WO2023235929A1 - Composés de benzopyrane fonctionnalisés et leurs utilisations - Google Patents

Composés de benzopyrane fonctionnalisés et leurs utilisations Download PDF

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WO2023235929A1
WO2023235929A1 PCT/AU2023/050505 AU2023050505W WO2023235929A1 WO 2023235929 A1 WO2023235929 A1 WO 2023235929A1 AU 2023050505 W AU2023050505 W AU 2023050505W WO 2023235929 A1 WO2023235929 A1 WO 2023235929A1
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alkyl
substituted
alkoxy
halo
haloalkyl
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PCT/AU2023/050505
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English (en)
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Daniel WENHOLZ
Olivier Laczka
Phillip Coghlan
Naresh Kumar
Graham Kelly
John Wilkinson
Quach TRUONG
Neil MALLO
Shashidhar NIZALAPUR
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Noxopharm Limited
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Priority claimed from AU2022901574A external-priority patent/AU2022901574A0/en
Application filed by Noxopharm Limited filed Critical Noxopharm Limited
Publication of WO2023235929A1 publication Critical patent/WO2023235929A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure relates generally to compounds with anti-cancer properties.
  • the disclosure relates to functionalised benzopyran compounds, the preparation thereof, and their use in methods for the treatment cancer.
  • Cancer is a group of diseases in which cells are aggressive (grow and divide without respect to normal limits), invasive (invade and destroy adjacent tissues), and/or metastatic (spread to other locations in the body). These three malignant properties of cancers differentiate them from benign tumours, which are self-limited in their growth and do not invade or metastasize (although some benign tumour types are capable of becoming malignant). Cancer may affect people at all ages, even foetuses, but risk for the more common varieties tends to increase with age. Cancer causes about 13% of all deaths.
  • Cytotoxic chemotherapeutic agents remain the most widely used anticancer treatment.
  • Benzopyran-based molecules are a particular class of molecules that possess anticancer properties.
  • Benzopyran is a polycyclic organic compound that results from the fusion of a benzene ring to a heterocyclic pyran ring.
  • benzopyran-based molecules suffer from poor bioavailability and/or pharmacokinetics.
  • R 1 and R 2 are independently selected from H, halo, alkyl, and substituted alkyl;
  • R 3 is H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, or substituted alkoxy;
  • R 4 is H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, substituted aryl, heteroaryl, substituted heteroaryl, or heterocyclyl;
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, amino, substituted amino, disubstituted amino, amido, substituted amido, disubstituted amido, or an amino acid;
  • R 6 is H, -OH, halo, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; or
  • R 5 and R 6 together with the atoms between them are cyclised to form a 5 membered heterocycle
  • R 7 is independently selected from H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, substituted alkoxy, haloalkoxy, amino, substituted amino, and disubstituted amino, wherein the substituent is Ci-Ce alkyl; wherein
  • R 8 is amino, substituted amino, disubstituted amino, substituted amido, disubstituted amido, substituted sulfonylamide, disubstituted sulfonylamide, or a 3 membered heterocycle; or
  • R 7 and R 8 together with the atoms between them are cyclised to form a 5 membered heterocycle, wherein R 8 is a N heteroatom;
  • R 9 , R 10 , R 12 and R 13 are independently selected from H, -OH, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and haloalkyl;
  • R 11 is H, -OH, alkoxy, substituted alkoxy, haloalkoxy, alkylester, alkyl, substituted alkyl, cycloalkyl, halo, or haloalkyl; or
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form a 5 membered heterocycle; at least 1 of R 10 , R 11 and R 12 is H; when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H; or
  • R 8 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, aryl, halo, haloalkyl, amino, substituted amino, disubstituted amino, substituted amido, disubstituted amido, or phenyl;
  • R 14 is H, alkyl, substituted alkyl, ketone, or substituted ketone;
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylhalide, amino, substituted amino, disubstituted amino, and halo; and
  • R 17 is independently selected from H, alkyl, substituted alkyl, ketone, substituted ketone, aryl, and substituted aryl.
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, or an amino acid.
  • the compound is not one of the following:
  • R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo, preferably H. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 and R 2 are independently selected from H, halo, alkyl, and substituted alkyl;
  • R 3 is H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, or substituted alkoxy;
  • R 4 is H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, substituted aryl, heteroaryl, substituted heteroaryl, or heterocyclyl;
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, or an amino acid;
  • R 6 is H, -OH, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; or
  • R 5 and R 6 together with the atoms between them are cyclised to form a 5 membered heterocycle
  • R 7 is independently selected from H, -OH, halo, haloalkyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, haloalkoxy, amino, substituted amino, and disubstituted amino, wherein the substituent is Ci-Ce alkyl;
  • R 20 and R 21 are independently selected from H, alkyl, substituted alkyl, alkoxy, aryl, benzyl, substituted carboxyl, alkylester, sulfoalkyl, aldehyde, ketone, and substituted ketone; or R 20 and R 21 together with the N atom between them form ethylene imine; or
  • R 7 and one of R 20 or R 21 together with the atoms between them are cyclised to form a 5 membered heterocycle
  • R 9 , R 10 , R 12 , and R 13 are independently selected from H, -OH, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and haloalkyl;
  • R 11 is H, -OH, alkoxy, substituted alkoxy, haloalkoxy, alkylester, alkyl, substituted alkyl, cycloalkyl, halo, or haloalkyl; or
  • R 11 and one R 10 or R 12 together with the atoms between them are cyclised to form a 5 membered heterocycle; at least 1 of R 10 , R 11 and R 12 is H; and when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H.
  • R 11 when R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 and R 2 are independently selected from H, halo, and C-i-Ce alkyl
  • R 3 is H, -OH, Ci-C 6 alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy;
  • R 4 is H, -OH, Ci-C 6 alkyl, Ci-Ce hydroxyalkyl, or -OR 4A , wherein R 4A is C-i-Ce alkyl;
  • Ci-C 6 haloalkyl wherein R 5A is C-i-Ce alkyl; R 6 is H, -OH, halo, Ci-Ce alkyl, or Ci-Ce alkoxy; or
  • R 7 is independently selected from H, -OH, Ci-Ce alkyl, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -NHR 7A , and -N(R 7A )2, wherein R 7A is C-i-Ce alkyl;
  • R 20 and R 21 are independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkylketone, Ci-Ce substituted carboxyl, Ci-Ce alkylester, Ci-Ce sulfoalkyl, and aldehyde; or
  • R 20 and R 21 together with the N atom between them form an ethylene imine
  • R 7 and one of R 20 or R 21 together with the atoms between them are cyclised to form
  • R 9 , R 10 , R 12 and R 13 are independently selected from H, -OH, halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyclopropyl, and Ci-Ce haloalkyl;
  • R 11 is H, -OH, -OR 11A , -C(O)OR 11 B , -CH2OH, Ci-C 6 alkyl, halo, or Ci-C 6 haloalkyl, wherein R 11A is Ci-Ce alkyl or Ci-Ce haloalkyl, and R 11 B is C-i-Ce alkyl;
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form at least 1 of R 10 , R 11 and R 12 is H; and when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H.
  • R 11 when R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3. [0019] In a preferred embodiment there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:
  • R 1 and R 2 are independently selected from H, and Ci-Ce alkyl
  • R 3 is H or -OH
  • R 4 is H
  • Ci-Ce haloalkyl wherein R 5A is C1-C6 alkyl
  • R 6 is H or Ci-C 6 alkyl
  • R 7 is independently selected from H and halo
  • R 20 and R 21 are independently selected from H, Ci-Ce alkyl, Ci-Ce alkylketone, Ci-Ce alkylester, Ci-Ce sulfoalkyl, and aldehyde; or
  • R 20 and R 21 together with the N atom between them form an ethylene imine
  • R 7 and one of R 20 or R 21 together with the atoms between them are cyclised to form
  • R 9 and R 13 are independently selected from H, halo, and Ci-Ce alkyl
  • R 10 and R 12 are independently selected from H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyclopropyl, and Ci-Ce haloalkyl;
  • R 11 is H, -OH, -OR 11A , Ci-Ce alkyl, halo, or Ci-Ce haloalkyl, wherein R 11A is Ci-Ce alkyl; or R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form at least 1 of R 10 , R 11 and R 12 is H; and when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H.
  • R 11 when R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, more preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 , R 2 R 3 and R 4 are H;
  • Ci-C 6 haloalkyl wherein R 5A is Ci-Ce alkyl
  • R 6 is H or Ci-C 6 alkyl
  • R 7 is independently selected from H and halo
  • R 20 and R 21 are both H or Ci-Ce alkyl
  • R 20 and R 21 together with the N atom between them form an ethylene imine; or one of R 20 and R 21 is Ci-Ce alkyl, Ci-Ce alkylketone, Ci-Ce alkylester, Ci-Ce sulfoalkyl, or aldehyde; or R 7 and one of R 20 or R 21 together with the atoms between them are cyclised to form one of R 20 and R 21 is H;
  • R 9 and R 13 are independently selected from H, halo, and Ci-Ce alkyl
  • R 10 and R 12 are independently selected from H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyclopropyl, and Ci-Ce haloalkyl;
  • R 11 is H, -OH, OR 11A , Ci-Ce alkyl, or halo, wherein R 11A is Ci-Ce alkyl; or
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form at least 1 of R 10 , R 11 and R 12 is H.
  • R 11 when R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, more preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 , R 2 R 3 R 4 R 7 , R 9 , R 13 are H; haloalkyl, wherein R 5A is Ci-Ce alkyl;
  • R 6 is H or Ci-Ce alkyl
  • R 10 and R 12 are independently selected from H, Ci-Ce alkyl, and cyclopropyl;
  • R 11 is H, -OH, OR 11A Ci-Ce alkyl, or halo, wherein R 11A is C1-C6 alkyl; wherein at least 1 of R 10 , R 11 and R 12 is H; and
  • R 20 and R 21 are both H; or one of R 20 and R 21 is H, and one of R 20 and R 21 is Ci-Ce alkylketone or aldehyde.
  • R 11 is not Ci- Ce alkyl.
  • R 20 and R 21 are H; one of R 10 and R 12 is H; and one of R 10 and R 12 is Ci-Ce alkyl; R 11 is not OH
  • R 1 , R 2 R 3 R 4 , R 6 R 7 R 9 R 13 , R 20 and R 21 are H;
  • R 5 is -OH or Ci-Ce haloalkyl
  • R 10 and R 12 are independently selected from H, C1-C3 alkyl, and C1-C3 haloalkyl;
  • R 11 is H, -OH, halo, or C1-C3 alkyl; and at least 1 of R 10 , R 11 and R 12 is H.
  • R 11 is not Ci-Ce alkyl.
  • R 20 , R 21 are H
  • one of R 12 and R 10 is H
  • one of R 10 and R 12 is Ci-Ce alkyl
  • R 11 is not OH
  • a compound according to Formula (1 -a) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:
  • R 1 , R 2 R 3 R 4 R 7 , R 9 , and R 13 are H;
  • R 5 is -OH, alkoxy, haloalkyl, or substituted haloalkyl
  • R 6 is H, or alkyl
  • R 10 and R 12 are independently selected from H, alkyl, and alkoxy;
  • R 11 is H, -OH, alkoxy, alkyl, or halo
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form a 5 membered heterocycle; at least 1 of R 10 , R 11 and R 12 is H; and
  • R 20 and R 21 are independently selected from H, Ci-Ce alkyl, Ci-Ce alkylketone, Ci-Ce sulfoalkyl, Ci-Ce alkylester, and aldehyde.
  • R 1 and R 2 are independently selected from H, halo, alkyl, and substituted alkyl;
  • R 3 is H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, or substituted alkoxy;
  • R 4 is H, -OH, alkyl, substituted alkyl, alkoxy, substitured alkoxy, substituted aryl, heteroaryl, substituted heteroaryl, or heterocyclyl;
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, amino, substituted amino, disubstituted amino, amido, substituted amido, disubstituted amido, or an amino acid;
  • R 6 is H, -OH, halo, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; or
  • R 14 is H, alkyl, substituted alkyl, ketone, or substituted ketone;
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylhalide, amino, substituted amino, disubstituted amino, and halo; and
  • R 17 is independently selected from H, alkyl, substituted alkyl, ketone, substituted ketone, aryl, and substituted aryl.
  • R 7 is H or halo; more preferably H, F, or Cl; even more preferably H. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, or an amino acid.
  • R 1 and R 2 are independently selected from H, halo, and Ci-Ce alkyl;
  • R 3 is H, -OH, Ci-C 6 alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy;
  • R 4 is H, -OH, Ci-C 6 alkyl, Ci-Ce hydroxyalkyl, or -OR 4A , wherein R 4A is Ci-Ce alkyl;
  • R 5 is H, -NH 2 , -OH, -OR 5A , -OC(O)R 5A , -OC(O)OR 5A , -OC(O)NHR 5A , or Ci-C 6 haloalkyl, wherein R 5A is Ci-Ce alkyl;
  • R 6 is H, -OH, halo, Ci-Ce alkyl, or Ci-Ce alkoxy; or
  • R 5 and R 6 together with the atoms between them are cyclised to form ;
  • R 7 is independently selected from H, -OH, Ci-Ce alkyl, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -NH2, -NHR 7A , and -N(R 7A )2, wherein R 7A is Ci-Ce alkyl;
  • R 8 is H, -OH, -OR 8A , C1-C6 alkyl, halo, Ci-C 6 haloalkyl, -NH2, -NHR 8B , -N(R 8B ) 2 , - NHC(O)R 8C , -NR 8B C(O)R 8B , -NHC(O)NH 2 , or -NHC(O)NHR 8B , wherein R 8A is Ci-C 6 alkyl or Ci-Ce haloalkyl, R 8B is Ci-Ce alkyl, and R 8C is H, Ci-Ce alkyl, C3-C6 cycloalkyl or Ci-Ce alkoxy;
  • R 14 is H, Ci-Ce alkyl, Ci-Ce alkylketone, or Ci-Ce arylketone;
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, -OH, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, amino, Ci-Ce alkylamino, Ci-Ce alkylketone, and halo; and
  • R 17 is independently selected from H, alkyl, Ci-Ce alkylketone, Ci-Ce arylketone, and aryl.
  • R 7 is H or halo; more preferably H, F, or Cl; even more preferably H. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 5 is H, -OH, -OR 5A , -OC(O)R 5A , -OC(O)OR 5A , - OC(O)NHR 5A , or Ci-Ce haloalkyl, wherein R 5A is Ci-Ce alkyl.
  • the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • R 1 , R 2 R 4 and R 17 are H;
  • R 3 is H, -OH, Ci-Ce alkyl, or Ci-Ce alkoxy
  • R 5 is H, NH2, -OH, Ci-C 6 alkyl, or -OR 5A , wherein R 5A is Ci-C 6 alkyl;
  • R 6 is H or Ci-C 6 alkyl
  • R 7 is independently selected from H, -OH, halo, and Ci-Ce alkoxy;
  • R 8 is -OH, -OR 8A , -NH2, -NHR 8B , -N(R 8B ) 2 , or -NHC(O)R 8C ; wherein R 8A is Ci-C 6 alkyl, R 8B is Ci-Ce alkyl, and R 8C is H, C1-C6 alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy;
  • R 14 is H or Ci-Ce alkyl
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, halo, -OH, Ci-Ce alkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy.
  • R 5 is H, OH, or -OR 5A , wherein R 5A is Ci-Ce alkyl.
  • R 7 is independently selected from H and halo. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • R 1 , R 2 R 4 R 14 , R 17 are H;
  • R 3 is H, -OH, Ci-Ce alkyl, or Ci-Ce alkoxy
  • R 5 is H, -NH 2 ,-OH, CI-C 6 alkyl, or -OR 5A , wherein R 5A is Ci-C 6 alkyl;
  • R 6 is H or Ci-Ce alkyl
  • R 7 is independently selected from H, -OH, halo, and Ci-Ce alkoxy;
  • R 8 is -OH, -OR 8A , -NH 2 , -NHR 8B , -N(R 8B ) 2 , or -NHC(O)R 8C , wherein R 8A is Ci-C 6 alkyl, R 8B is Ci-Ce alkyl ;R 8C is H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl or Ci-Ce alkoxy;
  • R 15 is H, -OH, or Ci-Ce alkoxy
  • R 16 is H, -OH, halo, Ci-Ce alkyl, or OR 16A , wherein R 16A is Ci-Ce alkyl or Ci-Ce haloalkyl
  • R 18 is H or Ci-Ce alkoxy
  • R 19 is H, -OH, or Ci-Ce alkoxy.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.
  • R 1 , R 2 R 3 R 4 R 6 , R 7 , R 14 , R 15 , R 17 , and R 19 are H.
  • R 5 is -OH.
  • R 8 is -OH, -OR 8A , -NH2, -NHR 8B , -N(R 8B ) 2 , or -
  • NHC(O)R 8C wherein R 8A is Ci-Ce alkyl, R 8B is Ci-Ce alkyl, and R 8C is H or Ci-Ce alkyl.
  • R 16 is H, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 1 , R 2 R 4 R 14 , R 17 and R 19 are H;
  • R 3 is H or Ci-C 6 alkyl
  • R 5 is H, -NH2, -OH, or Ci-C 6 alkyl
  • R 6 is H or Ci-Ce alkyl
  • R 7 is independently selected from H, halo, and Ci-Ce alkoxy
  • R 8 is -OH, -OR 8A , -NH2, -NHR 8B , -NR 8B 2 , -NHC(O)H or -NHC(O)R 8C , wherein R 8A and R 8B are Ci-Ce alkyl, and R 8C is Ci-Ce alkyl, Ci-Ce haloalkyl or C3-C6 cycloalkyl; R 15 is H, -OH, or Ci-Ce alkoxy;
  • R 16 is H, OH, halo, Ci-Ce alkyl, or OR 16A , wherein R 16A is Ci-Ce alkyl or Ci-Ce haloalkyl;
  • R 18 is H or Ci-C 6 alkoxy.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.
  • R 1 , R 2 R 3 R 4 R 6 R 7 R 14 , R 15 R 17 and R 19 are H.
  • R 5 is -OH.
  • R 16 is H, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 5 is H -OH, NH 2 , or Ci-C 6 alkyl
  • R 6 is H or Ci-C 6 alkyl
  • R 7 is H, halo, or Ci-Ce alkoxy
  • R 15 is H or, Ci-Ce alkyl, or Ci-Ce alkoxy
  • R 8 is amido or Ci-Ce alkoxy.
  • R 22 is H or alkyl, preferably H
  • R 26 , R 27 , R 28 , R 29 and R 30 are independently selected from H, -OH, alkyl, alkoxy, and halo, and at least 1 of R 27 , R 28 and R 29 is H;
  • R 31 , R 32 , R 33 , R 34 are independently selected from H, -OH, alkyl, alkoxy, and halo, preferably H;
  • R 35 is independently H, aldehyde, ketone, or alkyl.
  • R 31 , R 32 , R 33 , R 34 is halo, preferably F.
  • R 32 or R 34 is halo, more preferably F.
  • R 22 is H
  • R 23 , R 24 , and R 25 are independently selected from H, Ci-Ce alkyl, and halo;
  • R 26 , R 27 , R 28 R 29 and R 30 are independently selected from H, -OH, Ci-Ce alkyl, and halo, and at least 1 of R 27 , R 28 and R 29 is H;
  • R 31 , R 32 , R 33 , R 34 are independently selected from H, Ci-Ce alkyl, and halo, preferably H;
  • R 35 is independently H, aldehyde, ketone or Ci-Ce alkyl.
  • a composition comprising a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, and a pharmaceutically acceptable excipient.
  • composition comprising a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, and a pharmaceutically acceptable excipient and at least one additional anticancer agent.
  • a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a method of reducing the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject.
  • a method of sensitising a tumour in a subject in need thereof to radiation therapy, chemotherapy, immunotherapy, or a combination thereof comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject.
  • a method for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to a subject and an additional anti-cancer agent.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a compound of Formula (I), Formula (1-a), Formula (1-b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof in the manufacture of a medicament for the treatment of cancer in a subject, wherein the medicament is adapted for administration with an additional anti-cancer agent.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof in the manufacture of a medicament for the treatment of cancer in a subject, wherein the use further comprises an additional anti-cancer agent.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a therapeutically effective amount of a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof for the treatment of cancer in a subject in need thereof.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a therapeutically effective amount of a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof for reducing the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence.
  • a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof for sensitising a tumour in a subject in need thereof to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a therapeutically effective amount of a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof for the treatment of cancer in a subject in need thereof, wherein the use further comprises an additional anti-cancer agent.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof when used with an additional anti-cancer agent to treat cancer in a subject in need thereof.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • a method of preventing or treating fibrosis in an individual comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the individual, thereby preventing or treating fibrosis.
  • the individual does not have detectable cancer.
  • a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, in the manufacture of a medicament for preventing or treating fibrosis in an individual thereby preventing or treating fibrosis.
  • the individual does not have detectable cancer.
  • a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, for use in the prevention or treatment of fibrosis in an individual thereby preventing or treating fibrosis.
  • the individual does not have detectable cancer.
  • a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof when used in the prevention or treatment of fibrosis in an individual thereby preventing or treating fibrosis.
  • the individual does not have detectable cancer.
  • Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.
  • Figure 1 is a graph of the mean plasma concentration profiles of exemplary compounds described herein dosed in male SD rats.
  • Figure 2 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.
  • Figure 3 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.
  • Figure 4 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.
  • Figure 5 represents (A) a histological analysis of explants derived from patient 8 to evaluate (B) CAFs death, (C) cell proliferation and (D) cell death. A paired t- test was performed to compare the activity of NX767 for each modality against the control (untreated). Bar graphs show ⁇ SEM and the dots represent number of replicates.
  • Figure 6 represents (A) a histological analysis of explants derived from patient 9 to evaluate (B) tumour death, (C) CAFs death, (D) cell proliferation and (E) cell death. A paired t-test was performed to compare the activity of NX705 for each modality against the control (untreated). Bar graphs show ⁇ SEM and the dots represent number of replicates.
  • Figure 7 represents (A) a histological analysis of explants derived from patient 9 to evaluate (B) tumour death, (C) CAFs death, (D) cell proliferation and (E) cell death. A paired t-test was performed to compare the activity of NX767 for each modality against the control (untreated). Bar graphs show ⁇ SEM and the dots represent number of replicates.
  • Figure 8 represents (A) a histological analysis of explants derived from patient 10 to evaluate (B) tumour death, (C) CAFs death, (D) cell proliferation and (E) cell death. A paired t-test was performed to compare the activity of NX767 for each modality against the control (untreated). Bar graphs show ⁇ SEM and the dots represent number of replicates.
  • Figure 9 provides a summary of results of patients 1 , 2, 3 and 9 treated with NX705.
  • A tumour death
  • B cell proliferation
  • C CAFs death
  • Figure 10 provides a summary of results of patients 5, 6, 8, 9, and 10 treated with NX767.
  • A tumour death
  • B cell proliferation
  • C CAFs death
  • Figure 11 A provides a histological analysis of explants derived from patient
  • Figure 11B shows a paired t-test was performed to compare the activity of the tested compounds for each modality against the control (untreated).
  • Figure 12A provides a histological analysis of explants derived from patient
  • Figure 12B shows a paired t-test was performed to compare the activity of the tested compounds for each modality against the control (untreated).
  • Figure 13A provides a histological analysis of explants derived from patient
  • Figure 14A provides a histological analysis of explants derived from patient 16 to evaluate aSMA positive cells in explants treated with NX767, NX792-E1 and NX904-E1 .
  • Figure 14B shows a paired t-test was performed to compare the activity of the tested compounds for each modality against the control (untreated).
  • Figure 15 provides a summary of the cell proliferation assay of tested compounds tested at a dosage of 700 nM (control, NX767, NX808, NX792-E1 , NX816, NX904-E1 , NX809, NX819, NX820-E1 ), NX822, NX824 with MiaPaCa2 cells shown in Figure 16A and CAF shown in Figure 16B.
  • Figure 16 provides a summary of the cell proliferation assay of tested compounds tested at a dosage of 10.9 nM (control, NX767, NX808, NX792-E1 , NX816, NX904-E1 , NX809, NX819, NX820-E1 ), NX822, NX824 with MiaPaCa2 cells shown in Figure 16A and CAF cells shown in Figure 16B.
  • Figure 17 provides cell viability of MiaPaCa2 cells at 24 hours posttreatment.
  • the graph shows the cell viability as a % of control for from left to right the control, cells treated with compounds NX767, NX792-E1 , NX806-E1 , NX806-E1 , NX904-E1.
  • Figure 18 provides a summary of cell viability of CAF post-treatment after 24 hours of treatment with the graphs showing the cell proliferation as a % of the control for cells treated with NX767, NX792-E1 and NX904-E1 when dosed at 10.9nM (18A), 700nM (18B) and 1.5pM (18C)
  • Figure 19 provides a cell cycle analysis of MiaPaCa2 cells 4 hours posttreatment for cells treated with (from left to right) nothing (control), NX767, NX792-E1 , NX803-E1 , NX806-E1 , NX904-E1 with a dosage of 0.01 pM (19A), 0.7pM (19B), and 1.5pM (19C).
  • Figure 20A provides images of the results of GBO treatment with NX-782 and NX-786 at 40pM for 2 weeks.
  • Figure 20B provides quantitative analysis of (i) GBO size and (ii) propidium iodide (PI: measure of cell death) intensity for the three Glioblastoma patients in (A). Significance was determined by two-way ANOVA (area) and one-way ANOVA (PI intensity). Significance at p ⁇ 0.05.
  • Figure 21 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.
  • treatment includes delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the sign or symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition.
  • treating refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of signs or symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating.
  • the methods of the present invention can be to prevent or reduce the severity, or inhibit or minimise progression, of a sign or symptom of a disease or condition as described herein.
  • the methods of the present invention have utility as treatments as well as prophylaxes.
  • "preventing” or “prevention” is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder (i.e., causing at least one of the clinical signs or symptoms of the disease not to develop in an individual that may be exposed to or predisposed to the disease but does not yet experience or display signs or symptoms of the disease).
  • Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians.
  • the term “subject” or “patient” can be used interchangeably with each other.
  • the term “individual” or “patient” refers to an animal that is treatable by the compound and/or method, respectively, including but not limited to, for example, dogs, cats, horses, sheep, pigs, cows, and the like, as well as human, non-human primates.
  • the “subject” or “patient” may include both male and female genders. Further, it also includes a subject or patient, preferably a human, suitable for receiving treatment with a pharmaceutical composition and/or method of the present invention.
  • Ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • cancer as used herein is defined as disease characterised by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, vulvar cancer, hepatocellular cancer, gastric cancer, colon cancer, skin cancer, pancreatic cancer, colorectal cancer, nasopharyngeal cancer, renal cancer, liver cancer, brain cancer, glioblastoma, lymphoma, leukaemia, lung cancer, myeloma, non-squamous non-small cell lung cancer, melanoma, renal cell carcinoma, merkel cell carcinoma, head and neck squamous cell carcinoma, neuroblastoma, sarcoma, Non-Hodgkin lymphoma, Hodgkin’s lymphoma, bladder cancer, oesophageal cancer, kidney cancer, and stomach cancer, bil
  • the cancer is selected from: prostate cancer, pancreatic cancer, colorectal cancer, glioblastoma, lung cancer, renal cell cancer and bile duct cancer, more preferably pancreatic cancer, bile duct cancer and glioblastoma.
  • the cancer is pancreatic cancer. Additionally or alternatively in a particularly preferred embodiment the cancer is bile duct cancer. Additionally or alternatively in a particularly preferred embodiment the cancer is glioblastoma.
  • the cancer is associated with chronic inflammation-related fibrosis.
  • the cancer associated with chronic inflammation-related fibrosis is selected from: cervical cancer, vulvar cancer, hepatocellular cancer, gastric cancer, colon cancer, oesophageal cancer, head and neck squamous cell carcinoma, and pancreatic cancer.
  • Pre -cancerous or pre-neoplasia generally refers to a condition or a growth that typically precedes or develops into a cancer.
  • a "pre-cancerous” growth may have cells that are characterized by abnormal cell cycle regulation, proliferation, or differentiation, which can be determined by markers of cell cycle.
  • “Regression” and “regress” and “regresses” generally refers to the reduction in tumour size or growth of a tumour, resulting in the complete or partial involution or elimination of a tumour.
  • a condition or symptom associated" with the cancer may be any pathology that arises as a consequence of, preceding, or proceeding from the cancer.
  • the condition or relevant symptom may include, but is not limited to: jaundice; abdominal pain; loss of appetite; or a combination thereof.
  • the cancer is glioblastoma
  • the condition or relevant symptom may include, but is not limited to: headache; seizure; nausea and vomiting; impaired vision, speech, and/or hearing; or a combination thereof.
  • the condition or symptom may relate to organ dysfunction of the relevant organ having tumour metastases.
  • alkyl refers to a straight or branched chain hydrocarbon radical having from one to twelve carbon atoms, or any range between, i.e. it contains 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the alkyl group is optionally substituted with substituents.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
  • C1-C2 alkyl refers to an alkyl group, as defined herein, containing at least 1 , and at most 2, 4 or 6 carbon atoms respectively, or any range in between (eg alkyl groups containing 2-5 carbon atoms are also within the range of Ci-Ce).
  • cycloalkyl is intended to include mono-, bi- or tricyclic alkyl groups.
  • cycloalkyl groups have from 3 to 12, from 3 to 10, from 3 to 8, from 3 to 6, from 3 to 5 carbon atoms in the ring(s).
  • cycloalkyl groups have 5 or 6 ring carbon atoms.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the cycloalkyl group has from 3 to 8, from 3 to 7, from 3 to 6, from 4 to 6, from 3 to 5, or from 4 to 5 ring carbon atoms.
  • Biand tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems. Examples of bi- and tricyclic ring cycloalkyl systems include, but are not limited to, bicyclo[2.1 ,1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.
  • alkoxy refers to an alkyl group as defined herein covalently bound via an O linkage.
  • the alkoxy group is optionally substituted with substituents.
  • Examples of “alkoxy” as used herein include, but are not limited to methoxy, ethoxy, propoxy, isoproxy, butoxy, iso-butoxy, tert-butoxy and pentoxy.
  • C1-C2 alkoxy refers to an alkoxy group, as defined herein, containing at least 1 , and at most 2, 4 or 6 carbon atoms respectively, or any range in between (eg alkoxy groups containing 2-5 carbon atoms are also within the range of Ci-Ce).
  • a "substituent” as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • a "ring substituent” may be a moiety such as a halogen, alkyl group, or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, ie, a compound that can be isolated, characterized and tested for biological activity.
  • substituents include but are not limited to C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C7 heterocyclyl, C3-C7 cycloalkyl, Ci- Ce alkoxy, Ci-Ce alkylsulfanyl, Ci-Ce alkylsulfenyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino, acyl, carboxy, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term “halo” refers to the halogen radicals fluoro (-F), chloro (-CI), bromo (-Br), and iodo (-I).
  • halo is fluoro or chloro.
  • haloalkyl refers to an alkyl group as defined herein substituted with at least one halogen.
  • C1-C2 haloalkyl refers to an haloalkyl group, as defined herein, containing at least 1 , and at most 2, 4 or 6 carbon atoms respectively, or any range in between (e.g. haloalkyl groups containing 2-5 carbon atoms are also within the range of Ci-Ce).
  • Ci haloalkyl group could be, but is not limited to, chloromethyl, or dichloromethyl, or trichlromethyl.
  • haloalkoxy refers to an alkoxy group as defined herein substituted with at least one halogen.
  • amino or “amine” refers to the group -NH2.
  • substituted amino or “secondary amino” refers to an amino group having a hydrogen replaced with, for example a C1-C6 alkyl group (“Ci-Ce alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) or a carbonyl group to form an amideand so on.
  • C1-C3 alkylamino groups and C1-C3 alkylcarbonyl such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr), methylamido (-NHC(O)H), ethylamido (-NHC(O)CH3), propylamido (-NHC(O)CH2CH3).
  • disubstituted amino or “tertiary amino” refers to an amino group having the two hydrogens replaced with, for example a Ci-Cealkyl group, which may be the same or different (“dialkylamino”), an aryl and alkyl group (“aryl(alkyl)amino”) and so on.
  • Di(Ci-C3alkyl)amino groups are preferred, such as for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2) and variations thereof (eg N(Me)(Et) and so on).
  • nitro refers to the group -NO2.
  • cyano and “nitrile” refer to the group -CN.
  • substituted amido or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a Ci-Ce alkyl group (“Ci-Ce alkylamido” or “C1-C 6 alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on.
  • C1- C3 alkylamide groups are preferred, such as for example, methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt) and propylamide (-C(O)NHPr) and includes reverse amides thereof (eg NHMeC(O)-, -NHEtC(O)- and -NHPrC(O)-, and -NHC(O)Me, -NHC(O)Et, - NHC(O)Pr etc
  • disubstituted amido or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a Ci-Cealkyl group (“di(Ci- C6 alkyl)amido” or “di(Ci-C6 alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on.
  • Di(Ci-C3 alkyl)amide groups are preferred, such as for example, dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2) and dipropylamide ((- C(O)NPr2) and variations thereof (eg C(O)N(Me)Et and so on) and includes reverse amides thereof.
  • sulfonyl refers to the group -SO2H.
  • substituted sulfonyl refers to a sulfonyl group having the hydrogen replaced with, for example a Ci-Ce alkyl group (“sulfonylCi-Ce alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on.
  • Sulfonyl C1-C3 alkyl groups are preferred, such as for example, -SC Me, -SC Et and -SC Pr.
  • sulfate refers to the group OS(O)2OH and includes groups having the hydrogen replaced with, for example a Ci-Ce alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on.
  • alkylsulfates an aryl
  • aralkyl an aralkyl
  • C1-C3 alkylsulfates are preferred, such as for example, OS(O)2OMe, OS(O)2OEt and OS(O)2OPr.
  • sulfonate refers to the group SO3H and includes groups having the hydrogen replaced with, for example a Ci-Ce alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on.
  • alkylsulfonate an aryl
  • aralkyl an aralkyl
  • C1-C3 alkylsulfonates are preferred, such as for example, SOsMe, SOsEt and SOsPr.
  • amino acid refers to a moiety containing an amino group and a carboxyl group linked by at least one carbon.
  • An amino acid may refer a natural or non-natural amino acid, preferably a natural amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, preferably the amino acid is arginine, lysine or histidine, most preferably lysine.
  • carbamate refers to the group -COO- or -COOH.
  • carbamate refers to the group -OC(O)NH2.
  • the carbamate may be substituted, or may be disubstituted, for example with an alkyl group such as but not limited to Ci-Ce alkyl.
  • carbonate refers to the group -OC(O)O- or -OC(O)OH.
  • alkylcarbonate refers to a carbonate group having the hydrogen replaced with, for example a Ci-Ce alkyl group, an aryl or aralkyl group (“arylcabonate” or “aralkylcabonater”) and so on.
  • COaCi-Caalkyl groups are preferred, such as for example, methylcarbonate (COaMe), ethylcarbonate (COaEt) and propylcarbonate (COaPr).
  • esters refers to a carboxyl group having the hydrogen replaced with, for example a Ci-Ce alkyl group (“carboxylO-Ce alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
  • CO2C1-C3 alkyl groups are preferred, such as for example, methylester (CC Me), ethylester (CC Et) and propylester (CC Pr) and includes reverse esters thereof (eg -OC(O)Me, -OC(O)Et and -OC(O)Pr).
  • heterocyclyl refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 10 ring atoms (unless otherwise specified), of which 1 , 2, 3 or 4 are ring heteroatoms each heteroatom being independently selected from O, S and N.
  • the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10- membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms.
  • the term “3-10 membered heterocylyl”, as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms.
  • heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.
  • Heterocycle’s also encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.
  • aromatic heterocyclyl may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”.
  • the heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O.
  • the aromatic heterocyclyl groups may comprise 1 , 2, 3, 4 or more ring heteroatoms. In the case of fused aromatic heterocyclyl groups, only one of the rings may contain a heteroatom and not all rings must be aromatic.
  • Heteroaryl is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (eg bicyclic) ring systems containing one or more aromatic rings.
  • aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls.
  • the term “pseudoaromatic” refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
  • aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non-aromatic ring.
  • heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Aromatic heterocyclyl groups may be 5-membered or 6-membered mono- cyclic aromatic ring systems.
  • Examples of 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1 ,2,3 and 1 ,2,4 oxadiazolyls and furazanyl i.e.
  • thiazolyl isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1 ,2,3, 1 ,2,4 and 1 ,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1 ,2,3 and 1 ,3,4 thiadiazolyls) and the like.
  • 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like.
  • 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens).
  • heteroaryl groups containing an aromatic ring and a nonaromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1 ,4]dioxine, benzo[1 ,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.
  • the groups may be the same or different.
  • R a and R b are independently selected from alkyl, fluoro, amino, and hydroxyalkyl
  • a molecule with two R a groups and two R b groups could have all groups be an alkyl group (e.g., four different alkyl groups).
  • the first R a could be alkyl
  • the second R a could be fluoro
  • the first R b could be hydroxyalkyl
  • the second R b could be amino (or any other substituents taken from the group).
  • both R a and the first R b could be fluoro, while the second R b could be alkyl (/.e., some pairs of substituent groups may be the same, while other pairs may be different).
  • multiple instances of variables that may be selected from a list of alternatives are independently selected.
  • substituted aldehyde refers to an aldehyde group covalently linked to a further group, for example, a Ci -ealkyl group (“Ci-ealkylformyl” or “alkylaldehyde”), an aryl group (“arylaldehyde”), an aralkyl group (“aralkylaldehyde) and so on.
  • Ci-ealkylformyl or “alkylaldehyde”
  • arylaldehyde aryl group
  • aralkyl group aralkylaldehyde
  • acyl and “acetyl” refers to the group -C(O)CH3.
  • ketone refers to a carbonyl group which may be represented by - C(O)-.
  • substituted ketone refers to a ketone group covalently linked to at least one further group, for example, a C1-6 alkyl group (“C1-6 alkylacyl” or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), an aralkyl group (“aralkylketone) and so on. Ci -3 alkylacyl groups are preferred.
  • solvate refers to a complex of the compound and either stoichiometric or non-stoichiometric amounts of a solvent. Solvates are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • polymorph refers to the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the term “metabolite” refers to a derivative of a compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • the term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • stereoisomer includes but is not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • R 1 and R 2 are independently selected from H, halo, alkyl, and substituted alkyl;
  • R 3 is H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, or substituted alkoxy;
  • R 4 is H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, substituted aryl, heteroaryl, substituted heteroaryl, or heterocyclyl;
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, amino, substituted amino, disubstituted amino, amido, substituted amido, disubstituted amido, or an amino acid;
  • R 6 is H, -OH, halo, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; or
  • R 5 and R 6 together with the atoms between them are cyclised to form a 5 membered heterocycle
  • R 7 is independently selected from H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, substituted alkoxy, haloalkoxy, amino, substituted amino, and disubstituted amino, wherein the substituent is Ci-Ce alkyl; wherein
  • R 8 is amino, substituted amino, disubstituted amino, substituted amido, disubstituted amido, substituted sulfonylamide, disubstituted sulfonylamide, or a 3 membered heterocycle; or
  • R 7 and R 8 together with the atoms between them are cyclised to form a 5 membered heterocycle, wherein R 8 is a N heteroatom;
  • R 9 , R 10 , R 12 and R 13 are independently selected from H, -OH, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and haloalkyl;
  • R 11 is H, -OH, alkoxy, substituted alkoxy, haloalkoxy, alkylester, alkyl, substituted alkyl, cycloalkyl, halo, or haloalkyl; or
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form a 5 membered heterocycle; at least 1 of R 10 , R 11 and R 12 is H; when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H; or when
  • R 8 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, aryl, halo, haloalkyl, amino, substituted amino, disubstituted amino, substituted amido, disubstituted amido, or phenyl;
  • R 14 is H, alkyl, substituted alkyl, ketone, or substituted ketone;
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylhalide, amino, substituted amino, disubstituted amino, and halo; and
  • R 17 is independently selected from H, alkyl, substituted alkyl, ketone, substituted ketone, aryl, and substituted aryl.
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, or an amino acid.
  • the compound is not one of the following:
  • R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo, preferably H. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 and R 2 are independently selected from H, halo, alkyl, and substituted alkyl;
  • R 3 is H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, or substituted alkoxy;
  • R 4 is H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, substituted aryl, heteroaryl, substituted heteroaryl, or heterocyclyl;
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, or an amino acid;
  • R 6 is H, -OH, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; or
  • R 5 and R 6 together with the atoms between them are cyclised to form a 5 membered heterocycle
  • R 7 is independently selected from H, -OH, halo, haloalkyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, haloalkoxy, amino, substituted amino, and disubstituted amino, wherein the substituent is Ci-Ce alkyl;
  • R 20 and R 21 are independently selected from H, alkyl, substituted alkyl, alkoxy, aryl, benzyl, substituted carboxyl, alkylester, sulfoalkyl, aldehyde, ketone, and substituted ketone; or
  • R 20 and R 21 together form ethylene imine
  • R 7 and one of R 20 or R 21 together with the atoms between them are cyclised to form a 5 membered heterocycle
  • R 9 , R 10 , R 12 , and R 13 are independently selected from H, -OH, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and haloalkyl;
  • R 11 is H, -OH, alkoxy, substituted alkoxy, haloalkoxy, alkylester, alkyl, substituted alkyl, cycloalkyl, halo, or haloalkyl; or
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form a 5 membered heterocycle; at least 1 of R 10 , R 11 and R 12 is H; and when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H.
  • R 11 when R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 and R 2 are independently selected from H, halo, and C-i-Ce alkyl
  • R 3 is H, -OH, Ci-C 6 alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy;
  • R 4 is H, -OH, Ci-C 6 alkyl, Ci-Ce hydroxyalkyl, or -OR 4A , wherein R 4A is C-i-Ce alkyl;
  • Ci-C 6 haloalkyl wherein R 5A is C-i-Ce alkyl
  • R 6 is H, -OH, halo, Ci-Ce alkyl, or Ci-Ce alkoxy; or
  • R 7 is independently selected from H, -OH, Ci-Ce alkyl, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -NHR 7A , and -N(R 7A )2, wherein R 7A is C-i-Ce alkyl;
  • R 20 and R 21 are independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkylketone, Ci-Ce substituted carboxyl, Ci-Ce alkylester, Ci-Ce sulfoalkyl, and aldehyde; or
  • R 20 and R 21 together with the N atom between them form an ethylene imine; or R 7 and one of R 20 and R 21 together with the atoms between them are cyclised to form
  • R 9 , R 10 , R 12 and R 13 are independently selected from H, -OH, halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyclopropyl, and Ci-Ce haloalkyl;
  • R 11 is H, -OH, -OR 11A , -C(O)OR 11 B , -CH2OH, Ci-C 6 alkyl, halo, or Ci-C 6 haloalkyl, wherein R 11A is Ci-Ce alkyl or Ci-Ce haloalkyl, and R 11 B is Ci-Ce alkyl;
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form at least 1 of R 10 , R 11 and R 12 is H; and when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H.
  • R 11 when R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 and R 2 are independently selected from H, and Ci-Ce alkyl
  • R 3 is H or -OH
  • R 4 is H
  • Ci-Ce haloalkyl wherein R 5A is C-i-Ce alkyl
  • R 6 is H or C1-C6 alkyl
  • R 7 is independently selected from H and halo
  • R 20 and R 21 are independently selected from H, Ci-Ce alkyl, C1-C6 alkylketone, C1-C6 alkylester, C1-C6 sulfoalkyl, and aldehyde; or
  • R 20 and R 21 together with the N atom between them form an ethylene imine; or.
  • R 7 and one of R 20 or R 21 together with the atoms between them are cyclised to form
  • R 9 and R 13 are independently selected from H, halo, and C-i-Ce alkyl
  • R 10 and R 12 are independently selected from H, halo, C1-C6 alkyl, C1-C6 alkoxy, cyclopropyl, and Ci-Ce haloalkyl;
  • R 11 is H, -OH, -OR 11A , Ci-Ce alkyl, halo, or C1-C6 haloalkyl, wherein R 11A is C-i-Ce alkyl; or
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form at least 1 of R 10 , R 11 and R 12 is H; and when R 4 and R 5 are methoxy, at least one of R 3 , R 6 , R 7 , or R 9 -R 13 is not H.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, more preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 1 , R 2 R 3 and R 4 are H;
  • Ci-Ce haloalkyl wherein R 5A is C1-C6 alkyl
  • R 6 is H or C1-C6 alkyl
  • R 7 is independently selected from H and halo
  • R 20 and R 21 are both H or C1-C6 alkyl
  • R 20 and R 21 together with the N atom between them form an ethylene imine; or one of R 20 and R 21 is Ci-Ce alkyl, C1-C6 alkylketone, C1-C6 alkylester, C1-C6 sulfoalkyl or aldehyde; or
  • R 7 and one of R 20 and R 21 together with the atoms between them are cyclised to form one of R 20 and R 21 is H;
  • R 9 and R 13 are independently selected from H, halo, and C1-C6 alkyl
  • R 10 and R 12 are independently selected from H, halo, C1-C6 alkyl, C1-C6 alkoxy, cyclopropyl, and Ci-Ce haloalkyl;
  • R 11 is H, -OH, OR 11A , Ci-Ce alkyl, or halo, wherein R 11A is C1-C6 alkyl; or R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form at least 1 of R 10 , R 11 and R 12 is H.
  • R 11 when R 11 is -OH, one of R 10 or R 12 is not methoxy.
  • R 7 is H or halo; more preferably H or F; even more preferably H. In some embodiments, only one R 7 is halo, more preferably F. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • a substituent defined as “Ci-Ce” is preferred.
  • a substituent defined as Ci-Ce alkyl is in preferred embodiments C1-C3 alkyl, more preferably methyl.
  • a substituent defined as Ci-Ce alkoxy is preferably C1-C3 alkoxy, more preferably methoxy.
  • a substituent defined as Ci-Ce haloalkyl is preferably C1-C3 haloalkyl, more preferably Ci haloalkyl, even more preferably Ci fluoroalkyl.
  • a substituent defined as C3-C6 cycloalkyl is in preferred embodiments cyclopropyl.
  • R 1 , R 2 R 3 R 4 R 7 , R 9 , R 13 are H; haloalkyl, preferably C1-C3 haloalkyl, wherein R 5A is Ci-Ce alkyl, preferably C1-C3 alkyl;
  • R 6 is H or Ci-Ce alkyl, preferably C1-C3 alkyl;
  • R 10 and R 12 are independently selected from H, Ci-Ce alkyl, preferably C1-C3 alkyl, and cyclopropyl;
  • R 11 is H, -OH, OR 11A , Ci-Ce alkyl, or halo, wherein R 11A is Ci-Ce alkyl, preferably C1-C4 alkyl; wherein at least 1 of R 10 , R 11 and R 12 is H; and
  • R 20 and R 21 are both H; or one of R 20 and R 21 is H, and one of R 20 and R 21 is Ci-Ce alkylketone, preferably C1-C3 alkylketone, or aldehyde.
  • R 11 is not Ci- Ce alkyl.
  • R 20 and R 21 are H; one of R 10 and R 12 is H; and one of R 10 and R 12 is Ci-Ce alkyl; R 11 is not OH.
  • R 20 and R 21 is H, and one of R 20 and R 21 is Ci-Ce alkylketone; one of R 10 and R 12 is H, and one of R 10 and R 12 is CH3; R 11 is not H.
  • R 1 , R 2 R 3 R 4 , R 6 R 7 R 9 R 13 , R 20 and R 21 are H;
  • R 5 is -OH, or Ci-Ce haloalkyl, preferably C1-C3 haloalkyl;
  • R 10 and R 12 are independently selected from H, C1-C3 alkyl and C1-C3 haloalkyl;
  • R 11 is H, -OH, halo, or C1-C3 alkyl; and at least 1 of R 10 , R 11 and R 12 is H.
  • R 10 and R 12 are H
  • R 11 is not Ci-Ce alkyl.
  • R 20 and R 21 are H; one of R 12 and R 10 is H, and one of R 10 and R 12 is Ci-Ce alkyl, R 11 is not OH.
  • R 1 , R 2 R 3 R 4 R 7 , R 9 , and R 13 are H;
  • R 5 is -OH, alkoxy, haloalkyl, or substituted haloalkyl
  • R 6 is H, or alkyl
  • R 10 and R 12 are independently selected from H, alkyl, and alkoxy;
  • R 11 is H, -OH, alkoxy, alkyl, or halo
  • R 11 and one of R 10 or R 12 together with the atoms between them are cyclised to form a 5 membered heterocycle; at least 1 of R 10 , R 11 and R 12 is H;and
  • R 20 and R 21 are independently selected from H, Ci-Ce alkyl, Ci-Ce alkylketone, Ci-Ce sulfoalkyl, Ci-Ce alkylester, and aldehyde.
  • R 1 and R 2 are independently selected from H, halo, alkyl, and substituted alkyl;
  • R 3 is H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, or substituted alkoxy;
  • R 4 is H, -OH, alkyl, substituted alkyl, alkoxy, substitured alkoxy, substituted aryl, heteroaryl, substituted heteroaryl, or heterocyclyl;
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, amino, substituted amino, disubstituted amino, amido, substituted amido, disubstituted amido, or an amino acid;
  • R 6 is H, -OH, halo, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; or
  • R 5 and R 6 together with the atoms between them are cyclised to form a 5 membered heterocycle
  • R 7 is independently selected from H, -OH, halo, alkyl, substituted alkyl, haloalkyl, alkoxy, substituted alkoxy, haloalkoxy, amino, substituted amino, and disubstituted amino, wherein the substituent is Ci-Ce alkyl;
  • R 8 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, aryl, halo, haloalkyl, amino, substituted amino, disubstituted amino, substituted amido, or disubstituted amido;
  • R 14 is H, alkyl, substituted alkyl, ketone, or substituted ketone;
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, -OH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylhalide, amino, substituted amino, disubstituted amino, and halo; and
  • R 17 is independently selected from H, alkyl, substituted alkyl, ketone, substituted ketone, aryl, and substituted aryl.
  • R 7 is H or halo; more preferably H, F, or Cl; even more preferably H. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • R 5 is H, -OH, alkoxy, substituted alkoxy, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, alkylester, substituted alkylester, alkylcarbonate, substituted alkylcarbonate, alkylcarbamoyl, substituted alkylcarbamoyl, or amino acid.
  • R 1 and R 2 are independently selected from H, halo, and Ci-Ce alkyl;
  • R 3 is H, -OH, Ci-C 6 alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy;
  • R 4 is H, -OH, Ci-C 6 alkyl, Ci-Ce hydroxyalkyl, or -OR 4A , wherein R 4A is Ci-Ce alkyl;
  • R 5 is H, -NH 2 , -OH, -OR 5A , -OC(O)R 5A , -OC(O)OR 5A , -OC(O)NHR 5A , or Ci-C 6 haloalkyl, wherein R 5A is Ci-Ce alkyl;
  • R 6 is H, -OH, halo, Ci-Ce alkyl, or Ci-Ce alkoxy; or R 5 and R 6 together with the atoms between them are cyclised to form ;
  • R 7 is independently selected from H, -OH, Ci-Ce alkyl, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -NH2, -NHR 7A , and -N(R 7A )2, wherein R 7A is Ci-Ce alkyl;
  • R 8 is H, -OH, -OR 8A , C1-C6 alkyl, halo, Ci-C 6 haloalkyl, -NH2, -NHR 8B , -N(R 8B ) 2 , - NHC(O)R 8C , -NR 8B C(O)R 8B , -NHC(O)NH 2 , or -NHC(O)NHR 8B , wherein R 8A is Ci-C 6 alkyl or Ci-Ce haloalkyl, R 8B is Ci-Ce alkyl and R 8C is H, Ci-Ce alkyl, C3-C6 cycloalkyl, or Ci-Ce alkoxy;
  • R 14 is H, Ci-Ce alkyl, Ci-Ce alkylketone, or Ci-Ce arylketone;
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, -OH, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, amino, Ci-Ce alkylamino, Ci-Ce alkylketone, and halo; and
  • R 17 is independently selected from H, alkyl, Ci-Ce alkylketone, Ci-Ce arylketone, and aryl.
  • R 7 is H or halo; more preferably H, F, or Cl; even more preferably H. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • R 5 is H, -OH, -OR 5A , -OC(O)R 5A , -OC(O)OR 5A , - OC(O)NHR 5A , or Ci-Ce haloalkyl, wherein R 5A is Ci-Ce alkyl.
  • the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • R 1 , R 2 R 4 and R 17 are H;
  • R 3 is H,-OH, Ci-Ce alkyl, or Ci-Ce alkoxy
  • R 5 is H, NH2, -OH, Ci-C 6 alkyl, or -OR 5A , wherein R 5A is Ci-C 6 alkyl;
  • R 6 is H or Ci-Ce alkyl
  • R 7 is independently selected from H, -OH, halo, and Ci-Ce alkoxy
  • R 8 is -OH, -OR 8A , -NH 2 , -NHR 8B , -N(R 8B ) 2 , or -NHC(O)R 8C ; wherein R 8A is Ci-C 6 alkyl, R 8B is Ci-Ce alkyl, and R 8C is H, C1-C6 alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl or Ci-Ce alkoxy;
  • R 14 is H or Ci-Ce alkyl
  • R 15 , R 16 , R 18 and R 19 are independently selected from H, halo, -OH, Ci-Ce alkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy.
  • R 5 is H, OH, or -OR 5A , wherein R 5A is Ci-Ce alkyl.
  • R 7 is independently selected from H and halo. In some embodiments, only one R 7 is halo, preferably F or Cl. In some embodiments, R 7 is ortho to R 8 , preferably at position 3.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • R 1 , R 2 R 4 R 14 and R 17 are H;
  • R 3 is H, -OH, Ci-Ce alkyl, or Ci-Ce alkoxy
  • R 5 is H, -NH 2 ,-OH, CI-C 6 alkyl, or -OR 5A , wherein R 5A is Ci-C 6 alkyl;
  • R 6 is H or Ci-Ce alkyl
  • R 7 is independently selected from H, -OH, halo, and Ci-Ce alkoxy;
  • R 8 is -OH, -OR 8A , -NH 2 , -NHR 8B , -N(R 8B ) 2 , or -NHC(O)R 8C , wherein R 8A is Ci-C 6 alkyl, R 8B is Ci-Ce alkyl R 8C is H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl or Ci-Ce alkoxy; R 15 is H, -OH, or Ci-Ce alkoxy;
  • R 16 is H, -OH, halo, Ci-Ce alkyl or OR 16A , wherein R 16A is Ci-Ce alkyl or Ci-Ce haloalkyl;
  • R 18 is H or Ci-Ce alkoxy
  • R 19 is H, -OH, or Ci-Ce alkoxy.
  • Ci-Ce alkyl is in preferred embodiments C1-C3 alkyl, more preferably methyl.
  • a substituent defined as Ci-Ce alkoxy is preferably C1-C3 alkoxy, more preferably methoxy.
  • a substituent defined as Ci-Ce haloalkyl is preferably C1-C3 haloalkyl, more preferably Ci haloalkyl.
  • a substituent defined as C3-C6 cycloalkyl is preferably cyclopropyl.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.
  • R 1 , R 2 R 3 R 4 R 6 , R 7 , R 14 , R 15 , R 17 , R 18 and R 19 are H.
  • R 5 is -OH.
  • R 8 is -OH, -OR 8A , -NH2, -NHR 8B , -N(R 8B ) 2 , or -
  • NHC(O)R 8C wherein R 8A is Ci-Ce alkyl, R 8B is Ci-Ce alkyl, and R 8C is H or Ci-Ce alkyl.
  • R 16 is H, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 1 , R 2 , R 4 R 14 , R 17 and R 19 are H;
  • R 3 is H, or Ci-Ce alkyl, preferably C1-C3 alkyl;
  • R 5 is H, -NH2, -OH, or Ci-Ce alkyl, preferably C1-C3 alkyl;
  • R 6 is H, or Ci-Ce alkyl, preferably C1-C3 alkyl
  • R 7 is independently selected from H, halo, and Ci-Ce alkoxy, preferably C1-C3 alkoxy;
  • R 8 is -OH, -OR 8A , -NH2, -NHR 8B , -NR 8B 2 , -NHC(O)H or -NHC(O)R 8C , wherein R 8A and R 8B are Ci-Ce alkyl, preferably C1-C3 alkyl, and R 8C is Ci-Ce alkyl, preferably C1-C3 alkyl, Ci-Ce haloalkyl, preferably C1-C3 haloalkyl, or C3-C6 cycloalkyl, preferably cyclopropyl;
  • R 15 is H, -OH, or Ci-Ce alkoxy, preferably C1-C3 alkoxy;
  • R 16 is H, OH, halo, Ci-Ce alkyl, preferably C1-C3 alkyl, or OR 16A , wherein R 16A is Ci-Ce alkyl, preferably C1-C3 alkyl, or Ci-Ce haloalkyl, preferably C1-C3 haloalkyl; and
  • R 18 is H, or Ci-Ce alkoxy preferably C1-C3 alkoxy.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.
  • the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.
  • R 1 , R 2 R 3 R 4 R 6 R 7 R 14 , R 15 R 17 and R 19 are H.
  • R 5 is -OH.
  • R 16 is H, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 5 is H ,-OH, NH2, or C1-C6 alkyl, preferably C1-C3 alky;
  • R 6 is H, or Ci-Ce alkyl, preferably C1-C3 alkyl
  • R 7 is H, halo, or Ci-Ce alkoxy, preferably Ci-Ce alkoxy;
  • R 8 is -OH, -OR 8A , -NH2, -NR 8B 2 or -NHC(O)R 8C , wherein R 8A is Ci-C 6 alkyl, preferably C1-C3 alkyl, R 8B is Ci-Ce alkyl, preferably C1-C3 alkyl, and R 8C is Ci-Ce alkyl, preferably C1-C3 alkyl, or C3-C6 cycloalkyl, preferably cyclopropyl;
  • R 15 is H, or Ci-Ce alkyl, preferably C1-C3 alkyl, or Ci-Ce alkoxy, preferably C1-C3 alkoxy;
  • R 16 is H, halo, Ci-Ce alkyl, preferably C1-C3 alkyl, or OR 16A , where R 16A is Ci-Ce alkyl, preferably C1-C3 alkyl.
  • R 8 is amido or Ci-Ce alkoxy, preferably C1-C3 alkoxy.
  • R 22 is H or alkyl, preferably H
  • R 23 , R 24 , and R 25 are independently selected from H, -OH, alkyl, alkoxy, and halo, preferably H;
  • R 26 , R 27 , R 28 , R 29 and R 30 are independently selected from H, -OH, alkyl, alkoxy, and halo, and at least 1 of R 27 , R 28 and R 29 is H;
  • R 31 , R 32 , R 33 , R 34 are independently selected from H, -OH, alkyl, alkoxy, and halo, preferably H;
  • R 35 is independently H, aldehyde, ketone, or alkyl.
  • R 31 , R 32 , R 33 , R 34 is halo, preferably F.
  • R 32 or R 34 is halo, more preferably F.
  • R 22 is H
  • R 23 , R 24 , and R 25 are independently selected from H, Ci-Ce alkyl, preferably C1-C3 alkyl, and halo;
  • R 26 , R 27 , R 28 R 29 and R 30 are independently selected from H, -OH, Ci-Ce alkyl, preferably C1-C3 alkyl, and halo, and at least 1 of R 27 , R 28 and R 29 is H;
  • R 31 , R 32 , R 33 , R 34 are independently selected from H, Ci-Ce alkyl, preferably C1-C3 alkyl, and halo, preferably H;
  • R 35 is independently H, aldehyde, ketone, or Ci-Ce alkyl, preferably C1-C3 alkyl.
  • a compound of Formula (I), Formula (1 -a), or Formula (II) having the structure: or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof.
  • a compound of Formula (I) or Formula (1 -b) having the structure: or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof.
  • the compound of Formula (I) has a structure selected from any one of the following in Table 1 .
  • the compound of Formula (I) has a structure selected from any one of the following in Table 2.
  • the compound of Formula (I) has a structure selected from any one of the following in Table 3.
  • the compound of Formula (l-a) has a structure selected from any one of the following in Table 3A.
  • the compound of Formula (l-b) has a structure selected from any one of the following in Table 3B.
  • the compound of Formula (l-b) has a structure selected from any one of the following in Table 3C.
  • the compound of Formula (I) has a structure selected from any one of the following in Table 4.
  • compositions comprising, formulations and modes of administration
  • the compounds of Formula (I), Formula (1 -a), Formula (1 -b), or Formula (II) can be administered alone or in the form of a pharmaceutical composition.
  • the compounds of Formula (I) or Formula (II) are usually administered in the form of pharmaceutical compositions, that is, in admixture with at least one pharmaceutically acceptable excipient.
  • the proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.
  • a pharmaceutical composition comprising a compound of Formula (I), Formula (1-a), Formula (1-b), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, and at least one pharmaceutically acceptable excipient.
  • compositions include but is not limited to a solid or liquid filler, diluent or encapsulating substance that can be safely used in topical or systemic administration.
  • excipients including diluents and carriers
  • dosage forms such as tablets, pills, capsules, liquid dosage forms and the like, for administration to an individual.
  • Acceptable excipients are well known to those skilled in the art and include, but are not restricted to, saline, pyrogen-free or sterile water, sugars, sugar alcohols, starches, cellulose and its derivatives, gelatine, talc, colloidal silica, magnesium stearate, calcium sulphate, vegetable oils, synthetic oils, polyols, phosphate buffered solutions, emulsifiers, and lipids.
  • compositions of the invention typically include a therapeutically effective amount of one or more active ingredients in admixture with one or more pharmaceutically and physiologically acceptable formulation materials.
  • suitable formulation materials include, but are not limited to, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants.
  • a suitable vehicle may be water for injection, physiological saline solution, or artificial perilymph, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, cyclodextrin, beta-cyclodextrin, modified betacyclodextrin, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminium hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; e
  • Various dosage units are each preferably provided as a discrete dosage tablet, capsules, lozenge, dragee, gum, or other type of solid formulation.
  • Capsules may encapsulate a powder, liquid, or gel.
  • the solid formulation may be swallowed, or may be of a suckable or chewable type (either frangible or gum-like).
  • the present invention contemplates dosage unit retaining devices other than blister packs; for example, packages such as bottles, tubes, canisters, packets.
  • the dosage units may further include conventional excipients well-known in pharmaceutical formulation practice, such as binding agents, gellants, fillers, tableting lubricants, disintegrants, surfactants, and colorants; and for suckable or chewable formulations.
  • a compound of Formula (I), Formula (1-a), Formula (1-b), or Formula (II) may be administered in any form and route which makes the compound bioavailable.
  • compositions described herein may be administered systemically or directly to the site of disease or the site of the tumour.
  • compositions described herein may be administered orally, nasally, intravenously, intramuscularly, intraperitoneally, topically, subcutaneously, rectally, vaginally or by urethral application.
  • compositions described herein may be administered orally, nasally, or intravenously.
  • compositions intended for oral use may further comprise one or more components such as sweetening agents, flavouring agents, colouring agents and/or preserving agents in order to provide appealing and palatable preparations.
  • Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatine or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations.
  • Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent exemplified by those already mentioned above.
  • Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate.
  • An emulsion may also comprise one or more sweetening and/or flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such Formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such Formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
  • Compounds may be formulated for local or topical administration, such as for topical application to the skin.
  • Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components.
  • the therapeutically effective amount of a compound when the compound of the present invention is topically administered to a human, corresponds to preferably between about 0.01 to about 10% (w/w), or between about 0.1 to 10% (w/w), or between about 1 .0 to about 10% (w/w), between about 0.1 to about 5% (w/w), or between about 1 .0 to about 5% (w/w).
  • the therapeutically effective amount of a compound when the compound of the present invention is orally administered to a subject, corresponds preferably between about 1 to about 50 mg/kg, or between about 1 to 35 mg/kg. or between about 1 to 25 mg/kg, or between about 1 to about 10 mg/kg, between about 5 to about 25 mg/kg, or between about 10 to about 20 mg/kg.
  • Topical vehicles include organic solvents such as alcohols (for example, ethanol, iso-propyl alcohol or glycerine), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerine, lipid- based materials such as fatty acids, acylglycerols including oils such as mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes, proteinbased materials such as collagen and gelatine, silicone-based materials (both nonvolatile and volatile), and hydrocarbon-based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (for example, ethanol, iso-propyl alcohol or glycerine), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixtures of
  • a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
  • a topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches.
  • the physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation.
  • Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form.
  • Solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Creams and lotions are often similar to one another, differing mainly in their viscosity. Both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels, and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
  • Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerine, propylene glycol, and butylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
  • Suitable fragrances and colours include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5.
  • Other suitable additional ingredients that may be included in a topical Formulation include, but are not limited to, abrasives, absorbents, anticaking agents, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, beta-cyclodextrin, modified beta-cyclodextrin and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanedioL
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • cyclodextrins such as beta-cyclodextrin or modified beta-cyclodextrin may be used.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols.
  • inhalation formulations the composition or combination provided herein may be delivered via any inhalation methods known to a person skilled in the art.
  • inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
  • Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
  • Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
  • Suitable Formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by at least partially dispersing the active in one or more lipophilic bases and then shaping the mixture.
  • compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of active following administration.
  • sustained release formulations such as a capsule that creates a slow release of active following administration.
  • Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible, and may also be biodegradable.
  • the formulation provides a relatively constant level of active release. The amount of active contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated.
  • the present invention also provides a method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1-a), Formula (1-b), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject.
  • a method of reducing the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject.
  • a key barrier to drug delivery, immune cell penetration, and a promoter of tumour progression is the highly fibrotic and heterogeneous multicellular microenvironment of tumours, which is mainly orchestrated by stromal cancer- associated fibroblasts (CAFs).
  • a tumour mass may comprise fibrotic cells.
  • the tumour microenvironment is composed of a web of vasculature, extracellular matrix, stromal cells, immune cells and soluble signalling molecules which form a dynamic organ critical to the pathophysiology of cancer.
  • up to 20% of cancers are linked to chronic inflammation-related fibrosis, including, but not limited to, cervical cancer, vulvar cancer, hepatocellular cancer, gastric cancer, colon cancer, oesophageal cancer, head and neck squamous cell carcinoma, and pancreatic cancer. Therefore a novel therapeutic strategy that targets tumour cells and inhibits the pro-tumour properties of the tumour stroma is desirable.
  • the inventors surprisingly found that exemplary compounds described herein inhibit tumour cells and their surrounding CAFs.
  • the method for treating or preventing cancer is applicable to the treatment of cancer associated with chronic inflammation-related fibrosis.
  • Cancers associated with chronic inflammation-related fibrosis include, but are not limited to, cervical cancer, vulvar cancer, hepatocellular cancer, gastric cancer, colon cancer, oesophageal cancer, head and neck squamous cell carcinoma, and pancreatic cancer.
  • the method for treating or preventing cancer is applicable to the treatment of cancer cells that are not treated by traditional anti-cancer therapies, wherein the traditional anti-cancer therapies include radiation therapy, chemotherapy, immuno-oncology therapy, and combinations thereof.
  • the method for treating or preventing cancer is applicable to the treatment of cancer cells that have acquired resistance to traditional anti-cancer therapies, wherein the traditional anti-cancer therapies include radiation therapy, chemotherapy, immuno-oncology therapy, and combinations thereof.
  • the present invention provides a method of treating cancer in a subject in need thereof, wherein the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1-a), Formula (1-b), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject.
  • a method of sensitising a tumour in a subject in need thereof to radiation therapy, chemotherapy, immunotherapy, or a combination thereof comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject.
  • Subjects requiring treatment include those already having a benign, pre- cancerous, non-metastatic, or metastatic tumour as well as those in which the occurrence or recurrence of cancer is to be prevented.
  • the objective or outcome of treatment may be to reduce the number of cancer cells; reduce the primary tumour size; inhibit (ie, slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (ie, slow to some extent and preferably stop) tumour metastasis; inhibit, to some extent, tumour growth; and/or relieve to some extent one or more of the conditions or symptoms associated with the disorder.
  • Efficacy of treatment can be measured by assessing the duration of survival, time to disease progression, the response rates (RR), duration of response, and/or quality of life.
  • the method is particularly useful for delaying disease progression.
  • the method is particularly useful for extending survival of the human, including overall survival as well as progression free survival.
  • the method is particularly useful for providing a complete response to therapy whereby all signs of cancer in response to treatment have disappeared. This does not always mean the cancer has been cured.
  • the method is particularly useful for providing a partial response to therapy whereby there has been a decrease in the size of one or more tumours or lesions, or in the extent of cancer in the body, in response to treatment.
  • the cancer is pre-cancerous or pre-neoplastic.
  • the cancer is a secondary cancer or metastases.
  • the secondary cancer may be located in any organ or tissue, and particularly those organs or tissues having relatively higher hemodynamic pressures, such as lung, liver, kidney, pancreas, bowel and brain.
  • the methods of treatment described herein are for the minimisation or treatment of a condition or symptom in a subject that is associated with a cancer in the subject.
  • the methods according to the invention may be useful for preventing doubling time of the cancer cells or otherwise inhibiting tumour growth, either through cytotoxic effect on the tumour cells or otherwise by generally inhibiting cell replication.
  • the invention has particular application to a subject having organ dysfunction, scarring, alteration of normal extracellular matrix balance, increase in collagen deposition, increased collagen volume fraction, differentiation of fibroblasts to myofibroblasts, reduction in the level of matrix metalloproteinases and increase in the level of tissue Inhibitors of matrix metalloproteinases, increased levels of either N- terminal or C-terminal propeptide of type I procollagen (PINP or PICP), decreased levels of C-terminal telepeptide of Type I collagen (CTP or CITP), increased collagen deposition and impaired cardiac function measured by various non-invasive imagining techniques, and impaired renal function as measured by increased proteinurea and albuminurea, decreased glomerular filtration rate or doubling of creatinine levels.
  • PINP or PICP N- terminal or C-terminal propeptide of type I procollagen
  • CTP or CITP C-terminal telepeptide of Type I collagen
  • impaired cardiac function measured by various non-invasive imagining techniques
  • impaired renal function as measured by increased
  • the present invention provides a method for the treatment of age-induced fibrosis or organ fibrosis related to tissue injury, the method comprising the steps of: identifying a subject having age-induced fibrosis or organ fibrosis related to tissue injury; and administering to the subject in need thereof a therapeutically effective amount of a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, thereby treating fibrosis in the subject.
  • a compound according to Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof thereby treating fibrosis in the subject.
  • age-induced fibrosis may be reference to age-induced fibrosis of the heart (cardiac), kidney (renal), blood vessels (vascular), liver (hepatic), pancreas and lung (pulmonary).
  • the present invention provides a method for the treatment or prevention of fibrosis, the method comprising the step of administering a composition to the subject for treatment or prevention, wherein the composition comprises, consists essentially of or consists of, there is provided a compound according to Formula (I), Formula (1 -a), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof and a pharmaceutically acceptable diluent, excipient or carrier.
  • fibrosis therapy such as low targeting and permeability, and limited therapeutic effect.
  • the inventors surprisingly found that exemplary compounds described herein inhibit stromal cancer-associated fibroblasts (CAFs), which make up highly fibrotic and heterogeneous multicellular microenvironments of tumours. Given the compounds described herein have an effect on fibroblasts, they have utility in targeting fibroblasts for treating fibrosis.
  • Fibrosis is the thickening of extracellular matrix that is preceded by inflammation or physical tissue injury. Fibroblasts are the principal cell type that produces, maintains, and reabsorbs extracellular matrix.
  • Fibroblasts have the capacity to become activated by inflammatory cytokines to myofibroblasts that display up-regulated cellular migration, exaggerated extracellular matrix production, the endowment of a contractile apparatus, and increased chemical signaling secretion and responsiveness.
  • the compounds described herein have a direct cytotoxic effect on CAFs, ie they reduce their number and their ability to produce more collagen, the compounds described herein not only have utility in preventing or treating fibrosis but also in reversing established fibrosis
  • Fibrosis means the formation of excess fibrous connective tissue in a reparative process upon injury. Scarring is a result of continuous fibrosis that obliterates the affected organs or tissues architecture. As a result of abnormal reparative processes, which do not clear the formed scar tissue, fibrosis progresses further. Fibrosis can be found in various tissues, including the heart, the lungs, the liver, the skin, blood vessels and the kidneys.
  • Exemplary forms of fibrosis include, but are not limited to, cardiac fibrosis, liver fibrosis, kidney fibrosis, lung fibrosis, vascular fibrosis, dermal scarring and keloids, and Alzheimer's disease.
  • examples of fibrosis are described herein and include pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease and cardiac fibrosis associated with various cardiovascular diseases.
  • cardiac fibrosis is associated with hypertension, hypertensive heart disease (HHD), hypertensive cardiomyopathy (HCM), myocardial infarction (Ml), and restenosis or as a result of impaired renal function resulting from renal fibrosis.
  • HHD hypertensive heart disease
  • HCM hypertensive cardiomyopathy
  • Ml myocardial infarction
  • restenosis or as a result of impaired renal function resulting from renal fibrosis.
  • Organ fibrosis related to tissue injury includes fibrosis associated with cardiovascular disease and fibrosis that has occurred following an organ transplant, such as a kidney or liver transplant.
  • the pulmonary fibrosis is idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapours, drug-induced interstitial lung disease, or pulmonary hypertension.
  • the liver fibrosis is resulting from a chronic liver disease, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, alcoholic liver disease or nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha-1 - antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins.
  • the skin fibrosis is scarring, hypertrophic scarring, keloid scarring, dermal fibrotic disorder, psoriasis or scleroderma.
  • Said scarring may derived from a burn, a trauma, a surgical injury, a radiation or an ulcer.
  • Said ulcer can be a diabetic foot ulcer, a venous leg ulcer or a pressure ulcer.
  • the fibrosis is kidney fibrosis.
  • the kidney fibrosis may include, but not be limited to, diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis, glomerulonephritis or glomerular nephritis (GN), focal segmental glomerulosclerosis, membranous glomerulonephritis, or mesangiocapillary GN.
  • the liver fibrosis may include, but not be limited to, cirrhosis, and associated conditions such as chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis, autoimmune hepatitis).
  • Lung fibrosis may include idiopathic pulmonary fibrosis (IPF) or cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), and diffuse parenchymal lung disease (DPLD)).
  • Cardiac fibrosis congestive heart failure, cardiomyopathy, post-myocardial infarction defects in heart function; peripheral vascular disease; rheumatoid arthritis; glaucoma; age-related macular degeneration (wet AMD and dry AMD); emphysema, chronic obstructive pulmonary disease (COPD); multiple sclerosis; and chronic asthma may also be prevented, treated, or ameliorated with compositions, methods or uses as described herein.
  • the fibrotic disease is cardiac, renal, liver or interstitial fibrosis.
  • Scleroderma systemic sclerosis
  • sclero chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma) and internal organs (in severe cases).
  • patient stratification and drug efficacy can be measured through biopsy/visualization of reduced skin lesions and other objective measures assessed over 24 and 48 weeks.
  • diabetic nephropathy, IgA nephropathy or scleroderma are also fibrotic conditions for treatment and /or prevention.
  • the method or use further comprises the step of identifying an individual having fibrosis.
  • An individual may be identified as having fibrosis by determining if a subject has organ dysfunction, scarring, alteration of normal extracellular matrix balance, increase in collagen deposition, increased collagen volume no fraction, differentiation of fibroblasts to myofibroblasts, reduction in the level of matrix metalloproteinases and increase in the level of tissue Inhibitors of matrix metalloproteinases, increased levels of either N-terminal or C-terminal propeptide of type I procollagen (PINP or PICP) and decreased levels of C-terminal telopeptide of Type I Collagen (CTP or CITP), increased collagen deposition and impaired cardiac function measured by various noninvasive imaging techniques, impaired renal function measured by increased proteinurea and albuminurea, decreased glomerular filtration rate, doubling of plasma creatinine levels.
  • PINP or PICP N-terminal or C-terminal propeptide of type I procollagen
  • CTP or CITP C-termin
  • the present invention provides a method for the treatment of fibrosis in a subject comprising the steps of: identifying a subject having fibrosis; and administering to the subject in need thereof a therapeutically effective amount of a compound according to Formula (I), Formula (1 -a), or Formula (II) thereby treating fibrosis in the subject.
  • the compounds of the present invention may be active for promoting healing of wound and one or more of the following activities:
  • the methods of treatment described herein are for the minimisation or treatment of a condition or symptom in a subject that is associated with fibrosis in the subject.
  • the invention also provides a method of alleviating or ameliorating a symptom of fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a in compound according to Formula (I), Formula (1 -a), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, thereby alleviating or ameliorating a symptom of fibrosis in the subject.
  • the fibrosis is age-induced, as a result of underlying tissue injury or cardiovascular disease.
  • the method or use reduces progression of at least one clinically or biochemically observable characteristic of fibrosis, thereby treating fibrosis.
  • the method or use reverses at least one clinically or biochemically observable characteristic of fibrosis, thereby treating fibrosis.
  • the clinically or biochemically observable characteristic may be any one or more of the following organ dysfunction, scarring, alteration of normal extracellular matrix balance, increase in collagen deposition, differentiation of fibroblasts to myofibroblasts, reduction in the level of matrix metalloproteinases and increase in the level of tissue Inhibitors of matrix metalloproteinases.
  • collagen is a precursor or mature forms of collagen a1 Type 1 .
  • a parameter measured may be the presence of fibrosis, the content of collagen, fibronectin, or another extracellular matrix protein, the phosphatidic acid level or choline level, the proliferation rate of the cells or any extracellular matrix components in the cells or transdifferentiation of the cells to myofibroblasts.
  • kidney fibrosis can be detected by preventing a further loss of kidney function as measured by albuminurea or proteinurea, increased serum creatinine, a reduction in active fibrosis as measured by reduced levels of collagen fragments in urine samples, and by a reduction in the presence of myofibroblasts on kidney biopsy tissue.
  • a positive response to therapy would be to prevent a further decline in lung function as measured by spirometry, body plethysmography, and lung diffusion capacity.
  • blood levels of collagen fragments would also be reduced.
  • the term "antagonizing” used herein is intended to mean “decreasing” or “reducing”.
  • a sufficient period of time can be during one week, or between 1 week to 1 month, or between 1 to 2 months, or 2 months or more.
  • the compound of the present invention can be advantageously administered for life time period.
  • Compounds of the invention not only have utility as a monotherapy, but also as an adjunct therapy to traditional anti-cancer therapies. More particularly, as described above, compounds of the invention inhibit tumour cells and their surrounding CAFs. Accordingly compounds of the invention may enhance uptake of traditional anticancer therapies into tumour tissue and/or enhance penetration of immune cells into tumour tissue.
  • the compounds of Formula (I), Formula (1-a), Formula (1-b), or Formula (II) may be combined with one or more other pharmacologically active agents or therapies for the prevention or treatment of cancer.
  • composition comprising a compound according to Formula (I), Formula (1 -a), Formula (1 -b), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, a pharmaceutically acceptable excipient and at least one additional anti-cancer agent.
  • the additional anti-cancer agent may be a small molecule, polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof.
  • the additional anti-cancer agent may be a nucleic acid-based therapeutic, preferably an RNA molecule.
  • Exemplary RNA molecules include, but are not limited to, an RNA modulator, RNA inhibitor, interference RNA, micro RNA, messenger RNA, and short or long non-coding RNA.
  • Anti-cancer agent includes within its scope radiation therapy.
  • the additional anti-cancer agent may be any agent that is effective in the treatment of malignant, or cancerous, disease, including reducing the risk of or incidence of cancer.
  • the additional anti-cancer agent may be a chemotherapeutic agent, a therapeutic agent that inhibits a hormone receptor pathway, a cell cycle inhibitor, radiation therapy, immuno-oncology therapy, or a combination thereof.
  • Chemotherapeutic agents include but are not limited to platins, taxanes, anthracyclines and combinations thereof.
  • Platins include but are not limited to cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA- 12, phosphaplatin, phenanthriplatin, prolindac, triplatin tetranitrate, picoplatin, and satraplatin.
  • Taxanes include but are not limited to paclitaxel, docetaxel, and carbazitzxel.
  • Anthracyclines include but are not limited to doxorubicin, daunorubicin, epirubicin, and idarubicin.
  • Other anti-cancer agents include isoflavones.
  • the additional anti-cancer agent may include immuno-onoclogy therapy, such as CAR-T therapy and checkpoint inhibitor therapy.
  • the additional anti-cancer agent may be an agent that targets cell signalling pathways and cascades, G-couple protein receptor or other receptor modulator.
  • a method for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1-a), Formula (1-b), or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to a subject and an additional anti-cancer agent.
  • the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
  • the compound of Formula (I), Formula (1 -a), Formula (1 -b), or Formula (II) may be administered simultaneously, sequentially or separately in combination with the one or more additional anti-cancer agents.
  • a method of sensitising a tumour in a subject in need thereof to radiation therapy, chemotherapy, immunotherapy, or a combination thereof comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (1 -a), Formula (1 -b) or Formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof to the subject, wherein the method further comprises administering one or more additional anti-cancer agents.
  • the compound of Formula (I), Formula (1 -a), Formula (1-b), or Formula (II) is administered to the subject prior to the administration of the one or more additional anti-cancer agents.
  • the compound of Formula (I), Formula (1 -a), Formula (1 -b), or Formula (II) and the one or more additional anticancer agents may be administered concomitantly.
  • Compounds of the invention also have utility as an adjunct therapy to traditional anti-fibrotic therapies. More particularly, as described above, compounds of the invention inhibit Accordingly compounds of the invention may enhance uptake of traditional anti-fibrotic therapies into fibrotic tissue and/or enhance penetration of immune cells into fibrotic tissue.
  • the additional anti-fibrotic agent may be a small molecule, polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof.
  • the additional anti-fibrotic agent may be a nucleic acid-based therapeutic, preferably an RNA molecule.
  • RNA molecules include, but are not limited to, an RNA modulator, RNA inhibitor, interference RNA, micro RNA, messenger RNA, and short or long non-coding RNA.
  • Anti-cancer agent includes within its scope radiation therapy.
  • the skilled person will be able to readily determine the appropriate dose of the active compound required for prevention or treatment of cancer or alternatively for the prevention or treatment of fibrosis. It will be appreciated that the dose of active required, will depend on the severity of the disease and thus, the skilled person will determine the appropriate dose on a case by case basis.
  • the specific dose level 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, number of doses, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy.
  • therapeutically effective amount generally refers to an amount of one or more active ingredients of the invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more sign or symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more sign or symptoms of the particular disease, condition, or disorder described herein.
  • a therapeutically effective dosage is formulated to contain a concentration (by weight) of at least about 0.1% up to about 50% or more, and all combinations and sub-combinations of ranges therein.
  • the compositions can be formulated to contain one or more actives described herein in a concentration of from about 0.1 to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations of from greater than about 0.1%, for example, about 0.2, 0.3, 0.4 or 0.5%, to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or 30%.
  • compositions may contain from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or 20%, with concentrations of from greater than about 0.5%, for example, about 0.6, 0.7, 0.8, 0.9 or 1 %, to less than about 20%, for example, about 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10%.
  • the compositions can contain from greater than about 1% for example, about 2%, to less than about 10%, for example about 9 or 8%, including concentrations of greater than about 2%, for example, about 3 or 4%, to less than about 8%, for example, about 7 or 6%.
  • the active agent can, for example, be present in a concentration of about 5%. In all cases, amounts may be adjusted to compensate for differences in amounts of active ingredients actually delivered to the treated cells or tissue.
  • the method may utilise a sub-optimal or sub- therapeutic dose of the one or more additional anti-cancer agents.
  • a sub-optimal or sub- therapeutic dose is a dose that is unable to achieve the therapeutic goal. That goal may be for example, a reduction in tumour size, a reduction in increase or decrease of cancer biomarker expression, or mere stasis of tumour growth.
  • the method may utilise a sub-optimal or sub- therapeutic dose of the one or more additional anti-fibrotic agents.
  • a sub-optimal or sub- therapeutic dose is a dose that is unable to achieve the therapeutic goal. That goal may be for example, a reduction in fibrotic tissue size, a reduction in increase or decrease of fibrotic biomarker expression, or mere stasis of fibrotic tissue.
  • a sub-optimal dose is one which does not cause significant adverse side effects in the subject.
  • a sub-optimal dose can be determined according to methods well known in the art.
  • the sub-optimal doses may be expressed as a % reduction of a therapeutic or optimal dose.
  • a sub- optimal dose may be provided in 90%, or 80%, or 70%, or 60% or 50%, or 40%, or 30%, or 20%, or 10% of a therapeutic dose.
  • the frequency of administration may be once daily, 2, 3 or 4 times daily.
  • the treatment period may be for the duration of the detectable disease.
  • kit or article of manufacture including one or more compounds, pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph, and/or pharmaceutical compositions as described above.
  • kits for use in a therapeutic application(s) mentionedherein including: a container holding one or more compounds, pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph and/or pharmaceutical compositions as described herein; a label or package insert with instructions for use.
  • the kit may contain one or more further active principles or ingredients for treatment of cancer.
  • the kit may contain one or more further active principles or ingredients for treatment of fibrotic disease.
  • the kit may comprise (a) a therapeutic compound or composition; and (b) a second container with a second active principle or ingredient contained therein.
  • the kit in this embodiment of the invention may further comprise a package insert indicating the composition and other active principle can be used to treat cancer.
  • the kit may further comprise a package insert indicating the composition and other active principle can be used to treat fibrotic diease.
  • the kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bac
  • the kit or “article of manufacture” may comprise a container and a label or package insert on or associated with the container.
  • Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a therapeutic composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the label or package insert indicates that the therapeutic composition is used for treating the condition of choice.
  • the label or package insert includes instructions for use and indicates that the therapeutic or prophylactic composition can be used to treat a fibrotic disease described herein.
  • reaction mixture was stirred at room temperature for 10 min before adding a solution of 3-(prop-2-yn-1 - yloxy)phenol 3 (6.6 g, 44 mmol) in triethylamine (40 mL).
  • the reaction mixture was heated to 60 °C and stirred for 16 h, with reaction progress monitored by TLC analysis.
  • the reaction mixture was diluted with water and extracted with diethyl ether (3 x 250 mL).
  • the combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SC , and concentrated under vacuum.
  • the crude material was purified using flash column chromatography (gradient 15% to 20% ethyl acetate in hexane) to obtain 3-((3-arylprop-2-yn-1 -yl)oxy)phenol 5.
  • reaction mixture was then heated at 80 °C for 16 h. After confirmation of consumption of starting material by TLC analysis, the reaction mixture diluted with cold water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SO4 and concentrated under vaccuum. The crude was purified with combi flash (10% to 12% EtOAc in n-hexane) to obtain substituted tert-butyl 3-(4-aryl-7-hydroxy-2/-/-chromen-3-yl)-1 /-/-indole-1 - carboxylate 8.
  • combi flash (10% to 12% EtOAc in n-hexane)
  • reaction mixture was filtered through celite, washed with MeOH and concentrated under reduced pressure to obtain substituted tert-butyl 3-(4-aryl-7-hydroxychroman-3-yl)-1 /-/-indole-1 -carboxylate 9 and substituted tert-butyl 3-(4-aryl-7-hydroxychroman-3-yl)indoline-1 -carboxylate 10, which were carried forwards as a mixture to the next step.
  • the crude compound was purified by prep HPLC purification [2m M ammonium bicarbonate buffer and acetonitrile] to obtain substituted 3-(1 /-/-indol-3-yl)-4-arylchroman-7-ol 11 and substituted 3-(indolin-3-yl)-4-arylchroman- 7-ol 12.
  • Step-1 Synthesis of 3-(prop-2-yn-1-yloxy)phenol (3).
  • resorcinol 1 (10.0 g, 90.8 mmol) in dimethylformamide (100 mL) and potassium carbonate (18.8 g, 90.8 mmol) 3-Bromoprop-1 -yne 2 (16.2 g, 80% in toluene, 90.8 mmol) was added dropwise to the reaction mixture.
  • the reaction mass was stirred at 60 °C for 16 h with reaction progress monitored by TLC analysis.
  • the reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2 x 250 mL).
  • Step-3 General Procedure 11. • Step-4 - General Procedure 12.
  • Step-1 Synthesis of (2,4-dihydroxyphenyl)(4-nitrophenyl)methanone (3).
  • Step-2 Synthesis of 3-(3,4-dimethylphenyl)-4-(4-nitrophenyl)-2-oxo-2H-chromen- 7-yl acetate (5).
  • 2,4-dihydroxyphenyl)(4- nitrophenyl)methanone (3, 3.0 g, 11 .6 mmol)
  • (3,4-dimethylphenyl)acetic acid (4, 1 .9 g, 11 .6 mmol)
  • 3-(3,4-dimethylphenyl)-4-(4-nitrophenyl)-2-oxo-2H-chromen-7-yl acetate 5, 1.3 g, 26.16%) as yellow solid.
  • Step-4 Synthesis of NX-705.
  • 3-(3,4- dimethylphenyl)-4-(4-nitrophenyl)-2H-chromen-7-ol (6, 0.60 g, 1.61 mmol) in ethyl acetate (30 mL) and Pd/C 10% (0.30 g).
  • the residue was purified by column chromatography [Combiflash, silica gel), gradient 25% to 30% ethyl acetate in hexane] to obtain 4-(4-aminophenyl)-3-(3,4-dimethylphenyl)chroman-7-ol NX-705 10 (220 mg, 39.64 %) as a white solid.
  • cytotoxicity activity of compounds may be determined by a variety of methods, including in vitro and in vivo methods.
  • Cytotoxicity was determined using a CellTitre-G Io assay.
  • a stock solution of each compound was prepared at 10 mM in DMSO.
  • Plasma samples were put on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples within 15 minutes, which were stored at -70 °C until analysis.
  • Plasma analysis was performed using LC-MS/MS with a LC-MS/MS-37 Triple Quad 65000+. Separation performed using a Waters QCQUITY LIPLC C18 (2.1 x 500 mm, 1 .7 pm) column and gradient eluent of water and methanol (both mobile phases contained 0.025% formic acid and 1 mM of ammonium acetate).
  • Table 9 IC50 (pM) activity of comparative compounds tested against various cell lines [0313] Compounds of the invention show high cytotoxicity in various tumour derived cell lines.
  • Compounds of the invention show improved potency compared to comparative compounds in the growth inhibition of various tumour derived cell lines.
  • Pancreatic ductal adenocarcinoma (PDAC) tumour samples were collected from 5 patients undergoing surgical resection of their primary tumour.
  • Whole tumour explants (1 -2 mm diameter) were cultured on gelatin sponges soaked in culture media.
  • This model accurately maintains the 3D multicellular tumour and stromal architecture of human PDAC [Kokkinos et al, Scientific Reports, 11 ,1941 (2021 )]. Specifically, during this period, the tissue develop into explants which maintain the 3 dimensional architecture and fibrosis of the patient tumour, such that PDAC cells and CAFs are viable and proliferating.
  • the explants could be dosed to match the concentration equivalent to mice in vivo studies. This is possible as the compounds reach the explants via capillary action through the gelatin matrix as opposed to artificially bathing the tumour cells as occurs in tumour organoids. Additionally, a proof of concept study with abraxane showed if the explants were non responsive to treatment, the patient the explant was obtained from would go on to have recurrence of PDAC tumour despite gemcitabine and abraxane chemotherapy - paving the pathway for tailored precision medicine.
  • Explants derived from patient tissues undergoing pancreatic-oduodenectomy were placed on hemostatic gelatin sponges pre-soaked in culture medium and treated with two compounds (NX705, NX 767), each at three concentrations (10pg/mL, 20pg/mL, 50pg/mL and the control Opg/mL). Culture medium was replaced daily, and treatment was repeated on days 3, 6 and 9. On day 12, tumour explants were fixed in paraformaldehyde, paraffin embedded, and then stained by Haematoxylin and Eosin (H&E) for visualization of explant architecture.
  • H&E Haematoxylin and Eosin
  • tumour cell death cytokeratin
  • cancer associated fibroblasts a-smooth muscle actin
  • cell proliferation bromodeoxyuridine (BrdU)
  • TUNEL cell death
  • Histological results for patient 8 treated with NX767 are provided in Figure 5. Histological results for patient 9 treated with NX705 are provided in Figure 6. Histological results for patient 9 treated with NX767 are provided in Figure 7.
  • Figures 5A, 6A, 7A, 8A and 9A show Tunel staining IFA.
  • TUNEL green fluorescent cell death marker
  • DAPI blue fluorescent nuclei stain
  • Histological results for patient 13 treated with NX767, NX792-E1 and NX904- E1 are provided in Figure 11. Histological results for patient 14 treated with NX767, NX792-E1 and NX904-E1 are provided in Figure 12. Histological results for patient 15 treated with NX767, NX729-E1 , and NX904-E1 are provided in Figure 13. Histological results for patient 16 treated with NX767, NX792-E1 and NX904-E1 are provided in Figure 14.
  • Resected glioblastoma (GBM) tissue was obtained from 3 patients and cut into 1 mm pieces and embedded into optical cutting temperature OCT compound (matrix for cryostat sectioning of tissue specimens at ⁇ -10°C) in preparation for sectioning.
  • OCT compound matrix for cryostat sectioning of tissue specimens at ⁇ -10°C
  • the specimens were chopped into 0.6mm3 pieces and cryopreserved.
  • the pieces were cultured as described in Jacob et al*.
  • the glioblastoma organoids (GBO’s) were grown in conditioned culture medium until 2mm before further sectioning to 0.5- 0.8mm sizes for drug treatment.
  • the GBOs were treated with either NX-782, NX-786 or NX-904 at 40pM for 2 weeks.
  • Regimen was designed to mimic clinical administration.
  • Explants were fixed in 4% paraformaldehyde on day 15 for immune-histochemistry (IHC) analysis. The results of the analysis is shown in figures 20A and 20B [0325]
  • the experiments show that compounds of the invention change the morphology of GBO’s after treatment.
  • NX-782 and NX-904 cause blebbing and disruption of the plasma membrane.
  • NX-786 does not cause disruption of the membrane.. Relative to the untreated control, NX-782 shows significance cell death whilst NX-786 shows GBOs are cytostatic (cells are alive but not growing/proliferating).

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Abstract

La présente invention concerne de manière générale des composés ayant des propriétés anticancéreuses et/ou antifibrotiques. En particulier, l'invention concerne des composés de benzopyrane fonctionnalisés, leur préparation et leur utilisation.
PCT/AU2023/050505 2022-06-08 2023-06-08 Composés de benzopyrane fonctionnalisés et leurs utilisations WO2023235929A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006032086A1 (fr) * 2004-09-21 2006-03-30 Novogen Research Pty Ltd Dérivés de chromane, médicaments et utilisation à des fins thérapeutiques
WO2015117202A1 (fr) * 2014-02-07 2015-08-13 Novogen Limited Composés de benzopyrane fonctionnalisés et leur utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006032086A1 (fr) * 2004-09-21 2006-03-30 Novogen Research Pty Ltd Dérivés de chromane, médicaments et utilisation à des fins thérapeutiques
WO2015117202A1 (fr) * 2014-02-07 2015-08-13 Novogen Limited Composés de benzopyrane fonctionnalisés et leur utilisation

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PIERSMA BRAM, HAYWARD MARY-KATE, WEAVER VALERIE M.: "Fibrosis and cancer: A strained relationship", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - REVIEWS ON CANCER, ELSEVIER SCIENCE BV, AMSTERDAM., NL, vol. 1873, no. 2, 1 April 2020 (2020-04-01), NL , pages 188356, XP093116327, ISSN: 0304-419X, DOI: 10.1016/j.bbcan.2020.188356 *
PRASAD SURE SIVA, JOSHI DIRGHA RAJ, KIM IKYON: "Facile Access to 3,4-Disubstituted 2H-Chromenes via Domino [4+2] Annulation", SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE., vol. 53, no. 08, 1 April 2021 (2021-04-01), STUTTGART, DE. , pages 1503 - 1512, XP093116326, ISSN: 0039-7881, DOI: 10.1055/s-0040-1706089 *

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