GB2363377A

GB2363377A - Novel thieno[2,3-d]pyrimidinediones

Info

Publication number: GB2363377A
Application number: GB0014375A
Authority: GB
Inventors: Anthony Ingall; John Bantick; Matthew Perry
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2000-06-14
Filing date: 2000-06-14
Publication date: 2001-12-19
Anticipated expiration: 2020-06-14
Also published as: GB2363377B; GB0014375D0

Abstract

Thieno[2,3-d]pyrimidinediones of general formula (I) <EMI ID=1.1 HE=38 WI=58 LX=806 LY=823 TI=CF> <PC>wherein R, R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined in the specification, processes for their production, pharmaceutical compositions containing them and their use in therapy, in particular diseases of the respiratory tract, bone and joints, skin, gastrointestinal tract, allograft rejection, systemic and proliferative diseases such as cancer.

Description

100072 2363377 NOVEL COMPOUNDS The present invention relates to

thieno[2,3-d]pyrimidinediones, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

In accordance with the present invention, there is provided a compound of general formula 0 RI 3 2 R -,, N 1 " R 0 N R wherein:

10 R is -C(O)Arl, -QR 4)(R 5)Ar I or Ar 3; Ar I represents a 5- to 10-membered aromatic ring system wherein up to 3 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, oxo, nitro, cyano, NR 6 R 7 and 15 -CH2NR 8 R 9; R I and R 2 each independently represent a hydrogen atom, C 1-6 alkyl, C3- 6 alkenyl, CH2C3-5 cycloalkyl or C3-6 cycloalkyl; 3 represents a group X-R 10 or Ar 2 represents a bond or a group NR 1 2 20 Ar represents a 5- or 6-membered aromatic ring wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by one or more substituents independently selected from C1-4 alkyl, CI-4alkoxy, CI- 4alkylthio, acetyl, halogen, tfifluoromethyl, oxo, hydroxyl, amino (NH2), nitro, cyano and benzyl; 25 R 4 represents a hydrogen atom or C 1 -4 alkyl (e.g. methyl, ethyl, npropyl or n-butyl); R 5 represents a hydrogen atom or hydroxyl group; 100072 R 6 and R 7 each independently represent a hydrogen atom or C 1 -4 alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; R 8 and R 9 each independently represent a hydrogen atom or C 1 -4 alkyl, or 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; R 10 represents CI-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which may be optionally subsituted by one or more substituents independently selected from carboxyl, 12 13 14 15 16 hydroxyl, -C(O)-R, C3-6cycloalkyl, morpholinyl, -NR. R, SR, OR, phenyl 10 and halophenyl, or R 10 represents a C3-6 cycloalkylcarbonyl, -C(O)CH2CN, halophenylcarbonyl or trifluoromethy1carbonyl group; I I represents a hydrogen atom or a C 1 -6 alkyl group; 12 represents piperazinyl optionally substituted by a C 1 -6 alkyl group, or 15 R 12 represents a group -NR 17 R 18; 13 and R 14 each independently represent a hydrogen atom, or a C 1 -4 alkyl, CI-4 hydroxyalkyl or -C(O)-R 19 group, or 13 14 R and R, together with the nitrogen atom to which they are attached, form a 5- to 7-membered saturated heterocyclic ring which may be optionally substituted by one or 20 more substituents independently selected from CI-4 alkyl, hydroxyl and oxo; R 15 and R 16 each independently represent a 5- or 6-membered aromatic ring wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by one or more substituents independently selected from halogen atoms, cyano and C 1 -4 alkyl; 25 R 17 and R 18 each independently represent a hydrogen atom, or a CI-4 alkyl group optionally substituted by one or more substituents independently selected from halogen atoms and hydroxyl; R 19 represents a CI-6 alkyl or C3-6 cycloalkyl group, each of which may be optionally substituted by a hydroxyl group; and 100072 Ar 3 represents acenaphthenyl, indanyl or fluorenyl, each of which may be optionally substituted by one or more substituents independently selected from C1-4 alkyl, C1-4 alkoxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt or solvate thereof.

In the present specification, unless otherwise indicated, an alkyl, alkenyl or alkynyl group or an alkyl, alkenyl or alkynyl moiety in a substituent group may be linear or branched. It 4 5 1 5 will be appreciated that when R represents a group -C(R)(R)Ar, R may represent a hydroxyl group only when Ar I is bonded to -C(R 4)(R 5) through a carbon atom and not a 10 heteroatom. Furthermore, it should be understood that when R represents a group -C(O)Ar I, Ar I is bonded through a carbon atom and not a heteroatom to the moiety -C(O). A halophenyl substituent group is a phenyl group substituted by up to 5 halogen atoms (e.g. fluorine, chlorine, bromine or iodine). If there are two or more halogen atoms, these may be the same or different. A hydroxyalkyl may contain more than one hydroxyl group 3 10 10 15 but a single hydroxyl group is preferred. When R represents X-R, X is a bond and R represents C2-6 alkenyl or C2-6 alkynyl substituted by a hydroxyl or -NR 13 R 14 group, the substituent will not be attached to an unsaturated carbon atom. When R 3 represents 10 11 10 X-R, X is NR and R represents C2-6 alkenyl Or C2-6 alkynyl substituted by a hydroxyl or -NR 13 R 14 group, the substituent will not be attached to an unsaturated carbon 20 atom, and nor is R 10 linked to X through an unsaturated carbon atom.

4 5 1 4 5 R preferably represents -C(R)(R)Ar. R and R preferably both represent a hydrogen atom.

25 Ar I represents a 5- to 10-membered aromatic ring system wherein up to 3 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from C1-4 alkyl (e.g. methyl, ethyl, n-propyl or n- butyl), C1-4 alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, oxo, nitro, cyano, NR 6 R 7 and 100072 -CI-12NR 8 R 9. Preferred substituents to use are C, -4 alkyl, halogen and, especially, trifluoromethyl.

The aromatic ring system may be monocyclic or polycyclic (e.g. bicyclic), examples of 5 which include phenyl, naphthyl, pyrazolyl, thienyl, oxazolyl, imidazolyl, pyridinyl, pyridopyrrolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzoxazolyl, thiazolyl and benzotriazolyl. Preferably, the aromatic ring system is monocyclic and 5- or 6-membered, especially phenyl.

10 R 1 and R 2 each independently represent a hydrogen atom, Cl-6, preferably Cl-4, alkyl (e.g. methyl, ethyl, n-propyl, 1-methylethyl, nbutyl, 2-methylpropyl, n-pentyl or n-hexyl), C3-6, preferably C3-4, alkenyl (e.g. 1 -propenyl, 1 -butenyl, 1 -pentenyl or 1 -hexenyl), CH2C35 cycloalkyl (cyclopropyImethyl, cyclobutyImethyl or cyclopentylmethyl) or C3-6, preferably C5-6, cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

Most preferably R 1 and R 2 each independently represent a Cl-4 alkyl group.

R 6 and R 7 each independently represent a hydrogen atom or Cl -4 alkyl (e.g. methyl, ethyl, n-propyl or n-butyl), or together with the nitrogen atom to which they are attached form a 20 5- to 7-membered saturated heterocyclic ring.

R 8 and R 9 each independently represent a hydrogen atom or Cl-4 alkyl (e. g. methyl, ethyl, n-propyl or n-butyl), or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring.

Ar 2 represents a 5- or 6-membered aromatic ring wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by one or more (e.g. one, two or three) substituents independently selected from Cl-4 alkyl (e.g. methyl, ethyl, n-propyl orn-butyl), Cl-4alkoxy(e.g.

30 methoxy, ethoxy, n-propoxy or n-butoxy), Cl-4 alkylthio (e.g. methylthio, ethylthio, 100072 n-propylthio or n-butylthio), acetyl, halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, oxo, hydroxyl, amino, nitro, cyano and benzyl. A preferred substituent Is C 1-4 alkyl or acetyl. Examples of aromatic rings that can be used include phenyl, furyl, pyridyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, 5 triazolyl and tetrazolyl.

R 10 represents Cl-6, preferably Cl-4, alkyl, C2-6, preferably C2-5, alkenyl or C2-6, preferably C4-6, alkynyl, each of which may be optionally subsituted by one or more (e.g.

one, two or three) substituents independently selected from carboxyl, hydroxyl, 12 13 14 15 16 10 -C(O)-R ' C3-6 cycloalkyl, morpholinyl, -NR R ' SR ' OR ' phenyl and halophenyl, or R 10 represents a C3-6 cycloalkylcarbonyl, C(O)CF12CN, halophenylcarbonyl or trifluoromethylcarbonyl group.

R 11 represents a hydrogen atom or a C 1 -6, preferably C 1 -4, alkyl, especially methyl, group.

R 12 represents piperazinyl optionally substituted by a Cl -6, preferably C 1-4, alkyl, 17 18 especially methyl, group or a group -NR R.

R 13 and R 14 each independently represent a hydrogen atom or a C 1-4 alkyl (especially 20 methyl), Cl -4 hydroxyalkyl (particulary hydroxymethyl or hydroxyethyl) or -Q0)-R 19 13 14 group, or R and R ' together with the nitrogen atom to which they are attached, form a 5- to 7-membered saturated heterocyclic ring which may be optionally substituted by one or more (e.g. one, two or three) substituents independently selected from Cl -4 alkyl (especially methyl), hydroxyl and oxo.

R 15 and R 16 each independently represent a 5- or 6-membered aromatic ring wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by one or more (e.g. one, two or three) substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or 30 iodine), cyano and Cl -4 alkyl (especially methyl). Examples of aromatic rings that can 100072 6 be used include phenyl, furyl, pyridyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, triazolyl and tetrazolyl.

R 17 and R 18 each independently represent a hydrogen atom, or a C 1-4 alkyl (e.g. methyl, 5 ethyl, n-propyl or n-butyl) group optionally substituted by one or more (e.g. one, two or three) substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and hydroxyl.

R 19 represents a Cl-6, preferably Cl-4, and especially Cl-2, alkyl or C36, preferably 10 C3-5, and especially C3 cycloalkyl group, each of which may be optionally substituted by a hydroxyl group.

Ar 3 represents acenaphthenyl, indanyl or fluorenyl, each of which may be optionally substituted by one or more (e.g. one, two or three) substituents independently selected from 15 C1-4 alkyl (e.g. methyl, ethyl, n-propyl or n-butyl), Cl-4 alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), halogen (e.g. fluorine, chlorine, bromine or iodine) and trifluoromethyl.

Preferred compounds of the invention include:

20 5-(3 -Hydroxy-3 -methyl - 1 -butyn yl)- 1 -isobutyl -3 -methyl -6- [2(trifl uoromethyl)benzyl thieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione, 3 -Methyl -5- [3 -(4-meth yl- 1 -piperazinyl)-3-oxo- 1 -propenyll- 1 -(2methylpropyl)-6-[[2 (trifluoromethyl)phenyll methyl] -thieno[2,3-d]pyrimidine-2,4(1 H,3H)- dione, 3 - [1,2,3,4-Tetrahydro3 -methyl- 1 -(2-methylpropyl)-2,4-dioxo-6-[[2- 25 (trifluoromethyl)phenyll methyl] -thieno[2,3-dlpyrimidin-5-yll -2- propenoic acid, 5- [3 -Hydroxy-3 -methyl- 1 -buten yll -3 -methyl - 1 -(2-methylpropyl)-6- [ [2 (trifluoromethyl)phenyll methyl] -thieno [2,3-dlpyrimidine-2,4(1 H,311)dione, (E) and (Z)- 5- [2-eyclopentylethenyll -3 -methyl - 1 -(2methylpropyl) -6- [ [2 (trifluoromethyl)phenyl] methyl] -thieno [2,3 A1 pyrimidine2,4(1 H,3H)- dione, 100072 7 3-Methyl- 1 -(2-methylpropyl)-5-(3-thienyl)-6-[ [2- (trifluoromethyl)phenyll methyl] thieno[2,3-dlpyrimidine-2,4(1 H,3F1)-dione, -(5-Acetyl-2-thienyl)-3 -methyl- 1 -(2-methylpropyl)-6-[[2 (trifluoromethyl)phenyll methyl] -thieno [2,3A1 pyrimidine-2,4(1 H,3H)- dione, 5 5-(Hydroxymethyl) -3 -methyl- 1 -(2-methylpropyl)-6-[[2 (trifluoromethyl)phenyll methyl] -thieno[2,3-dlpyrimidine-2,4(1 H,3H)- dione, 3-Methyl- 1 -(2-methylpropyl)-5-(4-morpholinylmethyl)-6-[[2- (trifluoromethyl)phenyl] methyl] -thieno[2,3-dlpyrimidine-2,4(1 H,3H)- dione, 5- [(4-Hydrox y-3 -methyl- 1 -piperidinyl)methyll -3 -methyl - 1 -(2- methylpropyl)-6-[[2 10 (trifluoromethyl)phenyl]methyl] -thieno [2,3 -dl pyrimidinc-2,4(1 H, 3H)-dione, - [ [(2-Hydrox yethyl)methylamino] methyl] -3 -methyl- 1 -(2methylpropyl)-6-[[2 (trifluoromethyl)phenyl 1 methyl] -thieno [2,3 -d] pyrimidine-2,4(1 H,3H)- dione, 3-Methyl-5-[ [(2-methyl-3-furanyl)thiol methyl] - 1-(2-methylpropyl)-6- [[2 (trifl uoromethyl)phenyl 1 methyl] -thieno [2,3-dlpyrimidine-2,4(1 H,3H)- dione, 15 3-Methyl- 1 -(2-methylpropyl)-5-[(1,3,4-thiadiazol-2-ylthio)methyll-6- [[2- (tri fl uoromethyl)phenyl]methyl 1 -thieno [2,3-d]pyrimidine-2,4(1 H,31--1)-dione, 3-MethyPI -(2-methylpropyl)-5-[[(1 -methyl- 1 H-tetrazol-5-y1)thiol methyl] -6-[ [2 (trifluoromethyi)phenyll methyl] -thieno[2,3-d]pyrimidine-2,4(1 H,3H)- dione, 5- [ [(3 -Chlorophenyl)thiol methyl] - 3 -methyl- 1 -(2-methylpropyl)-6- [[2 20 (tri fl uoromethyl)phenyl]methyl] -thieno [2,3 -d] pyrimidine-2,4(1 H, 3H)-dione, 3-[[1,2,3,4-Tetrahydro-3-methyl- 1-(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyll methyl] -thieno [2,3-dlpyrimidin-5-yllmethoxy] benzonitrile, 1-(Cyclopropylmethyl)-3-methyl-5-(phenoxymethyl)-6-[[2(trifluoromethyl)phenyll methyl] -thieno[2,3-dlpyr-imidine-2,4(1 H,3H)dione, 3-Methyl- 1 -(2-methylpropyl)-5-[(4-oxo- 1 -piperidinyl)methyll-6-[[2 (trifluoromethyl)phenyll methyl] -thieno[2,3-dlpyrimidine-2,4(1 H,31---1)- di onc, 2-Hydroxy-N-[[ 1,2,3,4-tetrahydro-3 -methyl- 1 -(2-methylpropyl)-2,4- dioxo-6-[[2(trifluoromethyl)phenyll methyl] -thieno[2,3-dlpyrimidin-5-yl]methyl] acetamide, 100072 1 -Hydroxy-N-[[ 1,2,3,4-tetrahydro-3-methyl- I -(2-methylpropyl)-2,4- dioxo-6-[[2(trifluoromethyl)phenyllmethyl]-thieno[2,3-d]pyrimidin-5-yllmethyllcyclopropanecarboxamide, 1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-N,3-dimethyl- 1-(2-methylpropyl)-2, 4-dioxo- 5 6-[[2-(trifluo.romethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5- acetamid e, N-(2-Fluoroethyl)- 1,2,3,4-tetrahydro-3-methyl- I -(2-methylpropyl)-2,4- dioxo-6- [ [2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-acetamide, 1,2,3,4-Tetrahydro-3-methyl- I -(2-methylpropyl)-P,2,4-trioxo-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-propanenitrile, 10 3-Methyl- 1-(2-methylpropyl)-5-[(E)-2-phenylethenyl]-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione, Cyclopropanecarboxamide, N-[1,2,3,4-tetrahydro-3-methyl- I -(2methylpropyl)-2,4dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]thieno[2,3-d]pyrimidin-5-yll, 2,2,2-Trifluoro-N-[ 1,2,3,4-tetrahydro-3-methyl-I -(2-methylpropyl)-2,4dioxo-6-[[2- 15 (trifluoromethyl)phenyl]methyl]thieno[2,3-d]pyrimidin-5-yl]-acetamide, 5-(Dimethylamino)-3-methyl- I -(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione, 1,2,3,4-Tetrahydro-3-methyl-I -(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyl]methyti-iiiieno[2,3-d]pyrimidine-5-propanoic acid, 20 5-(3-Hydroxypropyl)-3-methyl- 1-(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyll-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione, 5-[(2-Fluorophenyl)hydroxymethyl]-3-methyl- I -(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione, 5-(2-Fluorobenzoyl)-3-methyl- 1-(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyll-thieno[2,3-d]pyrimidine-2,4(IH,3H)- dione, and their pharmaceutically acceptable salts and solvates.

The present invention further provides a process for the preparation of a compound of formula (1) as defined above which comprises, 3 2 (a) when R represents Ar, reacting a compound of general formula 100072 0 L 1 L 2 R-., N 1 R I. " 0 N S 11 R ID wherein L 1 represents a leaving group (e.g. a halogen atom such as bromine) and R, R 1 and R 2 are defined as in formula (1), with a (hetero) aromatic boronic acid of general formula OH Ar 2 B / 5 OH (m) wherein Ar 2 is defined as in formula (1), in the presence of a palladium (0) species; or 3 10 10 (b) whenR representsX-R ' X represents a bond and R represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in formula (I), reacting a compound of 101 10 formula (11) as defined in (a) above with a compound of general formula (IV), R - H, wherein R 101 represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in R 10 of formula (1) which comprises a terminal carbon-carbon double or triple bond, in the presence of a palladium (11) species and optionally either a copper (I) species or a coordinating ligand (e.g. a triaryl phospine ligand); or 3 10 10 (c) when R represents X-R ' X represents abond and R represents aCI- 6alkyl group optionally substituted as defined in formula (1), reacting a corresponding compound of formula (1) in which R 10 represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in formula (I) with hydrogen in the presence of a palladium or platinum catalyst; 20 or (d) when R 3 represents X-R 10, X represents a bond and R 10 represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in formula (I), oxidising a compound of formula (]D as described in (c) above; or 100072 3 10 10 (c) when R represents X-R ' X represents a bond and R represents a C3-6 cycloalkylcarbonyl, -C(O)CH2CN, halophenylcarbonyl or trifluoromethylcarbonyl group, reacting a compound of formula (H) as defined in (a) above, with a suitable Grignard reagent (e.g. ethyl magnesium bromide) and then with a compound of general 1011 IT 5 formula (V), R - H, wherein R represents a C3-6 cycloalkylcarbonyl, - C(O)CH2CN, halophenylcarbonyl or trifluoromethylcarbonyl group, followed by an oxidation reaction (e.g. using oxalyl chloride and dimethylsulphoxide); or (f) when R 3 represents X-R 10 and X represents a group NR 11, reacting a compound of 10 general formula 0 NHR 11 2 N R 0 N S 1 1 R (VI) 1 2 11 wherein R, R ' R and R are as defined in formula (1), with a compound of general 10 2 2 10 formula (VII), R L ' wherein L represents a leaving group and R is as defined in formula (1); or 3 10 10 (g) when R represents X-R ' X represents a bond and R represents CH2C0211, reacting a compound of general formula 0 C02 H 2 ",j -,! - R-: N 1 R 0 N S 11 R (VIII) wherein R, R 1 and R 2 are as defined in formula (1), with an activating agent (e.g. oxalyl chloride) followed by diazomethane, and causing the resulting intermediate to undergo a 100072 Wolff rearrangement in the presence of a metal oxide catalyst to obtain a compound of formula (1); and optionally after (a), (b), (c), (d), (e), (f) or (g) converting the compound of formula (1) 5 obtained to a further compound of formula (1) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (1).

Process (a) is conveniently carried out in an inert, aprotic solvent such as glyme (1,2 dimethoxyethane) at a temperature in the range from -20'C to 120'C, preferably from 10 50'C to 100'C.

Process (b) is conveniently carried out in an inert, aprotic solvent such as acetonitrile at a temperature in the range from -20'C to I OO'C, preferably from 50'C to I 001C. If the compound of formula (IV) is an alkene, the palladium (11) species is used with a 15 coordinating ligand whereas if the compound of formula (IV) is an alkyne, then the palladium (11) species is used with a copper (1) species. Examples of suitable sources of the palladium and copper species include Pd(PPh3)2CI2 and Cul.

Process (c) may be carried out in an alcoholic solvent such as ethanol at a temperature in 20 the range from I O'C to 50'C, preferably from 20'C to 30'C, in the presence of a catalyst (e.g. Pd-C) under an atmosphere of hydrogen at a pressure of I to 5 bar.

Any suitable oxidant may be used in process (d).

25 In process (e), reaction with the Grignard reagent may be performed in an inert, aprotic solvent such as tetrahydrofuran at a temperature in the range from -20'C to 50'C, preferably from O'C to 25'C. Subsequent reaction with the compound of general formula (V) is conveniently carried out in the same solvent at a temperature in the range from -20'C to 100'C, preferably from O'C to 25'C. The oxidation step may be performed in an 100072 inert solvent (e.g. dichloromethane) with oxalyl chloride and dimethylsulphoxide at a temperature in the range from O'C to 50'C, preferably from 150C to 2011C.

Process (f) is conveniently carried out in an inert, aprotic solvent such as tetrahydrofuran at 5 a temperature in the range from -200C to I OO'C, preferably from O'C to 25'C.

Process (g) may be carried out with a chlorinating agent (e.g. oxalyl chloride) in an inert solvent (e.g. dichloromethane) at a temperature in the range from O'C to 50'C, preferably from 15'C to 20'C, followed by treatment of the activated acid with diazomethane or, 10 preferably, trimethylsily1diazomethane in an inert solvent (e.g. dichloromethane) at a temperature in the range from O'C to 500C, preferably from 15'C to 20'C. The adduct may then be heated in a C 1-8 alcohol (preferably methanol) at a temperature of 50'C to 100'C, in the presence of a catalyst (preferably silver oxide), followed by heating at reflux in an alcoholic solvent (preferably ethanol) containing aqueous mineral acid (preferably 15 HCI).

Compounds of formulae (H) to (VIII) are either commercially available, are well known in the literature or may be prepared easily using known techniques. Compounds of formula (1) (e.g. acids) can be converted to further compounds of formula (1) (e.g. alcohols, which 20 in turn can be converted to aldehydes and ketones) according to known techniques.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or inten-nediate compounds may need to be protected by protecting groups. Thus, 25 the preparation of the compounds of formula (1) may involve, at an appropriate stage, the removal of one or more protecting groups.

The protection and deprotection of functional groups is fully described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 100072 Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (1) above may be converted to a pharmaceutically acceptable 5 salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.

10 Certain compounds of formula (1) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racernates. Tautomers and mixtures thereof also form an aspect of the present invention.

15 Isomers may be resolved or separated by conventional techniques, e.g. chromatography or fractional crystallisation. Enantiomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques (e.g. chiral High Performance Liquid Chromatography (HPLQ). Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which 20 will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) or may be made with achiral starting materials and chiral reagents. All stereoisomers are included within the scope of the invention.

25 The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.

The compounds of the invention are useful because they possess pharmacological activity in human and non-human animals. They are therefore indicated as pharmaceuticals for use 30 in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and 100072 14 hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).

Examples of these conditions are:

5 (1) (the respiratory tract) airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and 10 rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; 15 (2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Beheet's disease, Sjogren's syndrome and systemic sclerosis; (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous 20 dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis; (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, 25 mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema; (5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythernatosus, systemic lupus, 30 erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic 100072 syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; (6) (allograft rejection) acute and chronic following, for example, transplantation of 5 kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; and (7) cancer.

10 Accordingly, the present invention provides a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound of formula (1) or a 15 pharmaceutically acceptable salt or solvate thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and

20 "therapeutically" should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or 25 condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

The invention further provides a method of effecting immunosuppression (e. g. in the 30 treatment of allograft rejection) which comprises administering to a patient a 100072 therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate there of as hereiribefore defined.

The invention still further provides a method of treating, or reducing the risk of, an airways 5 disease (e.g. asthma or COPD) in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary 10 with the compound employed, the mode of administration, the treatment desired and the disorder indicated. However, in general, foreffecting immunosuppression, the daily dosage of the compound of formula (1) will be in the range from 0. 1 mg/kg, preferably from 0.3 mg/kg, more preferably from 0.5 mg/kg and still more preferably from I mg/kg up to and including 30 mg/kg. For the treatment of airways diseases, the daily dosage of is the compound of formula (1) will typically be in the range from 0.001 mg/kg to 30 mg/kg.

The compounds of formula (1) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (1) compound/salt/solvate (active 20 ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably less than 80 %w, e.g. from 0. 10 to 70 %w, and even more preferably less than 50 %w, of active ingredient, all percentages by weight being based on total composition.

Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as hereiribefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

100072 The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in 10 the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.

The invention will now be further explained by reference to the following illustrative examples.

Example 1 5-(3-Hvdroxy-3-meth-vl-l-butvnvl)-l-isobutyl-3-methyl-6-[2(trifluoromethv l)benzvllthienor2,3-dlpyrimidine-2,4(IH,3H)-dione OH 0 OH //y \ 4 N 0 I \ 0, N S F F "I I F 20 a) 6-Bromo-3-methyl-l-(2-methvlprop-vl)-thieno[2,3-dlpyrimidine-2,4(IH, 3H)-di one 100072 18 Bromine (2.79 mi) in dry dichloromethane (25 ml) was added dropwise to a solution of 3 methyl- 1 -(2-methylpropyl)-thieno[2,3-dlpyrimidine-2,4(1 H,3ffi-dione (12.0 g, WO 98/54190) in dry dichloromethane (100 ml) and stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure. The residue was 5 dissolved in ethyl acetate and washed with sodium metabisulfite solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a cream solid. (15. 85g) b) 5-Bromo-6-fkydroxy[2-(trifluoromethyl)phenyllmethyll-3-methyl-l-(2methylpropyl)-thieno[2,3-.efipyrimidine-2,4(1H,3H)-dione Lithium diisopropylamide (2.0M, 14.26 ml) was added dropwise to a solution of 6-bromo 3-methyl-l-(2-methylpropyl)thieno[2,3-dlpyrirnidine-2,4(1H,3H)-dione (8. 22 g) in dry 15 tetrahydrofuran (200 ml) at -78 'C. After 15 minutes, a solution of o- trifluoromethyl benzaldehyde (3.76 ml) in dry tetrahydrofuran (20 ml) was added and the reaction was stirred for 3 hours at -78 'C. The reaction mixture was poured into saturated ammonium chloride solution and allowed to warm to room temperature. The mixture was extracted with ethyl acetate and the combined extracts were washed with water, dried over 20 anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with 15% ethyl acetate in isohexane and the solid filtered off and dried under vacuum to give the sub-title compound as a cream solid (7.59 g).

c) 5-Bromo-l-isobutyl-3-methyl-6-[2-(trifluoromethyl)benzyll-thieno[2,3dlpyrimidine-2,4(1H,3H)-dione -B romo-6{hydroxy[2-(trifluoromethyl)phenyl] methyl} - 1 -isobutyl -3 methyl-thieno [2,3 - d]pyrimidine-2,4(1H,3H)-dione (33.47g) was dissolved in triethyl silane (100 mls) and 30 cooled to OOC before trifluoroacetic acid (100 mls) was added dropwise. After complete 100072 19 addition the resultant thick suspension was diluted by the addition of DCM (100 rnls) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and partitioned between DCM and 50% aqueous sodium hydrogen carbonate. The organic layer was collected, dried over magnesium sulfate, filtered and 5 concentrated in vacuo. The resultant off white solid was stirred vigorously with isohexane for I hour before being collected by filtration to yield 27.286g (84.5%) of the subtitle compound.

MS: [M+Hl+ 476 d) 5-(3-Hydroxy-3-methyl-l-butyn -1-isobutyl-3-methyl-642 (trifluoromethyl)benzyll-thienor2,3-dlplriniddine-2,4(IH,3H)-dion Copper (1) iodide (5 mg) was added to a stirred solution of 6-bromo-3- methyl1-(2 methylpropyl)-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione in a mixture of acetonitrile (2 15 ml), triethylamine (2 ml), dichloro(bistriphenylphosphine) palladium(II) (37 mg) and 2 methyl-3-butyn-2-ol (0.07 ml). The reaction mixture was heated at 95'C for 24 hours.

The mixture was cooled to room temperature, and filtered (hyflo). The filtrate was concentrated in vacuo and purified by biotage eluting with 1: 1 v/v ethyl acetate:hexane to afford the subtitle compound as a pale orange solid, MS: [M+H]+ 479 Example

3-Methyl-5-[3-(4-methyl-l-piperazinyl)-3-oxo-l-propenyll-l-(2methylpropyl)-6 -f[2- 25 (trifluoromethyl)phenvllmethyll-thieno[2,3-dlpyrimidine-2,4(IH,3H)- dione 100072 0 N \--/ N-CH3 N 1 CF3 0 ' 'N S Acryloyl chloride (0.65 ml) was added dropwise to a solution of 1 - methylpiperazine (0.94 ml) and triethylamine (2 ml) in acetonitrile (10 ml) in a pressure tube at O'C and stirred at room temperature for 1 hour. 5 -Bromo-3 -methyl -1-(2-methylpropyl)-6-[[2 5 (trifluoromethyl)phenyll methyl] -thieno [2,3 -d] pyrimidine-2,4(1 H, 3ffi-dione (0.40 g, Example lc)), palladium acetate (0.019 g) and tri-o-tolylphosphine (0. 051g) was added to the pressure tube and the reaction was heated at 70 'C for 21 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-5% ethanol in dichloromethane to 10 give a brown solid. The solid was triturated with acetonitrile to give the title compound as a white powder (0.042 g).

MS(ES') 549[M+HI+ 1 FINNIR(MC13) 8 0.95(6H,d); 2.21(1H,septet); 2.26(3H,s); 2.29-2.39(4H,m); 3.42(3H,s); 15 3.42-3.43(2H,m); 3.72-3.74(2H,m); 3.73(2H,s); 4.41(2H,s); 6.85(1H,d); 7.18(1H,d); 7.38(1H,t); 7.49(1H,t); 7.70(1H,d); 7.92(1H,d).

Example 3

3-[1,2,3,4-Tetrahydro-3-methyl-l-(2-methylprop -2,4-dioxo-6-[[2 Y1) 20 (trifluoromethyl)phen_vllmethyll-thieno[2.,3-dlpyrimidin-5-yll-2- propeno ic acid 100072 OH CF 3 S 0 - N S - / \1 r a) 3-[1,2,3,4-Tetrahvdro-3-methyl-l-(2-methylpropvl)-2,4-dioxo-6-[[2 (trifluoromethyl)phenyll methyl] -thieno[2,3-dl pyrimidin-5-Yll -2propenoic acid, methyl ester 5 5-Bromo-3 -methyl- 1 -(2-methylpropyl)-6- [ [2-(trifluoromethyl)phenyl] methyl] -thieno[2,3 dlpyrimidine-2,4(1H,3H)-dione, (1.0 g, Examplel part c)), methyl acrylate (0.95 ml), tri o-tolylphosphine (0.128 g), palladium acetate (0.047 g) and triethylamine (4 ml) in acetonitrile (20 ml) were stirred in a pressure tube at 7WC for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was concentrated 10 under reduced pressure and purified by flash silica chromatography eluting with a gradient of 0- 1 % ethanol in dichloromethane to give the sub-title compound as a brown foam (0.90 g).

MS (ES') 48 1 [M+H]+ 15 11---INMR(CD03) 3 0.97(6H,d); 2.23 (1 H, septet); 3.42(3H,s); 3.68(2H, d); 3.79(3H,s); 4.40(2H,s); 6.16(1H,d); 7.19(1H,d); 7.40(111j); 7.50(1H,t); 7.72(1H,d); 8. 24(1H,d).

b) 3-F1,2,3,4-Tetrahvdro-3-methvl-l-(2-methylprop^yl)-2,,4-dioxo-6-[[2(trifluoromethvl)phenyllmethyllthieno[2,3-dlpvrimidin-5-YII-2-propenoic acid 20 Lithium hydroxide monohydrate (0.20 g) and water (6 ml) were added to a solution of 3 [ 1,2,3,4-tetrahydro-3 -methyl- 1 -(2-methylpropyl) -2,4-dioxo-6- [ [2 (trifluorometh yl)phen yl] methyl] -thieno [2,3 -d] pyrimidin-5-yl 1 -2- propenoic acid, methyl ester (0.20 g) in tetrahydroftiran (7 ml) and stirred at room temperature for 20 hours. The solution was neutralised to pH7 and extracted with dichloromethane. The organic extracts 100072 were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a white solid (0. 10 g).

5 MS(ES+) 467[M+H]+ HNMR(CDC13) 8 0.94(6H,d); 2.17-2.27(IH,m); 3.42(3H,s); 3.71(2H,d); 4. 42(2H,s); 6.16(l H,d); 7.24(l H,d); 7.4 1 (1 H,t); 7.5 1 (1 H,t); 7.72(l H,d); 8. 36(l H,d).

Using the method of Example 3 part a) the following compounds were prepared:

Example 4

5-f3-Hydroxy-3-methyl-l-butenyll-3-methyl-l-(2-methylpropyl)-6-[[2(trifluorornethyl)phenyllmethyll-thienor2,3-dlpyrimidine-2,4(IH,3H)-dion 0 - OH 1 N 1 \11 - OF CF 3 S 0 N S - / \1 Y Prepared using 5-bromo-3-methylI -(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione and 2-methyl- 3-buten-2-ol. The crude product was purified by flash silica chromatography eluting with a gradient of 0-2% ethanol in dichloromethane to give the title compound as a cream foam 20 (0.20 g).

HNMR(CDC13) 8 0.98(6H,d); 1.36(6H,d); 2,22-2.3 1 (1 H,m); 3.41(3H,s); 3. 72(2H,d); 4.38(2H,s); 5.88(IH,d); 7.04(IH,d); 7.21(IH,d); 7.37(IH,t); 7.48(IH,t); 7. 69(IH,d).

100072 Example 5 (E) and W5-r2-c-yclopentylethenyll-3-methyl-l-(2-methylpropyl)-6-fr2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(IH,3H)-dion N I CF 3 S 0 N Y Prepared using 5-bromo-3-methyl- I -(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione and ????? (please provide details). The crude product was purified by flash silica chromatography eluting with a gradient of 5-20% ethanol in dichloromethane to give the title compound as a yellow oil (0. 17 g).

HNMR(CDC]3) 8 0.94(6H,d); 1.56-1.65(2H,m); 1.84(IH,quintet); 1.84-1,89(IH, m); 15 2.17-2.33(4H,m); 2.86-2.94(IH,m); 3.01-3.06(IH,m); 3.40+3.42(3H,s); 4. 25(2H,d); 4.38+4.26(2H,2xs,); 5.32+5.37(IH,2xs); 5.65-5.72(IH,m); 7.20(IH,d); 7. 36(IH,t); 7.45- 7.49(IH,m); 7.69(IH,d).

100072 Example 6

3-Methvl-l-(2-methylpropyl)-5-(3-thienvl)-6-[[2(trifluoromethvl)phenyllme thyllthieno[2,3-dlpyrimidine-2,4(1H,jffi-dione S ll N 0 1 N 1 S C F 3 r 5 5-Bromo-3 -methyl- 1-(2-methylpropyl)-6- [[2-(trifluoromethyl)phenyl] methyl] -thieno [2,3 dlpyrimidine-2,4(1H,3H)-dione, (0.35 g, Example 1 c)), thiophene-3- boronic acid (0.053 g), barium hydroxide octahydrate (0. 15 g) and tetrakis(triphenylphosphine)palladium (0) (0.0097 g) in ethylene glycol dimethyl ether (6 ml) and water (1 ml) were combined in a scaled vial and stirred with heating at 80 'C for 18 hours. After cooling, the reaction mixture was absorbed onto silica and purified by flash silica chromatography eluting with 25% ethyl acetate in isohexane to give an oil. The oil was triturated with isohexane, filtered and dried under vacuum to give the title compound as a beige solid (0.020 g).

m.p. 113-114 'C 1 H NMR (CDC13) 8 0.97 (d, J = 7.7 Hz, 6H), 2.30 (septet, J = 7.7 Hz, 1 H), 3.36 (s, 3H), 3.76 (d, J = 7.7 Hz, 21-1), 4.21 (s, 2H), 7.13 (dd, J = 1.7, 5.4 Hz, 1 H), 7.20 (dd, J = 1. 3, 2.9 Hz, 1 H), 7.39 (dd, J = 3.1, 5.0 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 7. 67 (d, J = 7.5 Hz, 1 H), 100072 Example

5-(5-Acetvl-2-thien.yl)-3-methyl-l-(2-methylpropyl)-6-[[2(trifluoromethyl)phenyll methyl] -thieno[2,3-úfl pyrimidine-2,4(1H,3H)dione 0 0 S 2, N 1 \ CF3 )," S 0 "N 5 5-Bromo-3-methyl1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenylj methyl] -thieno[2,3d]pyrimidine-2,4(1H,3H)-dione and 5-acetylthiophene-2-boronic acid were reacted by the method of Example 5. The crude product was purified by flash silica chromatography eluting with a gradient of 10-50% ethyl acetate in isohexane to give the title compound as an amber solid (0.054 g).

HNMR(CDC13) 3 0.97(61-1,d); 2.27(1H,septet); 2.57(3H,s); 3.36(3H,s); 3. 74(2H,d); 4.34(21A,s); 7.07(1 H,d); 7.22-7.3 1 (1 H,rn); 7.38(1 H,t); 7.50(1 H,t); 7.61 (1 H,d); 7.69(1 H,d).

15 Example 8

5-(Hvdroxymethyl)-3-methyl-l-(2-methylpropyl)-6-[[2(trifluoromethyl)phenyll methyl] -thieno[2,3-dl pyrimidine-2,4(1H,3H) dione.

0 0 F F 1. F 1 0 N S 100072 26 a) 1,2,3,4-Tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyriniidine-5-carboxylic acid, ethyl ester 5-Bromo-l-isobutyl-3-methyl-6-[2-(trifluoromethyl)benzyl]thieno[2,3d]pyri midine- 5 2,4(IH,3H)-dione (3.6g, Example I c)) was dissolved in tetrahydrofuran (150 ml) at room temperature under an atmosphere of nitrogen. To this solution was added isobutyl magnesium bromide (4.9mls, 2M in tetrahydrofuran). After 30 mins carbon dioxide gas was passed through the reaction and stirred for 2hrs. The reaction mixture was then concentrated in vacuo and redissolved in ethanol (100 ml). Concentrated HCI (I ml) was 10 added and the reaction was heated at reflux for 36hrs. The reaction was then concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The resultant gum was purified via chromotography eluting with 3:2 isohexane/diethyl ether to yield the sub title compound as a brown oil (2.3g) MS: [M+Hl+ = 469 b) 5-(Hydroxymethyl)-3-methyl-l-(2-methylpropyl)-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(IH,3H)-dion 20 The product of step a) (3.64g) was dissolved in dry tetrahydrofuran (100mls) to which LiAIH(O'BU)3 (22mls, IM in tetrahydrofuran) was added. The reaction was heated at 55'C for 18hrs before being quenched with water. The mixture was concentrated in vacuo and partioned between ethyl acetate and dilute HCL The organics were collected and dried over magnesium sulfate, filtered, concentrated in vacuo to yield a white solid. This solid 25 was ultrasonicated with hexane for I hr before being collected via filtration to give the title compound (2.218g) MS: [M+H]+ = 427 111 NMR (DMSO d-6) 5 0.80 (6H, d), 1.88-1.96(IH, m), 2.89 (311, s), 3.32 (211, d), 4.56 30 (2H, s), 4.62 (2H,s), 7.36(IH, d), 7.48(lH, t), 7.64 (IH, t), 7.73(IH, d).

100072 Example 9

3-Metkvl-l-(2-methylpropyl)-5-(4-morpholinylmethyl)-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrim.idine-2,4(1H,3H)-dione r_\0 0 N\_J F F N F F 0 N S The product of Example 8 (100ing) in DCM (3mls) and thionyl chloride (54ul) was stirred for 1 hr under an atmosphere of nitrogen. The mixture was then concentrated in vacuo and stored under a high vacuum for 4 hrs. The resultant residue was redissolved in DCM (I ml) 10 to which morpholine (260ul) was added. The reaction was stirred for 18hrs at room temperature. Water (2m1) was then added to the reaction and the organics were then collected, concentrated in vacuo and purified via chromotography eluting with 0 to 10% methanol in DCM to yield the title compund (59mg).

15 MS: [M+H]+ = 496 H NMR (DNISO d-6) 8 0.85 (6H, d), 2.08-2.16(1 H, m), 2.33 (4H,m), 3.24 (31-1, s), 3.43 (41-1, m), 3.66 (2H, d), 3.86 (2H, s), 4.42 (2H,s), 7.45(1 H, d), 7.48(1 H, t), 7.63 (1 H, 7.7 5 (1 H, d).

20 Using the method of Example 9, the following compounds were prepared:

100072 Example 10

5-[(4-Hydroxy-3 -methyl- 1-piperidin -3-methyl-l-(2-methy ro 1)-64[2-yl)methyll py (trifluoromethvl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(1H,3H)-dione, - 0 0, N, F F N F F S 0 N S Prepared using 3 -methyl -4-piperidinol.

MS: [M+H]'= 524 1 H NMR (DMSO d-6) 8 0.80 (3H, d), 0.86(6H,d), 1.24(2H, m), 1.69(2H,m), 10 2.02(1 H, t), 2.12(1 H, m), 2.71(211, m), 2.88 (1 H, m), 3.24(3H, s), 3.67 (2H, cl), 3.82 (2H, s), 4.43(2H, s), 4.45(1H, d), 7.48(2H, m), 7.63(1H, t),7.75(11A, cl).

Example 11

5- F [(2-HydroxyethyWmethylaminol methyl] -3-methyl-l -(2-methyl propyl)6- [[2 15 (trifluoromethyl)phenyllmethylL-thieno[2,3-dlpyrimidine-2,4(1H,3H)- dion r_\0 0 N, F F N F 0 N 1 S Prepared using 2-(methylamino)-ethanol 100072 MS: [M+H]+ = 484 1H NMR (DMSO d-6) 5 0.86(6H,d), 2.1 I(IH, m), 2.16 QH, s), 3.24(3H, s), 3.48 (2H, m), 3.66 (2H, d), 3.87(2H, s), 4.30(IH, t), 4. 42(2H, s), 7.44(IH, d), (IH, t), 7.63(IH, 5 t), 7.75(IH, d).

Example 1

3-Methyl-5-[[(2-methyl-3-furanyl)thiolmethyll-l-(2-methylpropyl)-6-f[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(IH,3H)-dione 0 P 0 S F F N F 0 N S The product of Example 8 (100mg) in dichloromethane (3mls) and thionyl chloride (54ul) was stirred for I hr under an atmosphere of nitrogen, The mixture was then concentrated in vacuo and stored under a high vacuum for 4 hrs. The resultant residue was redissolved 15 in dichloromethane (I ml) to which a solution of 3-furanthiol, 2- methyl-(2mls, 0. 1 M in tetrahydrofuran), NaOIJ (I ml, 0.2M in water) and triethylamine (I ml, OAM in tetrahydrofuran) was added. After I hr the reaction was allowed to evaporate to dryness before being partitioned between ethyl acetate and HCI (2M). The organics were collected and dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The 20 residue was purified via normal phase preparatory HPLC (High Performance Liquid Chromatography) to give the title compound (56mg).

MS: [M+Hl+ = 523 100072 H NMR (DMSO d-6) 8 0.82(6H, d), 2.05(1 H, m), 3.00(31-1, s), 3.62 (2H, d), 7.41 (1 H, d), 7.46 (1 H, t), 7.62 (1 H, t), 7.79 (1 H, d).

By the method of Example 12 the following compounds were prepared:

Example 13

3-Methyl-l-(2-methylpropyl)-5-[(1,3,4-thiadiazol-2-Ylthio)methyll-6-[[2(trifluoromethyl)phen-yllmethyll-thienor2,3-dlpvrimidine-2,4(1H,3H)-dion ,N N S 0 S \ 1 F F N F S 0 N S 10 Prepared using 1,3,4-thiadiazole-2-thiol.

MS: [M+HI+ = 527 H NMR (DMSO d-6) 3 0.84(6H, d), 2.08(1 H, m), 2.99 (3H, s), 3.612 (2H, d), 7.23(1 H, d), 7.48 (1 H, t), 7.59 (1 H, t), 7.76 (1 H, d).

Example 14

3-Methvl- 1 -(2-methylpropvl)-5-[[(1 -meth-yl- 1H-tetrazol-5-yl)thiol methyl] -64F2 (trifluorometh-yl)phenyllmethyll-thieno[2,3-dlp -2,4(1H,3H)-dion -vrimidine 100072 N N 1 N '.1 0 S F F N 1 1 \ F 0 N S Prepared using 1 -methyl- IH-tetrazole-5-thiol.

MS: [M+H]+ =525 5 'H NMR (DMSO d-6) 3 0.82(6H, d), 2.08(1 H, m), 2.99 (3H, s), 3.61 (2H, d), 7.24 (1 H, d), 7.47 (1 H, t), 7.59 (1 H, t), 7.68 (1 H, d).

Example 15

5- f [(3-Chlorophenvl)thiol methyl] -3-methyl- 1 -(2-methylpropyl)-6- [ [2 10 (trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(1H,3H)dione 7 \11 cl 0 F F N 0'-N 1 S Prepared using 3-chloro-benzenethiol.

MS: [M+HI+ = 553 100072 32 H NMR (DMSO d-6) 3 0.86 (6H, d), 2.08 (IH, td), 3.25 (3H, s), 3.63 (21-1, d), 4.08 (211, s), 4.59 (2H, s), 7.22-7.74 (8H, m).

Example 16

5 3-[[1,2,3,4-Tetrahvdro-3-methyl-l-(2-methylpropyl)-2,,4-dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thienor2,,3-dlpyrimidin-5-yllmethoxy]benzonitrile N 0 0 F F N F 0 N The product of Example 8 (100mg), triphenyl phosphine(O.35mmol), 10 diethyl azodicarboxylate (DEAD) (0.35mmol), 2,6-di'butyl phenol (0. 35mmol) and 3-hydroxy-benzonitrile (0.47mmol) were dissolved in tetrahydrofuran (3m)). The reaction was allowed to stand under an atmosphere of nitrogen for 72hrs before being allowed to evaporate to dryness. The residue was partitioned between dichloromethane and HCl (2M). The dichloromethane was collected and loaded onto silica for purification via is chromatography eluting with 0 to 100% diethyl ether in isohexane to yield 63mg of the title compound.

MS: [M+H]'= 528 1 H NMR (399.98 MHz, DMSO) 3 0.88 (d, 6H), 2.20 - 2.08 (m, IH), 3.22 (s, 3H), 3.68 (d, 20 2H), 4.41 (s, 2H), 5.44 (s, 2H), 7.13 7.09 (m, 111), 7.24 - 7.22 (m, 111), 7.32 - 7.29 1 H), 7.42 - 7.40 (m, 2H), 7.51 - 7.46 (m, 2H), 7.65 (t, 1 H), 7.74 (d, 1 H).

100072 Example I

1-(Cyclopropylmethyl)-3-metb-yl-5-(phenoxymethyl)-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(IH,3H)-dione 0 0 F F N I \ F 0 N S " Y - a) 1-(Cyclopropylmethyl)-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[[2 (trifluoromethvl)phenyllmethyll-thieno[2,3-tflpyrin-tidine-5-carboxylic acid I -(Cyclopropylmethyl)- 1,2,3,4-tetrahydro-3-methyl-2,4-dioxothieno[2,3-d]pyrimidine-5carboxylic acid (6.8g) was suspended in tetrahydrofuran (100 ml) and cooled to -78'C to 10 which lithium diisopropylamide (63 ml, IM) was added. After complete addition the solution was left for 30 min before 2-(trifluoromethyl)- benzaldehyde, (7.4mls) was added neat. After lh HCI(2M in water) was added and the reaction allowed to warrn to room temperature. The reaction was concentrated in vacuo and partitioned between ethyl acetate and HCI (2M in water). The organic phase was collected, dried over magnesium sulfate, 15 filtered and concentrated in vacuo and redissolved in diethyl ether, then washed with half saturated sodium hydrogen bicarbonate. The aqueous phase was collected and the diethyl ethyl was washed a seconded time with half saturated sodium hydrogen bicarbonate. The aqueous extracts were combined, acidified with HCI (conc.) and extracted with ethyl acetate. The organic phase was collected, dried over magnesium sulfate, filtered and 20 concentrated in vacuo to brown gum. The gum was redissolved in trifluoroacetic acid (10mls) and triethyl silane(5mls) and stirred at room temperature for 72hrs. The reaction was then concentrated in vacuo, and partioned between dichloromethane and water. The organics were collected, dried over magnesium sulfate, filtered and concentrated in vacuo 100072 34 before being purified by chromatography eluting with 20:1 dichloromethane: acetic acid and recrstallisation from ethyl acetate and isohexane, to yield 3.63g of the subtitle compound.

5 MS: [M+Hl+ = 439 b) 1-(Cyclopropylmethyl)-1,2,3,4-tetrah-vdro-3-methyl-2,4-dioxo-6-rr2(trifluoromethyl)phenyllmethyll-thienof2,3-dlpvrimidine-5-carboxylic acid, E!hyl ester 10 The product of step a) (6.63g) was dissolved in ethanol (50mls) and 4 drops of H2SO4 were added. The reaction mixture was heated at reflux under an atmosphere of nitrogen for 18hrs. The reaction mixture was then concentrated in vacuo and partitioned between half saturated sodium hydrogen bicarbonate and ethyl acetate. The organics were collected, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the subtitle 15 compound (6.65g).

MS: [M+Hl' = 467 c) 1-(Cyclopropvlmethyl)-5-(hydroxymethyl)-3-methyl-6- r[2_ 20 (trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(IH,3H)- dion The product of step b) (6.65g) was dissolved in tetrahydrofuran (200mls) and LiAIH(OtBU)3 (43mls, IM in tetrahydrofuran) was added. The reaction mixture was heated at 60'C for 18hrs. Water was then added and the reaction mixture was concentrated to dryness in vacuo. The residue was extracted into ethyl acetate and the solution was 25 dried over magnesium sulphate, filtered, and concentrated in vacuo to a greenish solid which was ultrasonicated in isohexanes for 3 hrs before being collected via filtration to yield 2.76g of the subtitle compound as a green solid.

MS: [M+Hl+ = 427 100072 d) 1-(CvclopropYImethyl)-3-methyl-5-(phenoxymethyl)-6-[[2w (trifluoromethvl)vhenyllmethyll-thieno[2,3-dlvyrimidine-2,4(1H,3H)-dione The product of step c) (50rng), triphenyl phosphine (46mg), DEAD (27RI), 2,6-di-t-butyl phenol (36rng) and phenol (1 6mg) were dissolved in tetrahydrofuran (5m1) and stirred at 5 room temperature under an atmosphere of nitrogen for 18hrs. The tetrahydrofuran was allowed to evaporate to dryness and the residue was partitioned between dichloromethane and F[C1 (2M). The organics were collected, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography eluting with 4:1 isohexanes:diethyl ether to yield a white solid which was triturated with isohexanes to 10 yield 14rngs of the title compound.

MS: [M+HI+ = 501 1 H NMR (DMS0) 3 0.49 - 0.37 (m, 414), 2.06 - 1.94 (m, I H), 3.24 (s, 3 H), 3.77 (d, 2H), 4.41 (s, 211), 5.41 (s, 2F1), 6.98 - 6.92 (m, 314), 7.32 - 7.26 (in, 2H), 7.48 (dd, 15 211), 7.64 (t, 1 H), 7.75 (d, I H).

Example 18 3-Methyl-l-(2-methylpropyl)-5-[(4-oxo-l-piperidinvl)meth 1 -62y (trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(1H,3M-dione 0 N 0 """ F N F F F 0: N S a) 5-[(4-Hydroxy-l-piperidinyl)methyll-3-methyl-l-(2-methylpropyl)-6- 2(trifluoromethyl)phenyll methyl] -thienof 2,3-cfl pyrimidine-2,4(1H,3H) dione The subtitle compound was prepared by the method of Example 9.

100072 b) 3-Methvl-l-(2-meth-vlpropyl)-5-[(4-oxo-l-piperidinvl)methyll-6-[[2 (trifluoromethyl)phenyl] methyl] -thieno[2,3-dlp-vriniidine-2,4(1H,3H)dione To a solution of oxalyl chloride (523ul) in dichloromethane (40m1) at - 78'C under an 5 atmosphere of nitrogen was added dropwise dimethyl sulfoxide (1.275m1) at such a rate as to maintain a reaction mixture temperature of <-60'C. Once the dimethyl sulfoxide had been fully added, the mixture was left for 30 minutes before the crude product of step a) (2mmols) was added as a solution in dichloromethane (2ml). 30 minutes after full addition, triethylamine (2.63 ml) was added and the reaction was allowed to warm to room 10 temperature. The reaction mixture was washed with water, dried over magnesium sulfate, and then concentrated in vacuo to give the crude compound. The material was purified by chromatography eluting with 1: 1 isohexane:diethyl ether to yield the title compound (8 1 mg).

15 MS: [M+H]+ = 508 H NMR (DMSO d6) 8 0.86(611, d), 2.13(1 H, m), 2.21(4M, m), 2.74 (4H, m), 3.24(3H, s), 3.67(211, d), 4.00(2H, s), 4.46(2H, s), 7.48(2H, m), 7.65 (1 H, t), 7.75 (1 H, d).

20 Example 19

2-Hydroxy-N-[[1,2,3,4-tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo-6[[2 (trifluoromethvl)phenyllmethyll-thieno[2,3-dlpvrimidin-5--yllmethyllacetani ide 0 0 0 N N F F 1 \ j 1 F c 0'-N 1 S 100072 37 a) 5-(Aminometh-yl)-3-methvl-l-(2-methylpropvl)-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-4pyrimidine-2,4(IH,3H)-dion The product of Example 8 (100mg) was dissolved in dichloromethane (2ml) and thionyl chloride (52 ul) was added. After I hr the reaction was concentrated in vacuo and stored 5 under a high vacuum for I hr. The residue was redissolved in dioxane (10ml) and this solution was added to a preformed mixture of 880 aqueous ammonia (10mls) and dioxane (10ml). The mixture was stirred at room temperature for 18 hrs before being concentrated in vacuo and extracted into ethyl acetate. The organics were collected, dried over magnesium sulfate and evaporated to yield a yellow foam (98mg).

MS: [M+H]' = 426 b) 2-Hydroxy-N-[[1,2,3,4-tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo6-[[2 (trifluoromethyl)phenyllmethyllthieno[2,3-dlpyriniidin-5-yllmethyllacetan-t ide 15 The product of step a) (98mg), glycolic acid (19mg), 1-(3dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (EDCl) (47.7mg) and I - hydroxybenzotriazole hydrate (HOBT) (34.7mg) were dissolved in dichloromethane (5ml) and stirred under an atmosphere of nitrogen for 72hrs. The mixture was then concentrated in vacuo, and the residue partitioned between ethyl acetate and HCI (2M). The organic phase was collected, 20 dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by normal phase preparatory High Pressure Liquid Chromatography (HPLC) to yield the title compound (40mg) as a white solid.

MS: [M+H]+ = 484 25 1 H NMR (DMSO) 5 0.85 (d, 6H), 2.14 - 2.07 (m, 1H), 3.28 (s, 311), 3. 65 (d, 2H), 3.79 (d, 211), 4.48 (s, 2H), 4.50 (s, 2H), 5.59 (t, I H), 7.35 (d, I H), 7.48 (t, I H), 7.61 (t, I H), 7.76 (d, IH), 7.93 (t, I H).

100072 Example 20

1-Hvdroxy-N-[[1,2,3,4-tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo-6[[2 (trifluoromethvl)phenylltnethyll-thieno[2,3-.llpyrirnidin-S-. ethyl -cyclopropanecarboxamide __0 0 IN F F F 1 ' c 0 N S Prepared by the method of Example 19.

MS: [M+HI+ = 5 10 10 1 H NMR (DMSO) 8 0.82 (q, 2H), 0.86 (d, 6H), 1.00 (q, 2H), 2,14 - 2.07 (m, M), 3.29 (s, 3H), 3.65 (cl, 21-1), 4.46 (s, 2H), 4.50 (d, 2H), 6.29 (s, I H), 7.32 (d, I H), 7.47 (t, I H), 7.60 (t, 1 H), 7.7 5 (cl, 1 H), 8.12 (t, 1 H).

Example 21

15 1,2,3,4-Tetrahydro-N-(2-hvdroxyethyl)-N,3-dimethyl-l-(2-methylpropyl)2,4-d ioxo-6[[2-(trifluoromethyl)l?henyllmethyll-thieno[2,3-dlpvriinidine-5acetaniide 0 0 0 Nr 1 N' -1 FF Y l, 1 \ F 0 NXS "",j 100072 39 a) 5-(Diazoacetyl)-3-methyl-l-(2-methyli)ropyl)-6-[[2= (trifluorornethyl)phenyllme thyll-thieno[2,3-4pyrimidine-2,4(lH,3H)-dion 1,2,3,4-Tetrahydro-3-methyl- 1-(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid, (prepared by 5 the method of Example 8a) (2.534g) was dissolved in dichloromethane (30ml) with dimethyl formamide (I drop) and oxalyl chloride (I ml) was added. The reaction mixture was stirred at room temperature for 18hrs, then concentrated in vacuo and stored under high vacuum at 60'C for 2hrs. The resultant yellow oil was redissolved in dichloromethane (50ml) and triethylamine (1.5 1 ml) and trimethylsily1diazomethane (6ml 10 of 2M solution in tetrahydrofuran) was added. The reaction was stirred for 72hrs before being quenched by addition of dilute aqueous acetic acid. The organic phase was collected, dried over magnesium sulfate, and concentrated in vacuo. The resultant material was purified by chromatography eluting with 3:1 isohexane:ethyl acetate to yield 1.5g of the subtitle compound.

M+H-N2 = 437 b) 1,2,3,4-Tetrahydro-3-methyl-l-(2-methylprol)yl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrin-tidine-5-acetic acid 20 The product of step a) (1.5g) was dissolved in methanol (50ml) and A920 (300mg) was added. The suspension was heated at reflux under an atmosphere of nitrogen for I h. The mixture was then filtered, evaporated to dryness in vacuo and the residue was redissolved in tetrahydrofuran (21ml), methanol (7ml) and lithium hydroxide (7ml of I M aqueous solution) and stirred for 18hrs. The reaction was acidified by addition of dilute HCI and 25 extracted thrice into ethyl acetate. The combined organic phases were dried over magnesium sulphate, and concentrated in vacuo to a yellow solid which was recrystallised from ethyl acetate and isohexane to yield the subtitle compound ( 1. 1 g).

MS: [M+Hl+ = 455 100072 1 H NMR (DNISO) 8 0.86 (d, 611), 2.16 - 2.08 (m, 111), 3.22 (s, 3H), 3.66 (d, 211), 3.91 (s, 211), 7.40 (d, 1 H), 7.47 (t, 1 H), 7.60 (t, 1 H), 7. 75 (d, 1 H), 12.25 (s, 1 H).

c) 1,2,3,4-Tetrahvdro-N-(2-h 1)-N,,3-dimethvl-l-(2-methylprovvl)-2,4 ydrox yethy 5 dioxo-6-[[2-(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-5- ace taniide The product of step b) (98mg) was dissolved in 1-methyl-2pyrrolidinone (NMP) (I ml) to which EDC1 (Iml), HOBT (lml) and N-methyl ethanolamine (Iml) was added. The reaction was stirred for 18hrs before being concentrated in vactio. The residue was partitioned between dichloromethane and water. The organic phase was adsorbed onto 10 silica and purified by chromatography eluting with 0-10% methanol in dichloromethaneto yield the title compound (62mg).

MS: [M+HI+ = 512 H NMR (DMSO d-6) 3 0.86(614, d), 2.08(1H, m), 3.32(314, s), 3.46(1 H,t), 3.51 15 (IH, t), 3.62(3H,m), 4.08(214, s), 4.22(2H, d), 4.56 (111, t), 4.8291H, t), 7.46(2H, m), 7.61 (1 H, m), 7.75 (1 H, d).

Example 22

N-(2-Fluoroethyl)-1,2,3,4-tetrahvdro-3-metkvl-l-(2-meth-vlpropvl)-2,4diox o-6-[[2- 20 (trifluoromethvl)phenyllmethyll-thieno[2,3-dlpyrin-iidine-5-acetamide 0 F 0 N -1 I N i F F F 0 N S Prepared using 2-fluoro-ethanamine according to the method of Example 21.

100072 MS: [M+HI+ = 500 1 H NMR (DNISO) 8 0.86 (d, 6H), 2.15 - 2.09 (m, M), 3.23 (s, 314), 3.39 - 3.36 (m, 2H), 3.66 (d, 214), 3.88 (s, 2JJ), 3.88 (s, 2H), 4.23 (t, 3H), 4.44 (t, I H), 7.45 (s, I H), 7.49 (t, 1 H), 7.62 (t, 1 H), 7.75 (d, 1 H), 8.03 (t, 1 H).

Example 23

1,2,3,4-Tetrahydro-3-methyl-l-(2-methylpropyl)-P,2,4-trioxo-6-[[2(trifluoromethyl)phenyll methyl] -thieno[2,3-dlpyrimidine-5propanenitrile - N 0 4 0 N F F F OIN a) 5-(Chloroacetyl)-3-methyl-l-(2-methylpropyl)-6[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(1H,3H)dione 1,2,3,4-Tetrahydro-3-methyl- 1 -(2-methylpropyl)-2,4-dioxo-6[[2(trifluoromethyl)phenyl] methyl] -thieno [2,3-d] pyrimi dine-5 -carbox ylic acid, (prepared by 15 the method of Example 8a) (3.665g) was suspended in dichloromethane (70m1) containing dimethyl formamide (1 drop) and treated with oxaly] chloride (1.47m1). 1 hr after gas evolution ceased the reaction was concentrated in vacuo and stored under high vacuum for 1h. The residue was redissolved in dichloromethane (50m1) and treated with triethylamine (I ml). To this solution was added trimethylsilyldiazomethane (7mls of 2M solution in 20 tetrahydrofuran) and the reaction was stirred at room temperature under an atmosphere of nitrogen for 4hrs before HCI (8mI, 4M in dioxane) was added. The reaction was stirred for 18hrs before being concentrated in vacuo and the residue was purified by chromatography eluting with 2:1 isohexane:diethyl ether. The product was recrystallised from ethyl acetate and isohexane to yield the subtitle compound as white needles(4. 616g) 100072 MS: [NI+HI+ = 47315 1 H NMR (DMSO) 8 0.87 (d, 6H), 2.14 - 2.07 (in, lH), 3.24 (s, 3H), 3.67 (d, 2H), 4.25 (s, 211), 4.84 (s, 2H), 7.49 (d, 1 H), 7.53 (t, 1 H), 7.67 (t, 1 H), 7.77 (t, 1 H), b) 1,2,3,4-Tetrahydro-3-meth-yl-l-(2-methylproPY1)-P,2,4-trioxo-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlp-yrimidine-5-propanenitrile The product of step a) (20Orng) was dissolved in dimethyl formarnide (10m1) and NaCN (44mg) was added. The reaction was heated at WC for 30mins under an atmosphere of 10 nitrogen. The reaction was partitioned between ethyl acetate and water. The organics were collected, dried over magnesium sulfate, and concentrated in vactio. The residue was purified by preparatory normal phase HPLC to yield the title compound (107mg).

MS: [M+H]' = 464 15 1 H NMR (DMSO) 8 0.86 (d, 6H), 2.13 - 2.06 (m, 111), 3.25 (s, 311), 3. 70 - 3.66 (m, 2H), 4.28 (s, 2H), 4.28 (s, 2H), 4.31 4.28 (m, 2H), 7.55 - 7.37 (m, 2H), 7.70 - 7.64 (m, 114), 7.77 (d, M), 11.61 (d, M).

Example 24

20 3-Methvl-l-(2-methylpropyl)-5-[(E)-2-phenylethen-YII-6-[[2 (trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(1H,3H)-dion 0 0 -p F F -g F N S 1 0'"N"" S "T, - 100072 The product of Example 8 (20Orng) was dissolved in dichloromethane (1Orril) and thionyl chloride (0.5m1) was added. The mixture was stirred for 1 hr under an atmosphere of nitrogen before being concentrated in vacuo and stored under high vacuum for 1 hr. The residue was redissolved in triethyl phosphite (5m1) and heated at 15TC under an 5 atmosphere of nitrogen for 3 hrs. The vessel was fitted with a distillation head and heated under a high vacuum to remove the excess triethyl phosphite. The residue was dissolved in tetrahydrofuran (5m1) and benzaldehyde (50rng) was added, then the mixture was cooled to -78'C. Lithium diisopropylamide (550ul of a IM solution in tetrahydrofuran/hexane) was added and the cooling bath removed. After 3hrs at room temperature benzaldehyde 10 (5Orng) was added and after 10 mins the reaction was quenched with water, concentrated in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The material was purified via normal phase preparatory HPLC eluting with 1-25% ethyl acetate in isohexane to yield 64mg of the title compound.

MS: [M+H]'= 500 1 H NMR (DMSO) 3 7.79 (d, lH), 7.70 (d, M), 7.67 (s, M), 7.52 (t, M), 7.44 (d, 2H), 7.40 - 7.36 (m, M), 7.30 - 7.25 (m, 2H), 6.75 (s, 111), 6.71 (s, M), 4.51 (s, 21-1), 3.68 (d, 2H), 3.26 (s, 3H), 2.16 2.10 (m, 111), 0.88 (d, 6H).

Example 25

Cyclopropanecarboxamide, N-F1,2,3,4-tetrahydro-3-methyl-l-(2methylpropyl)-2,4- dioxo-6-[[2-(trifluoromethvl)pbenylj methyl] thieno[2,3-dl pyrimidin-5- yll 100072 0 N, 0 F F N I I \ F 0 -5 N S a) 5-Amino-3-methyl-l-(2-methylpropyl)-6-[[2(trifluoromethyl)phenyllmethyll- thieno[2,3-dlpyrimidine-2,4(lH,3H)-dione 5 1,2,3,4-Tetrahydro-3-methyl- I -(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid made by the method of Example 8a) (3.316g), triethylamine (1.38ml) and diphenylphosphoryl azide (2.26ml) were heated at 900C under an atmosphere of nitrogen in tert- butanol for 18hrs.

The reaction was concentrated in vacuo and the residue redissolved in dichloromethane to (50ml) and trifluoroacetic acid (30ml). The mixture was allowed to stir for 36hrs before being concentrated in vacuo, and residual acid was removed by azeotroping with toluene.

The residue was partitioned between half saturated sodium hydrogen carbonate and dichloromethane. The organics were collected, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography, Cluting with 15 2:1 isohexane:diethyl ether to yield a highly crystalline solid which was recystallised from dichloromethane/isohexane to yield the subtitle compound (1.553g).

MS: [M+H]+ = 412 20 b) N-[1,2,3,4-Tetrahydro-3-methyl-l-(2-methylprop-yl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dipyrimidin-5-ylle-yelopropanecarboxamide 100072 The product of step a) (20Orng) was dissolved in dichloromethane (2ml) and triethylamine (130RI) before being treated with cyclopropanecarbonyl chloride (I mJ, of a I M solution in dichloromethane). The reaction was allowed to stand for 72hrs to produce needles of NEt3ACI. The reaction was washed with dil. HG, concentrated in vacuo and the residue 5 purified by chromatography, eluting with 0-100% diethyl ether in isohexane followed by preparatory reverse phase HPLC to yield the title compound (33mg).

MS: [M+HI+ = 480 1 H NMR (DMSO) 8 0.78 - 0.76 (m, 4H), 0.86 (d, J = 6.7 Hz, 6H), 1.90 - 1. 83 (m, 1 H), 10 2.16 - 2.07 (m, 1 H), 3.22 (s, 311), 3.64 (d, 211), 4.11 (s, 214), 7. 41 (d, 1 H), 7.49 (t,. 1 H), 7.62 (t, I H), 7.73 (d, I H), 9.77 (s, I H).

Example 26

2,2,2-Trifluoro-N-[1,2,3,4-tetrah.ydro-3-methvl-l-(2-methylprop^vl)-2,4diox o-6-[L2- 15 (trifluoromethyl)phenvilmethyllthieno[2,3-dlpyrimidin-5-Yll-acetamide F F F 0 4 t',' 0 F F N 1 "\ v 1 \ F 0 N S Prepared using trifluoroacetic anhydride according to the method of Example 25.

20 MS: [M+H]+ 508 Boiling Point 412 1 H NMR (DMSO) 8 0.88 (d, 6H), 2.17 2.10 (m, lH), 3.21 (s, 311), 3.68 (d, 2H), 4.20 (s, 2H), 7.42 (d, 1 H), 7.48 (t, 2F1), 7.63 (t, 1 H), 7.74 (d, 1 H), 11. 11 (s, 1 H).

100072 Example 27

5-(Dimethylamino)-3-methyl-l-(2-methylpropyl)-6-[[2 (trifluoromethyl)phenyll methyl 1-thienor2,3-fl pyrimidine-2,4(1H,3H)dion 0 N F F N 1 \ -v F 0 -N 1 S The product of Example 25 step a) (10Orng) was dissolved in 1 -methyl -2- pyrro 1 idinone (2m1) and methyl iodide (I ml) was added. After 18hrs the reaction mixture was concentrated in vacuo and the residue purified by chromatography cluting with 9:1 10 isohexane:diethyl ether followed by preparatory reverse phase HPLC to yield the title compound (11 mg).

MS: [M+HI+ = 440 1 H NMR (DMSO) 8 0.86 (d, 6H), 2.18 - 2.07 (m, I H), 2.71 (s, 6H), 3.27 (s, 5H), 3.66 15 (d, 2H), 4.32 (s, 211), 7.35 (d, 1 H), 7.46 (t, 1 H), 7.63 (t, 1 H), 7. 74 (d, 1 H).

Example 28

1,2,3,4-Tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpvriinidine-5-propanoic acid 0 OH 1-1 N 1 01 CF OF 0''N I S 3 \1 Y a) 1,2,3,4-Tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-5-propanoic acid, methyl ester 5 A slurry of 10% palladium on charcoal in ethanol was added to a solution of 3-[1,2,3,4 tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyl]methyl]thieno[2,3-d]pyrimidin-5-yl]-2-propenoic acid, methyl ester, (2.17 g, Example 3 step a)) in ethanol (75 ml) and hydrogenated at 4 bar for 48 hours. The solution was filtered through a glass fibre filter and the filtrate concentrated 10 under reduced pressure. The residue was purified by flash silica chromatography cluting with I% ethanol in dichloromethane to give the sub-title compound as a white solid (1.27 g).

m.p. 86-88 'C HNMR(CDC13) 5 0.95(6H,d); 2.20-2.29(IH,m); 2.69(2H,t); 3.20(2H,t); 3. 41(3H,s); 3.65(3H,s); 3.70(2H,d); 4.32(2H,s); 7.18(IH,d); 7.36(IH,t); 7.47(IH,t); 7. 69(IH,d).

b) 1,2,3,4-Tetrahydro-3-methyl-l-(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thienor2,3-dlPyrimidine-5-propanoic acid The product of step a) (1.09g), lithium hydroxide monohydrate (0. 19 g) and water (10 ml) in tetrahydrofuran (30 ml) were stirred at room temperature for 2 hours. Evaporation and purification of the residue by flash silica chromatography eluting with a gradient of 0-2% ethanol in dichloromethane gave the title compound as a white solid (0.81 g).

100072 m.p. 165-167 'C MS(APCI) 469[M+H]' 'HNMR(MC13) 8 0.94(611,d); 2.25(1H, septet); 2.72(2H,t); 3.19(31-1j); 3.42(3H,s); 5 3.70(2H,d); 4.31(2H,s); 7.17(1H,d); 7.36(11-1j); 7.47(1H,t); 7.69(1H,d).

Example 29

5-(3-Hvdroxypropyl)-3-methyl-l-(2-methylpropvl)-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-dlpyrimidine-2,4(1H,3H)-dion F F N 1 \" v 1 \ F 0 N S j The product of Example 27 (???? - is this correct ?) (674rng) was dissolved in tetrahydrofuran (20m1) and LiAIII(OSUb (4ml of IM solution in tetrahydrofuran) was added. The mixture was heated at 55'C under an atmosphere of nitrogen for 17hrs. The 15 reaction was quenched with water, concentrated in vacuo and purified via chromatography, cluting with 1: 1 diethyl ether:isohexane to give the title compound (392mg).

MS: [M+H]' = 455 H NMR (DMSO) 3 0.86 (d, 6H), 1.69 - 1.62 (m, 2H), 2.16 2.09 (m, 11-1), 2.88 - 2.85 20 (m, 211), 3.24 (s, 3 H), 3.40 (q, 211), 3.65 (d, 211), 4.29 (s, 2H), 4. 44 (t, 1 H), 7.34 (d, 1 H), 7.48 (t, I H), 7.64 (t, I H), 7.76 (d, I H) 100072 Example 3

5-[(2-Fluorophenvl)hydroxymethyll-3-methyl-l-(2-methylprop-yl)-6-[[2(trifluoromethyl)phenvil methyl] -thieno[2,3-dl pyrimidine-2,4(1H,3H)dione F 0 0 F F v 11 F F N 1 1 \ F 0 N S 5 5-Bromo- 1 -isobutyl- 3 -methyl-6- [2-(trifluoromethyl)benzyl 1 -thieno [2,3 -d] pyrimi dine 2,4(1H,3H)-dione (Example 1 part c)) (10Orng) was dissolved in tetrahydrofuran (2mls) and EtMgBr (250ul of 1M solution in tetrahydrofuran) was added. After 10 mins 2 fluorobenzaldehyde (250ul of a IM solution in tetrahydrofuran) was added. After 1 hr the reaction was quenched via addition of water. The reaction was concentrated in vacuo and 10 extracted into dichloromethane, concentrated in vacuo and the residue purified via chromatography eluting with 0- 100% diethyl ether in isohexane to yield the title compound (9mg).

M+H-H20=503 15 1 HNMR(DMSO)80.85(d,J=6.7Hz,6H),2.15-2.08(m, M),124(s, M), 3.68 - 3.65 (m, 3H), 4.45 - 4.26 (m, 311), 6.39 (d, M), 6.89 (d, M), 7.10 - 7.05 (m, 2H), 7.16 (d, 1 H), 7.26 - 7.22 (m, 1 H), 7.47 - 7.41 (m, I H), 7.54 - 7.50 (m, 2H), 7.69 (d, 1 H) 100072 Example 31

5-(2-Fluorobenzoyl)-3-methvl-l-(2-meth-vlpropyl)-6-[[2(trifluoromethvl)phenyllmethyll-thieno[2,3-dlpyriniidine-2,4(1H,3H)-dion F 0 0 N F F S 0 N S F 1 \ F F ", N %S 5 5-Bromo-1 -isobutyl-3 -methyl -6-[2-(trifluoromethyl)benzyl] thieno[2,3 -dl pyrimidine 2,4(1H,3H)-dione (Example 1 part c)) (100mg) was dissolved in tetrahydrofuran (2m1) and EtMgBr (2 1 Oul of a 1 M solution in tetrahydrofuran) was added. After 10 min 2-fluorobenzaldehyde (21Optl of a IM solution in tetrahydrofuran) was added. After 1 hr the reaction was quenched via addition of water. The reaction was concentrated in vacuo 10 and extracted into dichloromethane, concentrated in vacuo and purified by chromatography eluting with 0-75% diethyl ether in isohexane to yield 5-[(2- fluorophenyl)hydroxyrnethyll- 3 -methyl- 1 -(2-methylpropyl)-6- [ [2-(trifluoromethyl)phen yl] methyl] thi eno [2,3 - d]pyrimidine-2,4(1H,3H)-dione. This was redissolved in dichloromethane (Iml) and added to a mixture of oxalyl chloride (50ul) and dimethyl sulphoxide (10011) in is dichloromethane (I ml) at -78'C. After 30 mins triethylamine (260ul) was added and the reaction allowed to warm to room temperature. The reaction was then washed with water and evaporated to dryness before the residue was purified by chromatography eluting with 0-75% diethyl ether in hexane to yield the title compound (11 mg).

20 MS: [M+HI' = 519 1 H NMR (DMSO) 3 0.90 (d, 6H), 2.19 - 2.12 (m, I H), 3.11 (s, 311), 3.70 (d, 2P1), 4.23 (s, 211), 7.30 - 7.24 (m, 2H), 7.50 7.44 (m, 2H), 7.66 - 7.62 (m, 2F1), 7.71 - 7.67 (m, 211) 100072 Example 32 Inhibition of PMA/ionomycin-stimulated peripheral blood mononuclear cell proliferation The assay for PMA/ionomycin-stimulated PBMC proliferation was performed in 96-well flat bottomed microtitre plates. Compounds were prepared as I OmM stock solutions in dimethyl sulfoxide. A 50-fold dilution of this was prepared in RPMI and serial dilutions were prepared from this solution. IOVI of the 50-fold diluted stock, or dilutions of it, were 10 added to the well to give concentrations in the assay starting at 9.5PM and going down. Into each well was placed I x 10 5 PBMC, prepared from human peripheral blood from a single donor, in RPM11640 medium supplemented with 10% human serum, 2MM glutamine and penicillin/streptomycin. Phorbol myristate acetate (PMA) (0.5ng/ml final concentration) and ionomycin (500ng/ml final concentration) were added to these cells in 15 supplemented RPM11640 medium (as above) so that the final volume of the assay was 0.2ml. The cells were incubated at 37'C in a humidified atmosphere at 5% carbon dioxide for 72 hours. 3 H-Thymidine (0.5pCi) was added for the final 6 hours of the incubation.

The level of radioactivity incorporated by the cells was then determined and this is a measure of proliferation.

The title compounds of Examples I to 31 were found to exhibit an IA50 value of less than I X 10-6M in the above test.

100072

Claims

1. A compound of general formula R, 3

2 R-, N) I R 0 N 5 R wherein:

R is -C(O)Arl, -C(R 4)(R 5)Ar I or Ar 3; Ar I represents a 5- to 10-membered aromatic ring system wherein up to 3 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system 10 being optionally substituted by one or more substituents independently selected from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, oxo, nitro, cyano, NR 6 R 7 and -CH2NR 8 R 9; R I and R 2 each independently represent a hydrogen atom, C1-6 alkyl, C3- 6 alkenyl, CH2C3-5 cycloalkyl or C3-6 cycloalkyl; 15 R 3 represents a group X-R 10 or Ar 2 X represents a bond or a group NR I Ar 2 represents a 5- or 6-membered aromatic ring wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by one or more substituents independently selected from C1-4 alkyl, 20 C1-4 alkoxy, C1-4 alkylthio, acetyl, halogen, trifluoromethyl, oxo, hydroxyl, amino, nitro, cyano and benzyl; R 4 represents a hydrogen atom or C 1 -4 alkyl; R 5 represents a hydrogen atom or hydroxyl group; R 6 and R 7 each independently represent a hydrogen atom or C 1 -4 alkyl, or 25 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 100072 R 8 and R 9 each independently represent a hydrogen atom or C 1-4 alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; R 10 represents CI-6 alkyl, C2- 6 alkenyl or C2-6 alkynyl, each of which may be 5 optionally subsituted by one or more substituents independently selected from carboxyl, 12 13 14 15 16 hydroxyl, -C(O)-R, C3-6cycloalkyl, morpholinyl, -NR R, SR, OR, phenyl and halophenyl, or R 10 represents a C3-6 cycloalkylcarbonyl, -C(O)CH2CN, halophenylcarbonyl or trifluoromethylearbonyl group; 10 R I I represents a hydrogen atom or a C 1 -6 alkyl group; 12 represents piperazinyl optionally substituted by a C 1 -6 alkyl group, or 12 represents a group -NR 17 R 18; 13 and R 14 each independently represent a hydrogen atom, or a C 1 -4 alkyl, CI-4 hydroxyalkyl or -C(O)-R 19 group, or 13 14 15 R and R, together with the nitrogen atom to which they are attached, form a 5to 7-membered saturated heterocyclic ring which may be optionally substituted by one or more substituents independently selected from CI-4 alkyl, hydroxyl and oxo; R 15 and R 16 each independently represent a 5or 6-membered aromatic ring wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and 20 sulphur, the ring being optionally substituted by one or more substituents independently selected from halogen atoms, cyano and C 1 -4 alkyl; R 17 and R 18 each independently represent a hydrogen atom, or a C 1 -4 alkyl group optionally substituted by one or more substituents independently selected from halogen atoms and hydroxyl; 25 R 19 represents a CI-6 alkyl or C3-6 cycloalkyl group, each of which may be optionally substituted by a hydroxyl group; and Ar 3 represents acenaphthenyl, indanyl or fluorenyl, each of which may be optionally substituted by one or more substituents independently selected from CI-4 alkyl, CI-4 alkoxy, halogen and trifluoromethyl; 30 or a pharmaceutically acceptable salt or solvate thereof.

100072 4 5 1 2, A compound according to claim 1, wherein R represents -C(R)(R)Ar.

3. A compound according to claim 1 or claim 2, wherein Ar 1 represents phenyl, 5 naphthyl, pyrazolyl, thienyl, oxazolyl, imidazolyl, pyridinyl, pyridopyrrolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzoxazolyl, thiazolyl or benzotriazolyl, each of which may be optionally substituted by one to four substituents independently selected from Cl-

4 alkyl, Cl-4 alkoxy, halogen, trifluoromethyl, oxo, nitro, cyano, 6 7 8 9 NR R and -CH2NIZ R 4. A compound according to any one of claims 1 to 3, wherein R 1 and R 2 each independently represent a Cl -4 alkyl group.

5. A compound according to any one of claims 1 to 4, wherein R 3 represents a group 15 X-R 10 and X represents a bond.

6. A compound of formula (I) according to claim 1 being:

5-(3-Hydroxy-3-methyl-l-butynyl)-1 -isobutyl-3 -methyl -6- [2-(tri fluoromethyl)benzyl thieno[2,3-dlpyrimidine-2,4(1H,3H)-dione, 20 3-Methyl-5-[3-(4-methyl-l-piperazinyl)-3-oxo-l-propenyll- 1-(2methylpropyl)-6-[[2 (trifluoromethyl)phenyl]methyl] -thieno [2,3 A] pyri midine-2,4(1 H, 3 11)-dione, 3 - [1,2,3,4-Tetrahydro-3 -methyl1-(2-methylpropyl)-2,4-dioxo-6-[[2- (trifi uoromethyl)phenyll methyl] -thieno [2,3-d] pyrimidin-5-yl] -2- propenoic acid, 5- [3-Hydroxy-3 -methyl- 1 -butenyl]-3 -methyl- 1 -(2-niethylpropyl)-6- [ [2 25 (trifluoromethyl)phenyll methyl] -thieno [2,3-d] pyrimidine-2,4(1 H, 3H)-dione, (E) and (Z)5-[2-cyclopentylethenyl]-3-methyl-l-(2-methylpropyl)-6-[[2(trifluoromethyl)phen yl] methyl] -thieno [2,3-dl pyrimidine-2,4(1 H,311)dione, 3-Methyl- 1 -(2-methylpropyl)-5-(3-thienyl)-6 [[2(trifluoromethyl)phenyll methyl] - thieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione, 100072 5-(5 -Acetyl -2-thienyl)-3 -methyl- 1 -(2-methylpropyl)-6-[[2 (tri fluoromethyl)phenyll methyl] -thieno [2,3 -djpyrimidine-2,4(1 11, 314)-dione, 5-(Hydroxymethyl)-3 -methyl- 1 -(2-methylpropyl)-6-[[2 (trifluoromethyl)phenyl] methyl] -thieno [2,3-cl] pyrimidine-2,4(1 11, 311)-dione, 5 3-Methyl1-(2-methylpropyl)-5-(4-morpholinylmethyl)-6-[[2- (tri fl uorometh y1)phenyl] methyl] -thieno [2,3 Al pyrimidine-2,4(1 H, 311)-dione, 5[(4Hydroxy-3 -methyl- 1 -piperidinyl)methyll -3 -methyl- 1 -(2methylpropyl)-6 (trifi uoromethyl)phenyl] methyl] -thieno [2,3 A]pyrimidine-2,4(1 H,3H)- dione, - [ [(2-Hydroxyethyl)methylaminol methyl] - 3 -methyl - 1 -(2- methylpropyl)-6-[ [2 10 (tri fl uorometh yl)phenyll methyl] -thieno [2,3-dl pyrimidinc-2,4(1 11,314)-dione, 3 -Methyl -5 - [ [ (2-methyl -3 -furanyl)thiol methyl] - 1 -(2- methylpropyl)-6-[ [2 (trifluoromethyl)phenyl] methyl] -thieno [2,3 Al pyri midine-2,4(1 H,3 H)dione, 3-Methyl- 1 -(2-methylpropyl)-5-[(1,3,4-thiadiazol-2-ylthio)methyll-6[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-dlpyrimidine-2,4(1H,3H)-dione, 15 3-Methyl- 1 -(2-methylpropyl)-5-[[(1 -methyl- 1 H-tetrazol-5-y1)thio] methyl] -6- [[2 (tri fluoromethyl)phenyl]methyl] -thieno [2,3-d] pyrimidi ne-2,4(1 H,3H)- dione, 5- [ [(3 -Chlorophenyl)thiol methyl] -3-methyl1-(2-methylpropyl)-6-[[2 (trifluoromethyl)phenyl]methyll-thieno[2,3-d]pyrimidine-2,4(1 H,314)dione, 3- [ [1,2,3,4-Tetrahydro-3 -methyl- 1 -(2methylpropyl)-2,4-dioxo-6-[[2- 20 (tri fluoromethyl)phenyl]methyl] -thieno [2,3 A] pyri midin -5-yl 1 methoxy] - benzonitrile, 1 -(CycIopropylmethyl)-3-methyl-5-(phenoxymethyl)-6-[[2- (tri fluoromethyl)phenyll methyl] -thieno [2,3A1 pyrimidine-2,4(1 H,3H)clione, 3-Methyl- 1-(2-methylpropyl)-5-[(4-oxo- 1 -piperidinyl)methyll-6-[[2 25 (trifluorometh yl)phen yl]methyl 1-thieno [2,3 -dl pyrimidine-2,4(1 H, 3H)-dione, 2-Hydroxy-N-[[ 1,2,3,4-tetrahydro-3-methyl- 1 -(2-methylpropyl)-2,4-dioxo- 6-[[2- (tri fl uoromethyl)phen yll methyl] -thieno [2,3A1 pyrimidin-5-yl]methyl] -acetamide, 1 -Hydroxy-N-[[ 1,2,3,4-tetrahydro-3 -methyl- 1 -(2methylpropyl)-2,4- dioxo-6-[[2- (trifluoromethyl)phenyl]methyl] -thieno [2,3 -d] pyri midin -5-yl 1 methyl] - 30 cyclopropanecarboxamide, 100072 1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-N,3-dimethyl- I -(2-methylpropyl)-2, 4-dioxo6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-dlpyrimidine-5-acetamide, N-(2-Fluoroethyl)- 1,2,3,4-tetrahydro-3-methyl- I -(2-methylpropyl)-2,4dioxo-6-[[2(trifluoromethyl)phenyllmethyll-thieno[2,3-djpyrimidine-5-acetamide, 5 1,2,3,4-Tetrahydro-3-methyl- I -(2-methylpropyl)-P,2,4-trioxo-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-propanenitrile, 3-Methyl- I -(2-methylpropyl)-5-[(E)-2-phenylethenyl]-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(I 14,314)dione, Cyclopropanecarboxamide, N-[1,2,3,4-tetrahydro-3-methyl-l-(2methylpropyl)-2,4- to dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]thieno[2,3-d]pyrimidin-5- yl], 2,2,2-Trifluoro-N-[ 1,2,3,4-tetrahydro-3-methyl- I -(2-methylpropyl)-2,4dioxo-6-[[2(trifluoromethyl)phenyl]methyllthieno[2,3-d]pyrimidin-5-yl]-acetamide, 5-(Dimethylamino)-3-methyl- 1-(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl] methyl] -thieno [2,3-d] pyrimidine-2,4(l H,3H)di one, is 1,2,3,4-Tetrahydro-3-methyl- I -(2-methylpropyl)-2,4-dioxo-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-dlpyrimidine-5-propanoic acid, 5-(3-Hydroxypropyl)-3-methyl- I -(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(IH,3H)-dione, 5-[(2-Fluorophenyl)hydroxymethyll-3-methyl- I -(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(I H,3H)dione, 5-(2-Fluorobenzoyl)-3-methyl- I -(2-methylpropyl)-6-[[2(trifluoromethyl)phenyl] methyl] -thieno [2,3-d] pyrimidine-2,4(l H,3 H)di one, or a pharmaceutically acceptable salt or solvate of any one thereof.

25

7. A process for the preparation of a compound of formula (1) as defined in claim I which comprises, 3 2 (a) when R represents Ar, reacting a compound of general formula 100072 0 L 1 N 1 R 1 c 0 N

S 11 R (II) wherein L 1 represents a leaving group and R, R 1 and R 2 are defined as in formula (1), with a (hetero)aromatic boronic acid of general formula OH Ar 2 B / OH (I,,) 5 wherein Ar 2 is defined as in formula (1), in the presence of a palladium (0) species; or 3 10 10 (b) when R represents X-R ' X represents a bond and R represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in formula (I), reacting a compound of 101 formula (II) as defined in (a) above with a compound of general formula (IV), R - H, 10 wherein R 101 represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in R 10 of formula (1) which comprises a terminal carbon-carbon double or triple bond, in the presence of a palladium (I1) species and optionally either a copper (I) species or a coordinating ligand; or 3 10 10 15 (c) when R represents X-R ' X represents abond and R represents aCI- 6alkyl group optionally substituted as defined in formula (1), reacting a corresponding compound of formula (I) in which R 10 represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in formula (1) with hydrogen in the presence of a palladium or platinum catalyst; or 3 10 10 (d) when R represents X-R ' X represents a bond and R represents a C2-6 alkenyl or alkynyl group optionally substituted as defined in formula (I), oxidising a compound of formula (1) as described in (c) above; or 100072 3 10 10 (c) when R represents X-R ' X represents a bond and R represents a C3-6 cycloalkylcarbonyl, -C(O)CH2CM halophenylcarbonyl or trifluoromethylearbonyl group, reacting a compound of formula (11) as defined in (a) above, with a suitable IT Grignard reagent and then with a compound of general formula (V), R - H, wherein R IT represents a C3-6 cycloalkylcarbonyl, -C(O)CH2CN, halophenylcarbonyl or trifluoromethylearbonyl group, followed by an oxidation reaction; or 3 10 11 (f) when R represents X-R and X represents a group NR ' reacting a compound of general formula 0 NHR 11 R 2 ', N R 0 N S 11 10 R (VI) 1 2 11 wherein R, R ' R and R are as defined in formula (1), with a compound of general 10 2 2 10 formula (VII), R L ' wherein L represents a leaving group and R is as defined in formula (I); or 15 (g) when R 3 represents X-R 10, X represents a bond and R 10 represents CH.CO,)H, reacting a compound of general formula 0 CO H N R 0 N S 1 1 R (V111) 20 wherein R, R 1 and R 2 are as defined in formula (1), with an activating agent followed by diazomethane, and causing the resulting intermediate to undergo a WoIff rearrangement in the presence of a metal oxide catalyst to obtain a compound of formula (1); 100072 and optionally after (a), (b), (c), (d), (e), (f) or (g) converting the compound of formula (1) obtained to a further compound of formula (1) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (1).

5 8. A pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims I to 6 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A process for the preparation of a pharmaceutical composition as claimed in claim 8 10 which comprises mixing a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims I to 6 with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as 15 claimed in any one of claims I to 6 for use in therapy.

11. Use of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims I to 6 in the manufacture of a medicament for use in therapy.

12. Use of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in the treatment of an airways disease.

25

13. Use according to claim 12, wherein the airways disease is asthma or chronic obstructive pulmonary disease.

14. Use of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims I to 6 in the manufacture of a medicament for use 30 in the treatment of allograft rejection.

100072

15. A method of effecting immunosuppression which comprises administering to a patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims I to 6.

16. A method of treating, or reducing the risk of, an airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims I to 6.