Functionalised benzopyran compounds and uses thereof

Field of the invention

[0001] The present disclosure relates generally to compounds with anti-cancer properties. In particular the disclosure relates to functionalised benzopyran compounds, the preparation thereof, and their use in methods for the treatment cancer.

Cross reference

[0002] The application claims priority to Australian provisional application 2022901574 filed on 8 June 2022, Australian provisional application 2022902590 filed 8 September 2022 and Australian provisional application 2022902591 filed 8 September 2022. The contents of each of these applications are hereby incorporated by reference in their entireties.

Background of the invention

[0003] 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.

[0004] There have been significant break-throughs made in the treatment and prevention of a wide variety of cancers. For example, early screening programs as well as a variety of surgical techniques. However, these often prove physically and emotionally debilitating. Moreover, patients who have undergone surgery and subsequent chemotherapy often experience a recurrence.

[0005] 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. However, benzopyran-based molecules suffer from poor bioavailability and/or pharmacokinetics. [0006] There is a need to develop improved benzopyran-based molecules and improved methods for treating cancer.

[0007] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art.

Summary of the invention

[0008] In a first aspect there is provided a compound according to Formula (I): or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents either a single bond or a double bond;

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

“ ===== ” represents either a single bond or a double bond; and when

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.

[0009] In a preferred embodiment of the first aspect, 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.

[0010] In a preferred embodiment of the first aspect, the compound is not one of the following:

[0011] In a preferred embodiment of the first aspect, when

R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0012] In a preferred embodiment of the first aspect, 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.

[0013] In an embodiment of the first aspect there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

Formula 1 -a

“ ===== ” represents either a single bond or a double bond;

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.

[0014] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0015] In preferred embodiments, 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.

[0016] 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, 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 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, -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 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.

[0017] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0018] In preferred embodiments, 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; 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 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.

[0020] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0021] In preferred embodiments, 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.

[0022] In yet another 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 , 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; or

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.

[0023] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0024] In preferred embodiments, 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.

[0025] In yet another preferred embodiment there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond;

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.

[0026] In preferred embodiments, when R ¹⁰ , R ¹² , R ²⁰ , and R ²¹ are H, R ¹¹ is not Ci- Ce alkyl.

[0027] In preferred embodiments when 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

[0028] In preferred embodiments, when one of 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 or R ¹⁰ and R ¹² is CH3; R ¹¹ is not H.

[0029] In yet another preferred embodiment there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond;

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.

[0030] In preferred embodiments when R ¹⁰ and R ¹² are H, R ¹¹ is not Ci-Ce alkyl.

[0031] In preferred embodiments when R ²⁰ , 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 In yet another preferred embodiment there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond;

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; 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

R ²⁰ and R ²¹ are independently selected from H, Ci-Ce alkyl, Ci-Ce alkylketone, Ci-Ce sulfoalkyl, Ci-Ce alkylester, and aldehyde.

[0032] In an embodiment of the first aspect there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

Formula 1 -b

“ ===== ” represents either a single bond or a double bond;

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.

[0033] In preferred embodiments, 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.

[0034] In one embodiment, the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0035] In one embodiment, 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. In a preferred embodiment, there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

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.

[0036] In preferred embodiments, 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.

[0037] In one embodiment, 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.

[0038] In one embodiment, the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0039] In a preferred embodiment, there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

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; and

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.

[0040] In some embodiments, R ⁵ is H, OH, or -OR ^5A , wherein R ^5A is Ci-Ce alkyl.

[0041] In a preferred embodiment, 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.

[0042] In one embodiment the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0043] In another preferred embodiment there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond in the benzopyran/benzodihyropyran ring;

“ ===== ” represents either a single bond or a double bond in the indole/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; and

R ¹⁹ is H, -OH, or Ci-Ce alkoxy.

[0044] In some embodiments the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0045] In a preferred embodiment the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.

[0046] In some embodiments, R ¹ , R ² R ³ R ⁴ R ⁶ , R ⁷ , R ¹⁴ , R ¹⁵ , R ¹⁷ , and R ¹⁹ are H.

[0047] In some embodiments, R ⁵ is -OH.

[0048] In some embodiments, 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.

[0049] In some embodiments, R ¹⁶ is H, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0050] In another preferred embodiment of the first aspect there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond in the benzopyran/benzodihyropyran ring;

“ ===== ” represents either a single bond or a double bond in the indole/indoline ring;

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; and

R ¹⁸ is H or Ci-C ₆ alkoxy.

[0051] In some embodiments the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0052]

[0053] In a preferred embodiment the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.

[0054] In some embodiments, R ¹ , R ² R ³ R ⁴ R ⁶ R ⁷ R ¹⁴ , R ¹⁵ R ¹⁷ and R ¹⁹ are H.

[0055] In some embodiments, R ⁵ is -OH.

[0056] In some embodiments, R ¹⁶ is H, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0057] In another preferred embodiment, there is provided a compound according to Formula (1 -bl), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

1 -bl “ ===== ” represents either a single bond or a double bond in the indole/indoline ring;

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 ⁸ is -OH, -OR ^8A , -NH ₂ , -NR ^8B ₂ , or -NHC(O)R ^8C , wherein R ^8A is Ci-C ₆ alkyl, R ^8B is Ci-C ₆ alkyl, and R ^8C is Ci-Ce alkyl or C3-C6 cycloalkyl;

R ¹⁵ is H or, Ci-Ce alkyl, or Ci-Ce alkoxy; and

R ¹⁶ is H, halo, Ci-Ce alkyl, or OR ^16A , where R ^16A is Ci-Ce alkyl.

[0058] In another preferred embodiment, there is provided a compound according to Formula (1 -bll), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

1 -bll wherein R ⁸ is amido or Ci-Ce alkoxy.

[0059] In a second aspect, there is provided a compound according to Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein

wherein

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; and

R ³⁵ is independently H, aldehyde, ketone, or alkyl.

[0060] In some embodiments only one of R ³¹ , R ³² , R ³³ , R ³⁴ is halo, preferably F. In preferred embodiments R ³² or R ³⁴ is halo, more preferably F. In a preferred embodiment of the second aspect there is provided a compound according to Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein

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; and

R ³⁵ is independently H, aldehyde, ketone or Ci-Ce alkyl.

[0061] In a preferred embodiment of the first and second aspects there is provided 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.

[0062] In a preferred embodiment of the first and second aspects there is provided a compound of Formula (I), Formula (1 -a) or Formula (II) having the structure: or a pharmaceutically acceptable salt, solvate, metabolite, or polymorph thereof.

[0057] In a preferred embodiment of the first and second aspects there is provided a compound of Formula (I) or Formula (1 -b) having the structure: or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof.

[0058] In a preferred embodiment of the first and second aspects there is provided a compound of Formula (I) or Formula (1 -b) having the structure: or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof.

[0059] In a preferred embodiment of the first and second aspects there is provided a compound of Formula (I) or Formula (1 -b) having the structure: or a pharmaceutically acceptable salt, solvate, metabolite, or polymorph thereof.

[0060] In a preferred embodiment of the first and second aspects there is provided a compound of Formula (I), Formula (1 -a) or Formula (1 -b) having the structure [0061] In another aspect, there is provided 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.

[0062] In another aspect, there is provided 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 and at least one additional anticancer agent.

[0063] In another aspect, there is provided 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. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0064] In another embodiment, there is provided a method of reducing the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence, 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.

[0065] In another embodiment, there is provided a method of sensitising a tumour in a subject in need thereof 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.

[0066] In another embodiment there is provided a method for 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 a subject and an additional anti-cancer agent. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0067] In another aspect, there is provided use 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, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0068] In another embodiment, there is provided use of 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 reducing the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence.

[0069] In another embodiment, there is provided use 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, in the manufacture of a medicament for sensitising a tumour in a subject in need thereof to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0070] In another embodiment, there is provided use 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, 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. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0071] In another embodiment, there is provided use 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, in the manufacture of a medicament for the treatment of cancer in a subject, wherein the use further comprises an additional anti-cancer agent. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof. [0072] In another aspect, there is provided use of 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. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0073] In another embodiment, there is provided use of 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.

[0074] In another embodiment, there is provided use of 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.

[0075] In another embodiment, there is provided use of 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. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0076] In another aspect, there is provided 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 use in the treatment of cancer in a subject in need thereof. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0077] In another embodiment, there is provided 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 use in reducing the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence.

[0078] In another embodiment, there is provided 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 use in sensitising a tumour in a subject in need thereof to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0079] In another embodiment, there is provided 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 use in the treatment of cancer in a subject in need thereof, wherein the compound is adapted for administration with an additional anti-cancer agent. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0080] In another embodiment, there is provided 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 use in the treatment of cancer with an additional anti-cancer agent in a subject in need thereof. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0081] In another aspect, there is provided 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 to treat cancer in a subject in need thereof. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0082] In another embodiment, there is provided 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, when used to reduce the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence.

[0083] In another embodiment, there is provided 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, when used to sensitise a tumour in a subject in need thereof to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0084] In another embodiment, there is provided 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. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0085] In another aspect, there is provided a method of preventing or treating fibrosis in an individual, 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 individual, thereby preventing or treating fibrosis. In one embodiment, the individual does not have detectable cancer.

[0086] In another embodiment, there is provided use of 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. In one embodiment, the individual does not have detectable cancer.

[0087] In another embodiment, there is provided 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. In one embodiment, the individual does not have detectable cancer.

[0088] In another embodiment, there is provided 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. In one embodiment, the individual does not have detectable cancer. [0089] Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.

[0090] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the invention, as described herein.

[0091] Further aspects of the present disclosure and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.

Brief description of the drawings

[0092] Figure 1 is a graph of the mean plasma concentration profiles of exemplary compounds described herein dosed in male SD rats.

[0093] Figure 2 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.

[0094] Figure 3 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.

[0095] Figure 4 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.

[0096] 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.

[0097] 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. [0098] 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.

[0099] 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.

[0100] 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, (D) cell death. Bar graphs show ±SEM and the dots represent the number of patients (n=3 or 4).

[0101] 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, (D) cell death. Bar graphs show ±SEM and the dots represent the number of patients (n=4 or 5).

[0102] Figure 11 A provides a histological analysis of explants derived from patient

13 to evaluate aSMA and Cytokeratin in explants treated with NX767, NX792-E1 and NX904-E1 . Figure 11B shows a paired t-test was performed to compare the activity of the tested compounds for each modality against the control (untreated).

[0103] Figure 12A provides a histological analysis of explants derived from patient

14 to evaluate aSMA positive cells and Cytokeratin positive cells in explants treated with NX767, NX792-E1 and NX904-E1 . Figure 12B shows a paired t-test was performed to compare the activity of the tested compounds for each modality against the control (untreated).

[0104] Figure 13A provides a histological analysis of explants derived from patient

15 to evaluate aSMA positive cells and Cytokeratin positive cells in explants treated with NX767, NX792-E1 and NX904-E1 . Figure 13B shows a paired t-test was performed to compare the activity of the tested compounds for each modality against the control (untreated). [0105] 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).

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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)

[0110] 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).

[0111] 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. [0112] Figure 21 is a graph of the mean plasma concentration-time profiles of exemplary compounds described herein dosed in male SD rats.

Detailed description of the embodiments

[0113] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0114] All of the patents and publications referred to herein are incorporated by reference in their entirety.

Definitions

[0115] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0116] As used herein, except where the context requires otherwise, the term

"comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0117] The terms "treatment" or "treating" of a subject 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. The term "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.

[0118] In particularly preferred embodiments, 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. As such, the methods of the present invention have utility as treatments as well as prophylaxes. [0119] As used herein, "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.

[0120] Herein, 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. Unless otherwise specified, 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.

[0121] "About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, in some instances ±5%, in some instances ±1%, and in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0122] 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.

[0123] The term "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, bile duct cancer and the like.

[0124] In one preferred embodiment, 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. In a particularly preferred embodiment 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.

[0125] In another preferred embodiment, the cancer is associated with chronic inflammation-related fibrosis. Preferably, 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.

[0126] "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.

[0127] “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.

[0128] "A condition or symptom associated" with the cancer may be any pathology that arises as a consequence of, preceding, or proceeding from the cancer. For example, where the cancer is pancreatic cancer, the condition or relevant symptom may include, but is not limited to: jaundice; abdominal pain; loss of appetite; or a combination thereof. Where 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. Where the cancer is a secondary tumour, the condition or symptom may relate to organ dysfunction of the relevant organ having tumour metastases.

[0129] As used herein the term "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. Examples of "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.

[0130] As used herein, the terms "C1-C2 alkyl", "C1-C4 alkyl" and "C1-C6 alkyl" refer 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).

[0131] The term "cycloalkyl" is intended to include mono-, bi- or tricyclic alkyl groups. In some embodiments, 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). In some embodiments, cycloalkyl groups have 5 or 6 ring carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, 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.

[0132] As used herein, the term “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. [0133] As used herein, the terms "C1-C2 alkoxy", "C1-C4 alkoxy" and "C1-C6 alkoxy" refer 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).

[0134] A "substituent" as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, ie, a compound that can be isolated, characterized and tested for biological activity.

[0135] The terms "optionally substituted" or “may be substituted” and the like, as used throughout the specification, denotes that the group may or may not be further substituted or fused (so as to form a polycyclic system), with one or more non-hydrogen substituent groups. Suitable chemically viable substituents for a particular functional group will be apparent to those skilled in the art.

[0136] Examples of 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, alkoxycarbonyl, nitro, cyano, halo, ureido, Ci-Ce perfluoroalkyl. Preferably the substituents include amino, halo, Ci-Ce alkyl, amido, hydroxyl.

[0137] As used herein, the term "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). Preferably, ‘halo’ is fluoro or chloro.

[0138] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein substituted with at least one halogen. [0139] As used herein, the terms "C1-C2 haloalkyl", "C1-C4 haloalkyl" and "C1-C6 haloalkyl" refer 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).

[0140] For example a Ci haloalkyl group could be, but is not limited to, chloromethyl, or dichloromethyl, or trichlromethyl.

[0141] As used herein the term haloalkoxy refers to an alkoxy group as defined herein substituted with at least one halogen.

[0142] The term “amino” or “amine” refers to the group -NH2.

[0143] The term “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).

[0144] The term “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).

[0145] The term “nitro” refers to the group -NO2.

[0146] The term “cyano” and “nitrile” refer to the group -CN.

[0147] The term “amido” or “amide” refers to the group -C(O)NH2.

[0148] The term “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

[0149] The term “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.

[0150] The term “sulfonyl” refers to the group -SO2H.

[0151] The term “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.

[0152] The term “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. C1-C3 alkylsulfates are preferred, such as for example, OS(O)2OMe, OS(O)2OEt and OS(O)2OPr.

[0153] The term “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. C1-C3 alkylsulfonates are preferred, such as for example, SOsMe, SOsEt and SOsPr.

[0154] The term “amino acid” as herein defined 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.

[0155] The term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH. [0156] The term “carbamate” or “carbamoyl” 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.

[0157] The term “carbonate” refers to the group -OC(O)O- or -OC(O)OH.

[0158] The term “alkylcarbonate” as herein defined 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).

[0159] The term “ester” 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).

[0160] The term “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.

[0161] In this context, 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. For example, 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. Examples of heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.

[0162] Heterocycle’s also encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.

[0163] The term “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.

[0164] “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. The term 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. The term 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.

[0165] Examples of 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. In one embodiment, 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. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0166] Aromatic heterocyclyl groups may be 5-membered or 6-membered mono- cyclic aromatic ring systems.

[0167] 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. 1 ,2,5-oxadiazolyl), 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.

[0168] Examples of 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like. Examples of 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens).

[0169] Examples of 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.

[0170] When any two substituent groups or any two instances of the same substituent group are “independently selected” from a list of alternatives, the groups may be the same or different. For example, if R ^a and R ^b are independently selected from alkyl, fluoro, amino, and hydroxyalkyl, then 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). Alternatively, the first R ^a could be alkyl, the second R ^a could be fluoro, the first R ^b could be hydroxyalkyl, and the second R ^b could be amino (or any other substituents taken from the group). Alternatively, 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). In some embodiments, multiple instances of variables that may be selected from a list of alternatives are independently selected.

[0171] The term “aldehyde” refers to the group -C(O)H or -C(=O)H.

[0172] The term “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.

[0173] The term “formyl” refers to the group -C(O)H.

[0174] The terms “acyl” and “acetyl” refers to the group -C(O)CH3. [0175] The term “ketone” refers to a carbonyl group which may be represented by - C(O)-.

[0176] The term “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. As used herein, the term 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.

[0177] As used herein, the term 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.

[0178] As used herein, the term “metabolite” refers to a derivative of a compound that is formed when the compound is metabolized. The term "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.

[0179] 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. The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. As used herein, the term “stereoisomer” includes but is not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures.

[0180] As used herein, 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. Other pharmaceutically acceptable 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, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Compounds of the Invention

[0181] In embodiments there is provided a compound according to Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents either a single bond or a double bond;

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

===== ” represents either a single bond or a double bond; and when

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.

[0182] In a preferred embodiments, 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.

[0183] In a preferred embodiment, the compound is not one of the following:

[0184] In a preferred embodiment of the first aspect, when

R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0185] In a preferred embodiment of the first aspect, 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.

[0186] In an embodiment of the first aspect there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

Formula 1 -a “ ===== ” represents either a single bond or a double bond;

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; 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 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.

[0187] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0188] In preferred embodiments, 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.

[0189] 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, 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 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, -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.

[0190] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0191] In preferred embodiments, 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.

[0192] 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 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.

[0193] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy. [0194] In preferred embodiments, 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.

[0195] In yet another 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 , 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; or

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.

[0196] In one embodiment, when R ¹¹ is -OH, one of R ¹⁰ or R ¹² is not methoxy.

[0197] In preferred embodiments, 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.

[0198] In embodiments where a substituent is defined as “Ci-Ce", “C1-C3” is preferred. For example, 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.

[0199] A substituent defined as C3-C6 cycloalkyl is in preferred embodiments cyclopropyl.

[0200] In yet another preferred embodiment there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond;

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.

[0201] In preferred embodiments, when R ¹⁰ , R ¹² , R ²⁰ , and R ²¹ are H, R ¹¹ is not Ci- Ce alkyl.

[0202] In preferred embodiments when 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.

[0203] In preferred embodiments when one of 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.

[0204] In yet another preferred embodiment there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond;

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.

[0205] In preferred embodiments when R ¹⁰ and R ¹² are H, R ¹¹ is not Ci-Ce alkyl. [0206] In preferred embodiments when 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.

[0207] In yet another preferred embodiment there is provided a compound according to Formula (1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond;

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; 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

R ²⁰ and R ²¹ are independently selected from H, Ci-Ce alkyl, Ci-Ce alkylketone, Ci-Ce sulfoalkyl, Ci-Ce alkylester, and aldehyde.

[0208] In an embodiment of the first aspect there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

Formula 1 -b

“ ===== ” represents either a single bond or a double bond;

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.

[0209] In preferred embodiments, 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.

[0210] In embodiments the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0211] In one embodiment 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.

[0212] In a preferred embodiment there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

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.

[0213] In preferred embodiments, 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.

[0214] In one embodiment 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.

[0215] In one embodiment the indol/indoline ring is attached to the benzopyran/ benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0216] In a preferred embodiment there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

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; and

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.

[0217] In some embodiments, R ⁵ is H, OH, or -OR ^5A , wherein R ^5A is Ci-Ce alkyl.

[0218] In a preferred embodiment, 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.

[0219] In one embodiment the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0220] In another preferred embodiment there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond in the benzopyran/benzodihyropyran ring;

“ ===== ” represents either a single bond or a double bond in the indole/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; and

R ¹⁹ is H, -OH, or Ci-Ce alkoxy.

[0221] In embodiments where a substituent is defined as “Ci-Ce", “C1-C3” is preferred. For example 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.

[0222] In embodiments a substituent defined as C3-C6 cycloalkyl is preferably cyclopropyl.

[0223] In some embodiments the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0224] In a preferred embodiment the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.

[0225] In some embodiments 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.

[0226] In some embodiments R ⁵ is -OH.

[0227] In some embodiments 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.

[0228] In some embodiments R ¹⁶ is H, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0229] In another preferred embodiment of the first aspect there is provided a compound according to Formula (1 -b), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

“ ===== ” represents a single bond in the benzopyran/benzodihyropyran ring;

“ ===== ” represents either a single bond or a double bond in the indole/indoline ring;

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.

[0230] In some embodiments the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 2 or 3 of the indol/indoline ring.

[0231] In a preferred embodiment the indol/indoline ring is attached to the benzopyran/benzodihyropyran ring via position 3 of the indol/indoline ring.

[0232] In some embodiments R ¹ , R ² R ³ R ⁴ R ⁶ R ⁷ R ¹⁴ , R ¹⁵ R ¹⁷ and R ¹⁹ are H.

[0233] In some embodiments R ⁵ is -OH.

[0234] In some embodiments R ¹⁶ is H, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0235] In another preferred embodiment there is provided a compound according to Formula (1 -bl), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

1 -bl

” represents either a single bond or a double bond in the indole/indoline ring;

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; and

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.

[0236] In another preferred embodiment there is provided a compound according to Formula (1 -bll), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein:

1 -bll wherein R ⁸ is amido or Ci-Ce alkoxy, preferably C1-C3 alkoxy.

[0237] In embodiments there is provided a compound according to Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein

Formula (II) wherein

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; and

R ³⁵ is independently H, aldehyde, ketone, or alkyl.

[0238] In some embodiments only one of R ³¹ , R ³² , R ³³ , R ³⁴ is halo, preferably F. In preferred embodiments R ³² or R ³⁴ is halo, more preferably F.

[0239] In embodiments there is provided a compound according to Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, wherein

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; and

R ³⁵ is independently H, aldehyde, ketone, or Ci-Ce alkyl, preferably C1-C3 alkyl.

[0240] In a preferred embodiment there is provided 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.

[0241] In a preferred embodiment there is provided a compound of Formula (I), Formula (1-a) or Formula (II) having the structure: or a pharmaceutically acceptable salt, solvate, metabolite, or polymorph thereof.

[0057] In a preferred embodiment there is provided a compound of Formula (I) or Formula (1 -b) having the structure: or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof.

[0242] In a preferred embodiment of the first and second aspects there is provided a compound of Formula (I) or Formula (1-b) having the structure: or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof. [0243] In a preferred embodiment there is provided a compound of Formula (I) or Formula (1-b) having the structure: or a pharmaceutically acceptable salt, solvate, metabolite, or polymorph thereof.

[0244] In a preferred embodiment there is provided a compound of Formula (I), Formula (1-a) or Formula (1 -b) having the structure

[0245] In particular embodiments of the disclosure the compound of Formula (I) has a structure selected from any one of the following in Table 1 .

[0246] In particular embodiments of the disclosure the compound of Formula (I) has a structure selected from any one of the following in Table 2.

[0247] In particular embodiments of the disclosure the compound of Formula (I) has a structure selected from any one of the following in Table 3.

[0248] In particular embodiments of the disclosure the compound of Formula (l-a) has a structure selected from any one of the following in Table 3A.

[0249] In particular embodiments of the disclosure the compound of Formula (l-b) has a structure selected from any one of the following in Table 3B.

[0250] In particular embodiments of the disclosure the compound of Formula (l-b) has a structure selected from any one of the following in Table 3C.

[0251] In particular embodiments of the disclosure the compound of Formula (I) has a structure selected from any one of the following in Table 4.

Compositions, formulations and modes of administration

[0252] 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. In practice, 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. [0253] In another embodiment, there is provided 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.

[0254] The term “pharmaceutically acceptable excipient” includes but is not limited to a solid or liquid filler, diluent or encapsulating substance that can be safely used in topical or systemic administration. Such excipients (including diluents and carriers) enable the compositions to be formulated into 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.

[0255] Pharmaceutical 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. For example, 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.

[0256] Pharmaceutical 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. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as 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. Some examples of 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; ethyl alcohol, and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colouring agents, releasing agents, coating agents, sweetening, flavouring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0257] 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.

[0258] 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.

[0259] Compositions described herein may be administered systemically or directly to the site of disease or the site of the tumour.

[0260] Compositions described herein may be administered orally, nasally, intravenously, intramuscularly, intraperitoneally, topically, subcutaneously, rectally, vaginally or by urethral application. Preferably, compositions described herein may be administered orally, nasally, or intravenously.

[0261] 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. Such 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. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

[0262] 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.

[0263] 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.

[0264] 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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavouring and colouring agents, may also be present.

[0265] Pharmaceutical 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.

[0266] 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.

[0267] 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.

[0268] For any of the fibrotic diseases described herein, when the compound of the present invention is topically administered to a human, the therapeutically effective amount of a compound 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). In any of fibrotic diseases described herein, when the compound of the present invention is orally administered to a subject, the therapeutically effective amount of a compound 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.

[0269] Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. 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.

[0270] 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. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

[0271] 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.

[0272] 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.

[0273] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0274] 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 Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In addition, cyclodextrins such as beta-cyclodextrin or modified beta-cyclodextrin may be used.

[0275] 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.

[0276] A pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. For inhalation formulations, the composition or combination provided herein may be delivered via any inhalation methods known to a person skilled in the art. Such 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. 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.

[0277] 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.

[0278] 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.

[0279] Pharmaceutical compositions may be formulated as 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. Preferably, 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.

[0280] One skilled in the art can readily select the proper form and route of administration depending on the particular characteristics of the compound selected, the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances.

Methods of treatment

[0281] 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.

[0282] In another embodiment there is provided a method of reducing the incidence of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence, 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. [0283] 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). Up to 80% of a tumour mass may comprise fibrotic cells. Specifically, 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.

[0284] In another aspect, 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.

[0285] In another aspect, 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.

[0286] In another aspect, 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.

[0287] In certain embodiments, 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.

[0288] In another embodiment, there is provided a method of sensitising a tumour in a subject in need thereof 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] In one embodiment, the method is particularly useful for delaying disease progression.

[0293] In one embodiment, the method is particularly useful for extending survival of the human, including overall survival as well as progression free survival.

[0294] In one embodiment, 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.

[0295] In one embodiment, 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. [0296] In one embodiment, the cancer is pre-cancerous or pre-neoplastic.

[0297] In one embodiment, 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.

[0298] In one embodiment, 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.

[0299] In the above described embodiments, 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.

Methods of treating Fibrosis

[0254] 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.

[0255] 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.

[0256] In another aspect or embodiment of the invention, 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).

[0257] 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.

[0258] Several challenges exist for 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. Given 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

[0259] "Fibrosis", "Fibrotic disease" or "Fibro proliferative disease" 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. [0260] 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. In still further embodiments, 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. In still further embodiments, 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.

[0261] 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.

[0262] According to a preferred embodiment of the invention, 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.

[0263] According to a preferred embodiment of the invention, 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.

[0264] According to a preferred embodiment of the invention, 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. [0265] Preferably, 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.

[0266] In a preferred form, the fibrotic disease is cardiac, renal, liver or interstitial fibrosis.

[0267] Scleroderma (systemic sclerosis), a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma) and internal organs (in severe cases). Clinically, 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. As such, diabetic nephropathy, IgA nephropathy or scleroderma are also fibrotic conditions for treatment and /or prevention.

[0268] In the cardiovascular system a progressive age-related deposition of collagen in the vascular wall and in the cardiac interstitial and perivascular space, or collagen deposition related to cardiovascular or renal disease, leads to reduction of myocardial and arterial compliance.

[0269] In any aspect, 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.

[0270] 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.

[0271] The compounds of the present invention may be active for promoting healing of wound and one or more of the following activities:

- improving collagen organization and/or reducing wound cellularity in said wound;

- reducing collagen overproduction by fibroblast and epithelial cells in said wound;

- reducing epithelial mesenchymal transition in said wound;

- reducing fibroblast migration and activation in said wound;

- reducing and/or inhibiting dermal thickening in said wound;

- reducing and/or inhibiting recruitment of inflammatory cells to said wound.

[0272] In one embodiment, 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. Preferably, the fibrosis is age-induced, as a result of underlying tissue injury or cardiovascular disease.

[0273] In any aspect, the method or use reduces progression of at least one clinically or biochemically observable characteristic of fibrosis, thereby treating fibrosis.

[0274] In any aspect of the present invention, the method or use reverses at least one clinically or biochemically observable characteristic of fibrosis, thereby treating fibrosis.

[0275] 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. Preferably, collagen is a precursor or mature forms of collagen a1 Type 1 .

[0276] The existence of, improvement in, treatment of or prevention of a fibrotic disease may be by any clinically or biochemically relevant method of the subject or a biopsy therefrom. For example, 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. For example, inhibition of 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. Further, for example, in lung fibrosis, 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. In addition, blood levels of collagen fragments would also be reduced.

[0277] 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. For chronic condition, the compound of the present invention can be advantageously administered for life time period.

Combination treatment

[0278] 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.

[0279] 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.

[0280] In another aspect, there is provided 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, a pharmaceutically acceptable excipient and at least one additional anti-cancer agent.

[0281] 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.

[0282] 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. [0283] 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.

[0284] Without wishing to be bound by theory, the inventors hypothesise that compounds of the invention may enhance the migration of T-cells, NK cells, or cells of myeloid lineage into the tumour or tumour microenvironment. Accordingly, in certain embodiments, the additional anti-cancer agent may include immuno-onoclogy therapy, such as CAR-T therapy and checkpoint inhibitor therapy.

[0285] The additional anti-cancer agent may be an agent that targets cell signalling pathways and cascades, G-couple protein receptor or other receptor modulator.

[0286] In another aspect there is provided a method for 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 a subject and an additional anti-cancer agent. In one embodiment, the cancer is resistant to radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0287] 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.

[0288] In another aspect, there is provided a method of sensitising a tumour in a subject in need thereof 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, wherein the method further comprises administering one or more additional anti-cancer agents. Preferably, 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. Alternatively, 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.

[0289] 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.

[0290] 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.

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.

Dosing

[0291] 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.

[0292] It will be understood, that 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.

[0293] The phrase “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.

[0294] Typically, 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%. Exemplary 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.

[0295] In some embodiments, 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.

[0296] In some embodiments, 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.

[0297] Preferably 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. In certain embodiments, the sub-optimal doses may be expressed as a % reduction of a therapeutic or optimal dose. For example, 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.

[0298] 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

[0299] In another embodiment there is provided a 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.

[0300] In other embodiments there is provided a kit for use in a therapeutic application(s) mentionedherein, the kit 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.

[0301] In certain embodiments the kit may contain one or more further active principles or ingredients for treatment of cancer.

[0302] In certain embodiments the kit may contain one or more further active principles or ingredients for treatment of fibrotic disease.

[0303] 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. Alternatively the kit may may further comprise a package insert indicating the composition and other active principle can be used to treat fibrotic diease. Alternatively, or additionally, 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. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0304] 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. In one embodiment, 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.

[0305] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

Examples

Synthesis of compounds

General experimental details

[0306] Yields reported herein refer to purified products (unless specified). Analytical TLC was performed on Merck silica gel 60 F254 aluminium-backed plates. Compounds were visualised by UV light and/or stained with iodine, ninhydrin or potassium permanganate solution followed by heating. Flash column chromatography was performed on silica gel. ¹ H-NMR spectra were recorded on a Bruker 400 MHz, Avance II spectrometer with a 5mm DUL (Dual) 13C probe and Bruker 400 MHz, Avance III HD spectrometer with BBFO (Broad Band Fluorine Observe) probe. Chemical shifts (5) are expressed in parts per million (ppm) with reference to the deuterated solvent peak in which the sample is prepared. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br s (broad singlet). [0307] The following solvents, reagents or scientific terminology may be referred to by their abbreviations:

TLC Thin Layer Chromatography mL Millilitres mmol Millimoles h Hour or hours min Minute or minutes g Grams mg Milligrams eq Equivalents rt or RT Room temperature, ambient, about 25°C

MS Mass spectrometry

General Procedure 1. Substituted benzoyl chloride 2 (1 equiv.) was stirred in dichloromethane and aluminium trichloride (1 .5 equiv.) was added portion wise at 0 °C. The reaction mixture was stirred for 30 min at same temperature and resorcinol 1 (1 equiv.) was added to it in portion wise at same temperature. The resulting mixture was stirred at 45 °C for 16 h with reaction monitored by TLC analysis. After reaction completion, the mixture was quench with ice and solid material was filtered through sintered funnel. The filtrate was extracted with ethyl acetate (3 x 200 mL) and combined organic layer was washed with water (600 mL), brine (2 x 200 mL) and dried over anhydrous Na2SC . The volatiles were removed under vacuum to obtain the crude compound which was triturated with dichloromethane (20 mL).

General Procedure 2. Ketone (3, 1 equiv.), substituted phenyl acetic acid 4 (1 equiv.) were stirred in acetic anhydride (9 mL, 3v) and diisopropylethyl amine (9 mL, 3v) at 130 °C for 16 h. After confirmation of reaction completion via TLC analysis, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with water (100 mL), brine (2 x 100 mL), and dried over anhydrous Na2SC . The filtrate was concentrated under vacuum to get crude compound. The crude compound was stirred in ethanol (40 mL) and the precipitate was filtered through sintered funnel. The solid material was dried under reduced pressure at 50 °C to obtain the 2/-/-chromen-2-one product 5.

General Procedure 3. To a stirred solution of 2/-/-chromen-2-one 5 (1 equiv.) in tetrahydrofruan and borane dimethyl sulphide (15 equiv.) was added drop wise at 0 °C. The reaction mixture was stirred for 16 h at room temperature with reaction progress monitored by TLC. After reaction completion, the reaction mixture was quenched with aq. 2N HCI (30 mL) and extracted with ethyl acetate (3x 50 mL). The combined organic layer was washed with water (50 mL) and brine (2x 50 mL) solution. The organic layer was dried over anhydrous Na2SC , filtered and concentrated under vacuum to get crude material. The crude material was purified through column chromatography [Combiflash, silica gel, gradient ethyl acetate in hexane] to obtain the 2/-/-chromene product 6.

General Procedure 4. To a solution of 2/-/-chromene 6 (1 equiv.) in ethyl acetate (30 mL) was added Pd/C 10% (0.30 g). The reaction mixture and stirred at 65 °C in autoclave for 16 h under H2 atmosphere (100 psi). After consumption of starting material, the reaction mixture was filtered through celite, washed with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography [Combiflash, silica gel] to obtain the 2/-/-chroman product (220 mg, 39.64 %) as a racemic mixture of (3R,4S)- and (4R,3S)-enantiomers.

General Procedure 5. To a stirred solution of 3-aryl-4-(4-nitrophenyl)-2/-/-chromen-7-ol 1 (1 .0 equiv.) in DCM and TEA (3 equiv.) was added followed by addition of trifluoromethanesulfonyl trifluoromethanesulfonate (1.5 equiv.) at room temperature. The reaction mixture was stirred for 2 h at room temperature with reaction progress monitored by TLC analysis. The reaction mixture was quenched with water and extracted with DCM three times. The combined organic layer was washed with brine solution and dried over anhydrous Na2SC , filtered and concentrated under vacuum to get crude material. The crude was purified by combi flash in EtOAc : n-hexane to obtain 3-aryl-4-(4-nitrophenyl)-2/-/-chromen-7-yl trifluoromethanesulfonate 2.

General Procedure 6. To a stirred solution of 3-aryl-4-(4-nitrophenyl)-2/-/-chromen-7-yl trifluoromethanesulfonate 2 (1.0 equiv.), ethenylboronic acid (2.5 equiv.) and Na2COs (3 equiv.) in DMF. The reaction mixture was degassed with N2 gas and PdCl2(dppf) (0.1 equiv.) was added to it. The reaction mixture was heated at 1 10°C for 2h. The reaction progress was monitored by TLC and after consumption of starting material the reaction mixture diluted with cold water and extracted with ethyl acetate twice. The combined organic layer was washed with brine solution, dried over Na2SC and evaporated on rota to get crude material. The crude was purified with combi flash using EtOAc: Hexane to obtain 7-ethenyl-3-aryl-4-(4-nitrophenyl)-2H-chromene 3.

General Procedure 7. To a stirred solution of 7-ethenyl-3-aryl-4-(4-nitrophenyl)-2H- chromene 3 (1 equiv.) in 1 ,4 dioxane: water (2:1 ) and tetraoxoosmium 4% in water (0.05 equiv.) was added dropwise at 0°C. The reaction mass was stirred for 30 min at 0°C and sodium periodate (1 .5 equiv.) was added to it. The reaction mixture was stirred at room temperature for 7h. The reaction progress was monitored by TLC which showed consumption of starting material. The reaction mixture was was quenched with water and extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get crude material. The crude was purified by Combi-flash using to EtOAc:n-hexane to get 3-aryl-4-(4-nitrophenyl)-2/-/- chromene-7-carbaldehyde 4.

General Procedure 8. To a stirred solution of 3-aryl-4-(4-nitrophenyl)-2/-/-chromene-7- carbaldehyde 4 in DCM and diethylaminosulfur trifluoride (1 .5 equiv.) was added dropwise at 0°C. After confirmation of reaction completion by TLC analysis, the reaction mixture was quenched with saturated NaHCOa and extracted with DCM. The combined organic layer was concentrated under reduced pressure to get crude material. The crude was purified by combiflash using EtOAc : n-hexane and concentrated under reduced pressure to get 7-(difluoromethyl)-3-aryl-4-(4-nitrophenyl)-2/-/-chromene 5.

General Procedure 9. To a solution of 7-(difluoromethyl)-3-aryl-4-(4-nitrophenyl)-2/-/- chromene ( 0.20 g, 0.508 mmol) in ethyl acetate and Pd/C 10% (0.10 g) was added. The reaction mixture was stirred at 65 °C in autoclave for 16 h under H2 atmosphere (70 psi). The reaction progress was monitored by LCMS until consumption of starting material. The reaction mixture was filtered through celite, washed with ethyl acetate (50 mL) and concentrated under reduced pressure. The residue was purified by column chromatography [Combiflash, silica gel, gradient ethyl acetate in n-hexane to get 4-(7- (difluoromethyl)-3-aryl-2/-/-chromen-4-yl)aniline 6 and 4-(7-(difluoromethyl)-3- phenylchroman-4-yl)aniline 7. General Procedure 10. To a stirred solution of iodoarene 4 (20 mmol) in triethylamine (190 mL) was added copper (I) iodide (0.096 g, 0.51 mmol) and bis(triphenylphosphine)palladium chloride (0.47 g, 0.71 mmol). The 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. Upon consumption of starting material, 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.

General Procedure 11. To a stirred solution of 3-((3-aryl)prop-2-yn-1 -yl)oxy)phenol 5 (4.5 mmol) and sodium hydrogen carbonate (0.73 g, 9.0 mmol) in nitromethane (45 mL) and was added dropwise a solution of iodine (3.5 g, 14 mmol) in nitomethane (45 mL). The reaction mixture was then stirred for 16 h at room temperature in the absence of light. After confirmation of consumption of starting material by TLC analysis, the reaction mixture was quenched with saturated sodium thiosulfate solution (50 mL) and extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC , and concentrated under vacuum. The crude was purified by combi flash (10% EtOAc in n-hexane) to obtain 4-aryl-3-i odo-2 H- chromen-7-ol 6.

General Procedure 12. A stirred solution of 4-aryl-3-iodo-2/-/-chromen-7-ol 6 (0.64 mmol) and substituted tert-butyl 3-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 Flindole- 1 -carboxylate 7 (0.95 mmol) in dimethylformamide (7.5 mL) was degassed with N2 gas for 10 min before addition of Na2COa (0.53 g, 2.5 M aq solution) and 1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (23 mg , 0.031 mmol). The 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. General Procedure 13. To a solution of substituted tert-butyl 3-(4-aryl-7-hydroxy-2/-/- chromen-3-yl)-1 /-/-indole-1 -carboxylate 8 (1.6 mmol) in methanol (16 mL) was added Pd/C 10% (0.065 g). The reaction mixture was stirred at room temperature for 16 h under H2 (1 atm). After consumption of starting material, the 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.

General Procedure 14. To a stirred mixture of 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 from the previous step in DCM (5 mL) was added 4 M HCI in 1 ,4-dioxane (3 mL) dropwise at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 12 h. After confirmation of consumption of starting material by TLC analysis, the reaction mixture was concentrated under reduced pressure. 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.

General Procedure 15. A stirred solution of 4-(4-(dimethylamino)phenyl)-3-iodo-2/-/- chromen-7-ol 1 (0.25 g 0.64 mmol) and substituted boronic acid 2 (0.95 mmol) in dimethylformamide (7.5 mL) was degassed with N2 gas for 10 min before addition of Na2COs (0.53 g, 2.5 M aq solution) and 1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (23 mg , 0.031 mmol). The 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 3-substituted 4-(4-(dimethylamino)phenyl)-2/-/-chromen-7-ol 3. General Synthesis Scheme 1.

6 7

Experimental procedure for General Synthesis Scheme 1 :

Step-1 - General Procedure 1.

Step-2 - General Procedure 2.

Step-3 - General Procedure 3.

Step-4 - General Procedure 4.

General Synthesis Scheme 1 was used to prepare the following compounds, with modified functional groups as specified:

1 . NX-581 - Step-1 R = H; R' = 4-nitro; Step-2 R" = 3-methyl

2. NX-592 - Step-1 R = H; R' = 4-nitro; Step-2 R" = 3-fluoro

3. NX-593 - Step-1 R = H; R' = 4-nitro; Step-2 R" = 4-methyl

4. NX-599 - Step-1 R = H; R' = 4-nitro; Step-2 R" = 4-fluoro

5. NX-700 - Step-1 R = H; R' = 4-nitro; Step-2 R" = trifluoromethyl

6. NX-705 - Step-1 R = H; R' = 4-nitro; Step-2 R" = 3,4-dimethyl

7. NX-706 - Step-1 R = H; R' = 4-nitro; Step-2 R" = 4-hydroxy-3-methyl 8. NX-707 - Step-1 R = H; R' = 4-nitro; Step-2 R" = 4-hydroxy-3-methyl (byproduct)

9. NX-708 - Step-1 R = H; R' = 3-fluoro-4-nitro; Step-2 R" = 3-methyl

10. NX-710 - Step-1 R = CH3; and R' = 3-fluoro-4-nitro; Step-2 R" = 3-methyl

1 1. NX-714 - Step-1 R = H; R' = 4-nitro; Step-2 R = unsubstituted

12. NX-715 - Step-1 R = H; R' = 4-nitro; Step-2 R = 3-trifluromethyl

13. NX-745 - Step-1 R = H; R' = 4-nitro; Step-2 R = 3-cyclopropyl-4-fluoro

14. NX-758 - Step-1 R = H; R' = 4-nitro; Step-2 R = 3,4-methylenedioxy

15. NX-761 - Step-1 R = H; R' = 4-nitro; Step-2 R = 3,5-dimethyl

16. NX-765 - Step-1 R = H; R' = 4-nitro; Step-2 R = 4-chloro-3-methyl

17. NX-779 - Step-1 R = H; R' = 4-nitro; Step-2 R = 4-methoxy

18. NX-780 - Step-1 R = H; R' = 4-nitro; Step-2 R = 3,4-dimethoxy

General Synthesis Scheme 2.

Experimental procedure for General Synthesis Scheme 2:

Step-1 - General Procedure 5.

Step-2 - General Procedure 6.

Step-3 - General Procedure 7.

Step-4 - General Procedure 8.

Step-5 - General Procedure 9. General Synthesis Scheme 2 was used to prepare the following compounds, with modified functional groups as specified:

1 . NX-752 - Step-1 R = 3-methyl

2. NX-754 - Step-1 R = 3-methyl

3. NX-763 - Step-1 R = 3,4-dimethyl

General Synthesis Scheme 3.

Experimental procedure for General Synthesis Scheme 3:

Step-1 - Synthesis of 3-(prop-2-yn-1-yloxy)phenol (3). To a solution of 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. Upon consumption of starting material, the reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with ice cold water (3 x 250 mL) and brine solution (250 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was using through flash column chromatography (gradient 10% to 15% ethyl acetate in hexane) to obtain 3-(prop-2-yn-1-yloxy)phenol 3 (4.29 g, 32%) as yellow solid. LCMS: 148.98 [M+H] ⁺ .

Step-2 - General Procedure 10.

Step-3 - General Procedure 11. • Step-4 - General Procedure 12.

• Step-5 - General Procedure 13.

• Step-6 - General Procedure 14.

General Synthesis Scheme 3 was used to prepare the following compounds, with modified functional groups as specified:

1 . NX-733 - Step-2 R = 4-dimethylamine; Step-4 R' = unsubstituted

2. NX-770 - Step-2 R = 4-dimethylamine; Step-4 R' = 6-methoxy

3. NX-782 - Step-2 R = 4-methoxy; Step-4 R' = unsubstituted

4. NX-789 - Step-2 R = 4-dimethylamine; Step-4 R' = 6-methoxy

5. NX-792 - Step-2 R = 4-hydroxy; Step-4 R' = 6-methoxy

6. NX-796 - Step-2 R = 4-nitro; Step-4 R' = unsubstituted

7. NX-797 - Step-2 R = 4-acetamido; Step-4 R' = unsubstituted

8. NX-798 - Step-2 R = 4-dimethylamine; Step-4 R' = 6-methyl

9. NX-801 - Step-2 R = 4-formamido; Step-4 R' = unsubstituted

10. NX-803 - Step-2 R = 4-acetamido; Step-4 R' = 6-methoxy

11 . NX-804 - Step-2 R = 4-acetamido; Step-4 R' = 6-methoxy

12. NX-806 - Step-2 R = 4-nitro; Step-4 R' = 6-methoxy

13. NX-805 - Step-2 R = 4-acetamido; Step-4 R' = 5-methoxy

14. NX-808 - Step-2 R = 4-propionamido; Step-4 R' = unsubstituted

15. NX-809 - Step-2 R = 4-(2,2,2-trifluoroacetamido); Step-4 R' = unsubstituted

16. NX-810 - Step-2 R = 4-acetamido; Step-4 R' = 7-methoxy

17. NX-812 - Step-2 R = 4-acetamido; Step-4 R' = 6-hydroxy

18. NX-815 - Step-2 R = 4-acetamido; Step-4 R' = 5-hydroxy

19. NX-816 - Step-2 R = 4-hydroxy; Step-4 R' = unsubstituted

20. NX-819 - Step-2 R = 4-acetamido; Step-4 R' = 5,6-dimethoxy

21 . NX-822 - Step-2 R = 3-fluoro-4-hydroxy; Step-4 R' = 6-methoxy

22. NX-824 - Step-2 R = 4-hydroxy; Step-4 R' = 6-ethoxy

23. NX-826 - Step-2 R = 4-cyclopropanecarboxamido; Step-4 R' = 6-methoxy

24. NX-831 - Step-2 R = 4-hydroxy; Step-4 R' = 6-methyl

25. NX-833 - Step-2 R = 4-hydroxy; Step-4 R' = 6-isopropoxy

26. NX-834 - Step-2 R = 4-(methoxycarbonyl)amino; Step-4 R' = unsubstituted

27. NX-832 - Step-2 R = 4-acetamido; Step-4 R' = 5-hydroxy-6-methoxy 28. NX-835 - Step-2 R = 4-acetamido; Step-4 R' = 4,6-dimethoxy

29. NX-831 - Step-2 R = 4-methoxy; Step-4 R' = 6-methoxy

30. NX-839 - Step-2 R = 4-hydroxy-3-methoxy; Step-4 R' = 6-methoxy

31 . NX-841 - Step-2 R = 4-hydroxy; Step-4 R' = 6-chloro

32. NX-845 - Step-2 R = 4-acetamido; Step-4 R' = 6-triflouromethoxy

33. NX-847 - Step-2 R = 3,4-dihydroxy; Step-4 R' = 6-methoxy

34. NX-847 - Step-2 R = 3-chloro-4-dihydroxy; Step-4 R' = 6-methoxy

35. NX-904 - Step-2 R = 4-acetamido; Step-4 R' = unsubstituted

General Synthesis Scheme 4.

1 3 4

Experimental procedure for General Synthesis Scheme 4:

• Step-1 - General Procedure 15.

• Step-2 - General Procedure 4.

General Synthesis Scheme 4 was used to prepare the following compounds, with modified functional groups as specified:

1 . NX-740 - Step-1 R = 3-fluoro-5-methylphenyl

2. NX-741 - Step-1 R = 2-fluoro-3-methylphenyl

3. NX-742 - Step-1 R = 2-fluoro-5-methylphenyl

4. NX-749 - Step-1 R = 2-methylphenyl

5. NX-750 - Step-1 R = 3-/?-propylphenyl Scheme: Synthesis of NX-202

1 NX-588 Scheme: Synthesis of NX-591

Scheme: Synthesis of NX-595

NX-594 NX-598 Scheme: Synthesis of NX-705

Experimental procedure for synthesis of NX-705:

Step-1 - Synthesis of (2,4-dihydroxyphenyl)(4-nitrophenyl)methanone (3).

Followed General Procedure 1 using 4-nitrobenzoyl chloride (2, 20.0 g, 108 mmol), dichloromethane (200 mL), aluminiumtrichloride (21.6 g, 162 mmol) and resorcinol (1, 11 .9 g 108 mmol) to obtain the title compound (2,4-dihydroxyphenyl)(4- nitrophenyl)methanone as a yellow solid (3, 6.0 g, 21.48%). LCMS: 258.12 [M-H]’.

Step-2 - Synthesis of 3-(3,4-dimethylphenyl)-4-(4-nitrophenyl)-2-oxo-2H-chromen- 7-yl acetate (5). Followed General Procedure 2 using (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) to obtain 3-(3,4-dimethylphenyl)-4-(4-nitrophenyl)-2-oxo-2H-chromen-7- yl acetate (5, 1.3 g, 26.16%) as yellow solid. ¹ H-NMR (400 MHz; DMSO-ofe) : 5 8.24 (d, J =

8.8 Hz, 2H), 7.58 (d, J= 8.8 Hz, 2H), 7.42 (d, J= 2.0 Hz, 1 H), 7.10 (dd, J ¹ = 8.8 Hz, J ² = 2.4 Hz, 1 H), 7.02-6.93 (m, 3H), 6.84 (d, J= 7.6 Hz, 1 H), 2.31 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H). LCMS: 430.37 [M+H] ⁺ .

Step-3 - Synthesis of 3-(3,4-dimethylphenyl)-4-(4-nitrophenyl)-2H-chromen-7-ol

(6). Followed General Procedure 3 using 3-(3,4-dimethylphenyl)-4-(4-nitrophenyl)-2- oxo-2H-chromen-7-yl acetate (5, 1 .3 g, 3.03 mmol) in THF (39 mL) and borane dimethyl sulphide (4.3 mL, 45.45 mmol). The crude material was purified through column chromatography [Combiflash, silica gel, gradient 15% to 20% ethyl acetate in hexane] to obtain 3-(3,4-dimethylphenyl)-4-(4-nitrophenyl)-2H-chromen-7-ol ( 6, 0.6 g, 53.08 %) as a light yellow solid. ¹ H-NMR (400 MHz; DMSO-de) : 5 9.73 (s, 1 H), 8.18 (d, J= 8.4 Hz, 2H), 7.38 (d, J= 8.8 Hz, 2H), 6.90 (d, J= 8.0 Hz, 1 H ), 6.86 (s, 1 H ), 6.65 (d, J= 7.6 Hz, 1 H ), 6.41 (d, J = 8.4 Hz, 1 H ), 6.35 (d, J = 2.4 Hz, 1 H), 6.29 (dd, J ¹ = 8.4 Hz, J ² = 2.0 Hz,1 H), 5.01 (s, 2H), 2.13 (s, 3H), 2.09 (s, 3H). LCMS: 372.24 [M-H]’.

Step-4 - Synthesis of NX-705. Followed General Procedure 4 using 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. ¹ H-NMR (400 MHz; DMSO-de) : 5 9.21 (s, 1 H), 6.87 (d, J=7.60 Hz, 1 H), 6.64 (d, J=8.0 Hz, 1 H), 6.58 (s, 1 H ), 6.35 (d, J=8.0 Hz, 1 H ), 6.26-6.20 (m, 6H ), 4.78 (s, 2H), 4.29 (t, J=11 .2 Hz, 1 H), 4.10 (dd, J ¹ =10.4 Hz, J ² =2.4 Hz,1 H), 4.03 (d, J=5.2 Hz, 1 H), 3.37-3.35 (m, 1 H ), 2.13 (s, 3H), 2.08 (s, 3H). LCMS: 346.12 [M+H] ⁺ .

Scheme: Synthesis of NX-716 Scheme: Synthesis of NX-720

Scheme: Synthesis of NX-723

Scheme: Synthesis of NX-727 Scheme: Synthesis of NX-728

Scheme: Synthesis of NX-731 and NX-732 Scheme: Synthesis of NX-737

Scheme: Synthesis of NX-744

Scheme: Synthesis of NX-753

1 NX-753 Scheme: Synthesis of NX-755

Scheme: Synthesis of NX-757 Scheme: Synthesis of NX-760 Scheme: Synthesis of NX-774

Scheme: Synthesis of NX-776

Scheme: Synthesis of NX-778 Scheme: Synthesis of NX-781

Scheme: Synthesis of NX-790

Scheme: Synthesis of NX-802

Scheme: Synthesis of NX-813 Scheme: Synthesis of NX-814

Scheme: Synthesis of NX-827

Scheme: Synthesis of NX-828 and NX-829

Scheme: Synthesis of NX-838

Cytotoxicity activity of compounds

[0308] The cytotoxicity activity of compounds may be determined by a variety of methods, including in vitro and in vivo methods.

In vitro assay

[0309] Cytotoxicity was determined using a CellTitre-G Io assay. A stock solution of each compound was prepared at 10 mM in DMSO. IC50 values were determined by testing cell growth inhibition across 10 compound concentrations, starting at 50 pM and using 3-fold serial dilution in a 96-well plate. Each compound concentration was tested in technical duplicate. DMSO final concentration was normalised at 0.5%. Plates were incubated for 72 hours at 37 °C and 5% CO2. During data analysis, IC50 values were calculated with KLFit curve fitting software using 4 Parameter Logistic Model [fit = (A+ ((B-A)/ (1 + ((C/x) ^A D))))]. In vivo assay

[0310] In vivo pharmacokinetic profiles were determined using a 5 in 1 cassette SD rats (n = 3) following a single intravenous administration at 0.5-1 mg/kg. Stock solutions of each compound were prepared in DMSO at 10 mg/kg and were used to prepare a formulation of 0.2 mg/mL in DMSO, solutol HS15 and saline. Rats were given free access to food and water. Plasma was collected at time point of 0 (pre-dose), 0.083, 0.25, 0.5, 1 , 2, 4, 8 and 24 hours by manually restraining the animal and collecting 150 pL of blood via the tail vein into K2EDTA tubes. Blood 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).

Results - cytotoxicity activity of compounds

[0311] The IC50 (pM) activity of compounds tested against various cell lines is shown in Table 5 and Table 6 below.

Table 5: IC50 (pM) activity of compounds tested against various cell lines

Table 6: C50 (pM) activity of compounds tested against various cell lines

Comparative data

[0312] The IC50 (pM) activity of compounds in Table 7 was tested against various cell lines. Comparative activity data for compounds in Table 7 is shown in Table 8 and Table 9.

Table 7: comparative compounds tested

Table 8: IC50 (pM) activity of comparative compounds tested against various cell lines

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.

Table 10: IC50 (pM) acitvity of comparative compounds (NX-846 and NX-848) and compounds of the invention (NX-527 and NX-705) tested against various cell lines

Table 11 : IC50 (pM) of comparative compound (NX-739) with compound of the invention NX-581

[0314] Compounds of the invention show improved potency compared to comparative compounds in the growth inhibition of various tumour derived cell lines.

Dual activity of compounds - cytotoxicity and CAFs inhibition

[0315] In vitro studies were performed with ex vivo explant models. 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.

[0316] Importantly, 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.

[0317] Explants derived from patient tissues undergoing pancreatic-oduodenectomy (Whipple procedure), 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. The H&E stained explants were counterstained and evaluated for tumour cell death (cytokeratin), cancer associated fibroblasts (a-smooth muscle actin), cell proliferation (bromodeoxyuridine (BrdU)) and cell death (TUNEL) as described in Kokkinos et al (2021 ). Quantification of each stain was performed on QuPath as described in Sharbeen et al, Cancer Res, 81 , 3461 (2021 ).

Table 12: Patient tumour explant summary

[0318] 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.

Histological results for patient 10 treated with NX767 are provided in Figure 8.

[0319] A summary of histological results for patients 1 , 2, 3 and 9 treated with NX705 are provided in Figure 9. A summary of histological results for patients 5, 6, 8, 9 and 10 treated with NX767 are provided in Figure 10.

[0320] Figures 5A, 6A, 7A, 8A and 9A show Tunel staining IFA. TUNEL (green fluorescent cell death marker) was counterstained with DAPI (blue fluorescent nuclei stain) to demonstrate compounds increased cell death which is indicated by increased green and blue fluorescence (bright areas of the images).

[0321] Treatment of PDAC tumour explants with NX705 in 4/4 patients or NX767 in 5/5 patients resulted in reduced tumour cell and CAF frequency, decreased cell proliferation, and increased cell-death relative to DMSO vehicle treated explants. Compound efficacy was observed at the lowest concentration tested at 10pg/mL.

[0322] 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.

[0323]Treatment of PDAC tumour explants with NX792-E1 and NX904-E1 in 4/4 patients resulted in reduced tumour cell and CAF frequency. Cell proliferation was tested in 2 patients and shown to be decreased. All results are relative to DMSO vehicle treated explants. Compound efficacy was tested at 1 pg/mL.

[0323] Cell viability of MiaPaCa2 Cells at 24 hours post treatment was measured and the results are shown in Figure 17. MiaPaCa2 cell viability decreased after 24 hour drug treatment. Compounds of the invention showed some potency at all dosages tested, and all tested compounds showed increasing strong potency as doses escalated. At low doses (0.01 uM), cell viability ranged from 60-95% and at the higher dose (1 .5uM), cell viability for all compounds was 30-45%.

[0324] Cell cycle analysis of MiaPaCa2 cells post-treatment (4 hours) showed increased G2-M cell cycle arrest in MiaPaCa2 cells after 4 hours of treatment with compounds of the invention (NX767, NX792-E1 , NX803E1 , NX806-E1 , NX908-E1 ). These results are shown in Figure 19. This shows the compounds are arresting the cells at G2 and preventing them from growing and preparing for mitotic division. This in turn prevents the cells from dividing into two daughters and proliferating.

Glioblastoma organoids (GBOs) treatment protocol

[0324] 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.

Once frozen, 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. All compounds cause a reduction in the size of the GBO. 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).

[0326] Reference: Jacob et al A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity. Cell. 2020 Jan 9;180(1 ):188-204.e22. doi: 10.1016/j.cell.2O19.11 .036.