PYRIMIDINONES DERIVATIVES FOR THE TREATMENT OF ATHEROSCLEROSIS

Abstract: Pyrimidinone compounds of formula (I) are inhibitors of the enzyme Lp-PLA2 and of use in therapy, in particular for treating atherosclerosis.

Description: PYRIMIDINONES DERIVAΗVES FOR THE TREATMENT OF ATHEROSCLEROSIS The present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis. WO 95/00649 (SmithKline Beecham pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase N2 (Lp-PLN2), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it is referred to as LDL-PLN2. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, 6 April 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events. It has been shown that Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholme, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydro lyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholme and an oxidatively modified fatty acid. Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholme, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, lysophosphatidylcholme is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholme and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis. The increased lysophosphatidylcholme content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis. Furthermore, Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid oxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995). Patent applications WO 96/12963, WO 96/13484, WO 96/19451, WO 97/02242, WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKline Beecham pic) disclose inter alia various series of 4-thionyl/sulfmyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2- These are slowly reversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998). Patent applications WO 99/24420 and WO 00/10980 (SmithKline Beecham pic, published after the priority date of the present application) describe a new class of reversible, non-acylating inhibitors of the enzyme Lp-PLA2, in particular a class of pyrimidone compounds. The early 2-(alkylthio)pyrimidin-4-one chemical lead is described in Bioorganic and Medicinal Chemistry Letters, 2000, 10, 395-8. A further class of pyrimidone compounds has now been identified which are inhibitors of the enzyme Lp-PLA2- Accordingly, the present invention provides a compound of formula (I): in which: R 1 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cπ _ι g .alkyl, Cπ _i8)alkoxy, Cπ .ι g)alkylthio, arylC(i_i8)alkoxy, hydroxy, halogen, CN, COR^, carboxy, COOR^, CONR 5 R 6 , NR 5 COR 6 , SO 2 NR 5 R 6 , NR 5 SO2R 6 , NR 5 R 6 , mono to perfluoro- Cπ -4)alkyl and mono to perfluoro-Cπ _4)alkoxy, or, as a single substituent, optionally in combination with a further substituent as hereinbefore defined, CH2COOH or a salt thereof, CH COOR 7 , CH 2 CONR 8 R 9 , CH 2 CN, (CH 2 ) m NR 9 R 10 , (CH ) m OH or (CH2) m OR 8 where m is an integer from 1 to 3; R 2 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cπ .18) a lkyl, Cπ _\ 8.alkoxy, C(l-18) a ^ c y^ tmo ' arylCπ _ιg)alkoxy, hydroxy, halogen, CN, COR^, carboxy, COOR^, CONR 8 R 9 , NR 5 COR 6 , SO 2 NR 8 R 9 , N 5 SO2R 6 , NR 8 R 9 , mono to perfluoro- Cπ _4)alkyl, mono to and arylCπ -4)alkyl; R 3 is an aryl or a heteroaryl group; R 4 is CH 2 SO 2 NR 1 θR 1 !, CONR 12 R 13 , CONHNR 12 R 13 , or COR 12 ; R^ and R6 are independently hydrogen or Cπ -20) al ^y 1 ' f° r instance Cπ -4)alkyl (e.g. methyl or ethyl); R 7 is C(i_4)alkyl or a pharmaceutically acceptable in vivo hydro lysable ester group; R 8 and R 9 which may be the same or different is each selected from hydrogen, C(l-12 ) al Y 1 ' CH2R 14 , CHR 15 CO2H or a salt thereof, or R 8 and R 9 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, Cπ .4.alkyl, Cπ _4)alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; R!0 and R 1 which may be the same or different is each selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, benzyl, or Cπ .12 ) alkyl optionally substituted by Cπ .gλalkoxy, amino, mono- or di- Cπ _6)alkylamino, acylamino, Cπ _6 ) alkoxycarbonyl, carboxy, optionally substituted aryl, optionally substituted heteroaryl, or heterocyclyl, or R*0 and Rl ! together with the N to which they are attached form a 5- to 7 membered ring as hereinbefore defined for R 8 and R 9 ; R 12 and R 13 which may be the same or different is each selected from a value hereinbefore defined for RlO/R.11 with the proviso that R 12 and R 13 are not both simultaneously hydrogen or Cπ .12 ) a lky 1 ' Rl4 is COOH or a salt thereof, COOR 7 , CONR 5 R 6 , CN or CH 2 OH; R 1 ^ is an amino acid side chain such as CH2OH from serine; X is O or S; Y is a group of formula -A 1 -A 2 " A 3 - in which Nl and A 3 each represent a bond or a straight chain or branched Cπ _ιo) a lkyι ene group and A 2 represents a bond or O, S, SO, SO 2 , CO, C=CH 2 , CH=CH, C≡C, CONH, NHCO, or CR 5 R 6 , providing that when A 2 is O, S, SO, SO or CONH, A 3 contains at least two carbon atoms linking the A 2 group and the CH2 group in formula (I); Z is CR 'R 18 where R ' and R 18 are each hydrogen or Cπ _4)alkyl, or R 17 and R 18 together with the intervening carbon atom form a Cπ_6)cycloalkyl ring. Preferably, Z is CH2. Representative examples of R 1 when an aryl group include phenyl and naphthyl. Representative examples of Rl when a heteroaryl group include pyridyl, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl. Preferably R 1 is a 5- or 6- membered, monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatoms, preferably pyridyl, pyrimidyl or pyrazolyl, more preferably, pyrimidyl and optionally substituted by 1 or 2 substituents preferably selected from arylCπ _4)alkyl (e.g. benzyl), Cπ _ι 8)alkyl (e.g. methyl or ethyl), halogen (e.g. chlorine), hydroxy, Cπ _4)alkoxy (e.g. methoxy) and arylC(i_4)alkoxy (e.g. benzyloxy). More preferably, R is pyrimid-5-yl or a 2-oxo-pyrimid-5-yl group, optionally substituted at N-l by (e.g. undecyl, methyl or ethyl), or a 2- C(i_4)alkoxy- or arylCπ _4)alkoxy-pyrimid-5-yl group. Preferably, ZRI is pyrimid-5-ylmethyl or 2-oxo-pyrimid-5-ylmethyl in which the 2-oxo- pyrimid-5-yl moiety is as hereinbefore defined. Preferably X is S. Preferred compounds of formula (I) include those in which Y is a bond, i.e. A 1 , A 2 and A 3 each represent a bond. Other preferred examples of the groups A 1 and A 3 are straight chain Cπ .1 o)alkylene groups. When A 2 is other than a bond, A 1 is preferably a bond. Preferred examples of A 2 when other than a bond include CO. Other preferred examples of Y include CO(CH 2 )6- Representative examples of R 2 when an aryl group include phenyl and naphthyl. Representative examples of R 2 when a heteroaryl group include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl Preferably, R 2 is phenyl optionally substituted by 1, 2 or 3 substituents selected from halogen (e.g. chlorine or fluorine), Cπ _4)alkyl (e.g. methyl or ethyl)or Cπ _4.alkoxy (e.g. methoxy). Further optional substituents include phenyl and benzyl. Representative examples of R 2 YCH2X include 4-fluorobenzylthio group and 4-chlorophenyl-l-oxaheptylthio. Preferably, R 2 YCH2X is 4-fluorobenzylthio group. Preferably, R 3 is phenyl substituted at the 4 position by CONR 12 R 1 . Representative examples of R 1 ^ and R 1 ! include hydrogen, methyl and benzyl, which may be optionally substituted, for instance by fluoro. Representative examples of R 12 and R 13 include heteroaryl such as quinolinyl, thiazolyl, pyrazolyl, and pyrimidinyl which may be optionally substituted; heterocyclyl such as morpholinyl or piperidinyl; hydrogen; alkyl such as methyl, ethyl, propyl, butyl or heptyl which may be optionally substituted; benzyl, and phenyl which may be optionally substituted and R 1 and R 13 may together form a 5- or 6-membered ring such as morpholinyl. Representative substituents for an optionally substituted alkyl group include Cπ .^alkoxy, for instance, methoxy; amino, mono- or di- C^.g^alkylamino, for instance dimethylamino; acylamino, for instance methylcarboxy; Cπ .^alkoxycarbonyl, for instance, (m)ethoxycarbonyl; carboxy; optionally substituted aryl, for instance phenyl, optionally substituted heteroaryl, or heterocyclyl. Representative substituents for an optionally substituted aryl or heteroaryl group include Cπ .β^alkoxycarbonyl, aryl, and aryloxy optionally substituted in the remote aryl ring by halo, mono to perfluoro- Cπ _4)alkoxy, nitro. Pharmaceutically acceptable in vivo hydrolysable ester groups for R ' include those which break down readily in the human body to leave the parent acid or its salt. Representative examples of values of pharmaceutically acceptable in vivo hydrolysable ester groups for R 7 include: -CH(R a )O.CO.R b ; -CH(R a )O.CO.ORC; -CH(R a )CO.NR e R -R d NR e R f ; -CH 2 ORg; CH„ R h / o o & and in which: R a is hydrogen, (Cj-6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted; R D is (Cι-6)alkyl, (Cι-6)alkoxy(Cι-6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl, (Cι-6)alkyl(C3-7)cycloalkyl, l-amino(Cι-6)alkyl, or l-(Cι-6alkyl)amino(Cι-6)alkyl, each of which may be optionally substituted; or R a and R D together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R c is (Cι-6)alkyl, (C3-7)cycloalkyl, (C 1 -6)alkyl(C3-7)cycloalkyl; R d is (Cι-6)alkylene optionally substituted with a methyl or ethyl group; R e and R^ which may be the same or different is each (Cι-6)alkyl; or aryl(Cι-4) alkyl, optionally substituted with e.g. hydroxy; R n is hydrogen, (Cι-6)alkyl or phenyl; R 1 is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cι-6)-alkyl, or (Cι-g)alkoxy; and γl is oxygen or NH; for instance: (a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)ethyl, (l-aminoethyl)carbonyloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenylcarbonyloxymethyl and 4-methoxyphenyl- carbonyloxymethyl; (b) alkoxy/cycloalkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, t- butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl and -ethoxycarbonyloxy ethyl; (c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; (d) acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyl)aminocarbonylmethyl; (e) lactone groups such as phthalidyl and dimethoxyphthalidyl; (f) (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl; and (g) (2-methoxycarbonyl-E-but-2-en-yl)methyl. Representative examples of pharmaceutically acceptable in vivo hydrolysable ester groups for R 7 include: (2-methoxycarbonyl-E-but-2-en-yl)methyl, isobutyryloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenylcarbonyloxymethyl, 4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl, N,N-dimethylaminocarbonylmethyl, and (5- methyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl. It will be appreciated that in some instances, compounds of the present invention may include a carboxy group as a substituent. Such carboxy groups may be used to form salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Preferred salts include alkali metal salts such as the sodium and potassium salts. When used herein, the term 'alkyl' and similar terms such as 'alkoxy' includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n- propyl, wo-propyl, w-butyl, -sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl. When used herein, the term "hydrocarbyl" refers to a group having from 1 to 20 carbon atoms which may be in a straight chain or a branched chain and include a saturated carbocyclic ring having from 3 to 6 carbon atoms and which chain may contain unsaturation (double and/or triple carbon-carbon bonds). When used herein, the term 'aryl' refers to, unless otherwise defined, a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl. When used herein, the term 'heteroaryl' refers to a mono- or bicyclic heteroaromatic ring system comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclic heteroaromatic ring system may include a carbocyclic ring. Representative examples include pyridyl, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridazolyl and pyrazinyl, quinolyl and benzothiazolyl. When used herein, the terms 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively. Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere. Such compounds are found to act as inhibitors of Lp-PLA2 in in vitro assays . Particularly preferred compounds of formula (I) are l-( 4-(4-Nitrophenoxyphenyl)aminocarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid- 5-ylmethyl)pyrimidin-4-one; l-( 4-(4-(trifluromethy)phenoxyphenyl)aminocarbonylphenyl)-2-(4-fluorobenzyl)thio-5- (pyrimid-5-ylmethyl)pyrimidin-4-one; l-( 4-(N-Beιι-zyl-N-heptyl)aminocarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5- ylmethyl)pyrimidin-4-one; l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(2- e oxypyrimid-5-ylmethyl)pyrimidin-4-one; 1 -( 4-(4-(trifluromemyl)phenoxvphenyl)aminocarbonylphenyl)-2-(4-fluorobenzyl)thio-5- (2-ethoxypyrimid-5-ylmethyl)pyrimidin-4-one; l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-2- on-5-yhnethyl)pyrimidin-4-one; 1 -( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonyl phenyl)-2-(4-fluorobenzyl)thio-5- (pyrimid-2-on-5-ylmethyl)pyrimidin-4-one; l-( 4-(N-Be-n-zyl-N-heptylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(N- (carboxyme yl)pyrimid-2-on-5-yhnemyl)pyrimidin-4-one; l-( 4-(4-(trifluromemyl)phenoxyphenyl)aminocarbonylphenyl)-2-(4-fluoroberιzyl)thio-5- (N-(carboxymethyl)pyrirnid-2-on-5-ylmethyl)pyrimidin-4-one; and l-(4-(N-Methyl-N-(4-flurorbenzyl)sulphamoylmethyl)phenyl)- 2-(4-fluorobenzyl) thio- 5-(pyrimid-5-ylmethyl)-2-thiouracil. Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form. When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I). Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis. In a further aspect therefore the present invention provides a compound of formula (I) for use in therapy. The compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, compounds of formula (I) may have a general application in any disorder that involves lipid oxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders. Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis. Accordingly, in a further aspect, the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA 2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid oxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction. Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti- anginal, anti-inflammatory, an anti-hypertension agent or an agent for lowering Lp(a). Examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs. Examples of agents for lowering Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham). A preferred combination therapy will be the use of a compound of the present invention and a statin. The statins are a well known class of cholesterol lowering agents and include atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (also referred to as S- 4522, Astra Zeneca). The two agents may be administered at substantially the same time or at different times, according to the discretion of the physician. A further preferred combination therapy will be the use of a compound of the present invention and an anti-diabetic agent or an insulin sensitiser, as coronary heart disease is a major cause of death for diabetics. Within this class, preferred compounds for use with a compound of the present invention include the PPARgamma activators, for instance G1262570 (Glaxo Wellcome) and also the glitazone class of compounds such as rosiglitazone (Avandia, SmithKline Beecham), troglitazone and pioglitazone. In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats. Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral admimstration contains preferably from 0.1 to 25 mg) of a compound of the formula (I). The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. Compounds of formula (I) may be conveniently prepared by a process which comprises: (a) reacting a compound of formula (II): (II) (in which X, Y, Z, R* and R 2 are as hereinbefore defined) with a compound of formula (III):- R4-R -L1 (III) in which R 3 and R 4 are as hereinbefore defined and L^ is a leaving group e.g. bromine or iodine; (b) for the preparation of a compound of formula (I) in which X is S, reacting a compound of formula (IN): O HΝ R 1 Ν R J R 4 (IN) (in which Rl, R 3 , R 4 , and Z are as hereinbefore defined) with a compound of formula (V): 2 — Y — CH 2 — L 2 (V) (in which Y and R 2 are as hereinbefore defined and L 2 is a leaving group e.g. bromine or iodine); or (c) for the preparation of a compound of formula (I) in which X is O, reacting a corresponding compound of formula (I) in which X is S with a compound of formula (VI): 2 — Y— CH 2 — OH (VI) (in which Y and R 2 are as hereinbefore defined). In process (a) above, the reaction of the compounds of formulae (II) and (III) is advantageously effected at a temperature of 20-100 degrees C, in the presence of sodium hydride in a solvent such as dimethylformamide; or by the compound of formula (II) being pre-treated with tributyl tin chloride in the presence of di-isopropyl ethylamine, for example in a dichloromethane solvent at reflux temperature, followed by addition of (III). In process (b) above, the reaction of the compounds of formulae (IV) and (N) is advantageously effected in the presence of a base such as sodium ethoxide, potassium carbonate, preferably in a solvent such as ethanol or dimethylformamide, or a base such as di-isopropyl ethylamine, preferably in a solvent such as dichloromethane. The reaction in process (c) is conveniently effected in the presence of pyridine at an elevated temperature, containing a catalytic amount of 4-dimethylaminopyridine. The compound of formula (IN) used as starting material in process (b) can be conveniently prepared by reacting a compound of formula (Nil): SCΝ — CO — C — Z — R 1 CH / CH 3 0 (Nil) (in which Rl and Z are as hereinbefore defined) with a compound of formula (NIII): R4-R -ΝH 2 (NIII) (in which R 3 and R 4 are as hereinbefore defined) followed by addition of a base, eg sodium ethoxide. The compound of formula (Nil) used as starting material in the above process can be conveniently prepared by treating a compound of formula (IX): CICO — C — Z — R 1 CH / CH 3 O (IX) with for example potassium thiocyanate eg in a solvent such as acetonitrile. The compound of formula (IX) above can be prepared from the corresponding carboxylic acid for example by treatment with oxalyl chloride.The carboxylic acid can be obtained from a corresponding ester in conventional manner e.g. by basic hydrolysis using sodium hydroxide.The ester can be prepared for example by methylation of the enol group e.g. using dimethyl sulphate in the presence of a base such as potassium carbonate of a compound of formula (X): L>0 2 C Z^ R1 CH HO' (X) (in which Z and Rl are as hereinbefore defined and L 3 is a lower alkyl e.g. methyl group. The compound of formula (X) above can be prepared by treatment of a compound of formula (XI): L 3 O 2 CCH 2 — Z — R 1 (XI) (in which L 3 , Z and Rl are as hereinbefore defined) with for example sodium hydride and ethyl formate. The compound of formula (XI) can be prepared in conventional manner. The present invention will now be illustrated by the following examples. Intermediate 1 - 8-Bromo-l-(4-chIorophenyl)octan-l-one To a stirring suspension of aluminium chloride (33.6g) in dry dichloromethane (474ml) was added 8-bromo-n-octanoyl chloride (67.8g) over lOmin. Chlorobenzene (123ml) was then added over lOmin and the mixture allowed to stir at 25°C for 74h and stood for 64h. The mixture was poured into ice/water (540ml) and diethyl ether (1.3L). The organic layer was removed and was washed with water (540ml), saturated sodium hydrogen carbonate (540ml), water (400ml) and brine (400ml) and dried over magnesium sulfate. Removal of the organic layer under reduced pressure and chromatography of the residue on silica gel using 5% ethyl acetate in hexane gave 8-bromo-l-(4-chlorophenyl)octan-l- one (35.5g). Η-NMR (CDC1 3 ) δ 1.2-1.6 (6H,m), 1.6-1.95 (4H,m), 2.95 (2H,t), 3.42 (2H,t), 7.43 (2H,m) and 7.90 (2H,m). Intermediate 2 - Ethyl 3-(5-pyrimidinyl)acrylate- EtO ^-^ X A mixture of 5-bromopyrimidine (5.93g), ethyl acrylate (5.08g), palladium acetate (0.112g), triphenyl phosphine (0.23g) and triethylamine (4.5g) was stirred at 150°C in a pressure vessel for 6 hours. After cooling overnight, water (50ml) was added to the dark residue, and the product was extracted into toluene. Drying, charcoaling and evaporation gave a pale oil, which was triturated with pet. ether to obtain ethyl 3-(5- pyrimidyl)acrylate (4J8g). Η-NMR (CDC1 3 ) δ 1.36 (3H,t), 4.27 (2H,q), 6.59 (lH,d), 7.62 (lH,d), 8.88 (2H,s), 9.20 (lH,s). Intermediate 3 - Ethyl 3-(5-pyrimidyl)propionate To a solution of ethyl 3-(5-pyrimidyl)acrylate (4.75g) in ethanol (90ml) was added 5% palladium on charcoal (0.2g). The mixture was hydrogenated at an initial pressure of 50 psi, then filtered to remove catalyst and the solvent evaporated. Water was added, and the product extracted into ether. Drying, charcoaling and evaporation gave ethyl 3-(5- pyrimidyl)propionate (2.3g) as a yellow oil. Η-NMR (CDC1 3 ) δ 1.23 (3H,t), 2.69 (2H,t), 2.96 (2H,t), 4.14 (2H,q), 8.635 (2H,s) and 9.09 (lH,s). Intermediate 4 - Methyl 2-(5-pyrimidyl)methyl)-3-methoxy acrylate A mixture of methyl 3-(5-pyrimidyl)propionate (13.1g) and methyl formate (7.1ml) dissolved in dry dimethoxyethane (20ml) was added portionwise to a suspension of sodium hydride (60%, 4.0g) in DME (10ml) under argon. Reaction initiated rapidly and was stirred for a further 2h, diluted with dry diethyl ether (50ml) and filtered. The solid so separated was washed with further diethyl ether (50ml) and was dried in vacuo to give a solid that was dissolved in dry dimethyl formamide (50ml) and potassium carbonate (11.3g) added under argon. A solution of dimethyl sulfate (7.0ml) was then added over 1 hour. The mixture was stirred for 18h and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (200ml) and water (100ml). The aqueous layer was re-extracted with ethyl acetate (2 x 100ml) and the combined ethyl acetate layers washed with brine (50ml) and dried over sodium sulfate. The solvent was removed in vacuo to give methyl 2((5-pyrimidyl)methyl)-3-methoxyacrylate (9.1g). Intermediate 5 - 2-(5-Pyrimidyl)methyl)-3-methoxyacrylic acid- To methyl 2-((5-pyrimidyl)methyl)-3-methoxyacrylate (9.0g) was added, with stirring, a solution of sodium hydroxide (3.5g) in water (43ml) at RT under argon. After 20h, the pH of the solution was brought to 3.5 with concentrated hydrochloric acid. Sonication of the oil so formed gave 2-((5-pyrimidyl)methyl)-3-methoxyacrylic acid (5.4g) as a pale yellow solid. Intermediate 6 - Ethyl 3-(2-methoxypyrimidin-5-yl)acrylate A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethyl acrylate (47.5 ml, 0.439 mol), palladium (II) acetate (1.07 g, 0.0048 mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84 ml) were heated at 135°C with stirring under argon for 12 h. After allowing to cool the solid mass was dissolved in water and ethyl acetate, filtered, and the aqueous phase separated and further extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride, dried (MgSO 4 ) and evaporated. The solid thus obtained was triturated with ether/light petrol (1:3, 350 ml), filtered, washed and dried, yield 52.41 g (63%). 1H-NMR (CDC1 3 ) δ 1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45 (IH, d), 7.58 (IH, d), 8.67 (2H, s); MS (APCI+) found (M+H) = 209; C 10 H 12 N 2 O 3 requires 208. Intermediate 7 - Ethyl 3-(2-methoxypyrimidin-5-yl)propionate A suspension of ethyl 3-(2-methoxypyrimidin-5-yl)acrylate (52.4 g, 0.252 mol) in ethanol (400 ml) and triethylamine (50 ml) was treated with 10% palladium on carbon (3 g) and hydrogenated at 50 psi for 1.75 h. The catalyst was filtered off through hyflo and the filtrate evaporated. The residue was dissolved in dichloromethane, washed twice with saturated aqueous ammonium chloride, dried (MgSO 4 ) and evaporated to an oil, yield 41.2 g (78%). Η-NMR (CDC1 3 ) δ 1.23 (3H, t), 2.61 (2H, t), 2.87 (2H, t), 3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s); MS (APCI+) found (M+H) = 211; C 10 H 14 N 2 O 3 requires 210. Intermediate 8 - 2-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid, mixed methyl/ethyl esters To a stirring suspension of sodium hydride (0.83 g of a 60% dispersion in oil) in anhydrous 1, 2 -dimethoxy ethane (6 ml) was added dropwise a solution of methyl formate (1.54 ml) and ethyl 3-(2-methoxypyrimid-5-yl)propionate (3.5 g) in anhydrous 1,2- dimethoxyethane (6 ml) at such a rate as to maintain the reaction temperature at 25-30°C. After 1 h, ether was added and the precipitated oil allowed to settle. The solution was decanted off and replaced with fresh ether, and the oil slowly solidified. The solid 2- (hydroxymethylene) derivative was filtered, washed and dried, yield 3.8 g. A 1.33 g portion was suspended in dimethyl formamide (10 ml) together with anhydrous potassium carbonate (1.15 g), and a solution of dimethyl sulphate (0.48 ml) in dimethylformamide (10 ml) was added dropwise with stirring over 30 min. After 16 h the solvent was evaporated and the residue treated with water and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO 4 ) and evaporated to give the product as an oil, yield 0.91 g. *H-NMR (CDC1 3 ) δ 1.23 (3H, t), 3.46 (2H, s), 3.69 (3H, s, methyl ester), 3.88 (3H, s), 3.97 (3H, s), 4.16 (2H, q), 7.39 (IH, s), 8.40 (2H, s). 3:2 ratio of methyhethyl esters. MS (APCI+) found (M+l) = 253, 239 (ethyl and methyl esters); C 12 H 16 N 2 O 4 requires 252, C j 1 H 14 N 2 O 4 requires 238. Intermediate 9 - 2-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid A suspension of the mixed esters of intermediate 8 (0.9 g) in 2M aqueous sodium hydroxide (3.6 ml) was stirred at ambient temperature for 16 h to give a clear solution. This was diluted with water, extracted with dichloromethane and evaporated to about half volume, then acidified to pH 3-4 (2M hydrochloric acid) when the product crystallised out. The white solid was filtered, washed with ice-cold water and dried, yield 0.46 g. ! H- NMR (CDC1 3 ) δ 3.43 (2H, s), 3.91 (3H, s), 3.99 (3H, s,), 7.49 (IH, s), 8.42 (2H, s); MS (APCI+) found (M+l) = 225, C 10 H 12 N 2 O 4 requires 224. Intermediate 10- l-(4-Ethoxycarbonylphenyl) -5-(pyrimid-5-ylmethyl)-2-thiouracil 2-((5-pyrimidyl)methyl)-3-methoxyacrylic acid (6.1g) was slurried in dry dichloroethane (50ml) containing a drop of DMF and oxalyl chloride (8.0g) added over 5min. After stirring at RT for 3h, the solvent was removed in vacuo and additional dichloroethane added and again removed in vacuo to give a solid. The solid was slurried in dry acetonitrile (120ml) under Ar and dried, powdered potassium thiocyanate (4.58g) was added in one portion at RT and the mixture was stirred for 18h. Removal of the solvent in vacuo gave a solid which was susspended in dry DMF (117ml) and a portion (96ml) added to to triethylamine (5.4ml) and ethyl 4-aminobenzoate (4.47g). The mixture was stirred for 19h under argon where upon a solution of sodium (1.48g) in ethanol (30ml) was added in one portion. The mixture was heated on an oil bath (bath temp 100°C) for 2h, cooled and the solvent removed under reduced pressure. The residue was dissolved in water (120ml), brought to pH 5 with glacial acetic acid and cooled to 0°C. The solid so formed was filtered and dried in vacuo to give l-(4-Ethoxycarbonylphenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil ] H NMR (CDC1 3 ) δ: 1.41 (t, 3H), 3.69 (s, 2H), 4.39 (q, 2H), 7.30 (s, IH), 7.46 (d, 2H), 8.21 (d, 2H), 8.72 (s, 2H), 9.10 (s, IH). MS (ES+) Found (M+l) = 369; C 18 H 16 N 4 O 3 S requires 368. Intermediate 11 - l-(3-Ethoxycarbonylphenyl)- 5-(pyrimid-5-ylmethyl) -2- thiouracil Prepared analogously to intermediate 10. H NMR (CDC1 3 ) δ: 1.41 (t, 3H), 3.70 (s, 2H), 4.41 (q, 2H), 7.30 (s, IH), 7.35 (m, IH), 7.60 (m, 2H), 7.98 (m, IH), 8.15 (d, IH), 8.71 (s, 2H), 9.10 (s, IH). MS (ES+) Found (M+l) = 369; C 18 H 16 N 4 O 3 S requires 368. Intermediate 12 - l-(5-(Ethoxycarbonyl)fur-2-yl -5-(pyrimid-5-ylmethyl)-2- thiouracil Prepared analogously to intermediate 10. 1H NMR (CDC1 3 ) δ: 1.39 (t, 3H), 3.69 (s, 2H), 4.39 (q, 2H), 6.69 (d, IH), 7.28 (d, IH), 7.41 (s, IH), 8.72 (s, 2H), 9.12 (s, IH). MS (APCI+) Found (M+l) = 359; C 16 H 14 N 4 O 4 S requires 358. Intermediate 13 - l-(4-Ethoxycarbonylphenyl)- 5-(2-ethoxypyrimid-5-yImethyl)-2- thiouracil Prepared analogously to intermediate 10 from intermediate 9. H NMR (CDC1 3 ) δ: 1.41 (m, 6H), 3.60 (s, 2H), 4.4 (m, 4H), 7.23 (d, IH), 7.42 (t, 2H), 7.79 (d, IH), 8.05 (m, IH), 8.18 (d, IH), 8.44 (d, 2H). MS (APCI+) Found (M+l) = 413; C20H20N4O 4 S requires 412. Intermediate 15 - l-(4-benzoylphenyl) -5-(pyrimid-5-ylmethyl)-2-thiouracil Prepared analogously to intermediate 10, used crude. Intermediate 16 - l-(4-(N-MethylsulphamoyImethyl)phenyl)- 5-(pyrimid-5- ylmethyI)-2-thiouracil Prepared analogously to intermediate 10. J H NMR (d 7 DMF) δ: 2.77 (3H,s), 3.79(2H,s), 4.53(2H,s), 6.98(lH,q,J=4.5Hz), 7.61(4H,qj=8.5Hz), 8.05(lH,s), 8.87(2H,s), 9.08(lH,s),12.82(lH,brs). MS (APCI+) Found (M+H) = 404, C 17 H 17 N 5 O 3 S 2 requires 403. Intermediate 17 - l-(3-methoxycarbonylprop-l-oyl -5-(pyrimid-5-ylmethyl)-2- thiouracil Prepared analogously to intermediate 10. ! H NMR (d 7 DMF) δ: 2.88-3.00(2H,m), 3.68(2H,tj=6.5Hz), 3.90(3H,s), 4.00(2H,s),7.98(2H,dj=8.5Hz), 8.33(lH,s), 8.43(2H,d,j=8.5Hz), 9.08(2H,s), 9.28(lH,s), 13.12(lH,brs). MS (APCI+) Found (M+H) ■■ 411, C 20 H 18 N 4 O 4 S requires 410. Intermediate 18 - l-(4-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid- 5-y lmethy l)py rimidin-4-on e A mixture of 1 -(4-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5- ylmethyl)-2-thiouracil (3.06g) 4-flurobenzyl bromide (1.67g) and diisopropylethylamine (1.26g) was stirred overnight at room temperature in dichloromethane (75ml). The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was added directly to a silica gel column. Elution (ethyl acetate to methano ethyl acetate) gave l-(4-carboxylphenyl)-2-(4-fluorobenzyl)thio-5- (pyrimid-5-ylmethyl)pyrimidin-4-one ! H NMR (CDC1 3 ) δ: 1.40 (t, 3H), 3.74 (s, 2H), 4.37 (s, 2H), 4.41 (q, 2H), 6.95 (t, 2H), 7.05 (s, IH), 7.30 (m, 2H), 7.40 (d, 2H), 8.20 (d, 2H), 8.72 (s, 2H), 9.11 (s, IH). MS (APCI+) Found (M+l) = 477; C 25 H 21 FN 4 θ 3 S requires 476. Intermediate 19 - l-(3-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid- 5-ylmethyl)pyrimidin-4-one Prepared from intermediate 11 in an analogous method to intermediate 18. ! H NMR (CDC1 3 ) δ: 1.41 (t, 3H), 3.75 (s, 2H), 4.37 (s, 2H), 4.41 (q, 2H), 6.95 (t, 2H), 7.05 (s, IH), 7.30 (m, 2H), 7.50 (m, IH), 7.60 (t, IH), 7.97 (m, IH), 8.21 (d, IH), 8.72 (s, 2H), 9.10 (s, IH). MS (APCI+) Found (M+l) = 477; C 25 H 21 FN 4 O 3 S requires 476. Intermediate 20 - l-(5-(EthoxycarbonyI)fur-2-yI)-2-(4-fluorobenzyl)thio-5- (pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 12 in an analogous method to intermediate 18. ! H NMR (CDC1 3 ) δ: 1.38 (t, 3H), 3.72 (s, 2H), 4.38 (s, 2H), 4.39 (q, 2H), 6.60 (d, IH), 6.97 (t, 2H), 7.08 (s, IH), 7.20 (d, IH), 7.3 (m, 2H), 8.71 (s, 2H), 9.11 (s, IH). MS (APCI+) Found (M+l) = 467; C 23 H 19 FN 4 O 4 S requires 466. Intermediate 21 - l-(4-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(2- ethoxypyrimid-5-yImethyl)pyrimidin-4-one Prepared from intermediate 13 in an analogous method to intermediate 18. 'H NMR (CDCI 3 ) δ: 1.41 (m, 6H), 3.67 (s, 2H), 4.37 (m, 6H), 6.95 (m, 3H), 7.3 (m, 2H), 7.37 (d, 2H), 8.16 (d, 2H), 8.77 (s, 2H). MS (APCI+) Found (M+l) = 521; C 2 7H25FN 4 O 4 S requires 520. Intermediate 22 - l-(4-EthoxycarbonyIphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-l- yI)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 10 and 1 in an analogous method to intermediate 18. Η NMR (CDCI 3 ) δ: 1.3 (m, 6H), 1.42 (t, 3H), 1.65 (m, 4H), 2.91 (t, 2H), 3.15 (t, 2H), 3.73 (s, 2H), 4.44 (q, 2H), 7.03 (s, IH), 7.4 (m, 4H), 7.88 (d, 2H), 8.20 (d, 2H), 8.71 (s, 2H), 9.10 (s, IH). MS (APCI+) Found (M+l) = 605 / 607; C 32 H 33 ClN 4 O 4 S requires 605. Intermediate 23 - l-(4-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5- ylmethyl)pyrimidin-4-one To a solution of the ester (1.88g) in 1,4 dioxane (30ml) under argon was added a solution of sodium hydroxide (0.16g) in water (8ml). After stirring for 17h at room temperature the solvent was removed under reduced pressure at <25°C. The residue was diluted with water (12ml) extracted with EtO Ac and brought to pH2 with 10% aqueous sodium bisulphate. The solid so formed was filtered and dried in vacuo to give l-(4- Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one as a white solid, m.p.258-262° dec. l K NMR (DMSO-d 6 ) δ: 3.63 (s, 2H), 4.31 (s, 2H), 7.10 (t, 2H), 7.40 (m, 2H), 7.74 (d, 2H), 7.95 (s, IH), 8.10 (d, 2H), 8.77 (s, 2H), 9.01 (s, IH), 13.3 (br s, IH). MS (APCI+) Found (M+l) = 449; C 23 H 17 FN 4 O 3 S requires 448. Intermediate 24 - l-(3-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5- ylmethyl)pyrimidin-4-one Prepared from intermediate 19 in an analogous method to intermediate 23 as a white solid, m.p 157-160°. ! H NMR (DMSO-d 6 ) 8: 3.62 (s, 2H), 4.31 (s, 2H), 7.10 (t, 2H), 7.40 (m, 2H), 7.70 (t, IH), 7.87 (d, IH), 7.94 (s, IH), 8.10 (m, 2H), 8.77 (s, 2H), 9.01 (s, IH), 13.4 (br s, IH). MS (APCI+) Found (M+l) = 449; C 23 H 17 FN 4 O 3 S requires 448. Intermediate 25 - l-(5-Carboxyfur-2-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5- ylmethyl)pyrimidin-4-one Prepared from intermediate 20 in an analogous method to intermediate 23. Η NMR (DMSO-d 6 ) δ: 3.63 (s, 2H), 4.35 (s, 2H), 7.02 (d, IH), 7.12 (t, 2H), 7.34 (m, IH), 7.43 (m, 2H), 8.01 (s, IH), 8.75 (s, 2H), 9.02 (s, IH), 13.63 (br s, IH). MS (ES+) Found (M+l) = 439; C 2 ιH 15 FN 4 θ 4 S requires 438. Intermediate 26 - l-(4-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(2-ethoxypyrimid- 5-ylmethyl)pyrimidin-4-one Prepared from intermediate 21 in an analogous method to intermediate 23. Η NMR (DMSO-d 6 ) δ: 1.31 (t, 3H), 3.53 (s, 2H), 4.31 (m, 4H), 7.10 (t, 2H), 7.41 (m, 2H), 7.71 (d, 2H), 7.87 (s, IH), 8.08 (d, 2H), 8.53 (s, 2H). MS (ES+) Found (M+l) = 493; C 2 5H 21 FN 4 O 4 S requires 492. Intermediate 27 - l-(4-Carboxyphenyl)-2-(8-(4-chlorophenyI)-8-oxooct-l-yl)thio-5- (pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 22 in an analogous method to intermediate 23 as a white solid, m.p 92-96°. 1 H NMR (DMSO-d 6 ) δ: 1.3 (m, 6H), 1.6 (m, 4H), 2.9-3.1 (m, 4H), 3.61 (s, 2H), 7.57 (d, 2H), 7.74 (d, 2H), 7.95 (m, 3H), 8.10 (d, 2H), 8.75 (s, 2H), 9.02 (s, IH) 13.35 (br s, IH). MS (APCI+) Found (M+l) = 577 / 579; C 30 H 29 C1N 4 O 4 S requires 577. All anilines and amines used were obtained commercially and/or are known compounds. Example 1 - l-( 4-Phenylaminocarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid- 5-ylmethyl)pyrimidin-4-one To a suspension of l-(4-carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)- pyrimidin-4-one (O.lg) in dichloromethane (5ml) was added hydroxybenzotriazole (34mg), aniline (22mg) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45mg). After stirring under argon for 65h, the mixture was washed with brine (5ml) and the brine washed with dichloromethane (5ml). The combined organic layers were dried (MgSO 4 ) and the solvent removed under reduced pressure. Chromatography on a varian bond elute SCX column (dichloromethane) gave the desired product. Η NMR (DMSO-d 6 ) δ: 3.65 (s, 2H), 4.32 (s, 2H), 7.12 (m, 3H), 7.35-7.45 (m, 5H), 7.55 (t, IH), 7.72 (d, IH), 8.0 (m, 2H), 8.10 (d, 2H), 8.80 (s, 2H), 9.03 (s, IH), 10.38 (s, IH). MS (APCI+) Found (M+l) = 524; C29H22 FN 5 O 2 S requires 523. Example 2 - l-( 4-(4-(Dimethylamino)but-l-yl)aminocarbonylphenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. Η NMR (CDC1 3 ) δ: 1.7-1.95 (m, 4H), 2.60 (s, 6H), 2.83 (t, 2H), 3.51 (m, 2H), 3.73 (s, 2H), 4.35 (s, 2H), 6.94 (t, 2H), 7.05 (s, IH), 7.3 (m, 4H), 8.05 (d, 2H), 8.71 (s, 2H), 9.09 (s, IH). MS (APCI+) Found (M+l) = 547; C29H3i-FN6θ 2 S requires 546. Example 3 - l-( 4-(3-Methoxyprop-l-yl)aminocarbonylphenyI)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. Η NMR (CDC1 3 ) δ: 1.89 (m, 2H), 3.39 (s, 3H), 3.55 (m, 4H), 3.74 (s, 2H), 4.37 (s, 2H), 6.95 (t, 2H), 7.04 (s, IH), 7.08 (br s, IH), 7.3 (m, 2H), 7.35 (d, 2H), 7.88 (d, 2H), 8.71 (s, 2H), 9.09 (s, IH). MS (APCI+) Found (M+l) = 520; C 27 H26F 5O 3 S requires 519. Example 4 - l-( 4-(2-acetamidoeth-l-yl)aminocarbonylphenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (CDC1 3 ) δ: 1.98 (s, 3H), 3.35-3.55 (m, 4H), 3.74 (s, 2H), 4.35 (s, 2H), 6.95 (t, 2H), 7.20 (s, IH), 7.3 (m, 2H), 7.40 (d, 2H), 7.98 (d, 2H), 8.23 (m, IH), 8.74 (s, 2H), 9.07 (s, IH). MS (APCI+) Found (M+l) = 533; C 27 H25FN 6 O 3 S requires 532. Example 5 - l-( 4-(quinolin-6-ylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5- (pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (CDC1 3 ) δ: 3.76 (s, 2H), 4.35 (s, 2H), 6.95 (t, 2H), 7.21 (s, IH), 7.3 (m, 2H), 7.4 (m, IH), 7.48 (d, 2H), 7.75 (d of d, IH), 8.0-8.25 (m, 4H), 8.54 (m, IH), 8.74 (s, 2H), 8.82 (m, IH), 9.07 (s, IH). MS (APCI+) Found (M+l) = 575; C32H23 FN 6 O 2 S requires 574. Example 6 - l-( 4-(thiazol-2-ylaminocarbonyl)phenyl)-2-(4-fluorobenzyI)thio-5- (pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (CDC1 3 ) δ: 3.75 (s, 2H), 4.37 (s, 2H), 6.96 (t, 2H), 7.04 (d, IH), 7.18 (s, IH), 7.3-7.45 (m, 3H), 7.50 (d, 2H), 8.20 (d, 2H), 8.75 (s, 2H), 9.08 (s, IH). MS (APCI+) Found (M+l) = 531; C 26 H 19 FN 6 O 2 S 2 requires 530. Example 7 - l-( 4-(N-Benzyl-N-methylaminocarbonyl)phenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4- Prepared from intermediate 23 in the same manner as example 1. Η NMR (DMSO-d 6 ) δ: 2.9 (d, 3H), 3.62 (d, 2H), 4.31 (s, 2H), 4.45 (s, IH), 4.69 (s, IH), 7.10 (t, 2H), 7.18 (m, IH), 7.25-7.45 (m, 6H), 7.6-7.75 (m, 4H), 7.95 (m, IH), 8.80 (s, 2H), 9.02 (s, IH). MS (APCI+) Found (M+l) = 552; C 31 H 26 FN 5 O 2 S requires 551. Example 8 - l-( 4-(3-phenylprop-l-ylammocarbonyl)phenyl)-2-(4-fluorobenzyl)thio- 5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. Η NMR (DMSO-d 6 ) δ: 1.85 (m, 2H), 2.64 (t, 2H), 3.29 (q, 2H), 3.63 (s, 2H), 4.30 (s, 2H), 7.10 (t, 2H), 7.15-7.3 (m, 6H), 7.7 (m, 3H), 8.0 (m, 3H), 8.64 (t, IH), 8.77 (s, 2H), 9.03 (s, IH). MS (APCI+) Found (M+l) = 566; C32H28 FN5θ 2 S requires 565. Example 9 - l-( 4-(furan-2-ylmethylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio- 5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (CDC1 3 ) δ: 3.74 (s, 2H), 4.32 (s, 2H), 4.65 (d, 2H), 6.35 (m, 2H), 6.51 (t, IH), 6.94 (t, 2H), 7.08 (s, IH), 7.3 (m, 2H), 7.4 (m, 3H), 7.95 (d, 2H), 8.75 (s, 2H), 9.09 (s, IH). MS (APCI+) Found (M+l) = 528; C 28 H2 2 FN 5 O 3 S requires 527. Example 10 - l-( 4-(4-Phenoxyphenylaminocarbonyl)phenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (DMSO-d 6 ) δ: 3.65 (s, 2H), 4.32 (s, 2H), 7.00 (d, 2H), 7.05 (d, 2H), 7.10 (m, 2H), 7.35-7.45 (m, 4H), 7.55 (t, IH), 7.72 (d, IH), 7.8 (m, 3H), 8.0 (m, IH), 8.1 (d, 2H), 8.80 (s, 2H), 9.04 (s, IH), 10.45 (s, IH). MS (APCI+) Found (M+l) = 616; C 35 H 26 FN 5 O 3 S requires 615. Example 11 - l-( 4-(5-Methoxycarbonylfuran-2-ylaminocarbonyl)phenyl)-2-(4- flu orob enzy l)th io-5-(pyrimid-5-ylmethyl)py rimidin-4-on e Prepared from intermediate 23 in the same manner as example 1. Η NMR (DMSO-d 6 ) δ: 3.63 (s, 2H), 3.81 (s, 3H), 4.32 (s, 2H), 6.63 (d, IH), 7.11 (t, 2H), 7.4 (m, 3H), 7J9 (d, 2H), 7.97 (s, IH), 8.17 (d, 2H), 8.77 (s, 2H), 9.02 (s, IH), 12.12 (br s, IH). MS (ES+) Found (M+l) = 572; C 2 9H22 FN5O 5 S requires 571. Example 12 - l-( 4-(N-BenzyI-N-butyIaminocarbonyl)phenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. Η NMR (DMSO-d 6 ) δ: 0.58 (m, IH), 0.89 (t, 2H), 1.25-1.45 (m, 3H), 1.5-1.65 (m, IH), 3.08 (m, 2H), 3.61 (d, 2H), 4.29 (s, 2H), 4.44 (s, IH), 4.70 (s, IH), 7.09 (t, 2H), 7.25-7.45 (m, 5H), 7.55-7.75 (m, 5H), 7.95 (m, 2H), 8.77 (s, 2H), 9.02 (s, IH). MS (ES+) Found (M+l) = 594; C 34 H32FN 5 O 2 S requires 593. Example 13 - l-( 4-Morpholinocarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid- 5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (DMSO-d 6 ) δ: 3.62 (s, 10H), 4.31 (s, 2H), 7.10 (t, 2H), 7.41 (m, 2H), 7.59 (d, 2H), 7.69 (d, 2H), 7.93 (s, IH), 8.77 (s, 2H), 9.02 (s, IH). MS (ES+) Found (M+l) = 518; C 2 7H24FN 5 O 3 S requires 517. Example 14 - l-( 4-(N-Benzyl-N-(ethoxycarbonylmethyl)aminocarbony) phenyl)-2- (4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (DMSO-d 6 ) δ: 1.21 (t, 3H), 3.61 (d, 2H), 3.98 (m, 2H), 4.12 ( , 2H), 4.30 (s, 2H), 4.52 (s, IH), 4.70 (s, IH), 7.10 (t, 2H), 7.24 (d, IH), 7.25-7.35 (m, 2H), 7.35-7.55 (m, 4H), 7.56 (d, 2H), 7.69 (d, 2H), 7.93 (s, IH), 8.78 (s, 2H), 9.02 (s, IH). MS (APCI+) Found (M+l) = 624; C 3 4H3 0 F 5 O 4 S requires 623. Example 15 - l-( 4-(4-Methoxybenzyl)aminocarbonylphenyl)-2-(4- fluorobenz l)thio-5-φyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. Η NMR (DMSO-d 6 ) δ: 3.63 (s, 2H), 3.73 (s, 3H), 4.30 (s, 2H), 4.42 (d, 2H), 6.89 (d, 2H), 7.10 (t, 2H), 7.25 (d, 2H), 7.40 (m, 2H), 7.71 (d, 2H), 7.94 (s, IH), 8.02 (d, 2H), 8.78 (s, 2H), 9.01 (s, IH), 9.12 (t, IH). MS (APCI+) Found (M+l) = 568; C 31 H 26 FN 5 O 3 S requires 567. Example 16 - l-( 4-(4-Nitrophenoxyphenyl)aminocarbonylphenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. ] H NMR (DMSO-d 6 ) δ: 3.65 (s, 2H), 4.33 (s, 2H), 7.15 (m, 4H), 7.22 (d, 2H), 7.55 (t, IH), 7.75 (t, IH), 7.80 (d, 2H), 7.90 (d, 2H), 7.96 (m, IH), 8.10 (d, 2H), 8.26 (d, 2H), 8.80 (s, 2H), 9.02 (s, IH), 10.52 (s, IH). MS (APCI+) Found (M+l) = 661; C 35 H25FN 6 O 5 S requires 660. Example 17 - l-( 4-(N-Benzyl-N-carboxymethylaminocarbonyI)phenyI)-2-(4- fluorobenzyI)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from the product of example 14 in the same manner as intermediate 23. Η NMR (DMSO-d 6 ) δ: 3.62 (m, 2H), 3.81 (s, IH), 4.01 (s, IH), 4.31 (s, 2H), 4.51 (s, IH), 4.68 (s, IH), 7.10 (t, 2H), 7.20 (d, IH), 7.25-7.45 (m, 6H), 7.57 (m, 2H), 7.68 (m, 2H), 7.94 (m, IH), 8.75 (d, 2H), 9.01 (s, IH). MS (ES+) Found (M+l) = 596; C 32 H 26 FN 5 O 4 S requires 595. Example 18 - l-( 4-(4-(trifluromethy)phenoxyphenyl)aminocarbonylphenyl)-2-(4- fluorobenz l)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. Η NMR (DMSO-d 6 ) δ: 3.63 (d, 2H), 4.32 (s, 2H), 7.05-7.15 (m, 4H), 7.35-7.45 (m, 3H), 7.75 (t, IH), 7.80 (m, 2H), 7.90 (d, 2H), 7.96 (m, IH), 8.10 (m, 2H), 8.26 (d, 2H), 8.78 (s, 2H), 9.02 (s, IH), 10.45 (s, IH). MS (APCI+) Found (M+l) = 700; C 36 H25F 4 N 5 O 4 S requires 699. Example 19 - l-( 4-(4-Acetoxyphenyl)piperazinocarbonylphenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. Η NMR (DMSO-d 6 ) δ: 2.46 (s, 3H), 3.45 (m, 6H), 3.63 (s, 2H), 3.76 (br s, 2H), 4.33 (s, 2H), 7.00 (d, 2H), 7.11 (t, 2H), 7.42 (m, 2H), 7.64 (d, IH), 7.72 (d, 2H), 7.83 (d, 2H), 7.96 (m, 2H), 8.79 (s, 2H), 9.03 (s, IH). MS (APCI+) Found (M+l) = 635; C 35 H 31 FN 6 O 3 S requires 634. Example 20 - l-( 4-(4-Phenylbenzyl)aminocarbonylphenyl)-2-(4-fluorobenzyl)thio- 5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (DMSO-d 6 ) δ: 3.63 (s, 2H), 4.30 (s, 2H), 4.54 (d, 2H), 7.10 (t, 2H), 7.3-7.5 (m, 8H), 7.63 (m, 3H), 7.74 (m, 2H), 7.95 (s, IH), 8.04 (d, 2H), 8.78 (s, 2H), 9.02 (s, IH), 9.25 (t, IH). MS (APCI+) Found (M+l) = 614; C 36 H 28 FN 5 O 2 S requires 613. Example 21 - l-( 4-(N,N-dibenzylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5- (pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1. 'H NMR (DMSO-d 6 ) δ: 3.60 (s, 2H), 4.30 (s, 2H), 4.40 (s, 2H), 4.61 (s, 2H), 7.09 (t, 2H), 7.15 (m, 2H), 7.31 (br s, 5H), 7.35-7.5 (m, 5H), 7.50 (m, IH), 7.67 (m, 3H), 7.93 (s, IH), 8.75 (s, 2H), 9.03 (s, IH). MS (APCI+) Found (M+l) = 628; C37H3oFN 5 O 2 S requires 627. Example 22 - l-( 4-(N-BenzyI-N-heptyI)aminocarbonylphenyI)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 23 in the same manner as example 1 (ref. N-Benzyl-N-heptyl amine, RS.Narma and R Dahiya. Tetrahedron.1998,54,6293). 'H ΝMR (DMSO-d 6 ) δ: 0.75 (m, IH), 0.87 (m, 2H), 1.0 (m, 2H), 1.10 (m, IH), 1.26 (br s, 4H), 1.41 (m, IH), 1.60 (m, 2H), 2.89 (m, IH), 3.08 (m, IH), 3.61 (d, 2H), 4.30 (s, 2H), 4.44 (s, IH), 4.70 (s, IH), 7.09 (t, 2H), 7.3 (m, 2H), 7.35-7.5 (m, 5H), 7.55-7.75 (m, 4H), 7.95 (d, IH), 8.80 (s, 2H), 9.01 (s, IH). MS (APCI+) Found (M+l) = 636; C 3 7H3 8 FΝ 5 O 2 S requires 635. Example 23 - l-( 3-(N-Phenethyl-N-methylaminocarbonyl)phenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 24 in the same manner as example 1. 'H NMR (DMSO-d 6 ) δ: 2.7- 2.95 (m, 4H), 3.06 (s, 3H), 3.63 (s, 2H), 4.29 (d, 2H), 6.94 (d, IH), 7.00 (d, IH), 7.09 (m, 2H), 7.28 (s, 2H), 7.4 (m, IH), 7.55 (m, 2H), 7.65 (m, 2H), 7.72 (d, IH), 7.9 (s, IH), 8.0 (t, IH), 8J5 (s, 2H), 9.02 (s, IH). MS (APCI+) Found (M+l) = 566; C 32 H 28 FN 5 O 2 S requires 565. Example 24 - l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyl)-2-(4- fluorobenzyl)thio-5-(2-ethoxypyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 26 in the same manner as example 1. 'H NMR (CDC1 3 ) δ: 0.85 (m, 3H), 1.08 (m, 3H), 1.3 (m, 4H), 1.41 (t, 3H), 1.45-1.7 (m, 3H), 3.11 (m, IH), 3.46 (m, IH), 3.66 (s, 2H), 4.37 (m, 4H), 4.48 (br s, IH), 4.76 (br s, IH), 6.95 (m, 3H), 7.15 (m, IH), 7.32 (m, 8H), 7.53 (d, 2H), 8.44 (s, 2H). MS (ES+) Found (M+l) = 680; C39H 42 FN 5 O 3 S requires 679. Example 25 - l-( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonyIphenyl)-2-(4- fluorobenzyl)thio-5-(2-ethoxypyrimid-5-ylmethyl)pyrimidin-4-one Prepared from intermediate 26 in the same manner as example 1. H NMR (CDC1 3 ) δ: 1.42 (t, 3H), 3.67 (s, 2H), 4.36 (m, 4H), 6.9-7.1 (m, 7H), 7.20 (d, 2H), 7.3 (m, IH), 7.43 (d, 2H), 7.63 (d, 2H), 8.00 (m, 3H), 8.45 (s, 2H). MS (ES+) Found (M+l) = 744; C 38 H29F 4 N 5 O 5 S requires 743. Example 26 - l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-2-on-5-ylmethyl)pyrimidin-4-one To a solution of l-( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonylphenyl)-2-(4- fluorobenzyl) t-hio-5-(2-ethoxypyrimid-5-ybnethyl)pyrimidin-4-one (0.51 g) in dichloromethane (30ml) was added bromocatachol borane (0.63g). After stirring at room temperature for 42h, water (25ml) was added and the mixture stirred for l/2h. The aqueous layer was washed with dichloromethane (10ml) and the combined organic layers dried and the solvent removed under reduced pressure. Chromatography of the residue on silica gel ( 5%MeOH/DCM to 10% MeOH DCM ) gave 1 -( 4-(N-Benzyl-N- heptylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-2-on-5-ylmethyl)- pyrimidin-4-one. 'H NMR (CDC1 3 ) δ: 0.85 (m, 3H), 1.08 (m, 3H), 1.28 (m, 4H), 1.4-1.7 (m, 3H), 3.11 (m, IH), 3.50 (s, 3H), 4.34 (s, 2H), 4.48 (br s, IH), 4.75 (br s, IH), 6.93 (t, 2H), 7.14 (m, IH), 7.3 (m, 9H), 7.54 (d, 2H), 8.31 (s, 2H). MS (ES+) Found (M+l) = 652; C 3 7H 38 FN 5 O 3 S requires 651. Example 27 - l-( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonyl phenyl)-2-(4- fluorobenzyl)thio-5-(pyrimid-2-on-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to example 26 from the product of example 25. Η NMR (CDC1 3 ) δ: 3.37 (s, 2H), 4.33 (s, 2H), 7.1 (m, 6H), 7.40 (m, 4H), 7.75 (d, 2H), 7.82 (m, 3H), 8.09 (d, 2H), 8.2 (br s, 2H), 10.45 (s, IH), 11.80 (br s, IH). MS (ES+) Found (M+l) = 716; C 36 H 25 F 4 N 5 O 5 S requires 715. Example 28 - l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyl)-2-(4- fluorobenzyl)thio-5-(N-(ethoxycarbonylmethyl)pyrimid-2-on-5-ylmethyl)pyrimidin- 4-one l-( 4-( -Benzyl-N-hep1ylaminocarbonyl)phenyl)-2-(4-fluoroben-zyl)t-hio-5-(pyrimid-2- on-5-ylmethyl)pyrimidin-4-one (0.44g), ethyl bromoacetate (0.113g) and potassium carbonate (0.187g) were stirred togeather in dry DMF at 70 °C for 5 h. The solvent was removed under reduced pressure and the residue partitioned between water (5ml) and ethyl acetate (5ml). The aqueous layer was washed with ethyl acetate ( 3x5ml) and the combined organic layers dried and the solvent removed under reduced pressure. Chromatography of the residue on silica gel (EtO Ac to 5%MeOH/EtOAc ) gave l-( 4-(N- Benzyl-N-heptylaminocarbonyl) phenyl)-2-(4-fluorobenzyl)thio-5-(N- (ethoxycarbonylmemyl)pyrimid-2-on-5-ylmethyl)pyrimidin-4-one. 'H NMR (CDC1 3 ) δ: 0.87 (m, 3H), 1.09 (m, 3H), 1.29 (t, 3H), 1.3 (m, 4H), 1.4-1.7 (m, 3H), 3.12 (m, IH), 3.48 (s, 3H), 4.24 (q, 2H), 4.35 (s, 2H), 4.49 (br s, IH), 4.60 (s, 2H), 4.77 (br s, IH), 6.95 (t, 2H), 7.16 (m, IH), 7.35 (m, 9H), 7.56 (d, 2H), 7.91 (s, IH), 8.50 (s, IH). MS (APCI+) Found (M+l) = 738; C 41 H 44 FN5θ 5 S requires 737. Example 29 - l-( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonylphenyl)-2-(4- fluorobenzyl)thio-5-(N-(ethoxycarbonylmethyl)pyrimid-2-on-5-ylmethyI)pyrimidin- 4-one Prepared in an analogous manner to example 28 from the product of example 27. Η NMR (CDC1 3 ) δ: 1.26 (t, 3H), 3.51 (s, 2H), 4.21 (q, 2H), 4.34 (s, 2H), 4.58 (s, 2H), 6.9- 7.1 (m, 6H), 7.19 (d, 2H), 7.3 (m, 2H), 7.45 (d, 3H), 7.71 (d, 2H), 7.98 (d, IH), 8.10 (d, 2H), 8.52 (d, IH). MS (ES+) Found (M+l) = 802; C 4 oH 31 F 4 N5θ 7 S requires 801. Example 30 - l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyI)-2-(4- fluorobenzyl)thio-5-(N-(carboxymethyl)pyrimid-2-on-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to intermediate 23 from the product of example 28. Η NMR (DMSO-d 6 ) δ: 0.76 (m, 2H), 0.85 (m, 2H), 1.0 (m, 2H), 1.1 (m, IH), 1.24 (s, 4H), 1.41 (m, IH), 1 55 (m, IH), 3.08 (m, IH), 3.3 (m, IH), 3.37 (s, 2H), 4.09 (s, 2H), 4.31 (s, 2H), 4.38 (s, IH), 4.69 (s, IH), 7.10 (t, 2H), 7.17 (m, IH), 7.29 (m, 2H), 7.36 (s, 2H), 7.42 (m, 2H), 7.5-7.65 (m, 3H), 7.67 (d, IH), 7.83 (m, 2H), 8.47 (m, IH). MS (ES+) Found (M+l) = 710; C39H 40 -FN 5 O 5 S requires 709. Example 31 - l-( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonylphenyl)-2-(4- fluorobenzyI)thio-5-(N-(carboxymethyl)pyrimid-2-on-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to intermediate 23 from the product of example 29. 'H NMR (DMSO-d 6 ) δ: 3.41 (s, 2H), 4.33 (s, 2H), 4.52 (s, 2H), 7.12 (m, 6H), 7.4 (m, 4H), 7.82 (d, 2H), 7.85 (m, 3H), 8.05 (d, IH), 8.10 (d, 2H), 8.62 (d, IH), 10.45 (s, IH), 13.15 (br s, IH). MS (ES+) Found (M+l) = 774; C 38 H2 7 F 4 N 5 O 7 S requires 773. Example 32 - l-( 5-(4-(trifluromethyl)phenoxyphenylaminocarbonyl)furan-2-yl)-2- (4-fluorobenzyl)thio-5-(2-ethoxypyrimid-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to example 1 from intermediate 25 . Η NMR (DMSO- d 6 ) δ: 3.65 (s, 2H), 4.36 (s, 2H), 7.05-7.15 (m, 7H), 7.38 (d, 2H), 7.45 (m, 3H), 7.76 (d, 2H), 8.09 (s, IH), 8.75 (s, 2H), 9.04 (s, IH), 10.43 (s, IH). MS (APCI+) Found (M+l) = 9. Example 33 - l-(4-(thiazoI-2-ylaminocarbonyl)phenyl)-2-(8-(4-chlorophenyl)-8- oxooct-l-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to example 1 from intermediate 27 . 'H NMR (DMSO- d 6 ) δ: 1.35 (m, 6H), 1.56 (m, 4H), 2.95-3.05 (m, 4H), 3.62 (s, 2H), 7.6 (m, 4H), 7.72 (d, IH), 7.80 (d, IH), 7.97 (m, 4H), 8.28 (d, IH), 8.77 (s, 2H), 9.02 (s, IH), 12.82 (br s, IH). MS (APCI+) Found (M+l) = 659/661; C 3 3H 31 ClN 6 O3S2 requires 659. Example 34 - l-(4-(4-pyridylaminocarbonyI)phenyl)-2-(8-(4-chIorophenyl)-8- oxooct-l-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to example 1 from intermediate 27 . Η NMR (DMSO- d 6 ) δ: 1.30 (m, 6H), 1.56 (m, 4H), 2.95-3.1 (m, 4H), 3.62 (d, 2H), 7.57 (d, 2H), 7.75 (d, IH), 7.84 (d, IH), 7.9-8.0 (m, 6H), 8.11 (d, IH), 8.15 (d, IH), 8.60 (d, IH), 8.76 (s, 2H), 9.02 (s, IH), 11.10 (br s, IH). MS (APCI+) Found (M+l) = 653/655; C 3 5H33ClN 6 O 3 S requires 653. Example 35 - l-(4-(morpholin-4-ylcarbamoyl)phenyl)-2-(8-(4-chlorophenyl)-8- oxooct-l-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to example 1 from intermediate 27 . Η NMR (DMSO- d 6 ) δ: 1.28 (m, 6H), 1.56 (m, 4H), 2.96 (m, 4H), 3.0 (m, 4H), 3.61 (d, 2H), 3.68 (m, 4H), 7.58 (d, 2H), 7.71 (d, 2H), 7.89 (s, IH), 7.95 (m, 4H), 8.75 (s, 2H), 9.01 (s, IH), 9.70 (s, IH). MS (APCI+) Found (M+l) = 661/663; C 3 4H37ClN 6 O 4 S requires 661. Example 36 - l-(4-morpholinocarbonylphenyI)-2-(8-(4-chlorophenyl)-8-oxooct-l- yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one Prepared in an analogous manner to example 1 from intermediate 27 . Η NMR (DMSO- d 6 ) δ: 1.28 (br s, 6H), 1.56 (m, 4H), 3.0 (m, 4H), 3.29 (s, 4H), 3.60 (s, 2H), 3.65 (m, 4H), 7.6 (m, 4H), 7.69 (d, 2H), 7.91 (s, IH), 7.96 (d, 2H), 8.76 (s, 2H), 9.01 (s, IH). MS (ES+) Found (M+l) = 646/648; C 34 H3 6 ClN 5 O 4 S requires 646. Example 37 - l-(4-(4-methylpiperazinocarbonyl)phenyl)-2-(8-(4-chlorophenyl)-8- oxooct-l-yl)thio-5-(pyrimid-5-ylmethyI)pyrimidin-4-one Prepared in an analogous manner to example 1 from intermediate 27 . Η NMR (DMSO- d 6 ) δ: 1.28 (br s, 6H), 1.56 (m, 4H), 2.33 (s, 3H), 3.0 (m, 4H), 3.30 (s, 4H), 3.60 (s, 2H), 3.65 (m, 4H), 7.58 (m, 4H), 7.69 (d, 2H), 7.91 (s, IH), 7.96 (d, 2H), 8.76 (s, 2H), 9.01 (s, IH). MS (ES+) Found (M+l) = 659/661; C3 5 H 39 ClN 6 O 3 S requires 659. Example 38 - l-(4-benzoylphenyI)-2-(4-fluorobenzyl)thio -5-(pyrimid-5-ylmethyl)- 2-thiouracil Prepared in an analogous manner to intermediate 18 from intermediate 15 . Η NMR (CDC1 3 ) δ: 3.77(2H,s), 4.40(2H,s), 6.97(2H,tj=8.5Hz), 7.06(lH,s), 7.27-7.56(6H,m), 7.65(lH,t,j=7.5Hz), 7.80(2H,dj=7.5Hz), 7.91(2H,d,j=8.5Hz), 8.74(2H,s), 9.11(lH,s). MS (ES+) Found (M+H) = 509, C 29 H 21 N 4 O 2 F requires 508. Example 39 - l-(4-(N-Methyl-N-(4-flurorbenzyl)sulphamoylmethyl)phenyl)- 2-(4- fluorobenzyl) thio- 5-(pyrimid-5-ylmethyl)-2-thiouracil Prepared in an analogous manner to intermediate 18 from intermediate 16 . Η NMR (CDC1 3 ) δ: 2.71(3H,s), 3.75(2H,s), 4.11(2H,s), 4.25(2H,s) 4.35(2H,s), 6,89-7.06(4H,m), 7.18-7.26(5H,m), 7.35(2H,d,j=8.5Hz), 7.54(2H,d,j=8.5Hz), 8.73(2H,s), 9.10(lH,s). MS (ES+) Found (M+H) = 620, C 31 H 27 N 5 O 3 S 2 F 2 requires 619. Example 40 - l-(4-(N-Methylsulphamoylmethyl)phenyl)- 2-(4-fluorobenzyl) thio- 5- (pyrimid-5-ylmethyl)-2-thiouracil Prepared in an analogous manner to intermediate 18 from intermediate 16 . Η NMR (CDC1 3 ) δ: 2.74(3H,dJ=3.5Hz), 3.71(2H,s), 4.27(2H,s), 4.33(2H,s), 5.37(lH,dj=4Hz), 6.89(2H,t,j=7Hz), 7.23-7.35(5H,m), 7.51(2H,d,j=8.5Hz), 8.71(2H,s), 8.95(lH,s). MS (ES+) Found (M+H) = 512, C 24 H 22 N 5 O 3 S 2 F requires 511. Example 41 - l-(3-methoxycarbonylprop-l-oyl )-2-(4-fluorobenzyl) thio- 5- (pyrimid-5-ylmethyl)-2-thiouracil Prepared in an analogous manner to intermediate 18 from intermediate 16 . 'H NMR (CDC1 3 ) δ: 2.79(2H,m), 3.31(2H,m), 3.70(3H,s), 3.74(2H,s), 4.36(2H,s), 6.94(2H,tj=8.5Hz), 7.13(lH,s), 7.25-7.32(2H,m), 7.46(2H,dJ=8.5Hz), 8.11(2H,d,j=8.5Hz), 8.73(2H,s), 9.10(lH,s). MS (ES+) Found (M+H) = 519, C 2 χi 23 N 4 O 4 SF requires 518. Biological Data 1. Screen for Lp-PLN2 inhibition. Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 C in 50mM HEPES (N-2-hydroxyethylpiperazine-N'-2- ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4. (A) Assays were performed in 96 well titre plates. Recombinant LpPLA-2 was purified to homogeneity from baculovirus infected Sf9 cells, using a zinc chelating column, blue sepharose affinity chromatography and an anion exchange column. Following purification and ulrrafiltration, the enzyme was stored at 6mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up using automated robotics to a volume of 170μl. The reaction was initiated by the addition of 20μl of lOx substrate (A) to give a final substrate concentration of 20μM and 10 μl of diluted enzyme to a final 0.2nM LpPLA-2. The reaction was followed at 405 nm and 37 °C for 20 minutes using a plate reader with automatic mixing. The rate of reaction was measured as the rate of change of absorbance. Results The compounds hereinbefore described in the examples were tested as described above and all had IC50 values in the range 10 to 6500nM. Within this, prefered compounds (Examples 16, 18, 22, 24 to 27, 30, 31 and 39) had IC50 values in the range 10 to 40nM.

Claims: Claims 1. A compound of formula (I) : in which: R 1 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cπ -Xg)alkyl, C(1 _ι g^alkoxy, C(i_i8)alkylthio, arylC(i_ι )alkoxy, hydroxy, halogen, CN, COR 5 , carboxy, COOR 5 , CONR 5 R 6 , NR 5 COR 6 , SO 2 NR 5 R 6 , NR 5 SO2R 6 , NR 5 R 6 , mono to perfluoro- Cπ .4.alkyl and mono to perfluoro-Cπ .4. alkoxy, or, as a single substituent, optionally in combination with a further substituent as hereinbefore defined, CH2COOH or a salt thereof, CH 2 COOR 7 , CH 2 CONR 8 R 9 , CH 2 CN, (CH 2 ) m NR 9 R 10 , (CH 2 ) m OH or (CH2) m OR 8 where m is an integer from 1 to 3; R 2 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cπ _ g)alkyl, Cπ .j ^alkoxy, C(i_4)alkyl, mono to perfluoro-Cπ.4. alkoxyaryl, and arylCπ .4)alkyl; R3 is an aryl or a heteroaryl group; R 4 is CH 2 SO 2 NR 1 0R1 1 , CONR 12 R 13 , CONHNR 12 R 13 , or COR 12 ; R 5 and R^ are independently hydrogen or Cπ _20)alkyl, for instance Cπ .4)alkyl (e.g. methyl or ethyl); R is Cπ .4.alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group; R 8 and R 9 which may be the same or different is each selected from hydrogen, C(i_i2 ) alkyl, CH R 14 , CHR 15 CO2H or a salt thereof, or R 8 and R 9 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, Cπ _4)alkyl, Cπ _4)alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; RIO and R* which may be the same or different is each selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, benzyl, or Cπ _i2 ) al yl optionally substituted by amino, mono- or di- Cπ .gλalkylamino, acylamino, Cπ .gΛalkoxycarbonyl, carboxy, optionally substituted aryl, optionally substituted heteroaryl, or heterocyclyl, or R*0 and Rl together with the N to which they are attached form a 5- to 7 membered ring as hereinbefore defined for R 8 and R 9 ; R 2 and R* 3 which may be the same or different is each selected from a value hereinbefore defined for R10/R11 with the proviso that R* 2 and R 3 are not both simultaneously hydrogen or Cπ _\ 2 ) alkyl; R 14 is COOH or a salt thereof, COOR 7 , CONR 5 R 6 , CN or CH 2 OH; R 5 is an amino acid side chain such as CH2OH from serine; X is O or S; Y is a group of formula -A1-A 2~ A 3 - in which A I and A 3 each represent a bond or a straight chain or branched Cπ _ιo)alkylene group and A 2 represents a bond or O, S, SO, SO 2 , CO, C=CH 2 , CH=CH, C≡C, CONH, NHCO, or CR 5 R 6 , providing that when A 2 is O, S, SO, SO 2 or CONH, A 3 contains at least two carbon atoms linking the A 2 group and the CH2 group in formula (I); Z is CR 17 R 18 where R 17 and R 18 are each hydrogen or C(i_4)alkyl, or R 17 and R δ together with the intervening carbon atom form a Cπ-6) c y c l° a lkyl ring. 2. A compound of formula (I) as claimed in claim 1 in which Z is CH2. 3. A compound of formula (I) as claimed in claim 1 or 2 in which R* is an aryl group selected from phenyl and naphthyl or a heteroaryl group which comprises a 5- or 6- membered, monocyclic heteroaryl group comprising 1 or 2 nitrogen heteroatoms. 4. A compound of formula (I) as claimed in any one of claims 1 to 3 in which R 1 is pyrimidyl or pyrazolyl, optionally substituted by 1 or 2 substituents preferably selected from arylCπ _4)alkyl, Cπ .1 g .alkyl, halogen, hydroxy, Cπ .4. alkoxy and arylCπ .4. alkoxy. 5. A compound as claimed in claim 4 in which ZR* is pyrimid-5-ylmethyl or 2-oxo- pyrimid-5 -ylmethyl . 6. A compound of formula (I) as claimed in any one of claims 1 to 5 in which X is S. 7. A compound of formula (I) as claimed in any one of claims 1 to 6 in which Y is a bond. 8. A compound of formula (I) as claimed in any one of claims 1 to 7 in which R 2 is an aryl group selected from phenyl and naphthyl or a heteroaryl group selected from pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl. 9. A compound of formula (I) as claimed in claim 8 in which R 2 is phenyl optionally substituted by halogen 10. A compound of formula (I) as claimed in any one of claims 1 to 9 in which R 3 is phenyl substituted at the 4 position by CONR 12 R 13 . 11. A compound of formula (I) as claimed in any one of claims 1 to 10 in which R 1 and R 1 are independently selected from heteroaryl which may be optionally substituted; heterocyclyl; hydrogen; alkyl which may be optionally substituted; benzyl; and phenyl which may be optionally substituted or R 12 and R 13 together form a 5- or 6-membered ring such as morpholinyl. 12. A compound of formula (I) as claimed in claim 1 and as named in the title of any one of Examples 1 to 41. 13. A compound of formula (I) as claimed in claim 12 selected from: l-( 4-(4-Nitrophenoxyphenyl)aminocarbonylphenyl)-2-(4--l-luorobenzyl)thio-5-(pyrimid- 5 -ylmethyl)pyrimidin-4-one; 1 -( 4-(4-(trifluromemy)phenoxyphenyl)annnocarbonylphenyl)-2-(4-fluorobe-n-zyl)thio-5- (pyrimid-5-yhnemyl)pyrimidin-4-one; l-( 4-(K-Beιιzyl-N-h tyl)aminocarbonylphenyl)-2-(4-fluorobenzyl)tMo-5-(pvrirnid-5- ylmethyl)pyrimidin-4-one; l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(2- ethoxypyrimid-5-ylmethyl)pyrimidin-4-one; l-( 4-(4-(trifluromethyl)phenoxyphenyl)an-unocarbonylphenyl)-2-(4-fluorobenzyl)thio-5- (2-ethoxypyrimid-5-ylmethyl)pyrimidin-4-one; l-( 4-(N-Ben-zyl-N-heptylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-2- on-5-ylmethyl)pyrimidin-4-one; 1 -( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonyl phenyl)-2-(4-fluorobenzyl)thio-5- (pyrimid-2-on-5-ylmethyl)pyrimidin-4-one; l-( 4-(N-Benzyl-N-heptylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(N- (carboxymethyl)pyrimid-2-on-5-ylmethyl)pyrimidin-4-one; l-( 4-(4-(trifluromethyl)phenoxyphenyl)aminocarbonylphenyl)-2-(4-fluorobenzyl)thio-5- (N-(carboxymethyl)pyrimid-2-on-5-ylmethyl)pyrimidin-4-one; and 1 -(4-(N-Methyl-N-(4-flurorbenzyl)sulphamoylmethyl)phenyl)- 2-(4-fluorobenzyl) thio- 5-(pyrimid-5-ylmethyl)-2-thiouracil. 14. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier. 15. A compound of formula (I) as claimed claim 1 for use in therapy. 16. A compound of formula (I) as claimed in claim 1 for use in manufacture of a medicament for the treatment of atherosclerosis. 17. A method of treating atherosclerosis which method comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as claimed in claim 1 and a statin. 18. A process for preparing a compound of formula (I) which comprises: (a) reacting a compound of formula (II): (π) (in which X, Y, Z, R 1 and R 2 are as defined in claim 1) with a compound of formula (m):- R 3 -R 4 -Ll (in) in which R 3 and R 4 are as defined in claim 1 and L 1 is a leaving group; (b) for the preparation of a compound of formula (I) in which X is S, reacting a compound of formula (IN): O HΝ R' R 4 (IN) (in which R 1 , R 3 , R 4 , and Z are as hereinbefore defined) with a compound of formula (N): 2 2 —— ^ Y —— ™ CH-, 2 ,— L 2 (N) (in which Y and R 2 are as hereinbefore defined and L 2 is a leaving group); or (c) for the preparation of a compound of formula (I) in which X is O, reacting a corresponding compound of formula (I) in which X is S with a compound of formula (VI): 2 — Y— CH 2 — OH (VI) (in which Y and R 2 are as hereinbefore defined).

Inventors: FENWICK ASHLEY EDWARD, HICKEY DEIRDRE MARY BERNADETTE, IFE ROBERT JOHN, LEACH COLIN ANDREW, SMITH STEPHEN ALLAN, FENWICK, ASHLEY, EDWARD, HICKEY, DEIRDRE, MARY, BERNADETTE, IFE, ROBERT, JOHN, LEACH, COLIN, ANDREW, SMITH, STEPHEN, ALLAN
Applicants: FENWICK ASHLEY EDWARD, HICKEY DEIRDRE MARY BERNADETTE, IFE ROBERT JOHN, LEACH COLIN ANDREW, SMITH STEPHEN ALLAN, SMITHKLINE BEECHAM PLC, FENWICK, ASHLEY, EDWARD, HICKEY, DEIRDRE, MARY, BERNADETTE, IFE, ROBERT, JOHN, LEACH, COLIN, ANDREW, SMITH, STEPHEN, ALLAN
Application year: 2000
Main classification: C07D239
IPC codes: A61K31, A61K45, A61P3, A61P9, A61P25, A61P29, A61P43, C07D239, C07D401, C07D405, C07D417