PHARMACEUTICAL COMPOUNDS

The present application describes compounds, compositions, uses and methods for therapy, especially cancer therapy. In particular, the application relates to compounds for use in the treatment of cancer generally, and in particular gliomas. Background of the Invention

Chemotherapy drugs for the treatment of cancer are generally directed to inhibiting the reproduction of malignant cells and killing malignant cells, thereby preventing tumour growth or reducing tumour size. Some of the most commonly used cancer chemotherapy drugs include alkylating drugs, anthracycline antibiotics, taxanes, alkaloids, and topoisomerase inhibitors.

Alkylating drugs are the oldest anti-cancer drugs and are used to treat many types of cancer. Alkylating drugs are typically methylating agents or chloroethylating agents which cause apoptosis in malignant cells. Temozolomide, (brand name, Temodar®, Schering- Plough Corp.), is an oral alkylating agent used in the treatment of brain cancer (1-3), e.g. glioblastoma multiforme and oligodendroglioma, and of melanoma (4, 5). It has also been used to treat prostate cancer, pancreatic carcinoma, soft tissue sarcoma, and renal cell carcinoma (6-12). Temozolomide inhibits cell reproduction by inhibiting DNA replication (13).

Temodar® has unique characteristics compared with other alkylating agents. For example, it is administered orally, forms a small lipophilic molecule that crosses the blood-brain barrier, is less toxic than other alkylating agents, does not chemically cross- link DNA, and is effective on a wide variety of cancers. However, although Temodar® is the current chemotherapeutic standard for treating brain tumours, as many as 50% of brain tumours are resistant to Temodar® therapy (14, 15). Resistance to Temodar® is also found in melanoma (16, 17).

Anthracycline antibiotics include doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin and are commonly used to treat most types of cancers, e.g. leukemias, Hodgkin's lymphoma, cancers of the bladder, breast, stomach, lung, ovaries, and thyroid, soft tissue sarcoma, multiple myeloma, and others. Doxombicin acts by intercalating into DNA and preventing transcription and DNA synthesis (18). Doxorubicin is also a topoisomerase I inhibitor (19) and Pa poison (20). Topoisomerase inhibiting drugs include doxorubicin, etoposide, and teniposide, and are generally used to treat leukemia, lung, ovarian, and gastrointestinal cancers (21 , 22). These drugs act by inhibiting topoisomerase I or topoisomerase Pa or Pb, thereby preventing DNA replication, recombination, transcription and chromosome segregation (23, 24).

Although these drugs are initially effective, tumour cells have, or may, develop resistance to them. There are multiple mechanisms by which the cancer cells develop resistance to topoisomerase inhibitors, for example, endogenously produced ganglioside GM3 was shown to be involved in etoposide and doxombicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cell line (25).

Primary non-malignant and malignant brain and central nervous system tumours are expected to occur in more than 64,000 people in the United States in 201 1 (26). Gliomas represent 31% of all primary brain and central nervous system tumours, and over 80% of gliomas are malignant (26). The mortality rate of primary malignant brain and CNS tumours is high; approximately 22,020 new adult cases of brain and other nervous system cancers and 13,140 deaths occurred in 2010 (27). Malignant brain tumours account for 1.4% of all primary malignant cancers, and 2.2% of all cancer related deaths (28). Despite access to state-of-the-art surgical, radiation, and chemotherapies, survival rates for patients with newly diagnosed glioblastoma multiforme, the most common malignant glioma, was very poor. The median survival for GBM patients was 14.6 months and the 2 year survival of patients with GBM was 10.4% for radiotherapy alone and only 26.5% undergoing combined therapy treatment of Temodar® and radiation (29). The two to five year survival rate for malignant glioma has remained unchanged over the past 30 years. Thus, despite aggressive treatments, brain tumours generally recur, and are fatal. Ovarian cancer is the second most common gynaecologic cancer, and represents the leading cause of gynecologic cancer-related death in Europe and United States (30, 31 ).

It is estimated that 21 ,880 new cases and 13,850 deaths from ovarian cancer occurred in the United States in 2010 (27). Treatment of ovarian cancer involves surgery and chemotherapy, and sometimes radiotherapy. Platinum based compounds are standard first-line agents for ovarian cancer and initial response rates are high (32). However, subsequent relapse with acquired platinum resistance is frequent and closely linked to the poor survival associated with this cancer. Accordingly, a significant clinical need exists for additional chemotherapeutic agents that are toxic to a wide range of tumours and tumour cell types, in particular tumours and tumour cells that are resistant to current treatments such as radiotherapy, and resistant to other chemotherapeutic drugs. Therefore, it is an aim of the present invention to provide solutions to meet this need.

There is also a continuing requirement, not only to provide treatments as described above, but to improve treatments for all forms of cancer. In other words, there is a clinical need for improved compounds and compositions for treating brain cancers and ovarian cancers, as well as other cancers more generally. Therefore, it is a further aim of the present invention to provide further compounds and compositions for treating cancers generally, more specifically and brain and ovarian tumours.

It has been known for many years that barbituric acid derivatives have value as therapeutic agents. In the past they have been employed for their central nervous system depressant activity, finding use inter alia as sedatives and anti-convulsants. Due to their toxicity, they have largely been replaced by benzodiazepines in such treatments.

However, more recently barbiturates have found new indications as potential treatments for a variety of diseases. For example, Ciustea et al. discloses inter alia barbiturates for treating the vaccinia virus (smallpox) ("Identification of non-nucleoside DNA synthesis inhibitors of vaccinia virus by high throughput screening", J. Med. Chem., 51 , 6563-6570, 2008).

Barbiturates have also been proposed as cancer treatments. For example, WO 01/93841 discloses certain barbituric acid analogues as therapeutic agents which inhibit HIF-1 activity. This may be used to treat proliferative conditions, such as cancer.

It is also known to use merocyanine dyes (compounds related to thiobarbiturates) to treat leukemia (W089/12080). This treatment involves the use of the dye to photosensitize leukemic cells, followed by exposure to light. Merocyanine 540 has also been shown to have apoptotic activity (Chen Yen-Chou et al., "Photodynamic anticancer agent merocyanine 540 inhibits cell growth by apoptosis". Anticancer Research, 16, 5 A, 2781- 2788, 1996; D. L. Traul et al., "Induction of apoptosis and necrosis in leukemia and solid tumour cells by merocyanine 540-mediated PDT", Photochemistry and Photobiology, 59, Spec. Issue, 70S, 1994; Shazib et al., "Caspase proteases mediate apoptosis induced by anticancer agent preactivated MC540 in human tumour cell lines". Cancer Letters, 128, 1 , 1 1 -22, June 5 1998; Sieber et al., "Second generation merocyanine photosensitizers for photodynamic therapy", Trends in Photochemistry & Photobiology, 10, 1-13, 2003).

Some barbiturate derivatives have been proposed as possible modulators of apoptosis and therefore possible anti-cancer agents (WO201 1/094708). Several have been proposed as possible breast cancer and prostate cancer treatments (W02009/065897). Further proposed activities include: as inhibitors of MALT1 proteolytic and/or

autoproteolytic activity (W02009/065897); as a RAD51 protein modulator to protect against DNA damage (W02009/018219); as c-Rel activity inhibitors (W02007/120842) for treating inter alia cancer; as Pin-1 modulators (W02003/074497) for treating inter alia cancer; as potential cancer treatments when combined with indole (Palwinder et al., "Design, synthesis and anticancer activities of hybrids of indole and barbituric acid - identification of highly promising leads", Bioorganic & Medicinal Chemistry Letters, 19, 1 1 , 3054-3058, 2009); and as inhibitors decreasing the proliferation of cervix cancer cells (Shuangding et al., "Multidentate small-molecule inhibitors of vaccinia HI -related (VHR) phosphatase decrease proliferation of cervix cancer cells", Journal of Medicinal

Chemistry, 52, 21 , 6716-6723, 2009).

WO2013/024447 (Nuhope LLC) discloses barbiturate and thiobarbiturate compounds for use in treating cancers.

JPS 50125978 A (Yoshitomi Pharm Ind KK) discloses a series of thiomorpholine derivatives, including 2-cinnamylidene-3-thiomorpholinone-1 -oxide having the formula:

as UV protectants. However, JPS 50125978 A does not disclose or suggest that the thiomorpholine derivaties described therein may be useful in the treatment of cancers.

To date, although some barbiturates and their analogues have received attention, there is still considerable room for improvement in their anti-cancer properrties. The present inventors have surprisingly discovered a class of barbiturate analogues and related compounds which may provide therapies, such as treatments for cancer, especially for cancers that are resistant to current drugs such as Temodar®, and for cancers that are resistant to radiation. These compounds may be used to improve treatments for various forms of cancer.

The Invention In one embodiment (Embodiment 1.1 ) of the invention, there is provided a compound of the formula (1 ):

(1 )

or a salt or tautomer thereof;

wherein:

Q is SO or SO2;

n is 1 or 2

R ¹ is selected from hydrogen and a non-aromatic C1-6 hydrocarbon group;

R ² and R ³ are independently selected from hydrogen and a C1-6 hydrocarbon group (e.g. a saturated hydrocarbon group); or R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group (C=0), a cyclopropane-1 , 1-diyl group or a

cyclobutane-1 ,1-diyl group;

or R ¹ together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or more substituents selected from a C1-4 hydrocarbon group, halogen, hydroxy and amino;

R ⁴ and R ⁵ are independently selected from hydrogen and a non-aromatic (e.g. saturated) C1-6 hydrocarbon group; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropane-1 ,1-diyl group or a cyclobutane-1 ,1-diyl group;

Ar ¹ is selected from phenyl, thiophenyl and furanyl each optionally substituted with one or more substituents R ⁶ ;

R ⁶ is selected from halogen, hydroxy, nitro, cyano, Hyd, O-Hyd; C(=0)-Hyd, NH-Hyd, N(Hyd)2 and SC>2-Hyd ; and Hyd is an optionally fluorinated Ci- ₆ hydrocarbon (e.g. saturated hydrocarbon) group.

Particular and preferred compounds of the formula (1 ) are as defined in the Embodiments 1 .2 to 1 .1 18 below.

1 .2 A compound according to Embodiment 1.1 wherein Q is SO. 1 .3 A compound according to Embodiment 1.1 wherein Q is SO2.

1 .4 A compound according to any one of Embodiments 1 .1 to 1.3 wherein n is 1 .

1 .5 A compound according to any one of Embodiments 1.1 to 1.3 wherein n is 2.

1 .6 A compound according to any one of Embodiments 1.1 to 1 .5 wherein R ¹ is selected from hydrogen and a non-aromatic C1-5 hydrocarbon group; or together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or more substituents selected from a C1-4 hydrocarbon group (e.g alkyl, cycloalkyl or cyclopropylmethyl), halogen, hydroxy and amino.

1 .7 A compound according to Embodiment 1.6 wherein R ¹ is selected from hydrogen and a non-aromatic Ci _-4 hydrocarbon group; or together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or more substituents selected from a Ci _-4 hydrocarbon group (e.g alkyl, cycloalkyl or cyclopropylmethyl), halogen, hydroxy and amino.

1 .8 A compound according to Embodiment 1 .7 wherein R ¹ is selected from hydrogen and a non-aromatic (e.g. saturated) Ci _-4 hydrocarbon group; or together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or more substituents selected from a C1-2 hydrocarbon (e.g. alkyl) group or halogen.

1 .9 A compound according to Embodiment 1.8 wherein R ¹ is selected from hydrogen and a non-aromatic (e.g. saturated) Ci _-4 hydrocarbon group; or together with R ² forms a C2- ₄ alkylene linker. 1 .10 A compound according to any one of Embodiments 1 .1 to 1.5 wherein:

R ¹ is selected from hydrogen and a non-aromatic (e.g. saturated) Ci _-4 hydrocarbon group;

R ² and R ³ are independently selected from hydrogen and a C1-2 hydrocarbon (e.g. alkyl) group; or R ¹ together with R ² forms a C2- ₄ alkylene linker;

or R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group (C=0).

1 .10A A compound according to Embodiment 1 .10 wherein:

R ¹ is selected from hydrogen and a Ci _-4 alkyl, cycloalkyl or cycloalkylalkyl group;

R ² and R ³ are independently selected from hydrogen and methyl;

or R ¹ together with R ² forms a (CH2) ₃ linker;

or R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group (C=0). 1 .1 1 A compound according to any one of Embodiments 1 .1 to 1 .5 wherein R ¹ is selected from hydrogen and a non-aromatic (e.g. saturated) Ci- ₆ hydrocarbon group.

1 .12 A compound according to Embodiment 1 .1 1 wherein R ¹ is selected from hydrogen and a non-aromatic (e.g. saturated) C1-5 hydrocarbon group.

1 .13 A compound according to Embodiment 1.12 wherein R ¹ is selected from hydrogen and a non-aromatic (e.g. saturated) Ci _-4 hydrocarbon group.

1 .14 A compound according to any one of Embodiments 1.1 to 1 .13 wherein either R ¹ is hydrogen or, if it is a non-aromatic hydrocarbon group, the non-aromatic hydrocarbon group is selected from alkyl, cycloalkyl, alkylcycloalkyl and cycloalkylalkyl group.

1 .15 A compound according to Embodiment 1.14 wherein R ¹ is selected from hydrogen, methyl, ethyl, n-propyl, iso- propyl cyclopropyl, cyclopropylmethyl, n-butyl, iso butyl and tert- butyl.

1 .16 A compound according to Embodiment 1.15 wherein R ¹ is selected from hydrogen, methyl, ethyl, iso- propyl cyclopropyl and cyclopropylmethyl.

1 .17 A compound according to Embodiment 1 .16 wherein R ¹ is hydrogen. 1 .18 A compound according to Embodiment 1.16 wherein R ¹ is methyl.

1 .19 A compound according to Embodiment 1.16 wherein R ¹ is ethyl

1 .20 A compound according to Embodiment 1.16 wherein R ¹ is / ^' so-propyl. 1 .21 A compound according to Embodiment 1.16 wherein R ¹ is cyclopropyl.

1.22 A compound according to Embodiment 1.16 wherein R ¹ is cyclopropylmethyl.

1.23 A compound according to any one of Embodiments 1.1 to 1.5 wherein R ¹ together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or more substituents selected from a non-aromatic (e.g. saturated) Ci _-4 hydrocarbon (e.g. alkyl, cycloalkyl or cyclopropylmethyl)) group, halogen, hydroxy and amino.

1.24 A compound according to Embodiment 1.23 wherein R ¹ together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or more substituents selected from a C1-3 hydrocarbon (e.g. alkyl or cyclopropyl) group and halogen. 1.25 A compound according to Embodiment 1.24 wherein R ¹ together with R ² forms a

C2- ₄ alkylene linker which is optionally substituted with one or more substituents selected from methyl, ethyl and fluorine.

1.26 A compound according to Embodiment 1.25 wherein R ¹ together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or two methyl or fluorine substituents.

1.27 A compound according to Embodiment 1.26 wherein R ¹ together with R ² forms a C2- ₄ alkylene linker which is optionally substituted with one or two methyl substituents.

1.28 A compound according to Embodiment 1.27 wherein R ¹ together with R ² forms an unsubstituted C2- ₄ alkylene linker. 1.29 A compound according to Embodiment 1.28 wherein the C2- ₄ alkylene linker is selected from an ethylene, propylene or butylene linker.

1.30 A compound according to Embodiment 1.29 wherein the C2- ₄ alkylene linker is -CH2-CH2-CH2-.

1.31 A compound according to any one of Embodiments 1.1 to 1.5 and 1.1 1 to 1.22 wherein R ² and R ³ are independently selected from hydrogen and a non-aromatic (e.g. saturated) Ci _-4 hydrocarbon group.

1.32 A compound according to Embodiment 1.31 wherein R ² and R ³ are independently selected from hydrogen and a C1-3 hydrocarbon (e.g. alkyl or cyclopropyl) group. 1.33 A compound according to Embodiment 1.32 wherein R ² and R ³ are independently selected from hydrogen and a C1-2 hydrocarbon (e.g. alkyl) group.

1.34 A compound according to any one of Embodiments 1.31 to 1.33 wherein the hydrocarbon group is an alkyl group. 1.35 A compound according to Embodiment 1.31 wherein R ² and R ³ are independently selected from hydrogen, methyl, ethyl, n-propyl, iso- propyl and cyclopropyl.

1.36 A compound according to Embodiment 1.35 wherein R ² and R ³ are independently selected from hydrogen, methyl and ethyl.

1.37 A compound according to Embodiment 1.36 wherein R ² and R ³ are independently selected from hydrogen and methyl.

1.38 A compound according to Embodiment 1.37 wherein R ² and R ³ are both hydrogen.

1.39 A compound according to Embodiment 1.37 wherein one of R ² and R ³ is is methyl and the other is hydrogen. 1.40 A compound according to Embodiment 1.37 wherein R ² and R ³ are both methyl.

1.41 A compound according to any one of Embodiments 1.1 to 1.5 and 1.1 1 to 1.22 wherein R ² and R ³ , together with the carbon atom to which they are attached, form a carbonyl group (C=0), a cyclopropane-1 , 1-diyl or a cyclobutane-1 , 1-diyl group.

1.42 A compound according to Embodiment 1.41 wherein R ² and R ³ , together with the carbon atom to which they are attached form a carbonyl group (C=0).

1.43 A compound according to any one of Embodiments 1.1 to 1.5 and 1.11 to 1.22 wherein R ² and R ³ are independently selected from hydrogen, methyl, ethyl, n-propyl, iso propyl and cyclopropyl or, together with the carbon atom to which they are attached, form a carbonyl group (C=0), a cyclopropane-1 , 1-diyl or a cyclobutane-1 , 1-diyl group. 1.44 A compound according to Embodiment 1.43 wherein R ² and R ³ are independently selected from hydrogen, methyl and ethyl, or together with the carbon atom to which they are attached, form a carbonyl group (=0) or a cyclopropane-1 , 1-diyl group. 1.45 A compound according to Embodiment 1.44 wherein R ² and R ³ are independently selected from hydrogen and methyl or, together with the carbon atom to which they are attached, form a carbonyl group (=0).

1.46 A compound according to Embodiment 1.45 wherein R ² and R ³ together form a carbonyl group C(=0).

1.47 A compound according to any one of Embodiments 1.1 to 1.46 wherein R ⁴ and R ⁵ are independently selected from hydrogen and a non-aromatic (e.g. saturated) C1-5 hydrocarbon group; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropane-1 ,1-diyl group or a cyclobutane-1 ,1-diyl group. 1.48 A compound according to Embodiment 1.47 wherein R ⁴ and R ⁵ are independently selected from hydrogen and a non-aromatic (e.g. saturated) C1-4 hydrocarbon group; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropane- 1 , 1-diyl group or a cyclobutane-1 ,1-diyl group.

1.49 A compound according to Embodiment 1.48 wherein the C1-4 hydrocarbon group is selected from alkyl, cycloalkyl, alkylcycloalkyl and cycloalkylalkyl groups.

1.50 A compound according to Embodiment 1.49 wherein the C1-4 hydrocarbon group is selected from alkyl groups.

1.51 A compound according to Embodiment 1.48 wherein R ⁴ and R ⁵ are independently selected from hydrogen, methyl, ethyl, n-propyl, iso- propyl and cyclopropyl or, together with the carbon atom to which they are attached, form a cyclopropane-1 , 1-diyl or a cyclobutane-1 ,1-diyl group.

1.52 A compound according to Embodiment 1.51 wherein R ⁴ and R ⁵ are independently selected from hydrogen, methyl and ethyl or, together with the carbon atom to which they are attached, form a cyclopropane-1 , 1-diyl group. 1.53 A compound according to Embodiment 1.52 wherein R ⁴ and R ⁵ are independently selected from hydrogen and methyl.

1.54 A compound according to Embodiment 1.53 wherein R ⁴ and R ⁵ are both hydrogen. 1.55 A compound according to Embodiment 1.53 wherein one of R ⁴ and R ⁵ is hydrogen and the other is methyl.

1.56 A compound according to Embodiment 1.54 wherein R ⁴ and R ⁵ are both methyl.

1.57 A compound according to any one of Embodiments 1.1 to 1.5, 1.41 , 1.43, 1.44, 1.47, 1.48, 1.51 and 1.52 wherein no more than one cyclopropane-1 , 1-diyl or

cyclobutane-1 ,1-diyl group is present in the compound.

1.58 A compound according to any one of Embodiments 1.1 to 1.57 wherein Ar ¹ is phenyl or furanyl optionally substituted with one or more substituent R ⁶ .

1.59 A compound according to any one of Embodiments 1.1 to 1.57 wherein Ar ¹ is phenyl or thiophenyl optionally substituted with one or more substituent R ⁶ .

1.60 A compound according to any one of Embodiments 1.1 to 1.57 wherein Ar ¹ is phenyl optionally substituted with one or more substituent R ⁶ .

1.61 A compound according to any one of Embodiments 1.1 to 1.57 wherein Ar ¹ is furanyl optionally substituted with one or more substituent R ⁶ . 1.62 A compound according to any one of Embodiments 1.1 to 1.57 wherein Ar ¹ is thiophenyl optionally substituted with one or more substituent R ⁶ .

1.63 A compound according to any one of Embodiments 1.1 to 1.62 wherein Ar ¹ is unsubstituted or is substituted with 1 , 2, 3 or 4 substituents R ⁶ .

1.64 A compound according to Embodiment 1.63 wherein Ar ¹ is unsubstituted or is substituted with 1 , 2 or 3 substituents R ⁶ .

1.65 A compound according to Embodiment 1.64 wherein Ar ¹ is unsubstituted or is substituted with 1 or 2 substituents R ⁶ .

1.66 A compound according to Embodiment 1.65 wherein Ar ¹ is substituted with 1 or 2 substituents R ⁶ . 1.67 A compound according to Embodiment 1.65 wherein Ar ¹ is unsubstituted.

1.68 A compound according to Embodiment 1.65 wherein Ar ¹ is substituted with 1 substituent R ⁶ . 1.69 A compound according to Embodiment 1.65 wherein Ar ¹ is substituted with 2 substituents R ⁶ .

1.70 A compound according to any one of Embodiments 1.1 to 1.66, 1.68 and 1.69 wherein R ⁶ is selected from halogen, cyano, Hyd, O-Hyd and C(=0)-Hyd. 1.71 A compound according to Embodiment 1.70 wherein R ⁶ is selected from halogen, cyano, Hyd and O-Hyd.

1.72 A compound according to Embodiment 1.71 wherein R ⁶ is selected from fluorine, chlorine, bromine, cyano, Hyd and O-Hyd.

1.73 A compound according to Embodiment 1.72 wherein R ⁶ is selected from fluorine, chlorine, cyano, Hyd and O-Hyd.

1.74 A compound according to Embodiment 1.73 wherein R ⁶ is selected from fluorine, chlorine, Hyd and O-Hyd.

1.75 A compound according to any one of Embodiments 1.1 to 1.74 wherein Hyd is an optionally fluorinated C1-5 hydrocarbon group (e.g. a saturated optionally fluorinated hydrocarbon group).

1.76 A compound according to Embodiment 1.75 wherein Hyd is an optionally fluorinated C1-4 hydrocarbon group (e.g. a saturated optionally fluorinated hydrocarbon group).

1.77 A compound according to Embodiment 1.76 wherein Hyd is an optionally fluorinated C _1-3 hydrocarbon group (e.g. a saturated optionally fluorinated hydrocarbon group).

1.78 A compound according to Embodiment 1.77 wherein Hyd is an optionally fluorinated C1-2 hydrocarbon (e.g. alkyl) group.

1.79 A compound according to any one of Embodiments 1.1 to 1.78 wherein Hyd is an optionally fluorinated alkyl group.

1.80 A compound according to any one of Embodiments 1.1 to 1.79 wherein Hyd is an unsubstituted hydrocarbon group, a perfluorinated saturated hydrocarbon group, or a saturated hydrocarbon group substituted with 1 to 5 fluorine atoms. 1 .81 A compound according to Embodiment 1.80 wherein Hyd is selected from methyl, ethyl, iso- propyl, cyclopropyl, cyclopropylmethyl, tert- butyl, difluoromethyl and

trifluoromethyl.

1 .82 A compound according to Embodiment 1.81 wherein Hyd is selected from methyl, ethyl, / ^' so-propyl, cyclopropyl, difluoromethyl and trifluoromethyl.

1 .83 A compound according to Embodiment 1.82 wherein Hyd is selected from methyl, ethyl, difluoromethyl and trifluoromethyl.

1 .84 A compound according to any one of Embodiments 1.1 to 1.70 wherein R ⁶ is absent or is selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, iso- propyl, cyclopropyl, tert- butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy and acetyl.

1 .85 A compound according to Embodiment 1 .84 wherein R ⁶ is absent or is selected from fluorine, chlorine, cyano, methyl, ethyl, tert- butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy and difluoromethoxy. 1 .86 A compound according to Embodiment 1 .85 wherein R ⁶ is selected from fluorine, chlorine, methyl, tert- butyl, trifluoromethyl and trifluoromethoxy.

1 .87 A compound according to Embodiment 1 .86 wherein R ⁶ is selected from fluorine and chlorine.

1 .88 A compound according to Embodiment 1.86 wherein R ⁶ is fluorine

1 .89 A compound according to Embodiment 1.86 wherein R ⁶ is chlorine

1 .90 A compound according to Embodiment 1.86 wherein R ⁶ is methyl

1 .91 A compound according to Embodiment 1.86 wherein R ⁶ is tert- butyl

1 .92 A compound according to Embodiment 1 .86 wherein R ⁶ is trifluoromethyl.

1 .93 A compound according to any one of Embodiments 1 .1 to 1.57 wherein Ar ¹ is an unsubstituted phenyl ring.

1 .94 A compound according to any one of Embodiments 1 .1 to 1 .57 wherein Ar ¹ is selected from: (a) unsubstituted phenyl;

(b) monosubstituted phenyl wherein the substituent is selected from fluorine, chlorine, methyl, tert- butyl, trifluoromethyl and trifluoromethoxy; and

(c) disubstituted phenyl where the substituents are independently selected from chlorine and fluorine.

1.95 A compound according to Embodiment 1.94 wherein Ar ¹ is a phenyl ring substituted in a meta-position thereof with a substituent R ⁶ .

1.96 A compound according to Embodiment 1.95 wherein Ar ¹ is a phenyl ring substituted in a meta-position thereof with chlorine and optionally further substituted with a further substituent R ⁶ selected from chlorine and fluorine.

1.97 A compound according to Embodiment 1.94 wherein Ar ¹ is selected from phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,6- dichlorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-6- fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,5- difluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2- trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2- methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fe/f-butylphenyl, 3-fe/f-butylphenyl and 4-fe/f-butylphenyl.

1.98 A compound according to Embodiment 1.97 wherein Ar ¹ is selected from phenyl,

2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,6- dichlorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-6- fluorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,5- difluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4- trifluoromethoxyphenyl, 3-methylphenyl and 3-fe/f-butylphenyl.

1.99 A compound according to Embodiment 1.98 wherein Ar ¹ is selected from 2- chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl,

3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 3-chloro-6-fluorophenyl, 3-trifluoromethylphenyl and 3-fe/f-butylphenyl. 1 .100 A compound according to Embodiment 1.99 wherein Ar ¹ is 3-chlorophenyl.

1 .101 A compound according to Embodiment 1.99 wherein Ar ¹ is 3,4-dichlorophenyl.

1 .102 A compound according to Embodiment 1.99 wherein Ar ¹ is 3,5-dichlorophenyl.

1.103 A compound according to Embodiment 1.99 wherein Ar ¹ is 3-chloro-5-fluorophenyl

1.104 A compound according to Embodiment 1.1 having the formula (1 ):

(1 ) or a salt, tautomer or N-oxide thereof;

wherein:

Q is SO or SO2;

n is 1 or 2

R ¹ is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl and

cyclopropylmethyl;

R ² and R ³ are independently selected from hydrogen and methyl;

or R ¹ together with R ² forms a (CH2)3 group;

or R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group (C=0);

R ⁴ and R ⁵ independently selected from hydrogen or methyl;

Ar ¹ is a phenyl group optionally substituted with one or two subsitutents R ⁶ ; and

R ⁶ is selected from fluorine, chlorine, methyl, tert- butyl, trifluoromethyl and

trifluoromethoxy.

1.105 A compound of the formula (1 A):

or a salt or tautomer thereof;

wherein Q, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar ¹ are as defined in any one of Embodiments 1 .1 to 1 .104. 1 .106 A compound of the formula (1 B):

(1 B)

or a salt or tautomer thereof;

wherein Q, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar ¹ are as defined in any one of Embodiments 1.1 to 1 . 104. 1 .107 A compound according to any one of Embodiments 1 .1 to 1.106 which is other than a compound wherein, in combination, Q is SO, n is 2, R ² , R ³ , R ⁴ and R ⁵ are all hydrogen, R ¹ is methyl and Ar ¹ is 3-chlorophenyl.

1 .108 A compound according to any one of Embodiments 1 .1 to 1.106 which is other than a compound wherein, in combination, Q is SO, n is 2 and R ¹ is other than hydrogen. 1 .109 A compound according to any one of Embodiments 1 .1 to 1.106 which is other than a compound wherein, in combination, Q is SO and n is 2. 1.109A A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, Q is SO and Ar ¹ is an unsubstituted phenyl group.

1.109B A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, R ¹ is hydrogen and Ar ¹ is an unsubstituted phenyl group.

1.109C A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, n is 1 and Ar ¹ is an unsubstituted phenyl group. 1.109D A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, Q is SO, n is 1 and Ar ¹ is an unsubstituted phenyl group.

1.109D A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, Q is SO, R ¹ is hydrogen and Ar ¹ is an unsubstituted phenyl group.

1.109E A compound according to any one of Embodiment 1.1 to 1.106 provided that when Q is SO; R ¹ , R ² , R ³ , R ⁴ and R ⁵ are all hydrogen; and n is 1 , then Ar ¹ is other than an unsubstituted phenyl group.

1.109F A compound according to any one of Embodiment 1.1 to 1.106 provided that when Q is SO; R ¹ , R ² , R ³ , R ⁴ and R ⁵ are all hydrogen; and n is 1 , then Ar ¹ is:

(i) substituted phenyl; or

(ii) thiophenyl or furanyl each optionally substituted with one or more substituents R ⁶ (as defined in any one of Embodiments 1.1 to 1.106).

1.109G A compound according to any one of Embodiments 1.1. to 1.106 which is not (2E)-2-[(2E)-3-phenylprop-2-en-1 -ylidene]-4-thiomorpholine-1 ,3-dione.

1.110 A compound selected from the title compounds of Examples 1 to 57 herein.

1.1 10A A compound selected from the title compounds of Examples 1 and 3 to 57 herein. 1.11 1 A compound selected from the title compounds of Examples 1 to 49 and 52 to 57 herein.

1.1 11 A A compound selected from the title compounds of Examples 1 , 3 to 49 and 52 to 57 herein. 1.112 A compound selected from the title compounds of Examples 1 to 49 herein.

1.1 12A A compound selected from the title compounds of Examples 1 and 3 to 49 herein.

1.113 A compound according to any one of Embodiments 1.1 to 1.112A which is in the form of a salt.

1.114 A compound according to Embodiment 1.1 13 wherein the salt is an acid addition salt.

1.115 A compound according to Embodiment 1.1 13 or Embodiment 1.1 14 wherein the salt is a pharmaceutically acceptable salt.

1.116 A compound according to any one of Embodiments 1.1 to 1.112A which is not in the form of a salt.

1.117 A compound according to any one of Embodiments 1.1 to 1.116 which is in the form of a solvate.

1.118 A compound according to Embodiment 1.1 17 wherein the solvate is a hydrate. Definitions

The term“hydrocarbon” as used herein refers to aliphatic, alicyclic and aromatic groups having an all-carbon backbone and consisting of carbon and hydrogen atoms, except where otherwise stated. Examples of hydrocarbon groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, substituted by one or more substituents as defined herein. The term“non-aromatic hydrocarbon” refers to a hydrocarbon moiety that does not have aromatic character. The non-aromatic hydrocarbon can contain only carbon-carbon single bonds or it may contain one or more double or triple bonds. The term“saturated” as used herein in relation to hydrocarbon groups means that there ae no multiple (e.g. double or triple) bonds present in the hydrocarbon group. The term“alkylene” (e.g. as in Ci _-4 straight chain or branched chain alkylene) as used herein refers to an alkanediyl group, i.e. a divalent saturated acyclic straight chain or branched chain hydrocarbon group. Examples of straight chain alkylene groups include methylene (CH2), ethylene (CH2CH2) and propylene ((CH2CH2CH2). Examples of branched chain alkylene groups include CH(CH3), CH2CH(CH3)CH2 and

CH2(CH ₃ )CH ₂ CH2.

Salts

The compounds of the invention as defined in Embodiments 1.1 to 1.1 12A may be presented in the form of salts, when the compound contains a salt-forming moiety The salts referred to above (and also defined in embodiments 1.1 13, 1.1 14 and 1.115) are typically acid addition salts.

The salts can be synthesized from the parent compound by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free base form of the compound with the acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

Acid addition salts (as defined in Embodiment 1.114) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulphonic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1 S)-camphor-10- sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane- 1 ,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L- glutamic), ooxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, (+)-L-lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic, malonic, (±)- DL-mandelic, methanesulphonic, naphthalene-2-sulphonic, naphthalene-1 ,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulphonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins. The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et ai, 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

Geometric isomers and tautomers The compounds of the invention may exist in a number of different geometric isomeric, and tautomeric forms and references to the compounds of formula (1 ) as defined in Embodiments 1.1 to 1.118 include all such forms.

For example, the compounds of formula (1 ) can exist in both E and Z isomeric forms.

For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (1 ) or subgroups, subsets, preferences and examples thereof.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to the compounds include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.

The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and / isomers) or they may be characterised in terms of their absolute stereochemistry using the“R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4 ^th Edition, John Wiley & Sons, New York, 1992, pages 109-1 14, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separated by a number of techniques including chiral

chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulphonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (1 ) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1 ) may be present as a single optical isomer (e.g. enantiomer or

diastereoisomer). Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1 to 1.118 may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope ¹ H, ² H (D), and ³ H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹² C, ¹³ C and ¹⁴ C and ¹⁶ 0 and ¹⁸ 0.

The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

Solvates Compounds of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 may form solvates (as defined in Embodiments 1.117 and 1.1 18).

Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).

Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.

Particularly preferred solvates are hydrates, and examples of hydrates include

hemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to make and

characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

Prodruqs The compounds of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 18 may be presented in the form of a pro-drug.

By“prodrugs” is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1 ), as defined in any one of Embodiments 1.1 to 1.1 18. For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any hydroxyl groups present in the parent compound with, where

appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.)· For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. Complexes and clathrates

Also encompassed by formula (1 ) or subgroups, subsets, preferences and examples thereof are complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.

Biological Activity Compounds of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.118 have been shown to have cytotoxic effects on glioma cell lines. As such, they may be useful in preventing or treating cancers and in particular gliomas.

Accordingly, in further embodiments (Embodiments 2.1 to 2.9), the invention provides:

2.1 A compound as defined in any one of Embodiments 1.1 to 1.118 for use in medicine or therapy.

2.4 A compound as defined in any one of Embodiments 1.1 to 1.118 for use as an anti-cancer agent.

2.5 The use of a compound as defined in any one of Embodiments 1.1 to 1.118 for the manufacture of a medicament for the treatment of cancer. 2.6 A method of treating a cancer, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any one of Embodiments 1.1 to 1.118, optionally together with another anti-cancer agent or radiation therapy.

2.7 A compound as defined in any one of Embodiments 1.1 to 1.118 for use in enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer.

2.8 The use of a compound as defined in any one of Embodiments 1.1 to 1.118 for the manufacture of a medicament for enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer. 2.9 A method for the prophylaxis or treatment of a proliferative disease such as cancer, which method comprises administering to a patient in combination with radiotherapy or chemotherapy a compound as defined in any one of Embodiments 1.1 to 1.1 18. Examples of proliferative disorders (e.g. cancers) as defined in Embodiments 2.4 to 2.9 include, but are not limited to carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin, hematopoieitic tumours such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoieitic tumours of myeloid lineage, for example acute and chronic myelogenous leukaemias,

myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicular cancer; tumours of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; tumours of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Gliomas

One particular subset of cancers against which the compounds of Embodiments 1.1 to 1.1 18 should prove particularly active are gliomas Gliomas are a common type of primary brain tumour that originate in the glial cells in the brain, and account for about 30% of all primary brain and central nervous system tumours, and about 80% of all malignant brain tumours. Gliomas typically arise from three different types of cells that are normally found in the brain, namely astrocytes,

oligodendrocytes, and ependymal cells. Major types of gliomas include ependymomas (associated with ependymal cells), astrocytomas (associated with astrocytes),

oligodendrogliomas (associated with oligodendrocytes), brainstem glioma (which develops in the brain stem), optic nerve glioma (which develops in or around the optic nerve) and mixed gliomas (which contain cells from different types of glia).

An ependymoma is a type of glioma that develops from ependymal cells, usually in the lining of the ventricles of the brain or in the spinal cord. In children, they are most commonly found near the cerebellum. Ependymomas are rare, accounting for only about 2-3% of primary brain tumours. However, they account for about 8-10% of brain tumours in children and occur most often in children younger than 10 years of age.

Astrocytomas originate in the star-shaped glial cells (astrocytes) in the cerebrum.

Astrocytomas do not usually spread outside the brain and spinal cord and do not usually affect other organs but they are the most common glioma and can occur in most parts of the brain and occasionally in the spinal cord. Two broad classes of astrocytoma are generally recognised, namely those with narrow zones of infiltration (mostly invasive tumours; e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma), that often are clearly outlined on diagnostic images; and those with diffuse zones of infiltration (e.g., high-grade astrocytoma, anaplastic astrocytoma, glioblastoma). Glioblastoma multiforme is a malignant astrocytoma and the most common primary brain tumour among adult humans.

An oligodendrogliomas is a type of glioma that develops from oliogodendrocytes, which are the supportive tissue cells of the brain, and are usually found in the cerebrum. About 4% of primary brain tumours are oliogodendrogliomas and they are most common in young and middle-aged adults. Seizures are a very common symptom of these gliomas, as well as headache, weakness, or changes in behavior or sleepiness.

Brain stem gliomas, as the name suggests, are tumours found in the brain stem. Most brain stem tumours cannot be surgically removed because of the remote location and delicate and complex function this area controls. Brain stem gliomas occur almost exclusively in children, typically in school-age children.

A mixed glioma is a malignant glioma made up of more than one type of glial cell. This type of glioma may also be referred to as an oligoastrocytoma. Mixed gliomas are often found in the cerebrum, but may metastasize to other parts of the brain. Only about 1% of primary brain tumours are mixed gliomas and they are most commonly found in adult men.

An optic nerve glioma is a type of malignant glioma (brain tumour) found in the optic chiasm. Optic nerve gliomas often surround the optic nerves, and are frequently found in people who have neurofibromatosis. A person suffering from an optic nerve glioma typically experiences loss of vision, and may also suffer from hormone disturbances as the tumours are often found at the base of the brain where the structures responsible for hormonal control are located. Optic nerve gliomas are typically difficult to treat because of the sensitivity of the surrounding brain structures.

In addition to being classified according to the type of glial cell from which they originate or the region of the brain in which they develop, gliomas can also be classified according to their“grade”, which is a measure of the growth potential and aggressiveness of the tumour.

Thus, gliomas are most often referred to as "low-grade" or "high-grade" gliomas, the grade being determined by pathological evaluation of the tumour. Tumours can be further graded according to the World Health Organization (WHO) grading system, under which tumours are graded from I (least advanced disease— best prognosis) to IV (most advanced disease— worst prognosis).

Gliomas can also be classified according to whether they are located above or below the tentorium membrane which tentorium separates the cerebrum (above) region of the brain from the cerebellum (below). Supratentorial gliomas (i.e. tumours located above the tentorium in the cerebrum), are mostly found in adults (70%), whereas infratentorial gliomas (tumours located below the tentorium, in the cerebellum) are found mostly in children (70%).

A further class of gliomas consists of those tumours found in the pons of the brainstem. The brainstem has three parts (pons, midbrain and medulla); the pons controls critical functions such as breathing, making surgery on pontine gliomas extremely dangerous.

Accordingly, in further Embodiments 2.10 to 2.25, the invention provides:

2.10 A compound as defined in any one of Embodiments 1.1 to 1.118 for use in the treatment of gliomas and glioblastomas.

2.11 A compound for use according to Embodiment 2.10 wherein the glioma is an ependymoma.

2.12 A compound for use according to Embodiment 2.10 wherein the glioma is an astrocytoma.

2.13 A compound for use according to Embodiment 2.10 wherein the glioma is a glioblastoma. 2.14 A compound for use according to Embodiment 2.13 wherein the glioma is glioblastoma multiforme.

2.15 A compound for use according to Embodiment 2.10 wherein the glioma is an oligodendroglioma. 2.16 A compound for use according to Embodiment 2.10 wherein the glioma is a brainstem glioma.

2.17 A compound for use according to Embodiment 2.10 wherein the glioma is an optic nerve glioma.

2.18 A compound for use according to Embodiment 2.10 wherein the glioma is a mixed glioma.

2.19 A compound for use according to Embodiment 2.10 wherein the glioma is a low- grade glioma.

2.20 A compound for use according to Embodiment 2.10 wherein the glioma is a high- grade glioma. 2.21 A compound for use according to Embodiment 2.10 wherein the glioma is a supratentorial glioma.

2.22 A compound for use according to Embodiment 2.10 wherein the glioma is an infratentorial glioma.

2.23 A compound for use according to Embodiment 2.10 wherein the glioma is a pontine glioma.

2.24 The use of a compound as defined in any one of Embodiments 1.1 to 1.118 for the manufacture of a medicament for the treatment of a glioma as defined in any one of Embodiments 2.10 to 2.23.

2.25 A method of treating a glioma as defined in any one of Embodiments 2.10 to 2.23 in a subject in need thereof, which method comprises administering to the subject an effective therapeutic amount of a compound as defined in any one of Embodiments 1.1 to 1.118.

Methods for the Preparation of Compounds of the Invention The invention also provides processes for the preparation of a compound of the formula (1 ) and salts and tautomers thereof.

Accordingly, in another embodiment (Embodiment 3.1 ), the invention provides a process for preparing a compound as defined in any one of Embodiments 1.1 to 1.1 18, which process comprises:

(I) the reaction of a compound of the formula (10):

or a protected form thereof, with a compound of the formula (11 ): (1 1 ) or a protected form thereof; and thereafter optionally removing any protecting group present; or

(II) the reaction of a compound of the formula (12)

with a compound of the formula LG-R ¹ ; wherein LG is a suitable leaving group. The reaction described in (I) above is typically carried out in the presence of a base, typically an organic base, for example an amine such as piperidine or N,N- diisopropylethylamine (DIPEA). The reaction may be carried out in a polar solvent such as ethanol (EtOH), water (hhO), or mixtures thereof and the reaction mixture is typically conducted at room temperature, e.g. a temperature of less than 30°C. In the reaction described in (II) above, LG-R ¹ is a suitable alkylating agent. LG may be, for example, a halide or sulphonate (e.g. aryl sulphonate or alkyl sulphonate). When R ¹ is an alkyl mopiety, LG-R ¹ may be an alkyl iodide such as methyl iodide. The reaction is typically carried out in the presence of a base in a polar aprotic solvent such as dimethylformamide. The base must be capable of deprotonating the amide hydrogen in the compound of formula (12) and suitable bases include metal hydrides (e.g. NaH). The reaction is typically carried out at temperatures of less than 25°C, for example, less than 10°C, for a period of up to 1 hour.

Illustrative reaction schemes for the preparation of compounds of the formula (1 ) are set out below.

The compounds of formula (1 ) wherein Q is SO can be prepared as shown in Scheme 1 below.

Scheme 1 In step (a), 2-aminoalkanethiol (13) is reacted with ethyl chloroacetate (14) to form lactam (15). The reaction is typically carried out in a polar solvent, for example a polar protic solvent, such as an alcohol (e.g. methanol). A base is also typically added, for example a metal alkoxide (e.g. d-hONa).

When it is desired to prepare compounds of the formula (1 ) wherein R ¹ is a non-aromatic hydrocarbon group, the lactam (15) may be alkylated as shown in step (b) in Scheme 1 to give alkylated lactam (16). In the reaction described in (b) above, LG-R ¹ is a suitable alkylating agent. LG may be, for example, a halide or sulphonate (e.g. aryl sulphonate or alkyl sulphonate). When R ¹ is an alkyl group (such as methyl), LG-R ¹ may be an alkyl iodide such as methyl iodide. The reaction is typically carried out in the presence of a base in a non-aqueous polar solvent such as dimethylformamide. The base must be capable of deprotonating the amide hydrogen in the compound of formula (12) and suitable bases include metal hydrides (e.g. NaH). The reaction is typically carried out at temperatures of less than 25°C, for example, less than 10°C for a period of up to 1 hour.

When it is desired to prepare a compound of formula (1 ) in which R ¹ is hydrogen, the lactam (15) can be used directly in step (c). In step (c), the lactam (15) or (16) is oxidised with an oxidising agent such as hydrogen peroxide to form the sulphoxide. The reaction can be carried out in a polar solvent, for example an alcohol such as methanol, and is advantageously carried out in the presence of a Montmorillonite catalyst (e.g. Montmorillonite K).

In step (d), the sulphoxide (17) is then reacted with aldehyde (1 1 ) to form a compound of formula (1 ) using the conditions described above in relation to process variant (I).

The compounds of formula (1 ) wherein Q is S0 ₂ can be prepared as shown in Scheme 2 below.

Scheme 2

Lactams (15) and (16) can be prepared as described in relation to Scheme 1 above.

In order to form the sulphone (18), a stronger oxidising agent, such as a

peroxymonosulphate salt (for example, potassium peroxymonosulphate), is typically used in step (c). The oxidation may be carried out in a polar, protic solvent, for example water, an alcohol (such as t-BuOH) or mixtures thereof. The oxidation is typically carried out at temperatures of less than 5°C for a period of up to 2 hours.

Sulphone (18) can then be reacted with aldehyde (11 ) in step (d) to form a compound of formula (1 ) using the conditions described above in relation to process variant (I).

The aldehyde compounds of formula (11 ) can be prepared according to Scheme 3 shown below.

Scheme 3

Thus, as shown in Scheme 3, an aromatic aldehyde Ar ¹ -CHO is reacted with a Wittig reagent to give the aldehyde of formula (11 ). The reaction is typically carried out in an aprotic solvent such as dichloromethane at or around room temperature.

Once formed, one compound of the formula (1 ), or a protected derivative thereof, can be converted into another compound of the formula (1 ) by methods well known to the skilled person. Examples of synthetic procedures for converting one functional group into another functional group are set out in standard texts such as Advanced Organic

Chemistry, by Jerry March, 4 ^th edition, 119, Wiley Interscience, New York; Fiesers'

Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31 192-8)).

In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified by any of a variety of methods well known to those skilled in the art and examples of such methods include recrystallisation and chromatographic techniques such as column

chromatography (e.g. flash chromatography) and HPLC.

Novel intermediates of the formulae (15), (16) and (17) form another aspect (Embodiment 3.2) of the invention. Pharmaceutical Formulations

While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). Accordingly, in another embodiment (Embodiment 4.1 ) of the invention, there is provided a pharmaceutical composition comprising at least one compound as defined in any one of Embodiments 1.1 to 1 .1 18 together with a pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipient can be, for example, a carrier (e.g. a solid, liquid or semi-solid carrier), a diluent or bulking agent, a granulating agent, coating agent, binding agent, disintegrant, lubricating agent, preservative, antioxidant, buffering agent, suspending agent, thickening agent, flavouring agent, sweetener, taste masking agent or any other excipient conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201 -230).

A drug molecule that is ionizable can be solubilized to the desired concentration by pH adjustment if the drug's pK _a is sufficiently away from the formulation pH value. The acceptable range is pH 2-12 for intravenous and intramuscular administration, but subcutaneously the range is pH 2.7-9.0. The solution pH is controlled by either the salt form of the drug, strong acids/bases such as hydrochloric acid or sodium hydroxide, or by solutions of buffers which include but are not limited to buffering solutions formed from glycine, citrate, acetate, maleate, succinate, histidine, phosphate, tris(hydroxymethyl)-aminomethane (TRIS), or carbonate.

The combination of an aqueous solution and a water-soluble organic solvent/surfactant (i.e., a cosolvent) is often used in injectable formulations. The water-soluble organic solvents and surfactants used in injectable formulations include but are not limited to propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N- methyl-2-pyrrolidone (NMP; Pharmasolve), dimethylsulphoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60, and polysorbate 80. Such formulations can usually be, but are not always, diluted prior to injection. Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, and polysorbate 80 are the entirely organic water-miscible solvents and surfactants used in commercially available injectable formulations and can be used in combinations with each other. The resulting organic formulations are usually diluted at least 2-fold prior to IV bolus or IV infusion.

Alternatively increased water solubility can be achieved through molecular complexation with cyclodextrins.

The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. The pharmaceutical formulation can be prepared by lyophilising a compound of Formula (1 ) or acid addition salt thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms. A typical process is to solubilise the compound and the resulting formulation is clarified, sterile filtered and aseptically transferred to containers appropriate for lyophilisation (e.g. vials). In the case of vials, they are partially stoppered with lyo-stoppers. The formulation can be cooled to freezing and subjected to lyophilisation under standard conditions and then hermetically capped forming a stable, dry lyophile formulation. The composition will typically have a low residual water content, e.g. less than 5% e.g. less than 1 % by weight based on weight of the lyophile. The lyophilisation formulation may contain other excipients for example, thickening agents, dispersing agents, buffers, antioxidants, preservatives, and tonicity adjusters. Typical buffers include phosphate, acetate, citrate and glycine. Examples of antioxidants include ascorbic acid, sodium bisulphite, sodium metabisulphite, monothioglycerol, thiourea, butylated hydroxytoluene, butylated hydroxyl anisole, and

ethylenediaminetetraacetic acid salts. Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of para-hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzalkonium chloride and cetylpyridinium chloride. The buffers mentioned previously, as well as dextrose and sodium chloride, can be used for tonicity adjustment if necessary.

Bulking agents are generally used in lyophilisation technology for facilitating the process and/or providing bulk and/or mechanical integrity to the lyophilized cake. Bulking agent means a freely water soluble, solid particulate diluent that when co-lyophilised with the compound or salt thereof, provides a physically stable lyophilized cake, a more optimal freeze-drying process and rapid and complete reconstitution. The bulking agent may also be utilised to make the solution isotonic.

The water-soluble bulking agent can be any of the pharmaceutically acceptable inert solid materials typically used for lyophilisation. Such bulking agents include, for example, sugars such as glucose, maltose, sucrose, and lactose; polyalcohols such as sorbitol or mannitol; amino acids such as glycine; polymers such as polyvinylpyrrolidine; and polysaccharides such as dextran.

The ratio of the weight of the bulking agent to the weight of active compound is typically within the range from about 1 to about 5, for example of about 1 to about 3, e.g. in the range of about 1 to 2.

Alternatively they can be provided in a solution form which may be concentrated and sealed in a suitable vial. Sterilisation of dosage forms may be via filtration or by autoclaving of the vials and their contents at appropriate stages of the formulation process. The supplied formulation may require further dilution or preparation before delivery for example dilution into suitable sterile infusion packs.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

In one preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. In another preferred embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.

Pharmaceutical compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here. Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.

The solid dosage forms (eg: tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum. Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound.

Osmotic release and other delayed release or sustained release formulations may be prepared in accordance with methods well known to those skilled in the art.

The compound as defined in any one of Embodiments 1.1 to 1.118, or a prodrug thereof, may be formulated with a carrier and administered in the form of nanoparticles.

Nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in“Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13 ^th March 2006. Nanoparticles for drug delivery are also described in J.

Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et al., Mol. Cancer Ther. August 1 , (2006) 5, 1909.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a single package, usually a blister pack.

Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions.

Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.

Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.

Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound. Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

In embodiments of the invention, there are provided:

4.2 A pharmaceutical composition according to Embodiment 4.1 which is in a form for oral or parenteral administration.

4.3 A pharmaceutical composition according to Embodiment 4.2 which is in a form for oral administration.

4.4 A pharmaceutical composition according to Embodiment 4.3 which is selected from tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.

4.5 A pharmaceutical composition according to Embodiment 4.3 which is selected from tablets and capsules.

4.6 A pharmaceutical composition according to Embodiment 4.2 which is in a form for parenteral administration.

4.7 A pharmaceutical composition according to Embodiment 4.6 which is formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection or infusion.

4.8 A pharmaceutical composition according to Embodiment 4.6 or Embodiment 4.7 which is selected from aqueous and non-aqueous sterile injection solutions; and aqueous and non-aqueous sterile suspensions.

The compounds of Embodiments 1.1 to 1.118, and pharmaceutical compositions of Embodiments 4.1 to 4.8 will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within this range, particular sub- ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

Accordingly, in further embodiments, the invention provides:

4.9 A pharmaceutical composition according to any one of Embodiments 4.1 to 4.9 which is in unit dose form and contains from 1 nanogram to 2 grams of a compound of any one of Embodiments 1.1 to 1.118.

4.10 A pharmaceutical composition according to Embodiment 4.9 which contains from 0.1 milligrams to 2 grams of a compound of any one of Embodiments 1.1 to 1.1 18.

4.1 1 A pharmaceutical composition according to Embodiment 4.10 which contains from 10 milligrams to 1 gram of a compound of any one of Embodiments 1.1 to 1.118.

4.12 A pharmaceutical composition according to Embodiment 4.1 1 which contains from 50 milligrams to 500 milligrams of of a compound of any one of Embodiments 1.1 to 1.1 18.

4.13 A pharmaceutical composition according to Embodiment 4.9 which contains from 1 microgram to 20 milligrams of a compound of any one of Embodiments 1.1 to 1.1 18.

4.14 A pharmaceutical composition according to Embodiment 4.9 which contains from 1 microgram to 10 milligrams of a compound of any one of Embodiments 1.1 to 1.118.

4.15 A pharmaceutical composition according to Embodiment 4.9 which contains from 0.1 milligrams to 2 milligrams of a compound of any one of Embodiments 1.1 to 1.118. Methods of T reatment

It is envisaged that the compounds of Embodiments 1.1 to 1.1 18 will be useful either as sole chemotherapeutic agents or, more usually, in combination therapy with

chemotherapeutic agents or radiation therapy in the prophylaxis or treatment of a range of proliferative disease states or conditions. Examples of such disease states and conditions are set out above.

Accordingly, in a further embodiment (Embodiment 5.1 ), there is provided a

pharmaceutical combination comprising a compound of any one of Embodiments 1.1 to 1.1 18 (for example in the form of a pharmaceutical composition according to any one of

Embodiments 4.1 to 4.15) and a chemotherapeutic agent.

Particular examples of chemotherapeutic agents that may be co-administered with the compounds of Embodiments 1.1 to 1.1 18 (e.g. in accordance with Embodiment 5.1 ) include:

· Topoisomerase I inhibitors

• Antimetabolites

• Tubulin targeting agents

• DNA binder and topoisomerase II inhibitors

• EGFR inhibitors (e.g. Gefitinib - see Biochemical Pharmacology 78 2009 460- 468)

mTOR inhibitors (e.g. Everolimus)

PI3K pathway inhibitors (e.g. PI3K, PDK1 )

Akt inhibitors

Alkylating Agents (e.g. temozolomide, cyclophosphamide)

Monoclonal Antibodies.

Anti-Hormones

Signal Transduction Inhibitors

Proteasome Inhibitors

DNA methyl transferases

Cytokines and retinoids

Hypoxia triggered DNA damaging agents (e.g. Tirapazamine)

Aromatase inhibitors • Anti Her2 antibodies, (see for example

http://www.wipo. int/pctdb/en/wo.jsp?wo=20070561 18) ,

• Anti cd20 antibodies

• Inhibitors of angiogenesis

· HDAC inhibitors

• MEK inhibitors

• B-Raf inhibitors

• ERK inhibitors

• HER2 small molecule inhibitors (e.g. lapatinib)

· Bcr-Abl tyrosine-kinase inhibitors (e.g. imatinib)

• CDK4/6 inhibitor e.g. Ibrance

• Taxanes (e.g. paclitaxel, docetaxel, cabazitaxel)

• Platinum agents (e.g. cisplatin, carboplatin, oxaliplatin)

• Anthracyclines (e.g. Doxorubicin)

· Inhibitors of Bcl-2 family proteins e.g. ABT263 (navitoclax), a Bcl-2/Bcl-extra large

(Bcl-xL) inhibitor

The compounds may also be administered in conjunction with radiotherapy.

The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a pulsatile or continuous manner.

The compounds of the invention will be administered in an effective amount, i.e. an amount which is effective to bring about the desired therapeutic effect. For example, the "effective amount" can be a quantity of compound which, when administered to a subject suffering from cancer, slows tumour growth, ameliorates the symptoms of the disease and/or increases longevity.

The amount of the compound of the invention administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors.

The compounds are generally administered to a subject in need of such administration, for example a human or animal subject), preferably a human. A typical daily dose of the compound of any of Embodiments 1.1 to 1.118 can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required. The compound can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21 , or 28 days for example.

In one particular dosing schedule, a patient will be given an infusion of a compound for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.

More particularly, a patient may be given an infusion of a compound for periods of one hour daily for 5 days and the treatment repeated every three weeks. In another particular dosing schedule, a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.

In a further particular dosing schedule, a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.

Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

EXAMPLES

EXAMPLES 1 TO 57 The compounds of Examples 1 to 57 in Table 1 below are illustrative of the invention.

Experimental LC/MS Methods o

O

n H bo o o

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o

O

HPLC Methods n H bo o o

C/I o

o

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Cinnamaldehydes

The following cinnamaldehydes are commercially obtainable:

Intermediate B1

A suspension of 2-chlorobenzaldehyde (200 mg, 1.428 mmol) in dichloromethane was degassed with ISh for 15 minutes at room temperature, following which 2-(triphenyl- ⁵ - phosphanylidene)acetaldehyde (433 mg, 1.428 mmol) was added and the resulting reaction mixture stirred overnight. The crude reaction mixture was concentrated in vacuo and passed through a silica plug using 2% ethyl acetate in hexane as an eluent.

Concentration of the resulting solution afforded 89 mg of (2E)-3-(2-chlorophenyl)prop-2- enal as a solid, which was used directly.

Intermediates B2 to B25 below were made in an analogous manner.

Intermediate C 1

To a stirred solution of cysteamine hydrochloride (1 g, 8.849 mmol) in methanol (5 ml.) cooled to 0°C, was added 25% sodium methoxide in methanol (5.72 ml_, 26.54 mmol). The reaction mixture was stirred at room temperature for additional 10 minutes. Ethyl chloroacetate (1 .06 ml_, 8.849 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated in vacuo and purified by column chromatography using 0 to 80% ethyl acetate in hexane as an eluent, to generate 700 mg of thiomorpholin-3-one as a white solid. LCMS RT= 0.953 min (Method A; ESI-MS m/z(1 17.96), ¹ H-NMR (400 MHz, CDCIs) d ppm: 2.83-2.89 (t, 2H, NH- CH2-CH2-S), 3.34 (s, 2H, CO-CHz-S), 3.64-3.66 (t, 2H, NH-CH ₂ -CH ₂ -S), 7.28 (s, 1 H, NH)

Using the same method, the following intermediates were also made:

Intermediate D1

Thiomorpholin-3-one (3 g, 0.025 mole) was dissolved in DMF (140ml) and the resulting solution was cooled to 0°C followed by portion-wise addition of NaH (60% in oil dispersion) (1 1.16 g, 0.465 mole) under N ₂ atmosphere before stirring for 30 minutes at 0 °C. Methyl iodide (1.8 mL, 0.028 mole.) was added and reaction mixture was stirred at room temperature for 30 minutes. The crude reaction mixture was quenched with 1 M HCI (100ml) and extracted with dichloromethane. After concentration in vacuo, the crude mixture was purified by column chromatography by 0 to 4% methanol in chloroform as an eluent, generating 2.5g of 4-methylthiomorpholin-3-one as a solid. LCMS RT= 3.219 min (Method A); ESI-MS m/z(131.89) ¹ H-NMR (400 MHz, CDCIs) d ppm: 0.83-0.9 (t, 2H, NCH3-CH2-CH2-S), 2.85-2.89 (m, 4H, NCH3-CH2-CH2-S-CH2), 2.96 (s, 3H, NCH ₃ )

Using the same method, the following intermediates were also made: o

C/I n

H

bo o o

C/I o

N

o

m

Intermediate E1

Thiomorpholin-3-one (5. Og, 0.042 mole) was dissolved in methanol (250ml) and stirred at room temperature. To this solution was added Montmorillonite K 10 (10g,0.01 1 mole) followed by dropwise addition of a 30% solution of hydrogen peroxide (4.8ml_,0.044 mole). The resulting mixture was stirred at room temperature for 2 days. The crude reaction mixture was filtered and filtrate concentrated. The resulting residue was purified by column chromatography using 0 to 8% methanol in chloroform as an eluent to generate 2.65g of ^ ⁴ ,4-thiomorpholine-1 ,3-dione as a solid. ¹ H-NMR (400 MHz, DMSO- d ₆ ) d ppm: 2.52-3.0 (m, 2H, -CO-CH ₂ -SO-), 3.35-3.44 (m, 2H, NH-CH ₂ -CH ₂ -SO), 3.65-

3.76 (m, 2H, NH-CH2-CH2-SO), 8.03 (s, 1 H, -NH)

Using the same method, the following intermediates were also made:

Intermediate F1

Thiomorpholin-3-one (5. Og, 0.042 mol) was dissolved in a 1 :1 mixture of t-BuOH/Water (250ml_) and cooled to 0°C. Potassium peroxymonosulfate (31.37g, 0.051 mol) was added and the resulting mixture was stirred at room temperature for 1 hour. The crude reaction mixture was partially concentrated, in order to remove t-BuOH. The resulting mixture was extracted with EtOAc (2 x 200ml_). The organic layer was concentrated in vacuum, giving 1.3g, 20.44% of l ⁶ ,4-thiomorpholine-1 ,1 ,3-trione, which was used directly for subsequent steps. LCMS RT= 0.634min (Method B); ESI-MS m/z (150.05) ¹ H- NMR (400 MHz, DMSO-de) d ppm: 3.36-3.54 (m, 4H, NH-CH ₂ -CH ₂ -S0 ₂ ), 4.1 (s, 2H, CO- CH ₂ -S0 ₂ ), 8.3 (s, 1 H, NH).

Using the same method, the following intermediates were also made:

o os

Intermediate G

Thiomorpholin-3-one (100mg, 0.854 mmol) was dissolved in THF (18ml_) and stirred at room temperature. Cyclopropylboronic acid (439mg, 5.1 10 mmol) was added, followed by triethylamine (0.861 g, 8.524 mmol) and pyridine (1 .078g, 13.645 mmol). The resulting mixture was stirred at room temperature for 5-10 minutes. Cu(OAc) ₂ (0.620g,3.413 mmol) was added to reaction mixture at room temperature. The resulting mixture was

transferred to a sealed tube which was then heated at 100°C for 1.5 hours. The crude reaction mixture was cooled to room temperature, filtered, and the solid material was washed by EtOAc (20ml_x 2). The filtrate was diluted in EtOAc (150ml_) which was washed by 1 M HCI (50ml_ x 3). The organic layer was dried over Na ₂ S0 ₄ and

concentrated. The crude product was used directly in the next step.

Intermediate H

Tetrahydro-1 H,3H-pyrrolo[1 ,2-c]oxazol-3-one:

2-pyrolidinylmethanol (3g, 0.029 mole) was dissolved in dry toluene (100ml_) under an N2 atmosphere. Carbonyldiimidazole (9.6g, 0.059 mole) and 4-dimethylaminopyridine (0.36g, 0.002 mole) were added and the reaction mixture was refluxed at 100°C for 2 hours. The crude reaction mixture was cooled to room temperature and concentrated. The crude solid was diluted with dichloromethane (200ml_) and washed with water (100ml_) follow by 1 M HCI(100ml_). The organic layer was dried over Na ₂ S0 ₄ and concentrated to give the crude tetrahydro-1 H,3H-pyrrolo[1 ,2-c]oxazol-3-one (1.4g, 37.83%) which was used without further purification.

Hexahydro-1 H-pyrrolo[2,1 -c]thiomorpholin-4-one: Sodium metal (0.5g, 0.021 mole) was added portion-wise to propan-2-ol (280ml_) under N ₂ atmosphere and the resulting mixture was then stirred at room temperature until a homogeneous solution was formed. Methyl thioglycolate (3.48g, 0.032 mole) was added and the resulting mixture was stirred for 1 hour at room temperature. Tetrahydro-1 H,3H- pyrrolo[1 ,2-c]oxazol-3-one(1.4g,0.010 mole) was added and the resulting mixture was heated for 2 hours at 1 10°C. The crude reaction mixture was cooled to room temperature and partially concentrated under reduced pressure. The resulting suspension was extracted with EtOAc (300ml_). The organic layer was dried over Na ₂ S0 ₄ and

concentrated. The crude product was used directly in the next step. Intermediate I

Step 1 : Methyl thioglycolate (5.4g, 0.050 mole) was dissolved in dry methanol (80ml). To this was added 2-bromo-2-methylpropionamide (5.0g, 0.030 mole) followed by NaOMe (4.9g, 0.090 mole). The resulting mixture was refluxed for 16 hours. The crude reaction mixture was cooled to room temperature and concentrated. The resulting crude product was used directly in the next step.

Step 2: Step 1 product (1 7g) was dissolved in dry DMF (10ml_). The resulting solution was heated at 110°C in sealed tube for 16 hours. The crude reaction mixture was cooled to room temperature, and the reaction mixture quenched with 1 M HCI (50ml). The resulting mixture was extracted using EtOAc. The organic layer was dried over Na2S04 and concentrated. The crude product was used directly in the next step.

Example 1

To a stirred solution of (2E)-3-(3-chlorophenyl)prop-2-enal (Intermediate A2)

(0.998g,6.012mmol) and ^ ⁴ ,4-thiomorpholine-1 ,3-dione (Intermediate E1 ) (0.1 g, 0.751 mmol) in ethanol (1.5ml_) was added piperidine (0.1 mL) and the resulting mixture stirred at room temperature for 15 min. A white solid was precipitated. The crude reaction mixture was diluted with a minimum amount of ethanol (1 mL) and the solid filtered to provide (2Z)-2-[(2E)-3-(3-chlorophenyl)prop-2-en-1 -ylidene]-1 l ⁴ ,4-ίIΐίqGTΐofIΐoIίhb-1 ,3- dione and (2E)-2-[(2E)-3-(3-chlorophenyl)prop-2-en-1 -ylidene]-^ ⁴ ,4-thiomorpholine-1 ,3- dione (50mg, 23.69%) as a mixture of isomers. HPLC, Method F, Retention Time 1 1 .3 mins, ¹ H-NMR (400 MHz, DMSO-de) d ppm: 3.0-3.1 (dd, 1 H, -NH-CH2-CH2-SO2-), 3.24- 3.28 (b dd, 1 H, -NH-CH2-CH2-SO2-), 3.4-3.5 (dd, 1 H, -NH-CH2-CH2-SO2-), 3.9-4.0 (b dd, 1 H, -NH-CH2-CH2-SO2-), 7.4-7.5 (m, 4H, -Ar-H), 7.54-7.6 (m, 1 H), 7.65-7.0 (m, 2H), 7.8- 7.86 (d, 1 H), 8.23-8.24 (b d, 1 H, N-H).

Using the same method, the following Examples were also made: O

n H bo o o o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

o

C/I n H bo o o

C/I o

Example 50

(2E)-3-(3-chlorophenyl)prop-2-enal (0.140g, 0.840 mmol) and ^ ⁴ ,4-thiazepane-1 ,3-dione (0.1 g, 0.680 mmol) were dissolved in ethyl acetate/water (2.5ml/0.5 ml ) and placed in a microwave vial. The reaction mixture was stirred at room temperature for 15 minutes and piperidine (0.1 ml) was added. The reaction mixture was then heated to 80 °C for 18 hours. The crude reaction mixture was cooled to room temperature and diluted with water (50 ml) and extracted using dichloromethane (2 x 100 ml). The organic layer was washed with saturated sodium bicarbonate solution (2 x 50 ml) and brine (2 x 50 ml). The organic layer was dried with sodium sulphate and concentrated. The crude product was purified by flash column chromatography using 0 to 100% ethyl acetate in hexane to provide 26 mgs of (2Z)-2-[(2E)-3-(3-chlorophenyl)prop-2-en-1-ylidene]- l ⁴ ,4-thiazepane-1 ,3-dione and (2E)-2-[(2E)-3-(3-chlorophenyl)prop-2-en-1-ylidene]- l ⁴ ,4-thiazepane-1 ,3-dione as a mixture of isomers LCMS (Method D); ESI-MS m/z = 296, HPLC, Method G, Retention Time 10.50 mins, ¹ H-NMR (400 MHz, DMSO-de) d ppm: 1.82 (bs, 1 H, NH-CH ₂ -CH ₂ -CH ₂ - SO), 2.0 (bs, 1 H, NH-CH ₂ -CH ₂ -CH ₂ -SO), 3.0-3.34 (bs, 4H, NH-CH ₂ -CH ₂ -CH ₂ -SO), 6.98- 7.07 (m, 3H), 7.4-7.Q (m, 4H), 8.36 (s, 1 H).

Using the same method, the following Examples were also made: o

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EXAMPLE 58

Anti-tumour effects of compounds on glioma cell lines

Cytotoxic effect of test and comparative compounds on U87-MG, T98G, and CCF-STTG1 cells

Cells

Human glioblastoma cell lines (U87-MG_ATCC HTB-14, T98G_ATCC CRL-1690, CCF- STTG1_CRL-1718) were obtained from the American Type Culture Collection (ATCC). The cells were maintained in DMEM (Gibco #1 1885-076) containing 10% FBS (Gemini #100-106) and 1X Penicillin-Streptomycin-Glutamine (Gibco #10378-0167). The cells were cultured at 37 °C under CO2 in a cell culture incubator.

Assay

The cells were plated into clear flat bottom 96-well cell culture plates with a low

evaporation lid (Denville #T1096) using XL3000i multichannel pipettes (Denville #P3971- 9A) to be 4,000 cells per well in 100 pL except blank wells. The cells were then cultured overnight at 37 °C under CO2 in a cell culture incubator.

Compounds to be tested were prepared as 4 mM stock in DMSO and then 2-fold serial dilutions were performed in DMSO from the 4 mM stock solution. Amounts of 10 pL of each of the diluted compounds were transferred to 490 pL of DMEM and the solutions were mixed by vortex. An aliquot of 100 pL of compound and medium mixture (from low concentration to high concentration) was transferred into the pre-cultured cells (100 pL) from row 2 to row 8. Therefore, the final concentration of the compounds was 625 nM - 40 pM and the final concentration of DMSO was 1%. Blank wells were added with 200 pL of DMEM. TO the vehicle (DMSO) treated wells were added 100 pL from the mixture of DMSO and medium (10 pL of DMSO + 490 pL of DMEM).

After 3 days (72 hours) incubation at 37°C under 5% CO2 in a humidified incubator, the cells were subjected to a Sulforhodamine B (SRB) cytotoxicity assay. After shaking out the medium into a sink, the cells were washed once with cold PBS and then 200 pL of 10% trichloroacetic acid (TCA) (Sigma #T0699) solution was added to each well. The TCA treated cells were incubated at 4 °C for over 1 hour. Following shake out the TCA into the sink, cells were rinsed 3 times with tap water. After the final wash, the plates were left to dry upside-down. Next, 100 pL of SRB (Sigma #230162) solution were added to each well and the mixture was then incubated for 0.5 hour at room temperature. After washing the plates 3-5 times with 1% acetic acid, the plates were left to dry again. Finally, to each well in the plates were added 200 pl_ of 10 mM Tris and the plates were incubated with shaking for 1 hour. The absorbance was read at 560 nm using a microtitre plate reader (Molecular Devices Spectramax 340PC). The data for the wels treated with compounds of the invention were compared with the vehicle treated wells (100% control). The LC50 (50% lethal concentration) of compounds was determined using statistical software (GraphPad Prism 6) as a general indicator of a compound’s toxicity. The results are shown in the table below.

EXAMPLE 59

PHARMACEUTICAL FORMULATIONS

(i) Tablet Formulation

A tablet composition containing a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 may be prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 16 with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 16 in water containing 10% propylene glycol to give a concentration of active compound of 1.5 % by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.

(iv) Injectable Formulation

A parenteral composition for injection is prepared by dissolving in water a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 16 (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules. v) Injectable formulation III

A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 (e.g. in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilised by autoclaving. vi) Injectable formulation IV

A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg/ml. The vial is then sealed and sterilised by autoclaving.

(vii) Subcutaneous Injection Formulation

A composition for sub-cutaneous administration is prepared by mixing a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 with pharmaceutical grade corn oil to give a concentration of 5 mg/ml. The composition is sterilised and filled into a suitable container. viii) Lyophilised formulation

Aliquots of formulated compound of formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 are put into 50 ml vials and lyophilized. During lyophilisation, the

compositions are frozen using a one-step freezing protocol at (-45 °C). The temperature is raised to -10 °C for annealing, then lowered to freezing at -45 °C, followed by primary drying at +25 °C for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50 °C. The pressure during primary and secondary drying is set at 80 millitor. Equivalents

The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application. REFERENCES

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