A1 is piperazinyl.
[0269] In some embodiments of a compound of Formula (III), Ring A1 is pyranyl.
[0270] In some embodiments of a compound of Formula (III), Ring A1 is tetrahydrofuranyl.
[0271] In some embodiments of a compound of Formula (III), Ring A1 is morpholinyl.
[0272] In some embodiments of a compound of Formula (III), Ring A1 is C3-C8 cycloalkyl.
[0273] In some embodiments of a compound of Formula (III), Ring A1 is cyclopropyl.
[0274] In some embodiments of a compound of Formula (III), Ring A1 is cyclobutyl.
[0275] In some embodiments of a compound of Formula (III), Ring A1 is cyclohexyl.
[0276] In some embodiments of a compound of Formula (III), Ring A1 is cyclopentyl.
[0277] In some embodiments of a compound of Formula (III), Ring B1 is aryl.
[0278] In some embodiments of a compound of Formula (III), Ring B1 is phenyl.
[0279] In some embodiments of a compound of Formula (III), Ring B1 is biphenyl. [0280] In some embodiments of a compound of Formula (III), Ring B1 is heteroaryl.
[0281] In some embodiments of a compound of Formula (II), Ring B1 is fused bicyclic heteroaryl.
[0282] In some embodiments of a compound of Formula (III), Ring B1 is a 6- membered heteroaryl.
[0283] In some embodiments of a compound of Formula (III), Ring B1 is pyrimidinyl.
[0284] In some embodiments of a compound of Formula (II), Ring B1 is pyrazinyl.
[0285] In some embodiments of a compound of Formula (III), Ring B1 is pyridyl.
[0286] In some embodiments of a compound of Formula (III), Ring B1 is a 5- membered heteroaryl.
[0287] In some embodiments of a compound of Formula (III), Ring B1 is thiophenyl.
[0288] In some embodiments of a compound of Formula (III), Ring B1 is furanyl.
[0289] In some embodiments of a compound of Formula (III), Ring B1 is pyrrolyl.
[0290] In some embodiments of a compound of Formula (III), Ring B1 is thiazolyl.
[0291] In some embodiments of a compound of Formula (III), Ring B1 is oxazolyl.
[0292] In some embodiments of a compound of Formula (III), Ring B1 is isoxazolyl.
[0293] In some embodiments of a compound of Formula (III), Ring B1 is imidazolyl.
[0294] In some embodiments of a compound of Formula (III), Ring B1 is thiadiazolyl.
[0295] In some embodiments of a compound of Formula (III), Ring B1 is oxadiazolyl.
[0296] In some embodiments of a compound of Formula (III), Ring B1 is pyrazolyl.
[0297] In some embodiments of a compound of Formula (III), each R11 is independently halogen.
[0298] In some embodiments of a compound of Formula (III), each R11 is independently Ci-Ce alkyl. [0299] In some embodiments of a compound of Formula (III), each R11 is independently Ci-Ce haloalkyl.
[0300] In some embodiments of a compound of Formula (III), each R11 is hydrogen.
[0301] In some embodiments of a compound of Formula (III), n1 is 1 .
[0302] In some embodiments of a compound of Formula (III), n1 is 2.
[0303] In some embodiments of a compound of Formula (III), n1 is 3.
[0304] In some embodiments of a compound of Formula (III), n1 is 4.
[0305] In some embodiments of a compound of Formula (III), each R12 is independently halogen.
[0306] In some embodiments of a compound of Formula (III), each R12 is independently Ci-Ce alkyl.
[0307] In some embodiments of a compound of Formula (III), each R12 is independently Ci-Ce haloalkyl.
[0308] In some embodiments of a compound of Formula (III), each R12 is hydrogen.
[0309] In some embodiments of a compound of Formula (III), ml is 1 .
[0310] In some embodiments of a compound of Formula (III), ml is 2.
[0311] In some embodiments of a compound of Formula (III), ml is 3.
[0312] In some embodiments of a compound of Formula (III), ml is 4.
[0313] In some embodiments of a compound of Formula (III), each R13 is independently halogen.
[0314] In some embodiments of a compound of Formula (III), each R13 is independently Ci-Ce alkyl.
[0315] In some embodiments of a compound of Formula (III), each R13 is independently Ci-Ce haloalkyl. [0316] In some embodiments of a compound of Formula (III), each R13 is hydrogen.
[0317] In some embodiments of a compound of Formula (III), p1 is 1 .
[0318] In some embodiments of a compound of Formula (III), p1 is 2.
[0319] In some embodiments of a compound of Formula (III), p1 is 3.
[0320] In some embodiments of a compound of Formula (III), p1 is 4.
[0321] In some embodiments of a compound of Formula (III), R14 is hydrogen or Ci- Ce alkyl.
[0322] In some embodiments of a compound of Formula (III), R14 is Ci-Ce alkyl.
[0323] In some embodiments of a compound of Formula (III), R14 is hydrogen.
[0324] In some embodiments of a compound of Formula (III), each R15 is independently hydrogen.
[0325] In some embodiments of a compound of Formula (III), each R15 is independently halogen.
[0326] In some embodiments of a compound of Formula (III), each R15 is independently -OH.
[0327] In some embodiments of a compound of Formula (III), each R15 is independently Ci-Ce alkyl.
[0328] In some embodiments of a compound of Formula (III), each R15 is independently Ci-Ce haloalkyl.
[0329] In some embodiments of a compound of Formula (III), each R15 is methyl
[0330] In some embodiments of a compound of Formula (III), q1 is 1 .
[0331] In some embodiments of a compound of Formula (III), q1 is 2.
[0332] In some embodiments of a compound of Formula (III), q1 is 3.
[0333] In some embodiments of a compound of Formula (III), q1 is 4. [0334] In some embodiments of a compound of Formula (III), q1 is 5.
[0335] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (IV):
Figure imgf000047_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
Ring A2 is heteroaryl;
Ring B2 is cycloalkyl; heterocycloalkyl; aryl or heteroaryl each R21 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R22 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R23 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)RcRd, -NRaC(=O)Rb - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or - NRcRd and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa, or -NRcRd; each R25 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)RcRd, -NRaC(=O)Rb - NRaC(=O)ORa, 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, -ORa, or - NRcRd and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or Rc and Rd, 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 -NH2; n2 is 1 -4; m2 is 1 -4; p2 is 1 -4; and q2 is 1 -5.
[0336] Described herein are compounds of Formula (IV):
Figure imgf000049_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
Ring A2 is heteroaryl;
Ring B2 is aryl or heteroaryl; each R21 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R22 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R23 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)RcRd, -NRaC(=O)Rb - NRaC(=O)ORa, 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, -ORa, or - NRcRd and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa, or -NRcRd; each R25 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)RcRd, -NRaC(=O)Rb - NRaC(=O)ORa, 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, -ORa, or - NRcRd and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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; or
Rc and Rd, 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 -NH2;
[0337] In some embodiments of a compound of Formula (IV), Ring A2 is a 6- membered heteroaryl.
[0338] In some embodiments of a compound of Formula (IV), Ring A2 is pyrimidinyl.
[0339] In some embodiments of a compound of Formula (IV), Ring A2 is pyrazinyl.
[0340] In some embodiments of a compound of Formula (IV), Ring A2 is pyridyl.
[0341] In some embodiments of a compound of Formula (IV), Ring A2 is a 5- membered heteroaryl.
[0342] In some embodiments of a compound of Formula (IV), Ring A2 is thiophenyl.
[0343] In some embodiments of a compound of Formula (IV), Ring A2 is furanyl.
[0344] In some embodiments of a compound of Formula (IV), Ring A2 is pyrrolyl.
[0345] In some embodiments of a compound of Formula (IV), Ring A2 is thiazolyl. In some embodiments of a compound of Formula (IV), Ring A2 is oxazolyl.
[0346] In some embodiments of a compound of Formula (IV), Ring A2 is isoxazolyl.
[0347] In some embodiments of a compound of Formula (IV), Ring A2 is imidazolyl.
[0348] In some embodiments of a compound of Formula (IV), 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.
[0350] In some embodiments of a compound of Formula (IV), Ring B2 is aryl.
[0351] In some embodiments of a compound of Formula (IV), Ring B2 is phenyl.
[0352] In some embodiments of a compound of Formula (IV), Ring B2 is biphenyl.
[0353] In some embodiments of a compound of Formula (IV), Ring B2 is heteroaryl.
[0354] In some embodiments of a compound of Formula (IV), Ring B2 is a 6- membered heteroaryl.
[0355] In some embodiments of a compound of Formula (IV), Ring B2 is pyrimidinyl.
[0356] In some embodiments of a compound of Formula (IV), Ring B2 is pyrazinyl.
[0357] In some embodiments of a compound of Formula (IV), Ring B2 is pyridyl.
[0358] In some embodiments of a compound of Formula (IV), Ring B2 is a 5- membered heteroaryl.
[0359] In some embodiments of a compound of Formula (IV), Ring B2 is thiophenyl.
[0360] In some embodiments of a compound of Formula (IV), Ring B2 is furanyl.
[0361] In some embodiments of a compound of Formula (IV), Ring B2 is pyrrolyl.
[0362] In some embodiments of a compound of Formula (IV), Ring B2 is thiazolyl.
[0363] In some embodiments of a compound of Formula (IV), Ring B2 is oxazolyl.
[0364] In some embodiments of a compound of Formula (IV), Ring B2 is isoxazolyl.
[0365] In some embodiments of a compound of Formula (IV), Ring B2 is imidazolyl.
[0366] In some embodiments of a compound of Formula (IV), Ring B2 is thiadiazolyl.
[0367] In some embodiments of a compound of Formula (IV), Ring B2 oxadiazolyl. In some embodiments of a compound of Formula (III), Ring B2 is pyrazolyl. [0368] In some embodiments of a compound of Formula (IV), each R21 is independently halogen.
[0369] In some embodiments of a compound of Formula (IV), each R21 is independently Ci-Ce alkyl.
[0370] In some embodiments of a compound of Formula (IV), each R21 is independently Ci-Ce haloalkyl.
[0371] In some embodiments of a compound of Formula (IV), each R21 is hydrogen.
[0372] In some embodiments of a compound of Formula (IV), n2 is 1 .
[0373] In some embodiments of a compound of Formula (IV), n2 is 2.
[0374] In some embodiments of a compound of Formula (IV), n2 is 3.
[0375] In some embodiments of a compound of Formula (IV), n2 is 4.
[0376] In some embodiments of a compound of Formula (IV), each R22 is independently halogen.
[0377] In some embodiments of a compound of Formula (IV), each R22 is independently Ci-Ce alkyl.
[0378] In some embodiments of a compound of Formula (IV), each R22 is independently Ci-Ce haloalkyl.
[0379] In some embodiments of a compound of Formula (IV), each R22 is hydrogen.
[0380] In some embodiments of a compound of Formula (IV), m2 is 1 .
[0381] In some embodiments of a compound of Formula (IV), m2 is 2.
[0382] In some embodiments of a compound of Formula (IV), m2 is 3.
[0383] In some embodiments of a compound of Formula (IV), m2 is 4.
[0384] In some embodiments of a compound of Formula (IV), each R23 is independently halogen. [0385] In some embodiments of a compound of Formula (IV), each R23 is independently Ci-Ce alkyl.
[0386] In some embodiments of a compound of Formula (IV), each R23 is independently Ci-Ce haloalkyl.
[0387] In some embodiments of a compound of Formula (IV), each R23 is hydrogen.
[0388] In some embodiments of a compound of Formula (IV), p2 is 1 .
[0389] In some embodiments of a compound of Formula (IV), p2 is 2.
[0390] In some embodiments of a compound of Formula (IV), p2 is 3.
[0391] In some embodiments of a compound of Formula (IV), p2 is 4.
[0392] In some embodiments of a compound of Formula (IV), each R25 is independently hydrogen.
[0393] In some embodiments of a compound of Formula (IV), each R25 is independently halogen.
[0394] In some embodiments of a compound of Formula (IV), each R25 is independently -OH.
[0395] In some embodiments of a compound of Formula (IV), each R25 is independently Ci-Ce alkyl.
[0396] In some embodiments of a compound of Formula (IV), each R25 is independently Ci-Ce haloalkyl.
[0397] In some embodiments of a compound of Formula (IV), each R25 is methyl
[0398] In some embodiments of a compound of Formula (IV), q2 is 1 .
[0399] In some embodiments of a compound of Formula (IV), q2 is 2.
[0400] In some embodiments of a compound of Formula (IV), q2 is 3.
[0401] In some embodiments of a compound of Formula (IV), q2 is 4. [0402] In some embodiments of a compound of Formula (IV), q2 is 5.
[0403] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (V):
Figure imgf000055_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
Ring B3 is Cs-Cs cycloalkyl, C2-Cs heterocycloalkyl, aryl, heteroaryl; each R31 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-C6 alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Ci-Cs heteroalkyl, Ca-Cs cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Cs alkyl, Ci-Cs haloalkyl, -ORa, or -NRcRd; each R32 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa. Ci-C6 alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Ci-Cs heteroalkyl, Ca-Cs cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R34 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb -CO2Ra, -C(=O)NRcRd, Ci-C6 alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R35 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa. Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R36 and R37 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb -NO2, - NRcRd, -S(=O)2Rd, NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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;
Rb is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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 Rc and Rd are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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; or
Rc and Rd, 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 -NH2; n3 is 1 -4; m3 is 1 -4; and q3 is 1 -5
[0404] In some embodiments of a compound of Formula (V), Ring B3 is aryl.
[0405] In some embodiments of a compound of Formula (V), Ring B3 is phenyl.
[0406] In some embodiments of a compound of Formula (V), Ring B3 is naphthyl.
[0407] In some embodiments of a compound of Formula (V), Ring B3 is heteroaryl.
[0408] In some embodiments of a compound of Formula (V), Ring B3 is a 6- membered heteroaryl.
[0409] In some embodiments of a compound of Formula (V), Ring B3 is pyrimidinyl.
[0410] In some embodiments of a compound of Formula (V), Ring B3 is pyrazinyl.
[0411] In some embodiments of a compound of Formula (IV), Ring B3 is pyridyl.
[0412] In some embodiments of a compound of Formula (V), Ring B3 is a 5- membered heteroaryl.
[0413] In some embodiments of a compound of Formula (V), Ring B3 is thiophenyl.
[0414] In some embodiments of a compound of Formula (V), Ring B3 is furanyl. [0415] In some embodiments of a compound of Formula (V), Ring B3 is pyrrolyl.
[0416] In some embodiments of a compound of Formula (V), Ring B3 is thiazolyl.
[0417] In some embodiments of a compound of Formula (V), Ring B3 is oxazolyl.
[0418] In some embodiments of a compound of Formula (V), Ring B3 is isoxazolyl.
[0419] In some embodiments of a compound of Formula (V), Ring B3 is imidazolyl.
[0420] In some embodiments of a compound of Formula (V), Ring B3 is thiadiazolyl.
[0421] In some embodiments of a compound of Formula (V), Ring B3 is oxadiazolyl.
[0422] In some embodiments of a compound of Formula (V), Ring B3 is pyrazolyl.
[0423] In some embodiments of a compound of Formula (V), each R31 is independently hydrogen.
[0424] In some embodiments of a compound of Formula (V), each R31 is independently halogen.
[0425] In some embodiments of a compound of Formula (V), each R31 is independently Ci-Ce alkyl.
[0426] In some embodiments of a compound of Formula (V), each R3 is independently Ci-Ce haloalkyl.
[0427] In some embodiments of a compound of Formula (V), n3 is 1 .
[0428] In some embodiments of a compound of Formula (V), n3 is 2.
[0429] In some embodiments of a compound of Formula (V), n3 is 3.
[0430] In some embodiments of a compound of Formula (V), n3 is 4.
[0431] In some embodiments of a compound of Formula (V), each R32 is independently halogen.
[0432] In some embodiments of a compound of Formula (V), each R32 is independently Ci-Ce alkyl. [0433] In some embodiments of a compound of Formula (V), each R32 is independently Ci-Ce haloalkyl.
[0434] In some embodiments of a compound of Formula (V), each R32 is hydrogen.
[0435] In some embodiments of a compound of Formula (V), m3 is 1 .
[0436] In some embodiments of a compound of Formula (V), m3 is 2.
[0437] In some embodiments of a compound of Formula (V), m3 is 3.
[0438] In some embodiments of a compound of Formula (V), m3 is 4.
[0439] In some embodiments of a compound of Formula (V), each R34 is hydrogen or Ci-C6 alkyl.
[0440] In some embodiments of a compound of Formula (V), each R34 is Ci-Ce alkyl.
[0441] In some embodiments of a compound of Formula (V), each R34 is hydrogen.
[0442] In some embodiments of a compound of Formula (V), each R35 is independently hydrogen.
[0443] In some embodiments of a compound of Formula (V), each R35 is independently halogen.
[0444] In some embodiments of a compound of Formula (V), each R35 is independently -OH.
[0445] In some embodiments of a compound of Formula (V), each R35 is independently Ci-Ce alkyl.
[0446] In some embodiments of a compound of Formula (V), each R35 is independently Ci-Ce haloalkyl.
[0447] In some embodiments of a compound of Formula (V), each R35 is methyl.
[0448] In some embodiments of a compound of Formula (V), q3 is 1 .
[0449] In some embodiments of a compound of Formula (V), q3 is 2. [0450] In some embodiments of a compound of Formula (V), q3 is 3.
[0451] In some embodiments of a compound of Formula (V), q3 is 4.
[0452] In some embodiments of a compound of Formula (V), q3 is 5.
[0453] In some embodiments of a compound of Formula (V), each R36 and R37 is hydrogen, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.
[0454] In some embodiments of a compound of Formula (V), each R36 and R37 are hydrogen.
[0455] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (VI):
Figure imgf000060_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L43 is -C(R43)2C(R43)2 C(R43)2-;
L43 is a bond or -CR46R47-;
Ring B4 is heteroaryl or C2-C8 heterocycloalkyl; each R41 is independently halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R42 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, C1-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R43 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R44 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R45 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R45 on the same carbon are taken together to form an oxo; Ra is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
[0456] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (VI):
Figure imgf000063_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L43 is -C(R43)2C(R43)2 C(R43)2-;
L43 is a bond or -CR46R47-;
Ring B4 is heteroaryl or C2-C8 heterocycloalkyl; each R41 is independently halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R42 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R43 are independently hydrogen, halogen, CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R44 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R45 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R45 on the same carbon are taken together to form an oxo;
Ra is hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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;
Rb is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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 Rc and Rd are independently hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; or
Rc and Rd, 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 -NH2; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
[0457] In some embodiments of a compound of Formula (VI), L44 is a bond.
[0458] In some embodiments of a compound of Formula (VI), L44 is -CR46R47 -.
[0459] In some embodiments of a compound of Formula (VI), R46 and R47 are independently hydrogen.
[0460] In some embodiments of a compound of Formula (VI), R46 and R47 are independently halogen.
[0461] In some embodiments of a compound of Formula (VI), R46 and R47 are independently fluoro.
[0462] In some embodiments of a compound of Formula (VI), R46 and R47 are independently aryl.
[0463] In some embodiments of a compound of Formula (VI), R46 and R47 are independently heteroaryl.
[0464] In some embodiments of a compound of Formula (VI), R46 and R47 are independently -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, - S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd;
[0465] In some embodiments of a compound of Formula (VI), R46 and R47 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, -ORa or -NRcRd.
[0466] In some embodiments of a compound of Formula (VI), Ring B4 is heterocycloalkyl.
[0467] In some embodiments of a compound of Formula (VI), Ring B4 is C2-C8 heterocycloalkyl.
[0468] In some embodiments of a compound of Formula (VI), Ring B4 is pyrrolidinyl.
[0469] In some embodiments of a compound of Formula (VI), Ring B4 is piperidinyl.
[0470] In some embodiments of a compound of Formula (VI), Ring B4 is piperazinyl.
[0471] In some embodiments of a compound of Formula (VI), Ring B4 is pyranyl.
[0472] In some embodiments of a compound of Formula (VI), Ring B4 is tetrahydrofuranyl.
[0473] In some embodiments of a compound of Formula (VI), Ring B4 is morpholinyl.
[0474] In some embodiments of a compound of Formula (VI), Ring B4 is heteroaryl.
[0475] In some embodiments of a compound of Formula (VI), Ring B4 is 6-membered heteroaryl.
[0476] In some embodiments of a compound of Formula (VI), Ring B4 is pyrimidinyl.
[0477] In some embodiments of a compound of Formula (VI), Ring B4 is pyrazinyl.
[0478] In some embodiments of a compound of Formula (VI), Ring B4 is pyridyl.
[0479] In some embodiments of a compound of Formula (VI), Ring B4 is a 5- membered heteroaryl. [0480] In some embodiments of a compound of Formula (VI), Ring B4 is thiophenyl.
[0481] In some embodiments of a compound of Formula (VI), Ring B4 is furanyl.
[0482] In some embodiments of a compound of Formula (VI), Ring B4 is pyrrolyl.
[0483] In some embodiments of a compound of Formula (VI), Ring B4 is thiazolyl.
[0484] In some embodiments of a compound of Formula (VI), Ring B4 is oxazolyl.
[0485] In some embodiments of a compound of Formula (VI), Ring B4 is isoxazolyl.
[0486] In some embodiments of a compound of Formula (VI), Ring B4 is imidazolyl.
[0487] In some embodiments of a compound of Formula (VI), Ring B4 is pyrazolyl.
[0488] In some embodiments of a compound of Formula (VI), Ring B4 is thiadiazolyl.
[0489] In some embodiments of a compound of Formula (VI), Ring B4 is oxadiazolyl.
[0490] In some embodiments of a compound of Formula (VI), Ring B4 is C7-C9 heteroaryl.
[0491] In some embodiments of a compound of Formula (VI), Ring B4 is indolyl.
[0492] In some embodiments of a compound of Formula (VI), Ring B4 is indazolyl.
[0493] In some embodiments of a compound of Formula (VI), Ring B4 is benzofuranyl.
[0494] In some embodiments of a compound of Formula (VI), Ring B4 is a fused bicyclic ring.
[0495] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (Via):
Figure imgf000068_0001
pharmaceutically acceptable salt or prodrug thereof, wherein;
L43 is -C(R43)2C(R43)2 C(R43)2-;
Ring B4 is fused bicyclic heteroaryl comprising at least two nitrogen atoms in the rings, or fused heteroaryl comprising at least one non-aromatic ring; each R41 is independently halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R42 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R43 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R44 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R45 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R45 on the same carbon are taken together to form an oxo;
Ra is hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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;
Rb is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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 Rc and Rd are independently hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; or
Rc and Rd, 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 -NH2; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
[0496] In some embodiments of a compound of Formula (VI), the compound has the Formula (Via):
Figure imgf000070_0001
pharmaceutically acceptable salt or prodrug thereof, wherein;
L43 is -C(R43)2C(R43)2 C(R43)2-;
Ring B4 is fused bicyclic heteroaryl comprising at least two nitrogen atoms in the rings, or fused heteroaryl comprising at least one non-aromatic ring; each R41 is independently halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R42 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R43 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R44 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R45 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R45 on the same carbon are taken together to form an oxo;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n4 is 1 -5; m4 is 1 -4; and q4 is 1 -5.
[0497] In some embodiments of a compound of Formula (V) or Formula (Via), each R41 is independently halogen. [0498] In some embodiments of a compound of Formula (V) or Formula (Via), each R41 is independently fluoro.
[0499] In some embodiments of a compound of Formula (V) or Formula (Via), each R41 is independently Ci-Ce alkyl.
[0500] In some embodiments of a compound of Formula (V) or Formula (Via), each R41 is independently Ci-Ce haloalkyl.
[0501] In some embodiments of a compound of Formula (V) or Formula (Via), n4 is 1 .
[0502] In some embodiments of a compound of Formula (V) or Formula (Via), n4 is 2.
[0503] In some embodiments of a compound of Formula (V) or Formula (Via), n4 is 3.
[0504] In some embodiments of a compound of Formula (V) or Formula (Via), n4 is 4.
[0505] In some embodiments of a compound of Formula (V) or Formula (Via), n4 is 4.
[0506] In some embodiments of a compound of Formula (V) or Formula (Via), n4 is 5.
[0507] In some embodiments of a compound of Formula (V) or Formula (Via), each
R42 is independently halogen.
[0508] In some embodiments of a compound of Formula (V) or Formula (Via), each R42 is independently Ci-Ce alkyl.
[0509] In some embodiments of a compound of Formula (V) or Formula (Via), each R42 is independently Ci-Ce haloalkyl.
[0510] In some embodiments of a compound of Formula (V) or Formula (Via), each R42 is hydrogen.
[0511] In some embodiments of a compound of Formula (V) or Formula (Via), m4 is
1.
[0512] In some embodiments of a compound of Formula (V) or Formula (Via), m4 is
2.
[0513] In some embodiments of a compound of Formula (V) or Formula (Via), m4 is
3. [0514] In some embodiments of a compound of Formula (V) or Formula (Via), m4 is 4.
[0515] In some embodiments of a compound of Formula (V) or Formula (Via), each R43 is independently halogen.
[0516] In some embodiments of a compound of Formula (V) or Formula (Via), each R43 is independently Ci-Ce alkyl.
[0517] In some embodiments of a compound of Formula (V) or Formula (Via), each R43 is independently Ci-Ce haloalkyl.
[0518] In some embodiments of a compound of Formula (V) or Formula (Via), each R43 is hydrogen.
[0519] In some embodiments of a compound of Formula (V) or Formula (Via), each R44 is hydrogen or Ci-Ce alkyl.
[0520] In some embodiments of a compound of Formula (V) or Formula (Via), each R44 is Ci-C6 alkyl.
[0521] In some embodiments of a compound of Formula (V) or Formula (Via), each R44 is hydrogen.
[0522] In some embodiments of a compound of Formula (V) or Formula (Via), each R44 is methyl.
[0523] In some embodiments of a compound of Formula (V) or Formula (Via), q4 is 1 .
[0524] In some embodiments of a compound of Formula (V) or Formula (Via), q4 is 2.
[0525] In some embodiments of a compound of Formula (V) or Formula (Via), q4 is 3.
[0526] In some embodiments of a compound of Formula (V) or Formula (Via), q4 is 4.
[0527] In some embodiments of a compound of Formula (V) or Formula (Via), q4 is 5.
[0528] In some embodiments of a compound of Formula (V) or Formula (Via), Ring
B4 is fused bicyclic heteroaryl comprising at least two nitrogen atoms in the rings. [0529] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring B4 is cinnolinyl.
[0530] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring B4 is quinazolinyl.
[0531] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring B4 is quinoxalinyl.
[0532] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring B4 is indazolyl.
[0533] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring B4 is benzoimidazolyl.
[0534] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring B4 is selected from the group consisting of:
Figure imgf000075_0001
Figure imgf000075_0002
each optionally substituted with one or more R45; wherein: each R48 is independently hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, - CO2Ra, -C(=O)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
[0535] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring
R48 At >
B4 is , optionally substituted with one or more R45. [0536] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring
Figure imgf000076_0003
[0538] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring ionally substituted with one or more R45. odiments of a compound of Formula (VI) or Formula (Via), Ring
Figure imgf000076_0001
, optionally substituted with one or more R45.
[0540] In some embodiments of a compound of Formula (VI) or Formula (Via), Ring ptionally substituted with one or more R45. odiments of a compound of Formula (VI) or Formula (Via), Ring
Figure imgf000076_0002
, optionally substituted with one or more R45.
[0542] In some embodiments of a compound of Formula (VI) or Formula (Via), each R45 is independently hydrogen
[0543] In some embodiments of a compound of Formula (VI) or Formula (Via), each R45 is independently S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb -CO2Ra, - C(=O)NRcRd. [0544] In some embodiments of a compound of Formula (VI) or Formula (Via), R45 is independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or - NRcRd.
[0545] In some embodiments of a compound of Formula (VI) or Formula (Via), each R45 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, -ORa or -NRcRd.
[0546] In some embodiments of a compound of Formula (VI) or Formula (Via), two R45 on the same carbon are taken together to form an oxo.
[0547] In some embodiments of a compound of Formula (VI) or Formula (Via), R45 is hydrogen or C1-C5 alkyl.
[0548] In some embodiments of a compound of Formula (VI) or Formula (Via), each R48 is independently hydrogen.
[0549] In some embodiments of a compound of Formula (VI) or Formula (Via), each R48 is independently halogen.
[0550] In some embodiments of a compound of Formula (VI) or Formula (Via), each R48 is independently taken together to form an oxo.
[0551] In some embodiments of a compound of Formula (VI) or Formula (Via), each R48 is independently -CN, -ORa -SRa, -S(=O)Rb, -NO2.
[0552] In some embodiments of a compound of Formula (VI) or Formula (Via), each R48 is independently -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, - OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, -NRaC(=O)NRcRd.
[0553] In some embodiments of a compound of Formula (VI) or Formula (Via), each R48 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, -ORa, or -NRcRd. [0554] In some embodiments of a compound of Formula (VI) or Formula (Via), each R48 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 -ORa, or -NRcRd.
[0555] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (VII):
Figure imgf000078_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L53 is -C(R53)2C(R53)2 C(R53)2-;
L55 is O;
Ring B5 is aryl, heteroaryl or C2-C8 heterocycloalkyl; each R51 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, -(Ci-Ce alkyl)-NRcRd, 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, - ORa, or -NRcRd; each R52 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R53 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R54 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R55 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, (-S(=O)2Rd), -NO2, -NRcRd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2; Rb is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n5 is 1 -5; m5 is 1 -4; and
[0556] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000080_0001
; wherein:
L53 is -C(R53)2C(R53)2 C(R53)2-;
L55 is O;
Ring B5 is aryl, heteroaryl or C2-C8 heterocycloalkyl; each R51 is independently halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, -(Ci-C6 alkyl)-NRcRd, C1-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R52 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R53 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R54 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R55 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, (-S(=O)2Rd), -NO2, -NRcRd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n5 is 1 -5; m5 is 1 -4; and q5 is 1 -5.
[0557] In some embodiments of a compound of Formula (VII), Ring B5 is aryl.
[0558] In some embodiments of a compound of Formula (VII), Ring B5 is phenyl.
[0559] In some embodiments of a compound of Formula (VII), Ring B5 is naphthyl.
[0560] In some embodiments of a compound of Formula (VII), Ring B5 is heterocycloalkyl.
[0561] In some embodiments of a compound of Formula (VII), Ring B5 is C2-C8 heterocycloalkyl.
[0562] In some embodiments of a compound of Formula (VII), Ring B5 is pyrrolidinyl.
[0563] In some embodiments of a compound of Formula (VII), Ring B5 is piperidinyl.
[0564] In some embodiments of a compound of Formula (VII), Ring B5 is piperazinyl.
[0565] In some embodiments of a compound of Formula (VII), Ring B5 is pyranyl.
[0566] In some embodiments of a compound of Formula (VII), Ring B5 is tetrahydrofuranyl.
[0567] In some embodiments of a compound of Formula (VII), Ring B5 is morpholinyl.
[0568] In some embodiments of a compound of Formula (VII), Ring B5 is a 6- membered heteroaryl.
[0569] In some embodiments of a compound of Formula (VII), Ring B5 is pyrimidinyl.
[0570] In some embodiments of a compound of Formula (VII), Ring B5 is pyrazinyl.
[0571] In some embodiments of a compound of Formula (VII), Ring B5 is pyridyl.
[0572] In some embodiments of a compound of Formula (VII), Ring B5 is a 5- membered heteroaryl.
[0573] In some embodiments of a compound of Formula (VII), Ring B5 is thiophenyl.
[0574] In some embodiments of a compound of Formula (VII), Ring B5 is furanyl. [0575] In some embodiments of a compound of Formula (VII), Ring B5 is pyrrolyl.
[0576] In some embodiments of a compound of Formula (VII), Ring B5 is thiazolyl.
[0577] In some embodiments of a compound of Formula (VII), Ring B5 is oxazolyl.
[0578] In some embodiments of a compound of Formula (VII), Ring B5 is isoxazolyl.
[0579] In some embodiments of a compound of Formula (VII), Ring B5 is imidazolyl.
[0580] In some embodiments of a compound of Formula (VII), Ring B5 is thiadiazolyl.
[0581] In some embodiments of a compound of Formula (VII), Ring B5 is oxadiazolyl.
[0582] In some embodiments of a compound of Formula (VII), Ring B5 is pyrazolyl.
[0583] In some embodiments of a compound of Formula (VII), each R51 is independently halogen.
[0584] In some embodiments of a compound of Formula (VII), each R51 is independently Ci-Ce alkyl.
[0585] In some embodiments of a compound of Formula (VII), each R51 is independently Ci-Ce haloalkyl.
[0586] In some embodiments of a compound of Formula (VII), each R51 is independently fluoro.
[0587] In some embodiments of a compound of Formula (VII), n5 is 1 .
[0588] In some embodiments of a compound of Formula (VII), n5 is 2.
[0589] In some embodiments of a compound of Formula (VII), n5 is 3.
[0590] In some embodiments of a compound of Formula (VII), n5 is 4.
[0591] In some embodiments of a compound of Formula (VII), n5 is 5.
[0592] In some embodiments of a compound of Formula (VII), each R52 is independently halogen. [0593] In some embodiments of a compound of Formula (VII), each R52 is independently Ci-Ce alkyl.
[0594] In some embodiments of a compound of Formula (VII), each R52 is independently Ci-Ce haloalkyl.
[0595] In some embodiments of a compound of Formula (VII), each R52 is independently hydrogen.
[0596] In some embodiments of a compound of Formula (VII), m5 is 1 .
[0597] In some embodiments of a compound of Formula (VII), m5 is 2.
[0598] In some embodiments of a compound of Formula (VII), m5 is 3.
[0599] In some embodiments of a compound of Formula (VII), m5 is 4.
[0600] In some embodiments of a compound of Formula (VII), each R53 is independently halogen.
[0601] In some embodiments of a compound of Formula (VII), each R53 is independently Ci-Ce alkyl.
[0602] In some embodiments of a compound of Formula (VII), each R53 is independently Ci-Ce haloalkyl.
[0603] In some embodiments of a compound of Formula (VII), each R53 is independently hydrogen.
[0604] In some embodiments of a compound of Formula (VII), each R54 is hydrogen or Ci-C6 alkyl.
[0605] In some embodiments of a compound of Formula (VII), each R54 is Ci-Ce alkyl.
[0606] In some embodiments of a compound of Formula (VII), each R54 is hydrogen.
[0607] In some embodiments of a compound of Formula (VII), each R55 is independently hydrogen.
[0608] In some embodiments of a compound of Formula (VII), each R55 is independently halogen. [0609] In some embodiments of a compound of Formula (VII), each R55 is independently -OH.
[0610] In some embodiments of a compound of Formula (VII), each R55 is independently Ci-Ce alkyl.
[0611] In some embodiments of a compound of Formula (VII), each R55 is independently Ci-Ce haloalkyl.
[0612] In some embodiments of a compound of Formula (VII), each R55 is methyl.
[0613] In some embodiments of a compound of Formula (VII), q5 is 1 .
[0614] In some embodiments of a compound of Formula (VII), q5 is 2.
[0615] In some embodiments of a compound of Formula (VII), q5 is 3.
[0616] In some embodiments of a compound of Formula (VII), q5 is 4.
[0617] In some embodiments of a compound of Formula (VII), q5 is 5.
[0618] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (VIII):
Figure imgf000086_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L63 is -C(R63)2C(R63)2-;
L66 is O, NR66, S, SO, or SO2;
Ring B6 is aryl, heteroaryl, or C2-C8 heterocyclyl; each R61 is independently hydrogen, fluoro, chloro, bromo, iodo, -CN, -ORa, -SRa, -
S(=O)Rb -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, - OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, - NRaC(=O)Rb, -NRaC(=O)ORa, -N=CRaRb , Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, - ORa or -NRcRd; each R62 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R63 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R64 and R66 are independently hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, - C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, - ORa, or -NRcRd; each R65 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, (-S(=O)2Rd), -NO2, -NRcRd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n6 is 1 -5; m6 is 1 -4; and q6 is 1 -5.
[0619] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000089_0001
wherein:
L63 is -C(R63)2C(R63)2-;
L66 is O, NR66, S, SO, or SO2;
Ring B6 is aryl, heteroaryl, or C2-C8 heterocyclyl; each R61 is independently fluoro, chloro, bromo, iodo, -CN, -ORa, -SRa, -S(=O)Rb -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, -N=CRaRb, 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, - ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or - NRcRd; each R62 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R63 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R64 and R66 are independently hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, - C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, - ORa, or -NRcRd; each R65 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, (-S(=O)2Rd), -NO2, -NRcRd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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; or
Rc and Rd, 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 -NH2; n6 is 1 -5; m6 is 1 -4; and q6 is 1 -5
[0620] In some embodiments of a compound of Formula (VIII), L66 is O, NR66, or S.
[0621] In some embodiments of a compound of Formula (VIII), L66 is O or NR66.
[0622] In some embodiments of a compound of Formula (VIII), L66 is O.
[0623] In some embodiments of a compound of Formula (VIII), the compound has the
Formula (Villa):
Figure imgf000091_0001
(Villa), or a pharmaceutically acceptable salt or prodrug thereof, wherein: L63 is -C(R63)2C(R63)2-;
L66 is O, NR66, S, SO, or SO2;
Ring B6 is aryl, heteroaryl, or C2-C8 heterocyclyl; each R61 is independently fluoro, chloro, bromo, iodo, -CN, -ORa, -SRa, -S(=O)Rb -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, -N=CRaRb, 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, - ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or - NRcRd; each R62 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R63 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R64 and R66 are independently hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, - C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, Ci-Ce haloalkyl, - ORa, or -NRcRd; each R65 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, (-S(=O)2Rd), -NO2, -NRcRd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or Rc and Rd, 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 -NH2; n6 is 1 -5; m6 is 1 -4; and q6 is 1 -5
[0624] In some embodiments of a compound of Formula (VIII), the compound has the Formula (Villa):
Figure imgf000094_0001
(Villa), or a pharmaceutically acceptable salt or prodrug thereof, wherein:
L63 is -C(R63)2C(R63)2-;
L66 is O, NR66, S, SO, or SO2;
Ring B6 is aryl, heteroaryl, or C2-C8 heterocyclyl; each R61 is independently fluoro, chloro, bromo, iodo, -CN, -ORa, -SRa, -S(=O)Rb -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, -N=CRaRb, 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, - ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or - NRcRd; each R62 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, C1-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R63 are independently hydrogen, halogen, two R43 on the same carbon are taken together to form an oxo, CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;
R64 and R66 are independently hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, - C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, - ORa, or -NRcRd; each R65 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, (-S(=O)2Rd), -NO2, -NRcRd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; Ra is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n6 is 1 -5; m6 is 1 -4; and q6 is 1 -5
[0625] In some embodiments of a compound of Formula (Villa), L67 is NR66, or S.
[0626] In some embodiments of a compound of Formula (Villa), L66 is NR66.
[0627] In some embodiments of a compound of Formula (VIII) or Formula (Villa),
Ring B6 is aryl. [0628] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is phenyl.
[0629] In some embodiments of a compound of Formula (VIII) or Formula (Vllia), Ring B6 is napthyl.
[0630] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is heterocycloalkyl.
[0631] In some embodiments of a compound of Formula (VII) or Formula (Villa), Ring B6 is C2-C8 heterocycloalkyl.
[0632] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is pyrrolidinyl.
[0633] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is piperidinyl.
[0634] In some embodiments of a compound of Formula (VIII) or Formula (Vila), Ring B6 is piperazinyl.
[0635] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is pyranyl.
[0636] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is tetrahydrofuranyl.
[0637] In some embodiments of a compound of Formula (VII) or Formula (Vlia), Ring B6 is morpholinyl.
[0638] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is heteroaryl.
[0639] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is a 6-membered heteroaryl.
[0640] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is pyrimidinyl. [0641] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is pyrazinyl.
[0642] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is pyridyl.
[0643] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is a 5-membered heteroaryl.
[0644] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is thiophenyl.
[0645] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is furanyl.
[0646] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is pyrrolyl.
[0647] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is thiazolyl.
[0648] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is oxazolyl.
[0649] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is isoxazolyl.
[0650] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is imidazolyl.
[0651] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is thiadiazolyl.
[0652] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is oxadiazolyl.
[0653] In some embodiments of a compound of Formula (VIII) or Formula (Villa), Ring B6 is pyrazolyl. [0654] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R61 is independently halogen.
[0655] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R61 is independently Ci-Ce alkyl.
[0656] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R61 is independently Ci-Ce haloalkyl.
[0657] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R61 is independently fluoro.
[0658] In some embodiments of a compound of Formula (VIII) or Formula (Villa), n6 is 1 .
[0659] In some embodiments of a compound of Formula (VIII) or Formula (Villa), n6 is 2.
[0660] In some embodiments of a compound of Formula (VIII) or Formula (Villa), n6 is 3.
[0661] In some embodiments of a compound of Formula (VIII) or Formula (Villa), n6 is 4.
[0662] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R63 is independently halogen.
[0663] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R63 is independently Ci-Ce alkyl.
[0664] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R63 is independently Ci-Ce haloalkyl.
[0665] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R63 is hydrogen.
[0666] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R64 is hydrogen or Ci-Ce alkyl. [0667] In some embodiments of a compound of Formula (VIII) or Formula (Villa), R64 is independently Ci-Ce alkyl.
[0668] In some embodiments of a compound of Formula (VIII) or Formula (Villa), R64 is hydrogen.
[0669] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R65 is independently hydrogen.
[0670] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R65 is independently halogen.
[0671] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R65 is independently -OH.
[0672] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R65 is independently Ci-Ce alkyl.
[0673] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R65 is independently hydrogen or Ci-Ce haloalkyl.
[0674] In some embodiments of a compound of Formula (VIII) or Formula (Villa), each R65 is independently methyl.
[0675] In some embodiments of a compound of Formula (VIII) or Formula (Villa), q6 is 1 .
[0676] In some embodiments of a compound of Formula (VIII) or Formula (Villa), q6 is 2.
[0677] In some embodiments of a compound of Formula (VIII) or Formula (Villa), q6 is 3.
[0678] In some embodiments of a compound of Formula (VIII) or Formula (Villa), q6 is 4.
[0679] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (IV):
Figure imgf000101_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L83 is -C(R83)2C(R83)2C(R83)2-, -C(R83)2C(R83)2-, -OC(R83)2C(R83)-, or -SC(R83)2C(R83)- ;
E is -C(=O)NR84-, -NR84C(=O)-, -S(=O)2NR84-, -NR84S(=O)2-, NR84C(=O)=-, - OC(=O)NR84-, -NR84C(=O)NR84-, oxadiazole, thiadiazole, or sulphonamide;
L84 is a bond or -CR86R87-;
Rings D8 and B8 are independently aryl, heteroaryl, C2-C8 heterocyclyl, or C3-C8 cycloalkyl; wherein D8 is C-linked or N-linked; each R81 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R82 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd;
R84 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R85 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R85 on the same carbon are taken together to form an oxo;
R86 and R87 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, - S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci -Ce alkyl, Ci -Ce haloalkyl, -ORa, or -NRcRd.
Ra is hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n8 is 1 -5; m8 is 1 -4; and q8 is 1 -5.
[0680] Described herein are compounds of Formula (IV):
Figure imgf000103_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L83 is -C(R83)2C(R83)2C(R83)2-, -C(R83)2C(R83)2-, -OC(R83)2C(R83)-, or -SC(R83)2C(R83)- ;
E is -C(=O)NR84-, -NR84C(=O)-, -S(=O)2NR84-, -NR84S(=O)2-, NR84C(=O)=-, - OC(=O)NR84-, -NR84C(=O)NR84-, oxadiazole, thiadiazole, or sulphonamide; L84 is a bond or -CR86R87-;
Rings D8 and B8 are independently aryl, heteroaryl, C2-C8 heterocyclyl, or C3-C8 cycloalkyl; wherein D8 is C-linked or N-linked; each R81 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd;
R84 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R85 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R45 on the same carbon are taken together to form an oxo;
R86 and R87 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, - S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci -Ce alkyl, Ci -Ce haloalkyl, -ORa, or -NRcRd.
Ra is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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;
Rb is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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 Rc and Rd are independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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; or
Rc and Rd, 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 -NH2; n8 is 1 -5; m8 is 1 -4; and q8 is 1 -5.
[0681] In some embodiments of a compound of Formula (IV), L83 is a bond.
[0682] In some embodiments of a compound of Formula (IV), L83 is -CR83R83-.
[0683] In some embodiments of a compound of Formula (IV), L83 is -
C(R83)2C(R83)2C(R83)2-.
[0684] In some embodiments of a compound of Formula (IV), L83 is -OC(R83)2C(R83)-.
[0685] In some embodiments of a compound of Formula (IV), L83 is -SC(R83)2C(R83)-.
[0686] In some embodiments of a compound of Formula (IV), R83 is independently hydrogen.
[0687] In some embodiments of a compound of Formula (IV), R83 is independently halogen.
[0688] In some embodiments of a compound of Formula (IV), R83 is independently fluoro.
[0689] In some embodiments of a compound of Formula (IV), R83 is independently aryl. [0690] In some embodiments of a compound of Formula (VIII), R83 is independently heteroaryl.
[0691] In some embodiments of a compound of Formula (IV), R83 is independently - CN, -ORa, -SRa, -S(=O)Rb -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, - C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, - NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa, or -NRcRd;
[0692] In some embodiments of a compound of Formula (IV), R83 is independently Ca-Cs cycloalkyl, C2-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, -ORa or -NRcRd.
[0693] In some embodiments of a compound of Formula (IV), L83 is a bond.
[0694] In some embodiments of a compound of Formula (IV), L83 is -CR83R83-.
[0695] In some embodiments of a compound of Formula (IV), L83 is -
C(R83)2C(R83)2C(R83)2-.
[0696] In some embodiments of a compound of Formula (IV), D8 is aryl and B8 is heterocyclyl.
[0697] In some embodiments of a compound of Formula (IV), D8 is aryl and B8 is heteroaryl.
[0698] In some embodiments of a compound of Formula (IV), D8 is heteroaryl and B8 is heterocyclyl.
[0699] In some embodiments of a compound of Formula (IV), D8 is heteroaryl and B8 is aryl.
[0700] In some embodiments of a compound of Formula (IV), D8 is aryl and B8 is aryl.
[0701] In some embodiments of a compound of Formula (IV), D8 is heteroaryl and B8 is heteroaryl. [0702] In some embodiments of a compound of Formula (IV), R81 is halogen.
[0703] In some embodiments of a compound of Formula (IV), E is -C(=O)NR84-.
[0704] In some embodiments of a compound of Formula (IV), E is -NR84C(=O)-.
[0705] In some embodiments of a compound of Formula (IV), R84 is hydrogen or Ci-
Ce alkyl.
[0706] In some embodiments of a compound of Formula (IV), L84 is a bond.
[0707] In some embodiments of a compound of Formula (IV), L84 is -CR86R87 -.
[0708] In some embodiments of a compound of Formula (IV), R86 and R87are hydrogen or Ci-Ce alkyl.
[0709] In some embodiments of a compound of Formula (IV), L84 is a bond.
[0710] In some embodiments of a compound of Formula (IV), R86 and R87 are independently hydrogen.
[0711] In some embodiments of a compound of Formula (IV), R86 and R87 are independently halogen.
[0712] In some embodiments of a compound of Formula (IV), R86 and R87 are independently fluoro.
[0713] In some embodiments of a compound of Formula (IV), R86 and R87 are independently aryl.
[0714] In some embodiments of a compound of Formula (IV), R86 and R87 are independently heteroaryl.
[0715] In some embodiments of a compound of Formula (IV), R86 and R87 are independently -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, - S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; [0716] In some embodiments of a compound of Formula (IV), R86 and R87 are independently C3-8 cycloalkyl, C2-C8 heterocycloalkyl; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, Cl -Ce haloalkyl, -ORa or -NRcRd.
[0717] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently heterocycloalkyl.
[0718] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently C2-C8 heterocycloalkyl.
[0719] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently pyrrolidinyl.
[0720] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently piperidinyl.
[0721] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently piperazinyl.
[0722] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently pyranyl.
[0723] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are ndependently tetrahydrofuranyl.
[0724] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently morpholinyl.
[0725] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently aryl.
[0726] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently phenyl.
[0727] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently heteroaryl. [0728] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently a 6-membered heteroaryl.
[0729] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently pyrimidinyl.
[0730] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently pyrazinyl.
[0731] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently pyridyl.
[0732] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently a 5-membered heteroaryl.
[0733] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently thiophenyl.
[0734] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently furanyl.
[0735] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently pyrrolyl.
[0736] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently thiazolyl.
[0737] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently oxazolyl.
[0738] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently isoxazolyl.
[0739] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently imidazolyl.
[0740] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently pyrazolyl. [0741] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently thiadiazolyl.
[0742] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently oxadiazolyl.
[0743] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently C7-C9 heteroaryl.
[0744] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently indolyl.
[0745] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently indazolyl.
[0746] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently benzofuranyl.
[0747] In some embodiments of a compound of Formula (IV), Rings D8 and B8 are independently a fused bicyclic ring.
[0748] Described herein are compounds of Formula (IVa):
Figure imgf000111_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L83 is -C(R83)2C(R83)2C(R83)2-,
E is -C(=O)NR84-, -NR84C(=O)-;
L84 is a bond or -CR86R87-;
Rings D8 and B8 are independently heteroaryl or C2-C8 heterocyclyl; each R81 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd;
R84 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R85 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R85 on the same carbon are taken together to form an oxo;
R86 and R87 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, - S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci -Ce alkyl, Ci -Ce haloalkyl, -ORa, or -NRcRd.
Ra is hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n8 is 1 -5; m8 is 1 -4; and q8 is 1 -5.
[0749] Described herein are compounds of Formula (IVb):
Figure imgf000114_0001
pharmaceutically acceptable salt or prodrug thereof, wherein:
L83 is -C(R83)2C(R83)2C(R83)2-,
E is -C(=O)NR84-, -NR84C(=O)-;
L84 is a bond or -CR86R87-;
Rings D8 and B8 are independently aryl, heteroaryl or C2-C8 heterocyclyl, provided that at least one of D8 or B8 is heteroaryl or C2-C8 heterocyclyl; each R81 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ca-Cs cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ca-Cs cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd;
R84 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R85 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R45 on the same carbon are taken together to form an oxo;
R86 and R87 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, - S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci -Ce alkyl, Ci -Ce haloalkyl, -ORa, or -NRcRd.
Ra 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 -NH2;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n8 is 1 -5; m8 is 1 -4; q8 is 1 -5; and provided that when D8 is heteroaryl and L84 is a bond, then B8 is heteroaryl or C2-C8 heterocyclyl; or when D8 is phenyl, n is 1 , R81 is fluoro at the ortho position of the phenyl ring, and L84 is a bond, then B8 is C2-C8 heterocyclyl. [0750] Described herein are compounds of Formula (VI I Ic ):
Figure imgf000117_0001
pharmaceutically acceptable salt or prodrug thereof , wherein:
L83 is -C(R83)2C(R83)2C(R83)2-,
E is -NR84C(=O)-;
L84 is a bond or -CR86R87-;
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 C2-C8 heterocyclyl ring, wherein at least one R85 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 L84 is not a bond. each R81 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R83 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd;
R84 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, 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, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; or or two R83 substituents are taken together to form a ring; each R85 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, 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, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R85 on the same carbon are taken together to form an oxo; Ra is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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;
Rb 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n8 is 1 -5; m8 is 1 -4; and q8 is 1 -5.
[0751] In some embodiments, the tubulin polymerisation inhibitor is a compound of Formula (X):
(R91)n9 (R92)m9
(M) — " - L93— E— L94— (2)— (R95)q9
(X), or a pharmaceutically acceptable salt or prodrug thereof, wherein: L93 is -C(R93)2C(R93)2C(R93)2-, -C(R93)2C(R93)2-, -OC(R93)2C(R93)-, or -SC(R93)2C(R93)- ;
E is -C(=O)NR94-, -NR94C(=O)-, -S(=O)2NR94-, -NR94S(=O)2-, NR94C(=O)=-, - OC(=O)NR94-, -NR84C(=O)NR94-, oxadiazole, thiadiazole, or sulphonamide;
L94 is a bond or -CR96R87-;
Rings D9 and B9 are independently heteroaryl, C2-C8 heterocyclyl, or cycloalkyl; each R91 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R92 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; each R93 is independently hydrogen, halogen, -CN, -ORa -SRa -S(=O)Rb -NO2, -NRcRd, - S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, Ci-C6 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, -ORa or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa or -NRcRd; or two R93 substituents on the same carbon are taken together to form a C3-C8 cycloalkyl ring;
R94 is hydrogen, -S(=O)Rb, -S(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; each R95 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;or two R95 on the same carbon are taken together to form an oxo;
R96 and R97 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, - NRcRd, - S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-Cs heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or - NRcRd, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci -Ce alkyl, Ci -Ce haloalkyl, -ORa, or -NRcRd.
Ra is hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-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 -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; Rb is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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 Rc and Rd are independently 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 -NH2; or
Rc and Rd, 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 -NH2; n9 is 1 -5; m9 is 1 -4; and q9 is 1 -5.
[0752] In some embodiments of a compound of Formula (X), L93 is -C(R93)2C(R93)2C(R93)2-.
[0753] In some embodiments of a compound of Formula (X), L93 is -C(R93)2C(R93)2-.
[0754] In some embodiments of a compound of Formula (X), L93 is -OC(R93)2C(R93)-.
[0755] In some embodiments of a compound of Formula (X), L93 is -SC(R93)2C(R93)-.
[0756] In some embodiments of a compound of Formula (X), E is -C(=O)NR94-.
[0757] In some embodiments of a compound of Formula (X), E is -NR94C(=O)-.
[0758] In some embodiments of a compound of Formula (X), E is -S(=O)2NR94-.
[0759] In some embodiments of a compound of Formula (X), E is -NR94S(=O)2-. [0760] In some embodiments of a compound of Formula (X), E is -NR94C(=O)O-.
[0761] In some embodiments of a compound of Formula (X), E is -OC(=O)NR94-.
[0762] In some embodiments of a compound of Formula (X), E is -NR94C(=O)NR94-.
[0763] In some embodiments of a compound of Formula (X), E is oxadiazole.
[0764] In some embodiments of a compound of Formula (X), E is thiadiazole.
[0765] In some embodiments of a compound of Formula (X), E is sulfonamide.
[0766] In some embodiments of a compound of Formula (X), L94 is -CR96R97-.
[0767] In some embodiments of a compound of Formula (X), L94 is a bond.
[0768] Specific examples of tubulin polymerisation inhibitor are given in Table 1 , below.
Table 1. Examples of compounds of the present invention
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
[0769] The compounds of the present invention can be synthesised by any suitable method known to a person skilled in the art. For example, suitable methods for the preparing of these compounds have been disclosed in WO/2016/119017
(US10,745,355), WO/2019/148244 (US11 ,472,774), AU 2019200683, WO2019/113242 (US2019/0169127A1 ).
[0770] 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).
Cholesterol homeostasis disrupting agents
[0771] 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.
[0772] 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.
[0773] In some embodiments, the cholesterol homeostasis disrupting agent may be any agent capable of inducing expression of one or more of ABCA1 , ABCG1 , and ApoE.
[0774] In some embodiments, 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.
[0775] In some embodiments, the cholesterol homeostasis disrupting agent is selected from an LXR agonist, a PRDM7/9 inhibitor, a DHCR inhibitor or a combination thereof.
[0776] In some embodiments, the cholesterol homeostasis disrupting agent is selected from LXR-623, GW3965, T0901317, MRK-740, AY-9944 and SH-42.
[0777] In some embodiments, 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.
[0778] In some embodiments, 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. [0779] In some embodiments, 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.
Pharmaceutical compositions
[0780] 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.
[0781] Thus, the therapeutic use of these combinations along with pharmaceutically acceptable salts, solvates, hydrates, prodrugs of the active species, and also formulations and pharmaceutical compositions are within the scope of the present invention. Accordingly, 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.
[0782] 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. Other conventional additives include 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.
[0783] Pharmaceutical 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. The term "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. In certain embodiments, 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. For intravenous, intramuscular, subcutaneous, or intraperitoneal administration, one or more compounds may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient. Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride or glycine, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile. The formulations may be present in unit or multi-dose containers such as sealed ampoules or vials. Examples of suitable components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.
[0784] In the present methods, 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.
[0785] In the present methods, 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. In some embodiments, the cholesterol homeostasis disrupting agent is administered at a dose lower than the agent’s effective dose when used to treat high cholesterol. For example, 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.
[0786] It will be understood, however, that 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. A person skilled in the art will appreciate that the dosage regime or therapeutically effective amount of the combination to be administered may need to be optimized for each individual.
[0787] It will be appreciated that different dosages may be required for treating different disorders. An effective amount of an agent is that amount which causes a statistically significant decrease in neoplastic cell count, growth or size. Neoplastic disorders responsive to the agents of the present invention include, but are not limited to, brain cancer, including glioblastoma.
[0788] The terms "therapeutically effective amount" or "effective amount" refer to an amount of the compound of formula (I) that results in prevention, an improvement or remediation of the symptoms of a proliferative disorder. The 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.
[0789] 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.
[0790] 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).
[0791] The terms "treating", "treatment" and "therapy" are used herein to refer to curative therapy. Therefore, in the context of the present disclosure, the term "treating" encompasses curing and ameliorating the severity of cancer or its associated symptoms.
[0792] "Preventing" or "prevention" 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.
[0793] 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.
[0794] 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. In embodiments, the cellular proliferation is a cancer, such as a brain cancer, for example glioblastoma. Accordingly, 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.
[0795] 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.
[0796] 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.
[0797] 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.
[0798] In one embodiment, the proliferative disorder is a cancer.
[0799] In one embodiment, the cancer is a brain cancer (eg a solid tumour).
[0800] 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.
[0801] 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 fibrosarcoma and osteosarcoma, cancers of the female reproductive tract including uterine cancer, endometrial cancer, ovarian cancer, ovarian (germ cell) cancer and solid tumors in the ovarian follicle, vaginal cancer, cancer of the vulva, and cervical cancer, breast cancer (small cell and ductal), penile cancer, retinoblastoma, testicular cancer, thyroid cancer, trophoblastic neoplasms, and Wilms' tumor.
[0802] In one embodiment, the cancer is primary.
[0803] In one embodiment, the cancer is metastatic.
[0804] In one embodiment, the cancer is benign.
[0805] In one embodiment, the cancer is malignant
[0806] In one embodiment, 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, pilocytic astrocytoma, pinealoblastoma, pineocytoma, pleomorphic anaplastic neuroblastoma, pleomorphic xanthoastrocytoma, primary central nervous system lymphoma, sphenoid wing meningioma, subependymal giant cell astrocytoma, subependymoma and trilateral retinoblastoma. Therefore, preferably, 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).
[0807] In some embodiments, 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.
[0808] Alternatively, or in addition to, the compounds may be administered in further combination with other agents, for example, chemotherapeutic or immune-stimulating drugs or therapeutic agents.
[0809] The terms "combination therapy" or "adjunct 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.
[0810] In accordance with various embodiments of the present invention 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.
[0811] There are large numbers of 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. Alternatively, 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.
[0812] The methods described herein may comprise administering the active agents of the combinations simultaneously, separately or consecutively. By simultaneously it is meant that each of the active ingredients are administered at the same time in the same composition (or administered together). By 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. By 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. Typically, when 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. Preferably the tubulin polymerisation inhibitor is administered after or concurrently with the cholesterol homeostasis disrupting agent. Without wishing to be bound by theory, it is believed that through its activity, the cholesterol homeostasis disrupting agent results in the cancer cells (including the persisters) being more susceptible to tubulin polymerisation inhibitor activity.
[0813] Preferred combinations of the invention may be synergistic.
[0814] The co-administration of the compounds of the present combinations may be effected by administering a tubulin polymerisation inhibitor being in the same unit dose as the cholesterol homeostasis disrupting agent, or the tubulin polymerisation inhibitor and the cholesterol homeostasis disrupting agent may be presented in individual and discrete unit dose forms administered at the same, or similar, time. Sequential administration may be in any order as required, and may require an ongoing physiological effect of the first or initial compound to be current when the second or later compound is administered, especially where a cumulative or synergistic effect is desired. It will be appreciated that the compositions comprising the tubulin polymerisation inhibitor and the cholesterol homeostasis disrupting agent refer to both active agents being combined into the same physical composition. However, the invention is not limited to such compositions, as the methods described herein may involve administering these agents separately or sequentially via the same or different administration routes. Similarly, further active agents may be administered together, sequentially, or spaced apart in combination with the tubulin polymerisation inhibitor and the cholesterol homeostasis disrupting agent.
[0815] Also provided herein are methods of treating and/or preventing a proliferative disorder, comprising administering a therapeutically effective amount of a tubulin polymerisation inhibitor (such as a compound of any of fomulas (l)-(X)) to a subject in need thereof that is receiving or has received cholesterol homeostasis disruption therapy (for example therapy with a cholesterol homeostasis disrupting agent).
[0816] Also provided herein are methods of treating and/or preventing a proliferative disorder, comprising administering a therapeutically effective amount of cholesterol homeostasis disrupting agent to a subject in need thereof that is receiving or has received tubulin polymerisation inhibition therapy (for example therapy with a tubulin polymerisation inhibitor (such as a compound of any of fomulas (l)-(X))).
[0817] For various applications, any active compound described herein (including the tubulin polymerisation inhibitor and cholesterol homeostasis disrupting agent) may be provided in the form of a pharmaceutically acceptable salt, solvate, prodrug, N-oxide, tautomer, polymorph, or stereoisomer thereof.
[0818] Any active compound described herein (including the tubulin polymerisation inhibitor and cholesterol homeostasis disrupting agent) may be labelled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label like nanobodies, aptamers, peptides etc., enzymes or enzyme substrates. These labelled compounds of this invention are useful for mapping the location of receptors in vivo, ex vivo, in vitro and in situ such as in tissue sections via autoradiography and as radiotracers for positron emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like, to characterize those receptors in living subjects or other materials. The labelled compounds according to the present invention may be used in therapy, diagnosis and other applications such as research tools in vivo and in vitro, in particular the applications disclosed herein.
[0819] Also described herein are kits comprising:
- a tubulin polymerisation inhibitor; and
- instructions for its use to treat cancer in combination with a cholesterol homeostasis disrupting agent, for example, according to a method described herein.
[0820] Also described herein are kits comprising:
- a cholesterol homeostasis disrupting agent; and - instructions for its use to treat cancer in combination with a tubulin polymerisation inhibitor, for example, according to a method described herein.
[0821] Also described herein are kits comprising, in separate parts:
- a unit dose of a tubulin polymerisation inhibitor; and
- a unit dose of a cholesterol homeostasis disrupting agent.
[0822] Any tubulin polymerisation inhibitor and cholesterol homeostasis disrupting agent described herein may be included in these kits.
[0823] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.
[0824] Embodiments of the invention will now be discussed in more detail with reference to the examples which is provided for exemplification only and which should not be considered limiting on the scope of the invention in any way.
Examples
[0825] The invention is described in further detail with reference to the following nonlimiting examples. It will be understood to persons skilled in the art of the invention that many modifications may be made without departing from the spirit and scope of the invention.
Example 1
Supplier and catalogue numbers of tested drugs:
MRK-740: MedChemExpress Cat# HY-114209
MRK-740-NC: Sigma-Aldrich Cat# SML2536
LXR-623: MedChemExpress Cat# HY-10629
T0901317: Abeam Cat# ab146152
GW3965: Sigma-Aldrich Cat# G6295 SR9243: Sapphire Bioscience Cat#18420
AY 9944: Sapphire Bioscience Cat#14611
SH-42: Sapphire Bioscience Cat#34677
Cell Culture
[0826] Glioblastoma stem cell (GSC) lines were derived from glioblastoma patient specimens. Characterisation of these cell lines including RNA sequencing, mutational profiling, subtype assignment and proteomic data are available from QIMR Berghofer. GSC lines were cultured in KnockOut DMEM/F-12 basal medium supplemented with StemPro NSC SFM supplement, EGF (20 ng/mL), FGF-[3 (10 ng/mL) (ThermoFisher Scientific, Cat #A1050901 ) and additional supplements Antibiotic-Antimycotic solution (ThermoFisher Scientific, Cat # 15240096) and GlutaMAX-ICTS (2 mM) (ThermoFisher Scientific, Cat# A1286001 ), as adherent cells on flasks coated with MatriGel Matrix (0.1% v/v in PBS) (Corning Life Sciences, MA, USA; Cat # FAL354234). The protocols were approved by the Human Ethics Committee of The University of Sydney (HREC2013/131) and the Human Ethics Committee of the Royal Brisbane & Women’s Hospital (RBWH 2004/161 ). All cell cultures were routinely tested for mycoplasma infection, and the cumulative length of culturing did not exceed 10 passages.
Nuclear ID stain
[0827] Glioblastoma stem cells (1 .5 x 105) were seeded on Matrigel-coated black imaging 24-well plates (Miltenyi Biotec) and treated with CMPD1/WJA88 (25 pM) ± tested drugs (MRK-740, MRK-740-NC, LXR-623, T0901317, GW3965, SR9243, AY 9944; SH-42) for 14 days. Fresh media containing drugs was added every 3 days. Untreated (Day 0) and treated (Day 14) cells were stained with Nuclear-ID red stain (Enzo Lifesciences, Cat # ENZ-52406) at 1 :1 ,000 dilution in StemPro media. Cells were incubated with the stain for 30 min prior to washing with Phosphate Buffered Saline (PBS) three times. The final wash was retained for imaging. Images were taken using Zeiss Axio Scope. A1 and ZEN 2 - blue edition software (Zeiss). Fiji (Imaged) was used to quantify stained cells.
[0828] Results of nuclear ID stain experiments are shown in Figure 1, Figure 4, Figure 7 and Figure 10. Clonogenic outgrowth assay
[0829] Glioblastoma stem cells were seeded in 6-well plates (1 x 104cells/well) and treated with CMPD1/WJA88 (25 pM) ± tested drugs (MRK-740, MRK-740-NC, LXR-623, T0901317, GW3965, SR9243, AY 9944; SH-42) for 7 days. Cells were allowed to recover in drug-free media for an additional 7 - 21 days (depending on the cell line). Once visible colonies were formed in CMPD1 -only or WJA88-only samples, colonies were washed once with PBS, incubated with toluidine blue (1% w/v in water) for 4 h at 4 °C. Plates were imaged using Gel Doc XR+ with Image Lab Software (Bio-Rad) and confluency was assessed using Imaged software.
[0830] Results of clonogenic outgrowth assay experiments are shown in Figure 2, Figure 3, Figure 5, Figure 6, Figure 8, Figure 9, Figure 11 and Figure 12.
[0831] Figure 2 shows MRK-740 as a single agent is not effective. MRK-740 at 3 pM (confirmed target engagement and inhibition of PRDM7/9) does not affect viability of cells, because it decreases cholesterol (but not depletes it).
[0832] Figure 5 shows that LXR agonists at 1 pM (confirmed target engagement and activation of LXR transcriptional activity) do not affect viability. However there are numerous papers showing that LXR agonist at 5-20pM as single agents kill cancer cells. This is most likely related to off-targets and/or complete depletion of cholesterol. The same for DHCRi, where Figure 8 and Figure 9 show no efficacy for these compounds as single agents.
Patient-derived GBM6 xenografts
[0833] GBM6 glioblastoma cells (EGFR over-expression; EGFRvlll mutant) were cultured in StemPro medium (Life Technologies, Waltham, MA, USA) consisting of Dulbecco’s modified Eagle’s medium/F12 knock out medium, 100 U penicillin/streptomycin, 2 mM GlutaMAX, neurobasal supplement, 10 ng/mL basic fibroblast growth factor (FGF) and 10 ng/mL EGF, at 37 °C and 5% CO2.
[0834] Balb/c/nudes mice (ARC, Perth) were injected with 3x105 GBM6 cells in the cortex, tumour imaging was done on Day 5. Animals were randomised into 4 treatment groups (1. vehicle, 2. WJA88 50 mg/kg; 3. LXR-623 100 mg/kg; 4. WJA88 50 mg/kg+LXR-623 100 mg/kg) and treatments began on Day 6. WJA88 was formulated using 40% Captisol and administered using IP route. LXR-623 was formulated using 10% DMSO, 15% PEG 300, 5% Tween 80 and 70% Milli Q water and administrated orally (PO). Both drugs were administered for two weeks (5 days on, two days off), and no significant weight loss was observed. WJA88 was dosed at 50 mg/kg and LXR-623 was dosed at 100 mg/kg BID (i.e., 2 x 50mg/kg). Animals received ad-libitium food and water, with nutritional enrichment when required. Tumour growth was imaged once a week during and after the treatment to evaluate the efficacy of the combination.
[0835] Results are shown in Figure 13.

Claims

1 . A method of treating a proliferative disorder, the method comprising administering an effective amount of a combination of a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent.
2. A method of completely or partially preventing the recurrence of a solid tumour in a subject, the method comprising administering to the subject an effective amount of a combination of a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent, to thereby completely or partially prevent the recurrence of the solid tumour.
3. The method of claim 1 or 2, wherein the proliferative disorder and/or solid tumor is brain cancer.
4. The method of claim 3, wherein the brain cancer is glioblastoma.
5. The method of any one of claims 1 -4, wherein the cholesterol homeostasis disrupting agent is selected from an LXR agonist, a PRDM7/9 inhibitor, a DHCR inhibitor or a combination thereof.
6. The method of claim 5, wherein the cholesterol homeostasis disrupting agent is selected from LXR-623, GW3965, T0901317, MRK-740, AY-9944 and SH-42.
7. The method of any one of claims 1 -5, wherein the tubulin polymerisation inhibitor is a compound of Formula (I):
Ar Y.
R1 X Z
(I) wherein:
X is Ci-C6 alkyl or C2-C6 alkenyl;
Figure imgf000202_0001
W is O or S;
R2 is H, alkyl or alkenyl;
Z is selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl group, which may be optionally substituted;
R1 is a halo, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which heterocycloalkyl group is optionally substituted;
Ar is an aryl or heteroaryl group; or a pharmaceutically acceptable salt, solvate and/or prodrug thereof.
8. The method of any one of claims 1 -7, wherein the tubulin polymerisation inhibitor is selected from:
Figure imgf000203_0001
or a pharmaceutically acceptable salt, solvate and/or prodrug thereof.
9. A pharmaceutical composition comprising:
• a tubulin polymerisation inhibitor; and
• a cholesterol homeostasis disrupting agent.
10. A kit comprising:
• a tubulin polymerisation inhibitor; and
• instructions for its use to treat a proliferative disorder in combination with a cholesterol homeostasis disrupting agent.
11. A kit comprising:
• a cholesterol homeostasis disrupting agent; and
• instructions for its use to treat a proliferative disorder in combination with a tubulin polymerisation inhibitor.
12. Use of a tubulin polymerisation inhibitor in the manufacture of a medicament for treating a proliferative disorder in combination with a cholesterol homeostasis disrupting agent.
13. Use of a cholesterol homeostasis disrupting agent in the manufacture of a medicament for treating a proliferative disorder in combination with a tubulin polymerisation inhibitor.
14. A combination comprising a tubulin polymerisation inhibitor and a cholesterol homeostasis disrupting agent for use in treating a proliferative disorder.
15. A tubulin polymerisation inhibitor for use in treating a proliferative disorder in combination with a cholesterol homeostasis disrupting agent.
16. A cholesterol homeostasis disrupting agent for use in treating a proliferative disorder in combination with a tubulin polymerisation inhibitor.
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