This invention relates, inter alia, to the use of certain compounds in the treatment of a condition ameliorated by the inhibition of the A _2a receptor.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Parkinson's Disease (PD) is a common progressive neurodegenerative disorder with an estimated prevalence of 0.3 percent in the general population, rising to 5 percent in those over 85. The disease is characterised by tremor, rigidity and bradykinesia, which are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and a resulting depletion of dopamine in the striatum.

Due to an ageing population, the incidence of Parkinson's disease is rising. However, the most effective pharmacological treatment for the disease is still Levodopa (L-dopa), fifty years after its discovery as an antiparkinsonian agent (Chemical & Engineering News 2005, 83(25)).

L-dopa is the precursor of dopamine and achieves its pharmacological effect by increasing dopaminergic transmission (i.e. by raising the level of dopamine in the striatum). The physiological effect of L-dopa can also be achieved by the administration of directly-acting dopamine agonists such as bromocriptine or pergolide. While the above treatments are initially very effective at controlling some of the symptoms of Parkinson's Disease, particularly rigidity, continuing use results in a wide range of side effects that can be distressing to the patient (e.g. involuntary movements known as dyskinesias). Other treatments include inhibition of the dopamine metabolizing enzymes catechol-o- methyl transferase (COMT) or monoamine oxidases (MAOIs), or the use of anticholinergics. However, these treatments only provide mild to moderate benefit and suffer from a range of adverse side effects. Adenosine is known to be an endogenous modulator of a number of physiological functions. For example, adenosine acts on the cardiovascular system and is a strong vasodilator and a cardiac depressor and is known to have cardioprotective properties (see e.g. Norton et al. Am J Physiol. 1999; 276(2 Pt 2), H341-9; and Auchampach and Bolli Am J Physiol. 1999; 276(3 Pt 2), H11 13-6). Effects of adenosine on the central nervous system include sedative, anxiolytic and antiepileptic effects. Further, adenosine acts on the respiratory system by inducing bronchoconstriction. In the kidneys, adenosine exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses, meaning that adenosine may be involved in the pathology of certain types of acute kidney failure (Costello-Boerrigter, et al. Med Clin North Am. 2003 Mar; 87(2), 475-91 ; Gottlieb, Drugs. 2001 , 61(10), 1387-93). Adenosine also acts as a lipolysis inhibitor on fat cells (Feoktistov, et al., Pharmacol. Rev. 1997, 49, 381-402) and as an anti-aggregant on platelets.

The action of adenosine is mediated by a family of G-protein coupled receptors. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors, which have been classified as adenosine A-i , A _2a , A _2b and A ₃ . The A ₁ and A ₃ receptors inhibit the activity of the enzyme adenylate cyclase, whereas the A _2a and A _2b receptors stimulate the activity of the same enzyme, thereby modulating the level of cyclic AMP in cells. In the central nervous system, adenosine is a potent endogenous neuromodulator, which controls the presynaptic release of many neurotransmitters and is thus involved in motor function, sleep, anxiety, pain and psychomotor activity. The main adenosine receptor subtypes in the brain are A ₁ and A _2a . While the A ₁ adenosine receptor subtype is found throughout the brain in high density, the distribution of the A _2a receptor is more restricted and it is found in high density in the striatum (caudate-putamen, nucleus accumbens, olfactory tubercule), where it is co-localized with the dopamine D2 receptor on striatopallidal output neurons. The discrete localization of the A _2a receptor within the striatum and its ability to functionally antagonize the actions of the D2 receptor has led to the suggestion of the potential utility of A _2a receptor antagonists for the symptomatic treatment of Parkinson's disease (see, for example, Cunha et al., Curr Pharm Des. 2008, 14(15), 1512-1524).

Hence, A _2a antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's disease (Tuite P, et al., J. Expert Opin. Investig. Drugs. 2003; 12, 1335-52; Popoli P. et al. J Neurosci. 2002; 22, 1967-75; and Dall'lgna, et al., Experimental Neurology, 2007, 241-245). Furthermore, A _2a antagonists may be employed for the treatment of: attention related disorders such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD); psychoses; stroke, extra pyramidal syndrome (e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia (see Jenner P. J Neurol. 2000; 247 Suppl2: 1 143-50); and disorders of abnormal movement such as restless leg syndrome (RLS) and periodic limb movement in sleep (PLMS) (see, for example WO 02/055083, WO 05/044245, WO 06/132275 and Happe S, ef al., Neuropsychobiology. 2003, 48, 82-6). Adenosine A _2a antagonists are disclosed in US 2007037033 as useful agents for the treatment of amyotrophic lateral sclerosis. WO 01/058241 discloses the treatment of cirrhosis, fibrosis and fatty liver by employing adenosine A _2a antagonists. WO 06/009698 describes adenosine A _2a antagonists as useful for the mitigation of addictive behaviour. It has been recently demonstrated that adenosine A _2a antagonists may be employed for the treatment and prevention of dermal fibrosis in diseases such as scleroderma (Chan et al. Arthritis & Rheumatism, 2006, 54(8), 2632-2642).

In addition, A _2a antagonists may have therapeutic potential as neuroprotectants (Stone TW. et al., Drag. Dev. Res. 2001 , 52, 323-330), and in the treatment of sleep disorders (Dunwiddie TV et al., Ann. Rev. Neurosci. 2001 , 24, 31- 55) and migraine (Kurokowa et al., 2009. Program No. 714.4/B101. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience).

Adenosine A ₁ receptor activation has various effects on the cardiovascular system, including reducing heart rate and atrial contractility and the attenuation of the stimulatory action of catecholamines on the heart (see, for example, Jacobsen & Gao (2006) Nature Reviews Drug Discovery 5, 247-264 and Zablocki et al. (2004) Current Topics in Medicinal Chemistry 4, 839-854). Therefore, adenosine A ₁ receptor antagonism could cause an increase in both heart rate and force of contractility. Further, A ₁ receptor antagonism may also cause diuresis (see, e.g., Wolff et al., Drug Dev. Res. 1998, 45, 166 and Givertz et al., J. Am. Coll. Cardiol. 2007, 50, 1551 ). Additionally, CNS-penetrant adenosine A ₁ antagonists are known to reduce the seizure threshold and are potentially pro-convulsant (see, e.g. Cotter et al. (2008) Journal of Cardiac Failure 8, 631-640). Thus, there is a continuing need for compounds with selectivity for the A _2a receptor subtype relative to the A ₁ receptor subtype.

A number of compounds are currently being developed as A _2a receptor antagonists for the treatment of Parkinson's Disease. These compounds include KW6002 (istradefylline, EJ 1 ,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine) by Kyowa Hakko Kogyo, SCH- 420814 (preladenant, 2-(furan-2-yl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin- 1 - yl]ethyl]-7/-/-pyrazolo[4,3-e][1 ,2,4]-triazolo[1 ,5-c]pyrimidin-5-amine) by Schering-Plough, BIIB014 by Biogen Idee, Lu AA47070 by Lundbeck, ST-1535 by Sigma-Tau Farm iunite SpA, SYN 1 15 by Synosia, and ASP 5854 by Astellas.

However, the compounds mentioned above suffer from a number of drawbacks, such as low solubility (KW6002, SCH-420814, BIIB014 and Lu AA47070), light sensitivity (KW6002), low selectivity (Lu AA47070 and ASP 5854), potential toxicity due to the inclusion of known toxicophores (SCH-420814 and BIIB014) and limited efficacy in vivo (KW6002).

International patent applications WO 2006/076681 , WO 2008/01 1083, WO 03/035635, WO 2008/102350 and WO 2009/026657 disclose a number of isoflavone derivatives that are indicated to be useful in the treatment of neurodegenerative diseases. There is no suggestion or disclosure of compounds bearing a 5-membered heterocyclic ring in the 3- position of the central heterocycle, nor is there any suggestion that the disclosed compounds might be useful as A _2a receptor antagonists. International patent application WO 2005/007096 discloses N-phenyl- 7(hydroxylimino)cyclopropan[b]chromen-1 a-carboxamide as a mGlu-4 receptor (mGluFM) positive allosteric modulator useful in the treatment of movement disorders, including Parkinson's disease. International patent application WO 2005/1 12935 discloses quinazolinone derivatives as phosphoinositide kinase delta inhibitors, which may be useful in the treatment of neurodegenerative diseases.

International patent applications WO 2007/065662, WO 2002/076939, WO 2004/007461 and WO 2004/037193 disclose compounds comprising a 10-membered heterocyclic core, which compounds are indicated to have utility in the treatment of neurodegenerative disorders. There is no specific disclosure of compounds bearing a 5- membered heterocyclic ring in the 3-position of the central heterocycle, nor is there any suggestion that the disclosed compounds might be useful as A _2a receptor antagonists. International patent applications WO 2005/095360, WO 2008/150029 and WO 2009/053799 disclose quinolone derivatives and cinnolin-4-one derivatives, respectively. Although those compounds are indicated to be useful in treating neurodegenerative conditions, there is no suggestion or disclosure that those compounds might be useful as A _2a receptor antagonists.

Russian patent 2 066 322 discloses the compound 3-(4-methyl-2-thiazolyl)-6-propyl-7-(1- methyl-1-ethoxycarbonyl)-methoxychromone as having hypoglycemic, hypolipidemic and analeptic effects. However, there is no disclosure or suggestion of the use of that compound as an A _2a receptor ligand.

We have now discovered, surprisingly, that certain bicyclic, aromatic carbonyl compounds bearing certain heteroaromatic substituents are useful as A _2a receptor ligands.

Thus, according to the first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof for use in the treatment of a condition or disorder ameliorated by the inhibition of the A _2a receptor, wherein the compound of formula I has the structure

wherein:

X represents O, N or NR ² ,

or alternatively X may represent CR ^2a when B ⁵ represents N or when B ⁵ represents C and the structural unit -A ² (R ¹ )-A ¹ - represents-N(R ¹ )-C(R ³ )=; the structural unit -A ² (R ¹ )-A ¹ - represents

-C(R ¹ )=C(R ³ )- or -C(R ¹ )=N-, or

when X is N, the structural unit -A ² (R ¹ )-A ¹ - may alternatively represent

-N(R ¹ )-C(R ³ )=;

B ¹ represents C(R ⁴ ) or N; B ² represents C( ⁵ ) or N;

B ³ represents C(R ⁶ ) or N;

B ⁴ represents C(R ⁷ ) or N;

B ⁵ represents C

or, when X represents N or CR ^2a and the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )- or -C(R ¹ )=N-, B ⁵ may alternatively represent N;

provided that no more than two of B ¹ to B ⁵ represent N; the dashed line represents a double bond between the C-atom at the 9-position of the ring system and either X or B ⁵ ;

R ¹ represents a 5-membered heteroaryl group containing one or more heteroatoms selected from O, S and N, which group is

optionally ring-fused to phenyl or Het,

optionally substituted by one or more R ⁸ substituents and

attached to the rest of the molecule via an atom in the 5-membered ring;

Het represents a 5- or 6-membered heterocyclic group containing from one to three heteroatoms selected from O, S and N;

R ⁸ represents, independently at each occurrence, halo, OR ^a , N(R ^a ) ₂ , Ci _-6 alkyl, C ₂ _ ₆ alkenyl, C ₂ . ₆ alkynyl or C ₃ . ₆ cycloalkyl, which latter four groups are optionally substituted by one or more substituents selected from halo, OH and NH ₂ ;

R ^a represents, independently on each occurrence, H, Ci _-6 alkyl or C ₃ . ₆ cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo, OH and NH ₂ ;

H,

C-i-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl, C ₄ -6 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_4 alkyl, C ₂ . ₄ alkenyl, C ₂ . ₄ alkynyl, C ₃ . ₅ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from

OH, =0, halo, d_ ₄ alkyl and d_ ₄ alkoxy), phenyl, Het ^a , OR ^7a , S(0) _n R , S(0) ₂ N(R ^7c )(R ^7d ), N(R ^7e )S(0) ₂ R ^7f , N(R ^7g )(R ^7h ), L ¹ -C(0)-L ² -R ⁷ⁱ , and which C ₃ _ ₆ cycloalkyl or C ₄ -6 cycloalkenyl groups may additionally be substituted by =0, (c) S(0) ₂ R ^7j ,

(d) S(0) ₂ N(R ^7k )(R ⁷¹ ), L ³ -C(0)-L ⁴ - phenyl or

Het ^b ; 2 ^a and R ³ independently represent

(a) H

(b) halo;

(c) C-i-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl, C ₄ -6 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN , C- alkyl, C ₂ _ ₄ alkenyl, C ₂ _ ₄ alkynyl, C ₃ . ₅ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, d_ ₄ alkyl and d_ ₄ alkoxy), phenyl, Het ^a , OR ^7a , S(0) _n R ^7b , S(0) ₂ N(R ^7c )(R ^7d ), N(R ^7e )S(0) ₂ R ^7f , N(R ^7g )(R ^7h ), L ⁵ -C(0)-L ⁶ -R ⁷ⁱ , and which C ₃ - ₆ cycloalkyl or C ₄ -6 cycloalkenyl groups may additionally be substituted by =0, (d) S(0) _p R ^7j ,

(e) S(0) ₂ N(R ^7k )(R ⁷¹ ),

(f) L ⁷ -C(0)-L ⁸ -R ^7m ,

(g) OR ⁷ⁿ ,

(h) N(R ^7o )(R ^7p ),

(i) N(R ^7q )S(0) ₂ R ^7r ,

(j) phenyl or

(k) Het ^b ;

R ^7a to R ^7e and R ^7g to R ^7q independently represent, at each occurrence H or Ci_ ₄ alkyl, which latter group is optionally substituted by one or more substituents selected from halo, OH and NH ₂ , provided that R ^7b or R ^7j does not represent H when n or p, respectively, is 1 or 2;

R ^7f and R ^7r independently represent Ci_ ₄ alkyl optionally substituted by one or more substituents selected from halo, OH and NH ₂ ;

Het ^a and Het ^b independently represent, at each occurrence, 5-membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, which heterocyclic groups are optionally substituted by one or more substituents selected from halo, OH, C-i-4 alkyl and Ci_ ₄ alkoxy, which latter two groups are optionally substituted by one or more substituents selected from halo, OH and NH ₂ ;

R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent (a) H,

(b) halo,

(c) CN,

(d) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci _-6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C3- ₁₂ cycloalkyl or C ₄ . ₁₂ cycloalkenyl groups may additionally be substituted by =0,

(e) OR ^9a ,

(f) S(0) _r R ^9b ,

(g) S(0) ₂ N(R ^9c )(R ^9d ),

(h) N(R ^9e )S(0) ₂ R ^9f ,

(i) N(R")(R ^9h ),

(j) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

(k) aryl,

(I) Het ² , or

R ⁵ and R ⁶ , together with the C-atoms to which they are attached, may form a 6- membered aromatic or non-aromatic ring containing at least two C-atoms (the C-atoms to which R ⁵ and R ⁶ are attached) and, optionally, from one to three heteroatoms selected from O, S and N, which ring is optionally substituted by one to four R ¹⁰ substituents;

R ^8a to R ⁸ ' and R ^9a to R ⁹ ' independently represent, at each occurrence,

(a) H,

(b) C-i- ₁₂ alkyl, C ₂ - ₁₂ alkenyl, C ₂ - ₁₂ alkynyl, C ₃ . ₁₂ cycloalkyl, C ₄ . ₁₂ cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, d_ ₄ alkyl and C alkoxy), OR ^10a , S(O) _s R ^10b ,

S(O) ₂ N(R ^10c )(R ^10d ), N(R ^10e )S(O) ₂ R ^10f , N(R ^10g )(R ^10h ), L ¹³ -C(O)-L ¹⁴ -R ¹⁰ⁱ , aryl and Het ³ , and which C3- ₁₂ cycloalkyl or C4. ₁₂ cycloalkenyl groups may additionally be substituted by =0,

(c) aryl or

(d) Het ⁴ , provided that R and R do not represent H when q or r, respectively, is 1 or 2, and provided that R ^8f and R ^9f do not represent H; each aryl independently represents a C ₆ -i ₄ carbocyclic aromatic group, which group may comprise one, two or three rings and may be substituted by one or more R ¹⁰ substituents;

R ¹⁰ represents, independently at each occurrence,

(a) halo,

(b) CN,

(c) C-i-12 alkyl, C _2- 12 alkenyl, C _2- 12 alkynyl, C ₃ . ₁₂ cycloalkyl, C ₄ . ₁₂ cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, d_ ₄ alkyl and d_ ₄ alkoxy), OR ^11a , S(0) _t R ^{11 b} , S(0) ₂ N(R ^11c )(R ^11d ), N(R ^11e )S(0) ₂ R ^11f , N(R ^11g )(R ^11h ), L ¹⁵ -C(0)-L ¹⁶ -R ¹¹ⁱ , phenyl, naphthyl (which latter two groups are optionally substituted by one or more substituents selected from OH, halo, C1-4 alkyl and C1-4 alkoxy) and Het ⁵ , and which C3-12 cycloalkyl or C ₄ _i ₂ cycloalkenyl groups may additionally be substituted by =0,

(d) OR ^12a ,

(e) S(0) _u R ^12b ,

(f) S(0) ₂ N(R ^12c )(R ^12d ),

(g) N(R ^12e )S(0) ₂ R ^12f ,

(h) N(R ^12g )(R ^12h ),

(i) L ¹⁷ -C(0)-L ¹⁸ -R ¹²ⁱ ,

(j) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ alkyl and Ci_ alkoxy) or

(k) Het ⁶ ; R ^10a to R ¹⁰ⁱ , R ^11a to R ¹¹ⁱ and R ^12a to R ¹²ⁱ independently represent, at each occurrence,

(a) H,

(b) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl (which latter five groups are optionally substituted by one or more substituents selected from halo, OH, Ci_ ₆ alkyl, C ₃ _i ₂ cycloalkyl, C ₄ _i ₂ cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from OH,

=0, halo, C1-4 alkyl and d-4 alkoxy), d-6 alkoxy, NH ₂ , N(H)-d-6 alkyl, N(Ci- ₆ alkyl) ₂ , phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy) and Het ⁷ , and which C3-12 cycloalkyl or C4.12 cycloalkenyl groups may additionally be substituted by =0),

(c) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, CN, halo, Ci_ ₆ alkyl and Ci_ ₆ alkoxy) or

(e) Het ⁸ ,

provided that R ^10b , R ^11b or R ^12b does not represent H when s, t or u, respectively, is 1 or 2, and provided that R ^10f , R ^11f and R ^12f do not represent H;

Het ¹ to Het ⁸ independently represent 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from

(a) halo,

(b) CN,

(c) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, d_ ₄ alkyl and C alkoxy), OR ^13a , S(0) _v R ^13b , S(0) ₂ N(R ^13c )(R ^13d ), N(R ^13e )S(0) ₂ R ^13f , N(R ^13g )(R ^13h ), L ¹⁹ -C(O)-L ²⁰ -R ¹³ⁱ , phenyl, naphthyl (which latter two groups are optionally substituted by one or more substituents selected from OH, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy) and Het ^x , and which C3- ₁₂ cycloalkyl or C4. ₁₂ cycloalkenyl groups may additionally be substituted by =0,

(d) OR ^14a ,

(e) =0,

(f) S(0) _w R ^14b ,

(g) S(0) ₂ N(R ^14c )(R ^14d ),

(h) N(R ^14e )S(0) ₂ R ^14f ,

(i) N(R ^14g )(R ^14h ),

G) L ²¹ -C(0)-L ²² -R ¹⁴ⁱ ,

(k) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy) or

(I) Het ^y ; R ^13a to R ¹³ ' and R ^14a to R ¹⁴ ' independently represent, at each occurrence,

(a) H,

(b) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyi, C4-12 cycloalkenyl (which latter five groups are optionally substituted by one or more substituents selected from halo, OH, Ci _-6 alkyl, C ₃ . ₁₂ cycloalkyi, C ₄ . ₁₂ cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from OH, =0, halo, C1-4 alkyl and Ci_ ₄ alkoxy), Ci_ ₆ alkoxy, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy) and Het ^x , and which C ₃ . ₁₂ cycloalkyi or C ₄ . ₁₂ cycloalkenyl groups may additionally be substituted by =0),

(c) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy) or

(e) Het ^y ,

provided that R ^13b or R ^14b does not represent H when v or w, respectively, is 1 or 2, and provided that R ^13f and R ^14f do not represent H;

L ¹ to L ²² independently represent, at each occurrence, a direct bond, O, S, NH or N(R ¹⁵ ); n, p, q, r, s, t, u, v and w independently represent 0, 1 or 2;

R ¹⁵ represents

(a) d_ ₆ alkyl,

(b) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C ₁ . ₄ alkyl and C ₁ . ₄ alkoxy),

(c) C3.7 cycloalkyi (which latter group is are optionally substituted by one or more substituents selected from OH, =0, halo, C ₁ . ₄ alkyl and C ₁ . ₄ alkoxy) or

(e) Het ^y ;

Het ^x and Het ^y independently represent, at each occurrence, 5- or 6-membered heterocyclic groups containing from one to four heteroatoms selected from O, S and N, which heterocyclic groups may be substituted by one or more substituents selected from halo, =0 and Ci_ ₆ alkyl; and unless otherwise specified alkyl, alkenyl, alkynyl, cycloalkyi, and cycloalkenyl groups, well as the alkyl part of alkoxy groups, may be substituted by one or more halo atoms. Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium .

"Pharmaceutically functional derivatives" of compounds of formula I as defined herein includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound. Thus, for the purposes of this invention, the term also includes prodrugs of compounds of formula I.

The term "prodrug" of a relevant compound of formula I includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N- Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. 1-92, Elsevier, New York-Oxford (1985).

Compounds of formula I, as well as pharmaceutically acceptable salts, solvates and pharmaceutically functional derivatives of such compounds are, for the sake of brevity, hereinafter referred to together as the "compounds of formula I". Compounds of formula I may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

Compounds of formula I may exist as regioisomers and may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. For example, the following tautomers are included within the scope of the invention:

Compounds of formula I may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention. The term "disorder or condition ameliorated by the inhibition of the A _2a receptor" will be understood by those skilled in the art to include: a disease of the central nervous system such as depression, a cognitive function disease, a neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses; an attention related disorder (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extra pyramidal syndrome (e.g. dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); a disorder of abnormal movement (such as restless leg syndrome (RLS) and periodic limb movement in sleep (PLMS)); cirrhosis; liver fibrosis; fatty liver; dermal fibrosis (e.g. in diseases such as scleroderma); a sleep disorder; stroke; brain injury or neuroinflammation (e.g. migraine or any disorder or condition caused by ischemia, stroke, head injury or CNS inflammation); and addictive behaviour. The term "disorder or condition ameliorated by the inhibition of the A _2a receptor" will be understood by those skilled in the art to also include cancer (such as prostate, rectal, renal, ovarian, endometrial, thyroid, pancreatic, and, particularly, breast, colon, bladder, brain, glia, pineal gland and lung cancer (e.g. Lewis lung carcinoma) or melanoma).

Particular disorders or conditions that may be mentioned include addictive behaviour, ADHD and, particularly, neurodegenerative disease (e.g. Alzheimer's, Huntington's, and, particularly, Parkinson's Disease).

The compound for use mentioned in the above-mentioned aspect of the invention may be utilised in a method of medical treatment. Thus, according to further aspects of the invention, there is provided:

(i) the use of a compound formula I for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the A _2a receptor; and

(ii) a method of treatment of a disorder or condition ameliorated by antagonising the A _2a receptor, which method comprises the administration of an effective amount of a compound of formula I to a patient in need of such treatment. Embodiments of the invention that may be mentioned include those in which the compounds of formula I are selective inhibitors of the A _2a receptor.

When used herein in relation to inhibition of the A _2a receptor, the terms "selective" and "selectivity" includes references to the binding of a compound to the A _2a receptor with an IC ₅₀ value that is at least 10-fold lower (e.g. at least 20-, 50-, 100-, 500- or 1000-fold lower) than the IC ₅₀ value determined for the binding of the same compound to another adenosine receptor subtype (e.g. the A _2b , A ₃ or, particularly, A ₁ receptor sub-type) at the same temperature (e.g. room temperature, such as 298 K). Selectivity for the A _2a receptor can be over one other adenosine receptor subtype but, in certain embodiments of the invention, is over two or more (e.g. all other) adenosine receptor subtypes.

Antagonising the A _2a receptor may have neuroprotective effects. Thus, according to further aspects of the invention there are provided:

(i) a compound of formula I for use as a neuroprotectant;

(ii) the use of a compound of formula I for the manufacture of a medicament for use as a neuroprotectant; and

(iii) a method of mitigating damage to brain neurons caused by a neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis), stroke or other cerebral trauma, neurotoxins (e.g. mercury and compounds thereof, lead and compounds thereof, organic phosphates and nitrogen mustards), CNS infections (e.g. meningitis, encephalitis, poliomyelitis, tuberculosis, toxoplasmosis, neurosyphilis) or drug use (e.g. cocaine), which method comprises the administration of an effective amount of a compound of formula I to a patient at risk of damage to brain neurons from neurodegenerative disease, stroke or other cerebral trauma, neurotoxins, CNS infections or drug use.

References herein to patients at risk of damage to brain neurons from neurodegenerative disease, stroke or other cerebral trauma include references to patients who have been determined by clinical assessment to have a higher than average risk (as determined, for example, by comparison to normal individuals of the same age) of developing a neurodegenerative disease (e.g. Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis) or of having a stroke. For the avoidance of doubt, in the context of the present invention, the term "treatment includes references to therapeutic or palliative treatment of patients in need of such treatment, as well as to the prophylactic treatment and/or diagnosis of patients which are susceptible to the relevant disease states.

The terms "patient' and "patients" include references to mammalian (e.g. human) patients.

The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease). The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).

The term "halo", when used herein, includes references to fluoro, chloro, bromo and iodo.

The term "aryl" when used herein includes C ₆ -14 (such as C ₆ -13 (e.g. C ₆ -io)) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. C ₆ . _u aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Embodiments of the invention that may be mentioned include those in which aryl is phenyl.

For the avoidance of doubt, optional ⁸ substituents on the group R ¹ may be attached to: any suitable atom of the 5-membered heterocyclic ring (including the atoms at the 2-, 3-, 4- or 5-position of the ring, relative to the point of attachment of R ¹ to the rest of the molecule); and/or, if a ring-fused phenyl or Het group is present

any suitable atom on the fused phenyl or Het group.

The heterocyclic group Het is a 5- or 6-membered heterocycle that may be fully saturated, partly unsaturated, wholly aromatic or partly aromatic in character. Values of Het that may be mentioned include furanyl, furazanyl, imidazolyl, isoxazolidinyl, isoxazolyl, maleimido, oxadiazolyl, 1 ,2- or 1 ,3-oxazinanyl, oxazolyl, pyrazolyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, sulfolanyl, tetrahydrofuranyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, triazolyl, dioxanyl, hexahydropyrimidinyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1 ,2,3,4-tetrahydropyrimidinyl, 3,4,5,6- tetrahydropyrimidinyl and the like. Particular values of Het that may be mentioned include heteroaromatic groups containing from one to three N-atoms, such as pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl.

Monocyclic heteroaromatic groups that R ¹ may represent (i.e. when R ¹ is not ring fused to phenyl or Het) include, for example, furanyl, furazanyl, imidazolyl, isothiaziolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and the like. Bicyclic heteroaromatic groups that R ¹ may represent (i.e. when R ¹ is ring fused to either phenyl or Het) include, for example, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, indazolyl, indolyl, isoindolyl, purinyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[5,1-6]pyridinyl, pyrrolo[2,3-c]pyridinyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7- tetrahydrobenzopyrazolyl, thieno[5,1-c]pyridinyl and the like, which bicyclic heteroaromatic groups are attached to the rest of the molecule via an atom in the 5- membered ring. Particular values of the heteroaromatic groups that R ¹ may represent include oxadiazolyl (e.g. 1 ,3,4-oxadiazol-2-yl), thiadiazolyl (e.g. 1 ,3,4-thiadiazol-2-yl or 1 ,2,4-thiadiazol-5-yl), pyrazolyl (e.g. 1 ,2-pyrazol-1-yl), triazolyl (1 ,2,3-triazol-1-yl) or, particularly, thiazolyl (e.g. thiazol-4-yl or thiazol-2-yl). Heterocyclic (Het ¹ to Het ⁸ , Het ^a , Het ^b , Het ^x and Het ^y ) groups may be fully saturated, partly unsaturated, wholly aromatic or partly aromatic in character. Values of Het ¹ to Het ⁸ groups that may be mentioned include acridinyl, 1-azabicyclo[2.2.2]octanyl, azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzodioxepanyl, benzodioxepinyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzo[c]isoxazolidinyl, benzomorpholinyl, 2,1 ,3-benzoxadiazolyl, benzoxazinyl (including 3,4-dihydro-2A7-1 ,4-benzoxazinyl), benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e]pyrimidine, 2,1 ,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, 2,3-dihydrobenzimidazolyl, 2,3- dihydrobenzo[6]furanyl, 1 ,3-dihydrobenzo[c]furanyl, 1 ,3-dihydro-2,1 -benzisoxazolyl 2,3- dihydropyrrolo[2,3-6]pyridinyl, dioxanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,3-6]thiazolyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolidinyl, isoxazolyl, maleimido, morpholinyl, naphtho[1 ,2-0]furanyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, particularly, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl, 1 ,2- or 1 ,3-oxazinanyl, oxazolyl, oxetanyl, phenazinyl, phenothiazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[5,1-6]pyridinyl, pyrrolo[2,3- c]pyridinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, sulfolanyl, 3- sulfolenyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8- tetrahydrobenzo[e]pyrimidine, tetrahydrofuranyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1 ,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydroquinolinyl (including 1 ,2,3,4-tetrahydroquinolinyl and 5,6,7,8- tetrahydroquinolinyl), tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thieno[5,1- c]pyridinyl, thiochromanyl, thiophenetyl, triazolyl, 1 ,3,4-triazolo[2,3-6]pyrimidinyl, xanthenyl and the like. Values of Het ^a and Het ^b that may be mentioned include the 5- membered heterocyclic groups from the list above. Further, values of Het ^x and Het ^y that may be mentioned include the 5- and 6-membered heterocyclic groups from the list above.

Substituents on heterocyclic (Het ¹ to Het ⁸ , Het ^a , Het ^b , Het ^x and Het ^y ) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocyclic (Het ¹ to Het ⁸ , Het ^a , Het ^b , Het ^x and Het ^y ) groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocyclic (Het ¹ to Het ⁸ , Het ^a , Het ^b , Het ^x and Het ^y ) groups may also be in the N- or S- oxidised form.

Values of Het ¹ that may be mentioned include piperazinyl (e.g. piperazin-1-yl).

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent. For the avoidance of doubt, when a term such as "B ¹ to B ⁴ " is employed herein, this will be understood by the skilled person to mean any (i.e. some or all, as applicable) of B ¹ , B ² , B ³ and B ⁴ inclusively. Embodiments of the invention that may be mentioned include those that relate to compounds of formula I in which:

(1 ) X represents O, N or N ² ;

(2) R ⁴ and R ⁷ independently represent

(a) H,

(b) halo,

(c) CN,

(d) C-i-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl, C ₄ -6 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, CN, Ci_ ₂ alkyl, C ₃ . ₅ cycloalkyl (which latter group is optionally substituted by one or more substituents selected from OH, =0, halo, d_2 alkyl and d_ ₂ alkoxy), OH, NH ₂ , N(H)(d-4 alkyl) and N(Ci-4 alkyl) ₂ ,

(e) OH, O-C ₁ -4 alkyl, which latter group is optionally substituted in the alkyl part by one or more substituents selected from halo and OH, (f) S(0) ₂ -Ci-4 alkyl which group is optionally substituted in the alkyl part by one or more substituents selected from halo and OH,

(g) NH ₂ , N(H)(C ₁ _4 alkyl), N(C ₁ . ₄ alkyl) ₂ , which latter two groups are optionally substituted in the alkyl part by one or more substituents selected from halo and OH, or

(h) L ¹¹ -C(0)-L ¹² -Ci-4 alkyl, which group is optionally substituted in the alkyl part by one or more halo atoms; and/or

(3) L ¹¹ and L ¹² independently represent a direct bond, O, S or NH.

In certain embodiments of the invention, B ⁵ represents N and the compound of formula I may be represented as a compound of formula la,

wherein A ^1a represents C(R ³ ) or N, and B ¹ to B ⁴ and R ¹ are as defined above in relation to compounds of formula I, provided that no more than one of B ¹ to B ⁴ represents N. In certain other embodiments of the invention, B ⁵ represents C and the compound of formula I may be represented as a compound of formula lb,

wherein X, A ¹ , A ² , B ¹ to B ⁴ and R ¹ are as defined above in relation to compounds of formula I.

In particular embodiments of the invention, none of B ¹ to B ⁵ represent N and the compound of formula I may be represented as a compound of formula Ic,

wherein X, A , A , R and R to R are as defined above in relation to compounds of formula I.

In still further embodiments of the invention, the compound of formula I may be represented by a compound of formula Id or, particularly, le,

wherein R ¹ and R ³ to R ⁷ are as defined above in relation to compounds of formula I. Compounds of formula I (or la, lb, Ic or Id) that may be mentioned include the following, (a) When X represents N, the structural unit -A ² (R ¹ )-A ¹ - represents -N(R ¹ )-C= and B ¹ to B ⁵ represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ), C(R ⁷ ) and C, respectively

then R ⁷ represents

(a) H,

(b) halo,

(c) CN,

(d) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci _-6 alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and C1-4 alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by =0,

(e) S(0) _r R ^9b ,

(f) S(0) ₂ N(R ^9c )(R ^9d ),

(g) N(R ^9e )S(0) ₂ R ^9f ,

(h) N(R")(R ^9h ),

(i) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

0) aryl,

(k) Het ² or

(I) OR ^9x ,

wherein R ^9x represents

(a) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and Ci_4 alkoxy), OR ^10a , S(O) _s R ^10b , S(O) ₂ N(R ^10c )(R ^10d ), N(R ^10e )S(O) ₂ R ^10f ,

N(R ^10g )(R ^10h ), L ¹³ -C(O)-L ¹⁴ -R ¹⁰ⁱ , aryl and Het ³ , and which C ₃ _ ₁₂ cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by =0,

(b) aryl or

(c) Het ⁴

(e.g. R ⁷ represents

(a) H, (b) halo,

(c) CN,

(d) C-i-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH , =0, halo, Ci_ alkyl and d_ ₄ alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C3-12 cycloalkyl or C _4- 12 cycloalkenyl groups may additionally be substituted by =0,

(e) S(0) _r R ^9b ,

(f) S(0) ₂ N(R ^9c )(R ^9d ),

(g) N(R ^9e )S(0) ₂ R ^9f ,

(h) N(R")(R ^9h ),

(i) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

0) aryl or

(k) Het ² ),

i.e. R ⁷ is not -OH (or, alternatively, is not OR ^9a ).

When X represents N, the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C- and B ¹ to B ⁵ represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ), C(R ⁷ ) and C, respectively, then R ⁷ represents

(a) H,

(b) halo,

(c) CN,

(d) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH , =0, halo, C1.4 alkyl and C1-4 alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C ₃ _ ₁₂ cycloalkyl or C -12 cycloalkenyl groups may additionally be substituted by =0,

(e) S(0) _r R ^9b ,

(f) S(0) ₂ N(R ^9c )(R ^9d ),

(g) N(R ^9e )S(0) ₂ R ^9f ,

(h) N(R")(R ^9h ), (i) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

0) aryl or

(k) Het ²

(i.e. R ⁷ is not -OR ^9a ).

When X represents N, the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C- and B ¹ to B ⁵ represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ), C(R ⁷ ) and C, respectively, then R ¹ represents a 5-membered heteroaryl group containing two or more heteroatoms selected from O, S and N, which group is

optionally ring-fused to phenyl or Het,

optionally substituted by one or more R ⁸ substituents and

attached to the rest of the molecule via an atom in the 5-membered ring;

When X represents NR ² , the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )- or -C(R ¹ )=N-, and B ¹ to B ⁵ represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ), C(R ⁷ ) and C, respectively, then at least one of R ⁴ to R ⁷ represents

(a) CN,

(b) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN , Ci_ ₆ alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH , =0, halo, Ci_ ₄ alkyl and d_ ₄ alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C ₃ _ ₁₂ cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by =0,

(c) OR ^9a ,

(f) S(0) _r R ^9b ,

(d) S(0) ₂ N(R ^9c )(R ^9d ),

(e) N(R ^9e )S(0) ₂ R ^9f ,

(f) N(R")(R ^9h ),

(g) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

(h) aryl,

(i) Het ² , or

R ⁵ and R ⁶ , together with the C-atoms to which they are attached, may form a 6- membered aromatic or non-aromatic ring containing at least two C-atoms (the C- atoms to which R ⁵ and R ⁶ are attached) and, optionally, from one to three heteroatoms selected from O, S and N, which ring is optionally substituted by one to four R ¹⁰ substituents;

(i.e. at least one of R ⁴ to R ⁷ is other than H or halo). (e) When X represents O, the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )-, and B ¹ to B ⁵ represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ), C(R ⁷ ) and C, respectively, and R ³ represents H or CF ₃ , then R ⁶ does not represent

OH or

0-C(H)(CH ₃ )-C(0)0-CH ₂ CH ₃ .

(f) When X represents O, the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )-, and B ¹ to B ⁵ represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ), C(R ⁷ ) and C, respectively, then R ⁶ represents,

(a) H,

(b) halo,

(c) CN,

(d) C-i-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci _-6 alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and d_ ₄ alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C ₃ _ ₁₂ cycloalkyl or C _4- 12 cycloalkenyl groups may additionally be substituted by =0,

(e) OR ^9y ,

(f) S(0) _r R ^9b ,

(g) S(0) ₂ N(R ^9c )(R ^9d ),

(h) N(R ^9e )S(0) ₂ R ^9f ,

(i) N(R")(R ^9h ),

0) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

(k) aryl,

(I) Het ² , or

or R ⁶ , together with R ⁵ and the C-atoms to which R ⁵ and R ⁶ are attached, may form a 6-membered aromatic or non-aromatic ring containing at least two C- atoms (the C-atoms to which R ⁵ and R ⁶ are attached) and, optionally, from one to three heteroatoms selected from O, S and N, which ring is optionally substituted by one to four R ¹⁰ substituents;

R ^9y represents

(a) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci _-6 alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and Ci_4 alkoxy), OR ^10a , S(O) _s R ^10b , S(O) ₂ N(R ^10c )(R ^10d ), N(R ^10e )S(O) ₂ R ^10f , N(R ^10g )(R ^10h ), L ^13a -C(O)-L ¹⁴ -R ¹⁰ⁱ , aryl and Het ³ , and which C ₃ _ ₁₂ cycloalkyl or C4- ₁₂ cycloalkenyl groups may additionally be substituted by =0,

(b) aryl,

(c) Het ⁴ ; and

L ^13a represents O, S, NH or N(R ¹⁵ ).

For the avoidance of doubt, embodiments of the invention that may be mentioned include those in which any one or more of conditions (a) to (f) above apply. However, in particular embodiments of the invention, conditions (a), (b) and (d) all apply (or, alternatively, conditions (a), (c) and (d) all apply).

Further compounds of formula I (or la, lb, Ic, Id or le) that may be mentioned include those in which:

(a) R ¹ represents a 5-membered heteroaryl group containing two or more (e.g. two or three) heteroatoms selected from O, S and N, which group is

optionally ring-fused to phenyl or Het,

optionally substituted by one or more R ⁸ substituents and

attached to the rest of the molecule via an atom in the 5-membered ring;

(b) at least one of R ⁴ to R ⁷ represents

(a) halo,

(b) CN,

(c) Ci_i ₂ alkyl, C ₂ - ₁₂ alkenyl, C ₂ -i ₂ alkynyl, C ₃ _i ₂ cycloalkyl, C ₄ _i ₂ cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and d_ ₄ alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C3-12 cycloalkyl or C _4-12 cycloalkenyl groups may additionally be substituted by =0,

(d) OR ^9a ,

(e) S(0) _r R ^9b ,

(f) S(0) ₂ N(R ^9c )(R ^9d ),

(g) N(R ^9e )S(0) ₂ R ^9f ,

(h) N(R")(R ^9h ),

(i) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

0) aryl,

(k) Het ² , or

R ⁵ and R ⁶ , together with the C-atoms to which they are attached, may form a 6- membered aromatic or non-aromatic ring containing at least two C-atoms (the C- atoms to which R ⁵ and R ⁶ are attached) and, optionally, from one to three heteroatoms selected from O, S and N, which ring is optionally substituted by one to four R ¹⁰ substituents;

R ⁷ represents

(a) H,

(b) halo,

(c) CN,

(d) C ₁ - ₁₂ alkyl, C ₂ - ₁₂ alkenyl, C ₂ - ₁₂ alkynyl, C3- ₁₂ cycloalkyl, C4- ₁₂ cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci _-6 alkyl, C ₂ _6 alkenyl, C ₂ _6 alkynyl, C ₃ . ₈ cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and d_ ₄ alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C ₃ _ ₁₂ cycloalkyl or C4- ₁₂ cycloalkenyl groups may additionally be substituted by =0,

(e) S(0) _r R ^9b ,

(f) S(0) ₂ N(R ^9c )(R ^9d ),

(g) N(R ^9e )S(0) ₂ R ^9f ,

(h) N(R")(R ^9h ),

(i) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

0) aryl,

(k) Het ² or

(I) OR ^9x ,

wherein R ^9x represents (a) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci_ ₆ alkyl, -6 alkenyl, -6 alkynyl, C3-8 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₄ alkyl and d_ ₄ alkoxy), O ^10a , S(O) _s R ^10b , S(O) ₂ N(R ^10c )(R ^10d ), N(R ^10e )S(O) ₂ R ^10f , N(R ^10g )(R ^10h ), L ¹³ -C(O)-L ¹⁴ -R ¹⁰ⁱ , aryl and Het ³ , and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by =0,

(b) aryl or

(c) Het ⁴ .

Embodiments of the invention that may be mentioned include those that relate to compounds of formula I (or la, lb, lc, Id or le) in which:

(1 ) X represents N or, particularly, O;

(2) the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=N- or, particularly, -C(R ¹ )=C(R ³ )-;

(3) B ¹ to B ⁵ respectively represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ), C(R ⁷ ) and C (i.e. the compound is of formula lc);

(4) R ¹ represents a 5-membered heteroaryl group containing two or three heteroatoms selected from O, S and N, which group is optionally substituted by one or more (e.g. two or, particularly, one) R ⁸ substituents;

(5) each R ⁸ , if present, independently represents halo, OR ^a , N(R ^a ) ₂ , d-6 alkyl, C ₂ -6 alkenyl, -6 alkynyl or C ₃ . ₆ cycloalkyl, which latter four groups are optionally substituted by one or more substituents selected from halo, OH and NH ₂ ;

(6) R ^a represents, independently on each occurrence, H or d-4 alkyl optionally substituted by one or more substituents selected from halo, OH and NH ₂ ;

(7) R ² , if present, represents H, d-5 alkyl or C ₃ . ₅ cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo, OH, d-2 alkoxy, NH ₂ , N(H)(d-2 alkyl) and N(d-2 alkyl) ₂ ;

(8) R ^2a and R ³ , if present, independently represent

(a) H

(b) halo;

(c) d-5 alkyl or C ₃ . ₅ cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo, OH, d-2 alkoxy, NH ₂ , N(H)(d- ₂ alkyl) and N(d- ₂ alkyl) ₂ ;

(d) OH, 0-d_4 alkyl, which latter group is optionally substituted in the alkyl part by one or more substituents selected from halo and OH, (e) S(0) ₂ -Ci-4 alkyl which group is optionally substituted in the alkyl part by one or more substituents selected from halo and OH,

(f) NH ₂ , N(H)(Ci-4 alkyl), N (Ci_ ₄ alkyl) ₂ , which latter two groups are optionally substituted in the alkyl parts by one or more substituents selected from halo and OH, or

(g) C(0)-d_4 alkyl, OC(0)-d_ ₄ alkyl, OC(0)0-d_ ₄ alkyl, N(H)C(0)-d_ ₄ alkyl or C(0)N(H)-d-4 alkyl, which latter five groups are optionally substituted in the alkyl parts by one or more substituents selected from halo and OH;

(9) ⁴ and R ⁷ , if present, independently represent

(a) H,

(b) halo,

(d) d-5 alkyl or C ₃ . ₅ cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo, OH, d- ₂ alkoxy, NH ₂ , N(H)(d_ ₂ alkyl) and N(d_ ₂ alkyl) ₂ ,

(e) OH, O-d-4 alkyl, which latter group is optionally substituted in the alkyl part by one or more substituents selected from halo and OH,

(f) S(0) ₂ -d_4 alkyl which group is optionally substituted in the alkyl part by one or more substituents selected from halo and OH,

(g) NH ₂ , N(H)(d_ ₄ alkyl), N (d_ ₄ alkyl) ₂ , which latter two groups are optionally substituted in the alkyl parts by one or more substituents selected from halo and OH, or

(g) C(0)-d_ ₄ alkyl, OC(0)-d_ ₄ alkyl, OC(0)0-d_ ₄ alkyl, N(H)C(0)-d_ ₄ alkyl or C(0)N(H)-d- ₄ alkyl, which latter five groups are optionally substituted in the alkyl parts by one or more substituents selected from halo and OH; (10) R ⁵ and R ⁶ , if present, independently represent

(a) H,

(b) halo,

(d) d-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl, C ₄ - ₆ cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, CN, d-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, d-6 cycloalkyl

(which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, d-4 alkyl and d-4 alkoxy), OR ^8a , S(0) _q R ^8b , S(0) ₂ N(R ^8c )(R ^8d ), N(R ^8e )S(0) ₂ R ^8f , N(R ^8g )(R ^8h ), L ⁹ -C(O)-L ¹⁰ -R ⁸ⁱ , aryl and Het ¹ , and which C ₃ . ₆ cycloalkyl or -6 cycloalkenyl groups may additionally be substituted by =0,

(e) OR ^9a , (f) S(0) _r ^9b ,

(g) S(0) ₂ N(R ^9c )(R ^9d ),

(h) N(R ^9e )S(0) ₂ R ^9f ,

(i) N(R")(R ^9h ),

0) L ¹¹ -C(0)-L ¹² -R ⁹ⁱ ,

(k) aryl,

(I) Het ² , or

R ⁵ and R ⁶ , together with the C-atoms to which they are attached, may form a 6- membered aromatic or non-aromatic ring containing at least two C-atoms (the C- atoms to which R ⁵ and R ⁶ are attached) and, optionally, from one to three heteroatoms selected from O, S and N, which ring is optionally substituted by one to four R ¹⁰ substituents;

(1 1 ) R ^8a to R ⁸ ' and R ^9a to R ⁹ ' independently represent, at each occurrence,

(a) H,

(b) C-i-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C ₃ -6 cycloalkyl, C ₄ -6 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, CN, Ci- ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci _-2 alkyl and Ci _-2 alkoxy), OR ^10a , S(O) _s R ^10b , S(O) ₂ N(R ^10c )(R ^10d ), N(R ^10e )S(O) ₂ R ^10f , N(R ^10g )(R ^10h ),

L ¹³ -C(O)-L ¹⁴ -R ¹⁰ⁱ , aryl and Het ³ , and which C ₃ - ₆ cycloalkyl or C ₄ - ₆ cycloalkenyl groups may additionally be substituted by =0,

(c) aryl or

(d) Het ⁴ ,

provided that R ^8b and R ^9b do not represent H when q or r, respectively, is 1 or 2, and provided that R ^8f and R ^9f do not represent H;

(12) each aryl independently represents a C _6- io carbocyclic aromatic group, which group may comprise one or two rings and may be substituted by one or more R ¹⁰ substituents;

(13) R ¹⁰ represents, independently at each occurrence,

(a) halo,

(b) CN,

(c) C-i-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl, C ₄ -6 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, CN, C-i _-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl

(which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, C1-2 alkyl and C1-2 alkoxy), O ^11a , S(0) _t R ^11b , S(0) ₂ N(R ^11c )(R ^11d ), N(R ^11e )S(0) ₂ R ^11f , N(R ^11g )(R ^11h ), L ¹⁵ -C(0)-L ¹⁶ - R ¹¹ ', phenyl, naphthyl (which latter two groups are optionally substituted by one or more substituents selected from OH, halo, C1-2 alkyl and C1-2 alkoxy) and Het ⁵ , and which C ₃ . ₆ cycloalkyl or C ₄ . ₆ cycloalkenyl groups may additionally be substituted by =0,

(d) OR ^12a ,

(e) S(0) _u R ^12b ,

(f) S(0) ₂ N(R ^12c )(R ^12d ),

(g) N(R ^12e )S(0) ₂ R ^12f ,

(h) N(R ^12g )(R ^12h ),

(i) L ¹⁷ -C(0)-L ¹⁸ -R ¹²ⁱ ,

(j) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy) or

(k) Het ⁶ ;

R ^10a to R ¹⁰ⁱ , R ^11a to R ¹¹ⁱ and R ^12a to R ¹²ⁱ independently represent, at each occurrence,

(a) H,

(b) Ci _-8 alkyl, C ₂ . ₈ alkenyl, C ₂ . ₈ alkynyl, C ₃ . ₇ cycloalkyl, C ₄ . ₇ cycloalkenyl (which latter five groups are optionally substituted by one or more substituents selected from halo, OH, Ci_ ₅ alkyl, C ₃ . ₆ cycloalkyl, C . ₆ cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₂ alkyl and Ci_ ₂ alkoxy), Ci_ ₅ alkoxy, NH ₂ , N(H)-Ci _-5 alkyl, N(Ci_ ₅ alkyl) ₂ , phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₂ alkyl and C-i- ₂ alkoxy) and Het ⁷ , and which C ₃ . ₁₂ cycloalkyl or C ₄ . ₁₂ cycloalkenyl groups may additionally be substituted by =0),

(c) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, CN, halo, Ci_ ₅ alkyl and Ci_ ₅ alkoxy) or

(e) Het ⁸ ,

provided that R ^10b , R ^11b or R ^12b does not represent H when s, t or u, respectively, is 1 or 2, and provided that R ^10f , R ^11f and R ^12f do not represent H;

Het ¹ to Het ⁸ independently represent 5- to 10-membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, which heterocyclic groups may comprise one or two rings and may be substituted by one or more substituents selected from (a) halo,

(b) CN,

(c) C-i-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl, C ₄ -6 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, CN, Ci _-6 alkyl, C ₂ . ₆ alkenyl, C ₂ -6 alkynyl, C ₃ -6 cycloalkyl

(which latter three groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₂ alkyl and Ci_ ₂ alkoxy), O ^13a , S(0) _v R ^13b , S(0) ₂ N(R ^13c )(R ^13d ), N(R ^13e )S(0) ₂ R ^13f , N(R ^13g )(R ^13h ), L ¹⁹ -C(O)-L ²⁰ -R ¹³ ', phenyl, naphthyl (which latter two groups are optionally substituted by one or more substituents selected from OH, halo, C-i_ ₂ alkyl and C-i-2 alkoxy) and Het ^x , and which C ₃ . ₆ cycloalkyl or C ₄ . ₆ cycloalkenyl groups may additionally be substituted by =0,

(d) OR ^14a ,

(e) =0,

(f) S(0) _w R ^14b ,

(g) S(0) ₂ N(R ^14c )(R ^14d ),

(h) N(R ^14e )S(0) ₂ R ^14f ,

(i) N(R ^14g )(R ^14h ),

0) L ²¹ -C(0)-L ²² -R ¹⁴ⁱ ,

(k) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₄ alkyl and Ci_ ₄ alkoxy) or

(I) Het ^y ;

(16) R ^13a to R ¹³ ' and R ^14a to R ¹⁴ ' independently represent, at each occurrence,

(a) H,

(b) C-i-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl, C ₄ . ₆ cycloalkenyl (which latter five groups are optionally substituted by one or more substituents selected from halo, OH, Ci_ ₅ alkyl, C ₃ . ₅ cycloalkyl, C . ₅ cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from OH, =0, halo, Ci_ ₂ alkyl and Ci_ ₂ alkoxy), Ci_ ₅ alkoxy, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, C-i_ ₂ alkyl and C-i_ ₂ alkoxy) and Het ^x , and which C ₃ -6 cycloalkyl or C ₄ . ₆ cycloalkenyl groups may additionally be substituted by =0),

(c) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci _-2 alkyl and Ci _-2 alkoxy) or

(e) Het ^y , provided that ^13b or R ^14b does not represent H when v or w, respectively, is 1 or 2, and provided that R ^13f and R ^14f do not represent H;

(17) L ¹ , L ² and L ⁴ to L ²² independently represent, at each occurrence, a direct bond, O, NH or N(R ¹⁵ );

(18) L ³ represents O or, particularly, a direct bond;

(19) n, p, q, r, s, t, u, v and w independently represent 0 or 2;

(20) R ¹⁵ represents

(a) Ci_5 alkyl,

(b) phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, Ci_ ₂ alkyl and Ci_ ₂ alkoxy),

(c) C3-5 cycloalkyi, or

(e) Het ^y ;

(21 ) Het ^x and Het ^y independently represent, at each occurrence, 5-membered heterocyclic groups containing from one to four heteroatoms selected from O, S and N, which heterocyclic groups may be substituted by one or more substituents selected from halo and Ci_ ₂ alkyl;

(22) unless otherwise specified alkyl, alkenyl, alkynyl, cycloalkyi, and cycloalkenyl groups, as well as the alkyl part of alkoxy groups, may be substituted by one or more chloro or, particularly, fluoro atoms.

Further embodiments of the invention that may be mentioned include those that relate to compounds of formula I (or la, lb, lc, Id or le) in which:

(1 ) each R ⁸ , if present, independently represents halo or, particularly, Ci _-6 alkyl (e.g. methyl);

(2) R ² , if present, represents Ci_ ₆ alkyl optionally substituted by one or more halo atoms;

(3) R ³ , if present, represents C ₁ .3 alkyl optionally substituted by one or more halo atoms (e.g. R ³ , if present, represents isopropyl, CH ₂ CF ₃ , CHF ₂ , CF ₃ or, particularly, methyl, ethyl or trifluoromethyl) or, particularly, H;

(4) R ⁴ , if present, represents H or Ci_ ₅ alkyl optionally substituted by one or more halo atoms (e.g. R ⁴ , if present, represents H or Ci_ ₃ alkyl optionally substituted by one or more halo atoms, such as trifluoromethyl, ethyl or, particularly, methyl or H); (5) R ⁵ , if present, represents halo (e.g. chloro or bromo), -OR ^9a , -OC(0)R ⁹ ' or, particularly, H or Ci _-6 alkyl optionally substituted by one or more substituents (e.g. one substituent) selected from halo and Het ¹ (e.g. R ⁵ , if present, represents CF ₃ ,

CHF ₂ , CH ₂ CF ₃ , methyl, propyl, pentyl, hexyl or, particularly, H or ethyl); (6) ⁶ , if present, represents H, C ₁ -6 alkyl (which latter group is optionally substituted by one or more halo atoms (to provide, for example, CF ₃ , CHF ₂ , CH ₂ CF ₃ )) or, particularly, -OR ^9a or -OC(0)R ⁹ ' (e.g. R ⁶ , if present, represents H, methyl or, particularly, -OR ^9a or -OC(0)R ⁹ⁱ );

(7) R ⁵ and R ⁶ , together with the C-atoms to which they are attached, form a 6- membered aromatic or non-aromatic ring optionally containing at least two C- atoms and, optionally, from one to three heteroatoms selected from O and N (e.g. to form a phenyl, pyridyl, pyranyl, piperidinyl or morpholinyl ring), which ring is optionally substituted by one to three R ¹⁰ substituents;

(8) R ¹⁰ represents, independently at each occurrence,

(a) halo,

(b) Ci-5 alkyl optionally substituted by one or more substituents selected from halo, C3-5 cycloalkyl, OH, O-C ₁ - ₂ alkyl and NH ₂ ,

(c) OR ^12a or

(i) OC(0)R ¹²ⁱ ;

(9) R ⁷ , if present, represents halo (e.g. bromo) or, particularly, H or Ci_ ₆ alkyl optionally substituted by one or more halo atoms (e.g. R ⁷ , if present, represents CF ₃ , CHF ₂ , CH ₂ CF ₃ , ethyl or, particularly, methyl or H);

(10) each R ^9a , if present, independently represents

H,

C ₁ -6 alkyl, C ₂ . ₆ alkenyl, which latter two groups are optionally substituted by one or more substituents (e.g. one substituent) selected from C ₃ . ₆ cycloalkyl, aryl, -C(O)OR ¹⁰ⁱ , -CN and -C(O)N(R ¹⁵ )(R ¹⁰ⁱ ), or

(e.g. each R ^9a , if present, independently represents

H,

C ₁ -4 alkyl (such as n-butyl, n-propyl, / ^' so-propyl or, particularly, ethyl or methyl), C ₃ . ₄ alkenyl, which latter two groups are optionally substituted by one substituent selected from C ₃ . ₅ cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from halo and Ci_ ₂ alkyl (such as one halo or methyl substituent)), -C(O)OR ¹⁰ⁱ , -CN and -C(O)N(H)(R ¹⁰ⁱ ));

(1 1 ) each R ⁹ ', if present, independently represents H, aryl, or, particularly, Ci _-6 alkyl optionally substituted by one or more substituents selected from halo, N(H)(R ^10h ), aryl and -OR ^10a (e.g. each R ⁹ ', if present, independently represents phenyl optionally substituted by halo or, particularly, each R ⁹ ', if present, independently represents Ci _-5 alkyl optionally substituted by NH ₂ ); (12) ^10a and R ^12a independently represent, at each occurrence, H or C ₁ -4 alkyi optionally substituted by one or more halo atoms (e.g. each R ^10a , if present, independently represents methyl, ethyl or, particularly, H);

(13) each R ^10h , if present, independently represents H or C ₁ -4 alkyi optionally substituted by or more substituents selected from halo, OH and Ci_ ₄ alkoxy (e.g. each R ^10h , if present, independently represents methyl, ethyl, 2-hydroxyethyl or, particularly, H);

(14) R ¹⁰ ' and R ¹² ' independently represent, at each occurrence, H or Ci_ ₆ alkyi optionally substituted by one or more substituents (e.g. one substituent) selected from halo, OH, Ci_ ₄ alkoxy and aryl (e.g. each R ¹⁰ , if present, independently represents H or Ci_4 alkyi optionally substituted by OH or phenyl, such as H, methyl, ethyl, 2-hydroxyethyl, i-butyl or benzyl);

(15) each aryl, if present, independently represents a C ₆ -io carbocyclic aromatic group (e.g. naphthyl or, particularly, phenyl) optionally substituted by one or more substituents selected from halo and Ci_ ₄ alkyi (e.g. each aryl, if present, independently represents phenyl optionally substituted by one or more substituents selected from fluoro, chloro, bromo, methyl or ethyl);

(16) each Het ¹ , if present independently represents a 5- or 6-membered aromatic or fully saturated heterocyclic group containing from one to three heteroatoms selected from O, S and N, which heterocyclic group is optionally substituted by one or more substituents (e.g. one substituent) selected from halo and Ci_ ₄ alkyi, which latter group is optionally substituted by one or more substituents selected from halo and OH (e.g. each Het ² , if present represents a 6-membered fully saturated heterocyclic group containing from one or two N-atoms, which heterocyclic group is optionally substituted by Ci_ ₂ alkyi, which latter group is optionally substituted by OH);

(17) unless otherwise specified alkyi, alkenyl and cycloalkyi, as well as the alkyi part of alkoxy groups, may be substituted by one or more chloro or, particularly, fluoro atoms.

Particular compounds of formula Id and le (or formula I, la, lb or lc) that may be mentioned include those in which:

(1 ) R ¹ is a 9-membered, bicyclic heteroaryl group selected from benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl and indazolyl, which bicyclic heteroaryl group is attached to the rest of the molecule via an atom on the 5-membered ring, or, particularly, R ¹ is a 5- membered monocyclic heteroaryl group selected from furazanyl, imidazolyl, isothiaziolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, thiazolyl and triazolyl, which ¹ heteroaryl group is optionally substituted by two or, particularly, one R ⁸ substituents (e.g. R ¹ is benzothiazolyl, oxazolyl, oxadiazolyl, or, particularly, thiadiazolyl or thiazolyl each of which groups is optionally substituted by methyl);

(2) R ³ represents methyl, ethyl, trifluoromethyl or, particularly, H ;

(3) R ⁴ represents methyl or, particularly, H ;

(4) R ⁵ represents halo (e.g. chloro or bromo), methyl, propyl, pentyl, hexyl or, particularly, H or ethyl;

(5) R ⁶ represents H, methyl or, particularly, -OR ^9a or -OC(0)R ⁹ⁱ ;

(6) R ⁷ represents ethyl or, particularly, methyl or H;

(7) R ⁸ , if present, represents Ci- ₂ alkyi (e.g. methyl);

(8) R ^9a represents

H,

C1-4 alkyi (such as n-butyl, n-propyl, / ^' so-propyl or, particularly, ethyl or methyl) or C3-4 alkenyl, which latter two groups are optionally substituted by one substituent selected from cyclopropyl, phenyl (which latter group is optionally substituted by halo or methyl), -C(O)OR ¹⁰ⁱ , -CN and -C(O)N(H)(R ¹⁰ⁱ )

(e.g. R ^9a represents H or Ci_ ₄ alkyi optionally substituted by cyclopropyl, phenyl (which latter group is optionally substituted by halo or methyl), -C(0)OH, -C(0)0-Ci_ ₄ alkyi (which latter group is optionally substituted in the alkyi part by phenyl), -C(0)NH ₂ and -C(0)N(H)-Ci_ ₂ alkyi (which latter group is optionally substituted in the alkyi part by -OH);

each R ⁹ ', if present, independently represents phenyl optionally substituted by halo or, particularly, R ⁹ ' represents Ci_ ₅ alkyi optionally substituted by N H ₂ (e.g. R ⁹ ' represents phenyl, halophenyl, methyl, ethyl, / ^' so-propyl, aminomethyl, 1- aminoethyl or 5-aminopentyl);

each R ¹⁰ ', if present, independently represents H or Ci_ ₄ alkyi optionally substituted by OH or phenyl (e.g. H , methyl, ethyl, 2-hydroxyethyl, i-butyl or benzyl);

unless otherwise specified alkyi, and the alkyi part of alkoxy groups may be substituted by one or more fluoro atoms.

Other compounds of formula I that may be mentioned include the compounds of the examples described hereinafter. Thus, embodiments of the invention that may be mentioned include those in which the compound of formula I is a compound selected from the list:

(i) {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl]oxy}acetic acid;

(ii) 6-ethyl-7-[(2-methylprop-2-ene-1-yl)oxy]-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/- chromen-4-one;

(iii) 5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl acetate;

(iv) 7-methoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-6-propyl-4/-/-chromen-4-one;

(v) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-{[(2E)-3-phenylprop-2-en-1-yl]oxy}-4H- chromen-4-one;

(vi) 7-hydroxy-2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(vii) ethyl {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7- yl]oxy}acetate};

(viii) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-propoxy-4/-/-chromen-4-one;

(ix) 7-butoxy-6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(x) 6-ethyl-7-[(4-fluorobenzyl)oxy]-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xi) 7-[(2-chlorobenzyl)oxy]-6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xii) 7-methoxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xiii) methyl {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7- yl]oxy}acetate;

(xiv) 7-hydroxy-8-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-2-(trifluoromethyl)-4/-/- chromene-4-one;

(xv) 6-ethyl-7-hydroxy-2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xvi) methyl {[6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7- yl]oxy}acetate;

(xvii) methyl 2-{[6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7- yl]oxy}propanoate;

(xviii) 3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-6-propyl-4/-/-chromen-7-yl acetate;

(xix) i-butyl {[6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7- yl]oxy}acetate;

(xx) 7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-6-pentyl-4H-chromen-4-one;

(xxi) 7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-6-propyl-4/-/-chromen-4-one;

(xxii) 2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-6-propyl-4/-/-chromen-7-yl acetate;

(xxiii) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl

(6-amino)hexanoate;

(xxiv) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl 2-aminopropanoate; (xxv) 2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl acetate; (xxvi) 6-ethyl-2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl acetate;

(xxvii) 2,6-diethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl propanoate;

(xxviii) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl aminoacetate;

(xxix) 8-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl 2-chlorobenzoate;

(xxx) 3-(2-methyl-1 ,3-thiazol-4-yl)-4-oxo-6-propyl-4/-/-chromen-7-yl acetate;

(xxxi) 6,8-dibromo-2-methyl-3-(1 ,3-thiazol-2-yl)quinazolin-4(3/-/)-one;

(xxxii) 7-hydroxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xxxiii) 6-ethyl-7-methoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xxxiv) 5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-(propan-2-yloxy)-4/-/-chromen-4-one;

(xxxv) 7-(cyclopropylmethoxy)-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4- one;

(xxxvi) 7-ethoxy-6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xxxvii) 6,7-dimethoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-quinazolin-4(3/-/)-one;

(xxxviii) {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl]oxy}acetonitrile;

(xxxix) 6-ethyl-7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one,

or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof.

In certain further embodiments of the invention, the compound of formula I may be represented by a compound of formula If,

wherein B ¹ to B ⁴ , R ¹ and R ³ are as defined above in relation to compounds of formula I (or la, lb, lc, Id or le).

Compounds of formula If that may be mentioned include those in which:

(1 ) R ¹ is oxazolyl (e.g. oxazol-2-yl), oxadiazolyl (e.g. 1 ,3,4-oxadiazolyl, such as 1 ,3,4- oxadiazol-2-yl), thiadiazolyl (e.g. 1 ,2,4-thiadiazolyl, such as 1 ,2,4-thiadiazol-5-yl), or, particularly, thiazolyl (e.g. thiazol-4-yl or, particularly, thiazol-2-yl) or benzothiazol-2-yl, each of which R ¹ groups is optionally substituted by methyl (providing, for example, 2-methyl-1 ,3,4-oxadiazol-2-yl, benzothiazol-2-yl, 3- methyl-1 ,2,4-thiadiazol-5-yl, 2-methylthiazol-4-yl or, particularly, 4-methylthiazol-

2-yi); (2) R ⁵ , if present, represents halo (e.g. bromo), -OR ^9a , -OC(0)R ⁹ ' or, particularly, H or C^ alkyl (e.g. R ⁵ , if present, represents H or ethyl).

Compounds of formula If that may be mentioned include those in which:

at least one of B ¹ to B ⁴ (e.g. one of B ¹ to B ⁴ , such as B ³ ) represents C(OR ^9a ) in which R ^9a represents

branched C ₃ -6 alkyl, or

Ci_6 alkyl substituted by C ₃ -6 cycloalkyi or CN; and

alkyl and cycloalkyi may be substituted by one or more fluoro atoms.

Still further compounds of formula If that may be mentioned include those in which:

(1 ) R ¹ is benzothiazol-2-yl, oxazolyl, oxadiazolyl, or, particularly, thiadiazolyl or thiazolyl, each of which groups is optionally substituted by methyl;

(2) R ³ represents methyl, ethyl, trifluoromethyl or, particularly, H;

(3) B ¹ represents C(R ⁴ );

(4) B ² represents C(R ⁵ );

(5) B ³ represents C(R ⁶ );

(6) B ⁴ represents C(R ⁷ );

(7) R ⁴ represents H or Ci_ ₄ alkyl (e.g. H or, particularly, methyl);

(8) R ⁵ represents OR ^9a , -OC(0)R ⁹ⁱ , d_ ₄ alkyl (e.g. ethyl) or, particularly, H;

(9) R ⁶ represents H, d_ ₄ alkyl or, particularly, OR ^9a or -OC(0)R ⁹ⁱ , provided that one of R ⁵ and R ⁶ represents OR ^9a or -OC(0)R ⁹ⁱ ;

(10) R ⁷ represents Ci_ alkyl (e.g. ethyl or methyl) or, particularly, H;

(1 1 ) R ^9a represents

branched C ₃ ^ alkyl (e.g. /so-propyl) or

C†- ₃ alkyl (e.g. methyl) substituted by C ₃ . ₅ cycloalkyi (e.g. cyclopropyl) or CN;

(12) unless otherwise specified alkyl and cycloalkyi groups may be substituted by one or more fluoro atoms.

In certain embodiments of the invention, the compound of formula If may be represented by a compound of formula Ig,

ig

wherein R ¹ , R ⁴ and R ⁶ are as defined above.

Compounds of formula Ig that may be mentioned include those in which:

(1 ) R ¹ is oxadiazolyl (e.g. 1 ,3,4-oxadiazolyl, such as 1 ,3,4-oxadiazol-2-yl), thiadiazolyl (e.g. 1 ,2,4-thiadiazolyl, such as 1 ,2,4-thiadiazol-5-yl), benzothiazol-2- yl, or, particularly, thiazolyl (e.g. thiazol-4-yl or, particularly, thiazol-2-yl), each of which groups is optionally substituted by methyl (providing, for example, 2- methyl-1 ,3,4-oxadiazol-2-yl, benzothiazol-2-yl, 3-methyl-1 ,2,4-thiadiazol-5-yl, 2- methylthiazol-4-yl or, particularly, 4-methylthiazol-2-yl);

(2) R ⁴ represents H or, particularly, methyl;

(3) R ⁶ represents H or, particularly, OR ^9a ;

(4) R ^9a represents

branched C ₃ ^ alkyl (e.g. /so-propyl) or

Ci_2 alkyl substituted by C ₃ . ₅ cycloalkyl or CN (providing, for example, cyclopropylmethyl or cyanomethyl);

(5) unless otherwise specified alkyl and cycloalkyl groups may be substituted by one or more fluoro atoms.

Thus, in particular embodiments of the invention, the compound of formula I (or If or Ig) is selected from:

(xxxv) 5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-(propan-2-yloxy)-4H-chromen-4-one;

(xxxvi) 7-(cyclopropylmethoxy)-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one; (xxxix) {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4H-chromen-7-yl]oxy}acetonitrile; (xl) 6-ethyl-7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one,

or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof.

Further embodiments of the invention that may be mentioned include those in which the compound of formula I (or formula la, lb, Ic, Id, le, If, Ig or Ih) is isotopically labelled. However, other, particular embodiments of the invention that may be mentioned include those in which the compound of formula I (or formula la, lb, Ic, Id, le, If, Ig or Ih) is not isotopically labelled.

The term "isotopically labelled", when used herein includes references to compounds of formula I (or formula la, lb, Ic, Id, le, If, Ig or Ih) in which there is a non-natural isotope (or a non-natural distribution of isotopes) at one or more positions in the compound. References herein to "one or more positions in the compound" will be understood by those skilled in the art to refer to one or more of the atoms of the compound of formula I (or formula la, lb, lc, Id, le, If, Ig or Ih). Thus, the term "isotopically labelled" includes references to compounds of formula I (or formula la, lb, lc, Id, le, If, Ig or Ih) that are isotopically enriched at one or more positions in the compound.

The isotopic labelling or enrichment of the compound of formula I (or formula la, lb, lc, Id, le, If, Ig or Ih) may be with a radioactive or non-radioactive isotope of any of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and/or iodine. Particular isotopes that may be mentioned in this respect include ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ 0, ¹⁷ 0, ¹⁸ 0, ³⁵ S, ¹⁸ F, ³⁷ CI, ⁷⁷ Br, ⁸² Br and ¹²⁵ l).

When the compound of formula I is labelled or enriched with a radioactive or nonradioactive isotope, compounds of formula I that may be mentioned include those in which at least one atom in the compound displays an isotopic distribution in which a radioactive or non-radioactive isotope of the atom in question is present in levels at least 10% (e.g. from 10% to 5000%, particularly from 50% to 1000% and more particularly from 100% to 500%) above the natural level of that radioactive or non-radioactive isotope.

The use of certain compounds of formula I in medicine may be novel. Thus, further aspects of the invention relate to:

(a) a compound of formula If, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for use in medicine (or for use as a pharmaceutical); and

(b) a pharmaceutical formulation including compound of formula If, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,

wherein the compound of formula If is one in which

B ² is N or C(R ⁵ ),

R ¹ is oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazol-2-yl or thiazolyl,

R ⁵ represents H, halo, d_ ₂ alkyl, OR ^9a or -OC(0)R ⁹ⁱ ,

B ¹ , B ³ , B ⁴ , R ³ , R ^9a and R ⁹ ' are as defined above in relation to compounds of formula I (or la, lb, lc, Id, le, If or Ig) and unless otherwise specified alkyl, alkenyl, alkynyl, cycloalkyi, and cycloalkenyl groups, as well as the alkyl part of alkoxy groups, may be substituted by one or more halo (e.g. fluoro) atoms. Certain compounds described herein may be novel. Thus, a further aspect of the invention relates to a compound of formula If, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, wherein:

B ¹ to B ⁴ , R ¹ and R ³ are as defined above in relation to compounds of formula I (or la, lb, lc, Id, le, If or Ig);

provided that at least one of B ¹ to B ⁴ (e.g. one of B ¹ to B ⁴ , such as B ³ ) represents C(OR ^9a ), in which R ^9a represents

branched C ₃ -6 alkyl, or

Ci-6 alkyl substituted by C ₃ -6 cycloalkyi or CN; and

unless otherwise specified alkyl and cycloalkyi groups are optionally substituted by one or more halo atoms.

Similarly, other compounds of formula I may be novel (either per se or for use in medicine). In this respect, other aspects of the invention relate to:

(a) a compound of formula Ih, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for use in medicine (or for use as a pharmaceutical);

(b) a pharmaceutical formulation including compound of formula Ih, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(c) a compound of formula Ih, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof,

wherein the compound of formula Ih has the structure

wherein

represents C ₁ -4 alkyl optionally substituted by one or more halo (e.g. fluoro) atoms, and R ³ and B ¹ to B ⁴ are as defined above in relation to compounds of formula I (or la, lb, Ic, Id, le, If or lg);

Embodiments of these aspects of the invention that may be mentioned include those in which:

(1 ) R ^8x represents Ci_ ₂ alkyl optionally substituted by fluoro (to provide, for example, CF ₃ , CHF ₂ or, particularly, methyl);

(2) B ¹ to B ⁴ respectively represent C(R ⁴ ), C(R ⁵ ), C(R ⁶ ) and C(R ⁷ );

(3) R ⁴ represents H or Ci_ ₄ alkyl (e.g. methyl or, particularly, H);

(4) R ⁵ represents, H, d_ ₄ alkyl, -OC(0)R ⁹ⁱ or, particularly, OR ^9a ;

(5) R ⁶ represents H, d_ ₄ alkyl, -OC(0)R ⁹ⁱ or, particularly, OR ^9a ; provided that at least one of R ⁵ and R ⁶ represents OR ^9a (e.g. both of R ⁵ and R ⁶ represent OR ^9a );

(6) R ⁷ represents C ₁ -4 alkyl (e.g. ethyl or methyl) or, particularly, H;

(7) R ^9a represents d-6 alkyl optionally substituted by one or more substituents selected from halo (e.g. fluoro), C ₃ -6 cycloalkyl and CN (e.g. R ^9a represents cyclopropylmethyl, cyanomethyl, / ^' so-propyl or, particularly, methyl);

(8) unless otherwise specified alkyl and cycloalkyl groups may be substituted by one or more fluoro atoms. Thus, in particular embodiments of the invention, the compound of formula I (or Ih) is: (xxxvii) 6,7-dimethoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-quinazolin-4(3/-/)-one,

or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof. For the avoidance of doubt, references herein to compounds of formula I include, where the context permits, references to any of compounds of formula I, la, lb, Ic, Id, le, If, Ig or Ih. Further, references to any of compounds of formula I, la, lb, Ic, Id, le, If, Ig or Ih includes references to such compounds per se, as well as to pharmaceutically acceptable salts or solvates, or pharmaceutically functional derivatives of such compounds.

In accordance with the invention, compounds of formula I may be administered alone (i.e. as a monotherapy, such as a monotherapy of a condition or disorder ameliorated by inhibition of the A _2a receptor). In alternative embodiments of the invention, however, compounds of formula I may be administered in combination with another therapeutic agent (e.g. another therapeutic agent for the treatment of a condition or disorder ameliorated by inhibition of the A _2a receptor).

Thus further aspects of the invention relate to the following.

A compound of formula I, as hereinbefore defined, and another therapeutic agent for use in the treatment of a condition or disorder ameliorated by the inhibition of the A _2a receptor.

In this aspect of the invention, the compound of formula I, as hereinbefore defined, may be administered sequentially, simultaneously or concomitantly with the other therapeutic agent.

A compound of formula I, as hereinbefore defined, for use in the treatment of a condition or disorder ameliorated by the inhibition of the A _2a receptor, wherein the compound of formula I is administered sequentially, simultaneously or concomitantly with another therapeutic agent.

Use of a compound of formula I, as hereinbefore defined, and another therapeutic agent for the preparation of a medicament for the treatment of a condition or disorder ameliorated by the inhibition of the A _2a receptor, wherein the compound of formula I is administered sequentially, simultaneously or concomitantly with the other therapeutic agent.

Use of a compound of formula I, as hereinbefore defined, for the preparation of a medicament for the treatment of a condition or disorder ameliorated by the inhibition of the A _2a receptor, wherein the medicament is administered in combination with another therapeutic agent..

A method of treatment of a disorder or condition ameliorated by antagonising the A _2a receptor, which method comprises the administration of an effective amount of a compound of formula I, as hereinbefore defined, and another therapeutic agent to a patient in need of such treatment. (f) A combination product comprising

(A) a compound of formula I, as hereinbefore defined, and (B) another therapeutic agent,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier. (g) A combination product as defined at (f) above use in the treatment of a condition or disorder ameliorated by the inhibition of the A _2a receptor.

The use of a combination product as defined at (f) above for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by the inhibition of the A _2a receptor.

(i) A method of treatment of a disorder or condition ameliorated by antagonising the A _2a receptor, which method comprises the administration of an effective amount of a combination product as defined at (f) above.

When used herein, the term "another therapeutic agent' includes references to one or more (e.g. one) therapeutic agents (e.g. one therapeutic agent) that are known to be useful for (e.g. that are known to be effective in) the treatment of: a disease of the central nervous system such as depression, a cognitive function disease, a neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses; an attention related disorder (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extra pyramidal syndrome (e.g. dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); a disorder of abnormal movement (such as restless leg syndrome (RLS) and periodic limb movement in sleep (PLMS)); cirrhosis; liver fibrosis; fatty liver; dermal fibrosis (e.g. in diseases such as scleroderma); a sleep disorder; stroke; brain injury or neuroinflammation (e.g. migraine or any disorder or condition caused by ischemia, stroke, head injury or CNS inflammation); and addictive behaviour. In particular embodiments of the invention that may be mentioned, the one or more other therapeutic agents do not exert their therapeutic effect by way of binding to an adenosine receptor (e.g. the A _2a receptor).

Particular other therapeutic agents that may be mentioned include, for example, levodopa (L-DOPA), dopamine agonists (e.g. pramipexole, ropinirole or rotigotine), monoamine oxidase B inhibitors (e.g. selegiline or rasagiline), catechol O-methyl transferase inhibitors (e.g. entacapone or tolcapone), amantadine, acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine or galantamine) and glutamate inhibitors (e.g. memantine).

When used herein, the term "administered sequentially, simultaneously or concomitantly" includes references to:

administration of separate pharmaceutical formulations (one containing the compound of formula I and one or more others containing the one or more other therapeutic agents); and

administration of a single pharmaceutical formulation containing the compound of formula I and the other therapeutic agent(s).

The combination product described above provides for the administration of component (A) in conjunction with component (B), and may thus be presented either as separate formulations, wherein at least one of those formulations comprises component (A) and at least one comprises component (B), or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including component (A) and component (B)).

Thus, there is further provided:

(I) a pharmaceutical formulation including a compound of formula I, as hereinbefore defined and another therapeutic agent, in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation"); and

(II) a kit of parts comprising components:

(i) a pharmaceutical formulation including a compound of formula I, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(ii) a pharmaceutical formulation including another therapeutic agent, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (i) and (ii) are each provided in a form that is suitable for administration in conjunction with the other. Component (i) of the kit of parts is thus component (A) in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier. Similarly, component (ii) is component (B) in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Compounds of formula I may be administered by any suitable route, but may particularly be administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublingually or buccally), rectally, transdermally, nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form. Particular modes of administration that may be mentioned include oral, intravenous, cutaneous, subcutaneous, nasal, intramuscular or intraperitoneal administration

Compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration, a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g. Langer, Science (1990) 249, 1527.

Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice. The amount of compound of formula I in any pharmaceutical formulation used in accordance with the present invention will depend on various factors, such as the severity of the condition to be treated, the particular patient to be treated, as well as the compound(s) which is/are employed. In any event, the amount of compound of formula I in the formulation may be determined non-inventively by the skilled person. Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of formula I may be administered at varying therapeutically effective doses to a patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease. Administration may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula I. In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

As mentioned above, compounds of formula I (or formula la, lb, Ic, Id, le, If, Ig or Ih) may bind selectively to A _2a receptors, and may therefore have utility as diagnostic agents for determining the presence and/or location (either in vivo or in vitro) of adenosine A _2a receptors.

Thus, according to a further aspect of the invention there is provided a method (e.g. an in vivo or, particularly, an ex vivo method) of determining the presence and/or location of adenosine A _2a receptors in a tissue sample, said method comprising contacting the tissue sample with a compound of formula I (or formula la, lb, Ic, Id, le, If, Ig or Ih) and then detecting by a visualising method the location of the compound of formula I in the sample. Visualising methods that may be mentioned include spectroscopic detection methods (e.g. fluorescence detection, magnetic resonance imaging, etc.) or, when the compound of formula I is isotopically labelled or enriched with a radioisotope (such as ³ H, ¹¹ C, ³⁵ S, ¹⁸ F, or ¹²⁵ l), radioactivity detection methods (e.g. alpha-, beta- or gamma-detection by standard autoradiography, phosphor or scintillation methods known to those skilled in the art, or positron emission tomography (which latter method may be employed, for example, when the compound of formula I is isotopically labelled or enriched with ¹¹ C, or, particularly, ¹⁸ F)).

The aspects of the invention described herein (e.g. the above-mentioned compounds, combinations, methods and uses) may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise. Side effects that may be mentioned in this respect include gastrointestinal side effects and various side effects caused by A ₁ receptor antagonism (e.g. cardiovascular side effects, diuresis and CNS side effects (e.g. increased risk of convulsions)).

Compounds of formula I may be known and/or may be commercially available. Other compounds of formula I (e.g. that are not commercially available) may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.

According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which process comprises:

(i) for compounds of formula lb in which the structural unit -A ² ( ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )- or -N(R ¹ )-C(R ³ )= and R ³ represents H or optionally substituted d_ ₆ alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C ₃ -6 cycloalkyl or C ₄ -6 cycloalkenyl, reaction of a compound of formula II,

wherein X' represents OH, NH ₂ or NH ² , A ^2a represents NH or CH ₂ and B ¹ to B ⁴ , R ¹ and R ² are as defined hereinbefore, with a compound of formula III,

wherein R ³ represents H, Ci _-6 alkyl, C ₂ . ₆ alkenyl, C ₂ -6 alkynyl, C ₃ -6 cycloalkyl or C ₄ -6 cycloalkenyl (which latter five groups are optionally substituted as described above in relation to R ³ ), and each R ^alk1 independently represents Ci_ ₆ alkyl, under reaction conditions known to those skilled in the art, for example in a suitable solvent (e.g. pyridine), in the presence of a suitable base (e.g. piperidine) and at a suitable temperature (e.g. from 50 to 80 ^° C), e.g. as described in international patent application WO 2003/088903;

(ii) for compounds of formula I in which the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )- or -C(R ¹ )=N-, reaction of a compound of formula IV,

wherein L ^a represents a suitable leaving group (e.g. bromo or iodo) and A ^1a represents C(R ³ ) or N, and X and B ¹ to B ⁵ , are as defined hereinbefore, with a compound of formula

V,

,alk2

/

O

_/ B-R ¹ V

o

^N ,alk2

R ^a

wherein R ^alk2 represents H or Ci_ ₆ alkyl and R ¹ is as defined hereinbefore and B takes its normal meaning (i.e. boron), under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. dioxane, water or a mixture thereof), in the presence of a suitable base (e.g. sodium carbonate), in the presence of a suitable catalyst (e.g. tetrakis(triphenylphosphine)palladium (0)) and at a suitable temperature (e.g. from room temperature to 120 ^° C), e.g. as described in international patent application WO 2009/053799;

(iii) for compounds of formula lb in which the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )-, R ³ represents H or optionally substituted C _1-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl or C ₄ . ₆ cycloalkenyl, and X represents O or NR ² , reaction of a compound of formula VI,

wherein X' is as defined above, and R ¹ and B ¹ to B ⁴ , are as defined hereinbefore, with a compound of formula VII,

wherein R ³ is as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. R ³ C(0)ONa, wherein R ³ is as defined for formula VII), in the presence of suitable solvent (e.g. dichlorobenzene) and at a suitable temperature (e.g. room temperature to 180 ^° C), e.g. as described in international patent application WO 2003/088903;

(iv) for compounds of formula lb in which the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )-, R ³ represents optionally substituted Ci- ₆ alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C ₃ -6 cycloalkyl or C ₄ . ₆ cycloalkenyl, and X represents O or NR ² reaction of a compound of formula VIII,

wherein L ^b represent a suitable leaving group (e.g. -S(0)CH ₃ , -S(0) ₂ CH ₃ ), X" represents O or N(R ² ), and R ¹ and B ¹ to B ⁴ are as defined hereinbefore, with a compound of formula IX,

(R ^{3 "} ) ₂ CuLi IX

wherein R ³ represents Ci _-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl or C ₄ -6 cycloalkenyl (which latter five groups are optionally substituted as described above in relation to R ³ ), under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. tetrahydrofuran) and at a suitable temperature (e.g. room temperature to 80 ^° C), e.g. as described in international patent application WO 2003/088903;

(v) for compounds of formula lb in which the structural unit -A ² (R ¹ )-A ¹ - represents -N(R ¹ )-C(H)= and X represents N, reaction of a compound of formula X,

wherein B ¹ to B ⁴ , are as hereinbefore defined, with a compound of formula XI,

R ¹ -NH ₂ XI

wherein R ¹ is as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. xylenes) and at a suitable temperature (e.g. room temperature to 80 ^° C); (vi) for compounds of formula lb in which the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )-, R ³ represents H or optionally substituted C^e alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ -6 cycloalkyl or C ₄ -6 cycloalkenyl, and X represents O, reaction of a compound of formula XII,

wherein R ³ ' and R ¹ are as hereinbefore defined, with a compound of formula XIII,

wherein L ^c represents a suitable leaving group (e.g. chloro or bromo) and L ^d represents a suitable leaving group (e.g. fluoro), and B ¹ to B ⁴ are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example by:

(a) enolising the compound of formula XII in the presence of a suitable base (e.g. lithium bis(trimethylsilyl)amide), in a suitable solvent (e.g. THF) at a suitable temperature (e.g. at -78 to -54 ^° C); (b) adding the compound of formula XIII, at a suitable temperature (e.g. -78 ^° C) and optionally in a suitable solvent (e.g. THF);

(c) quenching the reaction mixture and isolating the crude product; and

(d) cyclising the crude product in the presence of a suitable base (e.g. potassium carbonate) in a suitable solvent (e.g. DMF) and at a suitable temperature (e.g. room temperature to 100 ^° C),

e.g. as described in international patent application WO 03/088903;

(vii) for compounds of formula lb in which the structural unit -A ² (R ¹ )-A ¹ - represents -C(R ¹ )=C(R ³ )-, R ³ represents H or optionally substituted alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C ₃ -6 cycloalkyl or C ₄ -6 cycloalkenyl, and X represents O, cyclisation of a compound of formula XIV,

wherein R ³ , X, R ¹ and B ¹ to B ⁴ , are as defined hereinbefore, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF), in the presence of a suitable base (e.g. potassium carbonate) and at a suitable temperature (e.g. room temperature to 140 ^° C), e.g. as described in international patent application WO 03/088903; and (viii) for compounds of formula I in which R ¹ is oxazolyl or imidazolyl, cyclisation of a compound of formula XV,

wherein D ¹ represents O or NH, y and z independently represent 0 or 1 (e.g. when y and z are 0, the side-chain attached to A ² represents -C(D ¹ )-NH-CH ₂ -C(0)H or when y and z are 1 , the side-chain attached to A ² represents -C(D ¹ )-NH-CH(R ⁸ )-C(0)R ⁸ ), and X, A ¹ , A ² , R ⁸ and B ¹ to B ⁵ are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. toluene), a suitable dehydrating agent (e.g. P(0)CI ₃ ), and at a suitable temperature (e.g. from room temperature to 1 1 1 ^° C), e.g. as described in international patent application WO 2009/053799.

Compounds of formula II, VI, VIII, XIII, XIV may be prepared by synthetic methods analogous to those described in international patent application WO 2003/088903, or, alternatively, are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein (or processes described in references contained herein), or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions.

Compounds of formula IV and XV may be prepared by synthetic methods analogous to those described in international patent application WO 2009/053799 or, alternatively, are known in the literature, or may be obtained either by analogy with the processes described herein (or processes described in references contained herein), or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions.

Compounds of formula X are either known in the literature, or may be obtained either by analogy with the processes described herein (or processes described in references contained herein), or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Compounds of formulae III, V, VII, IX, XI, XII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein (or processes described in references contained herein), or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions.

Substituents, such as R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ , in compounds of formula I (or precursors thereto and other relevant intermediates) may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions (e.g. carbonyl bond reductions in the presence of suitable and, if necessary, chemoselective, reducing agents such as LiBH ₄ or NaBH ₄ ), oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. Compounds of formula I may be isolated from their reaction mixtures using conventional techniques.

It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes. Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.

The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3 ^rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).

As used herein, the term "functional groups" includes references to, in the case of unprotected functional groups, hydroxyl, thiol, amino, carboxyl and, in the case of protected functional groups, lower alkoxy, N-, O- or S-acetyl or carboxylic acid ester.

Non-limiting examples which embody certain aspects of the invention will now be described.

Biological Tests The cell lines mentioned below were all purchased from the European Collection of Cell Cultures (ECACC: http://www.hpacultures.org.uk/collections/ecacc.jsp).

Test A

HEK293-hA _2a [ ³ H]-ZM241385 binding assay

Test compounds

All test compounds were prepared as a stock solution of 10 mM in 100% DMSO.

Inhibition binding assays were performed using 2.5 μg of membranes prepared from HEK293 cells transiently transfected with human adenosine A _2a receptor. Membranes were incubated in 50 mM Tris-HCI (pH 7.4) in the presence of varying concentrations of test compound at 25 C for 1 h before termination of the assay by rapid filtration onto GF/C or GF/B grade Unifilter plates using a TomTec cell harvester, followed by 5 x 0.5 ml washes with double distilled H ₂ 0. Nonspecific binding was defined in the presence of 1 μΜ CGS15943. Bound radioactivity was determined by liquid scintillation counting (Trilux Microbeta ^® Counter) and inhibition curves were analysed using a four-parameter logistic equation. IC ₅₀ values were converted to K, values with the Cheng-Prusoff equation using a K _D value of 0.8 nM.

Examples

Where no preparative routes are included, the relevant intermediate is commercially available (e.g. from Interbioscreen, Otava, Biofocus DPI, Princeton Biomolecular Research Inc or ChemDiv Inc).

General Procedures Commercial reagents were utilized without further purification. Room temperature refers to 25-27 °C. Melting points, wherever reported, are uncorrected. IR spectra were taken using KBr and in solid state on the FT-IR, Shimadzu 8400S. Unless otherwise stated, all mass spectra were carried out using ESI conditions on the Shimadzu, LC-MS-2010 EV. ¹ H-NMR spectra were recorded at 400 MHz on a Bruker instrument. Deuterated solvents were used as specified in the detailed experimental section using TMS as an internal reference standard. Chemical shift values are expressed in parts per million, i.e. (δ)- values. The following abbreviations are used for the multiplicity for the NMR signals: s=singlet, b=broad, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=doublet of doublets, dt=double of triplets, m=multiplet. NMR and mass spectroscopy results were corrected to account for background peaks. Specific rotations wherever applicable were measured at room temperature using the sodium D (589 nm). Chromatography refers to column chromatography performed using 60 - 120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. The TLC for monitoring the reaction means the TLC run using the specified mobile phase and the Silica gel F254 as a stationary phase from Merck.

Example 1

The following compounds were obtained from Interbioscreen, Otava, Biofocus DPI, Princeton Biomolecular Research Inc or ChemDiv Inc:

(i) {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl]oxy}acetic acid;

(ii) 6-ethyl-7-[(2-methylprop-2-ene-1-yl)oxy]-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/- chromen-4-one;

(iii) 5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl acetate;

(iv) 7-methoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-6-propyl-4/-/-chromen-4-one;

(v) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-{[(2E)-3-phenylprop-2-en-1-yl]oxy}-4H- chromen-4-one;

(vi) 7-hydroxy-2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(vii) ethyl {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl]oxy}acetate};

(viii) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-propoxy-4H-chromen-4-one;

(ix) 7-butoxy-6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(x) 6-ethyl-7-[(4-fluorobenzyl)oxy]-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xi) 7-[(2-chlorobenzyl)oxy]-6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xii) 7-methoxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xiii) methyl {[5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7- yl]oxy}acetate;

(xiv) 7-hydroxy-8-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-2-(trifluoromethyl)-4H-chromene- 4-one;

(xv) 6-ethyl-7-hydroxy-2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one;

(xvi) methyl {[6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4H-chromen-7-yl]oxy}acetate; (xvii) methyl 2-{[6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7- yl]oxy}propanoate; (xviii) 3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-6-propyl-4/-/-chromen-7-yl acetate;

(xix) i-butyl {[6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl]oxy}acetate;

(xx) 7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-6-pentyl-4/-/-chromen-4-one;

(xxi) 7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-6-propyl-4/-/-chromen-4-one;

(xxii) 2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-6-propyl-4H-chromen-7-yl acetate;

(xxiii) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl (6-amino)hexanoate;

(xxiv) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl 2-aminopropanoate;

(xxv) 2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl acetate;

(xxvi) 6-ethyl-2-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl acetate; (xxvii) 2,6-diethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl propanoate;

(xxviii) 6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl aminoacetate;

(xxix) 8-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl 2-chlorobenzoate;

(xxx) 3-(2-methyl-1 ,3-thiazol-4-yl)-4-oxo-6-propyl-4/-/-chromen-7-yl acetate;

(xxxi) 6,8-dibromo-2-methyl-3-(1 ,3-thiazol-2-yl)quinazolin-4(3/-/)-one;

(xxxii) 6-ethyl-7-methoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one.

General Procedure for the Preparation of 7-Hydroxychromone Derivatives

Step 1 : A resorcinol derivative (39.4 mmol) and (4-methyl-1 ,3-thiazol-2-yl)acetonitrile (5.5 g, 39.4 mmol) were added to borontrifluoride diethyletharate (70 mL, 45% in ether) and the resulting mixture was stirred for 10 minutes at room temperature. Dry HCI gas was then bubbled through the mixture for 6 h at 30-40 °C and the resulting mixture was stirred for 24 hrs at room temperature, diluted with water (300 mL), and then refluxed for 1 hour. The pH of the mixture was then adjusted to pH 3 with ammonia solution and the resulting precipitate was filtered and washed with water (56 mL). The crude compound, Intermediate A, was used in the next step without any further purification.

Step 2: A solution of Intermediate A (32.3 mmol) in pyridine (34 mL) was treated with triethylorthoformate (19.1 g, 129 mmol) and piperidine (1.0 mL) and heated for 4 hrs at 70-80 °C. The reaction was monitored by TLC (hexane/ethyl acetate, 5:5), and upon completion, the mixture was concentrated in vacuo and purified by gradient flash chromatography, affording Product A. (i) 7-Hydroxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one

Step 1 : 1-(2,4-Dihydroxy-6-methylphenyl)-2-(4-methyl-1 ,3-thiazol-2-yl)-ethanone (8.50 g, 80%) was prepared from 5-methylresorcinol monohydrate and 2-(4-methyl-1 ,3-thiazol-2- yl)acetonitrile (5.5 g, 39.4 mmol) according to the general procedure.

Mass spectroscopy: (ESI +ve) 263.9 [M+H] ⁺ .

Step 2: 7-Hydroxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one (1.45 g, 14%) was prepared from 1-(2,4-dihydroxy-6-methyl-phenyl)-2-(4-methyl-1 ,3-thiazol-2-yl)- ethanone (8.50 g, 32.3 mmol, see step 1 above) and triethylorthoformate (19.1 g, 129 mmol) according to the general procedure.

HPLC: 99.2% (284 nm)

Mass spectroscopy: (ESI +ve) 273.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 2.39 (s, 3H), 2.74 (s, 3H), 6.76 (d, 2H), 7.29 (s, 1 H), 9.00 (s, 1 H), 10.82 (s, 1 H).

(ii) 6-Ethyl-7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one

Step-1 : 1-(5-Ethyl-2,4-dihydroxyphenyl)-2-(4-methyl-1 ,3-thiazol-2-yl)-ethanone (1.65 g, 80%) was prepared from 4-ethylresorcinol (1.0 g, 7.23 mmol) and 2-(4-methyl-1 ,3- thiazol-2-yl)acetonitrile (1.0 g, 7.23 mmol) according to the general procedure.

Mass spectroscopy: (ESI +ve) 277.9 [M+H] ⁺ .

Step-2: 6-Ethyl-7-hydroxy-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one (0.65 g, 40%) was prepared from 1-(5-ethyl-2,4-dihydroxyphenyl)-2-(4-methyl-1 ,3-thiazol-2-yl)- ethanone (1.65 g, 5.95 mmol, see step 1 above) and triethyl orthoformate (3.53 g, 23.8 mmol) according to the general procedure. HPLC: 96.6% (289 nm)

Mass spectroscopy: (ESI +ve) 287.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 1.1 1 (t, 3H), 2.48 (s, 3H), 2.55 (q, 2H), 6.90 (s, 1 H), 7.36 (s, 1 H), 7.80 (s, 1 H), 8.94 (s, 1 H).

Example 3

General Procedure for O-Alkylation of 7-Hydroxychromone Derivatives

A solution of Product A (0.73 mmol) in A/,A/-dimethyl acetamide (1 .5 mL) was treated with an alkyl halide (0.80 mmol) and K ₂ C0 ₃ (0.15 g, 0.80 mmol), then stirred for 90 minutes at 90 °C. After completion of the reaction (as determined by TLC using as eluant hexane/ethylacetate, 5:5), the mixture was poured into water (30 mL) and extracted with ethylacetate (20 * 3 mL); the organic extracts were combined, dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude compound was purified by gradient flash chromatography, affording Product B.

(i) 5-Methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-(propan-2-yloxy)-4/-/-chromen-4-one 5-Methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-7-(propan-2-yloxy)-4/-/-chromen-4-one (60 mg, 26 %) was prepared from 7-hydroxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4- one (0.20 g, 0.73 mmol; see Example 2(i) above) and 2-bromopropane (0.10 g, 0.80 mmol) according to the general procedure.

HPLC: 92.7% (265 nm)

Mass spectroscopy: (ESI +ve) 315.9 [M+H] ⁺ .

1H NMR: (400 MHz, CDCI3) δ: 1.56 (d, 6H), 2.50 (s, 3H), 2.92 (s, 3H), 4.64 (m, 1 H), 6.75

(m, 2H), 6.98 (s, 1 H), 8.94 (s, 1 H).

(ii) 7-(Cyclopropylmethoxy)-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one 7-Cyclopropylmethoxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one (0.10 g, 42%) was prepared from 7-hydroxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen- 4-one (0.20 g, 0.73 mmol; see Example 2(i) above) and (bromomethyl)-cyclopropane (0.1 1 g, 0.1 1 mmol) according to the general procedure.

HPLC: 99.9% (283 nm)

Mass spectroscopy: (ESI +ve) 327.9 [M+H] ⁺ .

H NMR: (400 MHz, CDCI3) δ: 0.40 (m, 2H), 0.71 (m, 2H), 1.30 (m, 1 H), 2.52 (s, 3H), 2.89 (s, 3H), 3.88 (d, 2H), 6.76 (m, 2H), 7.00 (s, 1 H), 9.09 (br s, 1 H).

(iii) {[5-Methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl}oxy]-acetonitrile {[5-Methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4-oxo-4/-/-chromen-7-yl}oxy]-acetonitrile (0.08 g, 68%) was prepared from 7-hydroxy-5-methyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-

4-one (0.10 g, 0.36 mmol; see Example 2(i) above) and bromoacetonitrile (0.05 g, 0.40 mmol) according to the general procedure.

HPLC: 99.6% (280 nm)

Mass spectroscopy: (ESI +ve) 312.9 [M+H] ⁺ .

H NMR: (400 MHz, c/ ₆ -DMSO) δ: 2.49 (s, 3H), 2.84 (m, 3H), 5.33 (b, 2H), 7.03 (s, 1 H),

7.27 (m, 2H), 9.12 (s, 1 H).

(iv) 7-Ethoxy-6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one

7-Ethoxy-6-ethyl-3-(4-methyl-1 ,3-thiazol-2-yl)-4/-/-chromen-4-one (80 mg, 47%) was prepared from 1-(2,4-dihydroxy-5-ethylphenyl)-2-(4-methyl-1 ,3-thiazol-2-yl)-ethanone

(0.15 g, 0.52 mmol; see Example 2(ii)) and bromoethane (0.06 g, 0.57 mmol) according to the general procedure.

HPLC: 99.0% (280 nm)

Mass spectroscopy: (ESI +ve) 315.9 [M+H] ⁺ .

1H NMR: (400 MHz, c/ ₆ -DMSO) δ: 1.18 (t, 3H), 1.39 (t, 3H), 2.41 (s, 3H), 2.66 (m, 2H),

4.20 (m, 2H), 7.20 (s, 1 H), 7.32 (s, 1 H), 7.89 (s, 1 H), 9.14 (s, 1 H).

Example 4

Synthesis of Qui

Intermediate B

General Procedure for the Preparation of Benzoxazinones An anthranilic acid derivative (50.7 mmol) was treated with triethyl orthoformate (150 mL, 1.00 mol) neat, at T for 15 min, then the mixture was heated for 5 hrs at 140 °C. After completion of the reaction (as determined by TLC using as eluant ethyl acetate/hexane, 5:5), the mixture was concentrated in vacuo and the crude compound was purified by gradient flash chromatography, eluting with 30% ethyl acetate in hexane to afford the target compound, Intermediate B.

General Procedure for the Preparation of 3-Arylquinazolinones via

Benzoxazinones

Intermediate B Product C

A solution of Intermediate B (4.80 mmol) in xylene (15 mL) was treated with an arylamine (4.80 mmol) at RT for 5 min and the resulting mixture was heated for 5 hrs at 130 °C. After completion of the reaction (as determined by TLC using as eluant ethyl acetate/hexane, 5:5), the mixture was concentrated in vacuo, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The organic layers were combined, dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude compound was purified by gradient flash chromatography, eluting with 10% ethyl acetate in hexane to afford the target compound, Product C.

(i) 6,7-Dimethoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-3/-/-quinazolin-4-one

(a) 6,7-Dimethoxy-4A7-3, 1 -benzoxazin-4-one

6,7-Dimethoxy-4/-/-3,1-benzoxazin-4-one (10 g, 95%) was prepared from 2-amino-4,5- dimethoxybenzoic acid (10.0 g, 50.7 mmol) and triethyl orthoformate (150 mL,1.00 mol) according to the general procedure.

Mass spectroscopy: (ESI +ve) 207.9 [M+H] ⁺ ; (b) 6,7-Dimethoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-quinazolin-4(3A7)-one

6,7-Dimethoxy-3-(4-methyl-1 ,3-thiazol-2-yl)-quinazolin-4(3/-/)-one (90.0 mg, 6%) was prepared from 6,7-dimethoxy-4/-/-3,1-benzoxazin-4-one (1.00 g, 4.80 mmol, see step (a) above) and 2-amino-4-methyl thiazole (0.55 g, 4.80 mmol) according to the general procedure.

HPLC: 99.7% (247 nm)

Mass spectroscopy: (ESI +ve) 303.9 [M+H] ⁺

1H NMR: (400 MHz, DMSO) δ: 2.48 (d, 3H), 4.04 (s, 3H), 4.1 1 (s, 3H), 6.89 (s, 1 H), 7.26 (s, 1 H), 7.60 (s, 1 H), 9.22 (s, 1 H).

Example 5

Compounds of Examples 1 to 4 were found to possess activity in biological tests described above. Biological activity determined by Test A includes IC ₅₀ and pKi values for human A _2a receptor, and compounds of Examples 1 to 5 were found to possess pKi values in excess of 5. For example, the compounds of Examples 1 (ii), 1 (xxviii), 3(ii) and 4(i) were found to possess pKi values for human A _2a receptor of 7.41 , 7.42, 7.42 and 6.00, respectively.

Abbreviations

CoA = co-enzyme A

DCM = dichloromethane

DMAP = N-N-dimethyl-4-aminopyridine

DMF = dimethylformamide

DMSO = dimethylsulfoxide

ES = electro spray

Et ₂ 0 = diethyl ether

EtOAc = ethyl acetate

EtOH = ethanol

LC = liquid chromatography

MeOH = methanol

MS = mass spectrometry

NMR = nuclear magnetic resonance

rt = room temperature

THF = tetrahydrofuran

TLC = thin layer chromatography Prefixes n-, s-, /-, t- and tert- have their usual meanings: normal, secondary, /so, and tertiary.