Thienopyrimidinediones and their use in the modulation of autoimmune disease

Abstract

The invention relates to thienopyrimidinediones of formula (1): in which R 1 , R 2 , R 3 , Q, and Ar are defined in the specification. The invention also relates to processes for the preparation of the compounds of formula (1), pharmaceutical compositions containing these compounds, and use of these compounds in therapy, in particular in immunosuppression therapy.

1 . A method of inhibiting the proliferation of T cells, comprising administering to a patient a therapeutically effective amount of a compound of formula (1): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-5 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; R 3  is a group CO-G or SO 2 -G, where G is a 5- or 6-membered ring containing a nitrogen atom and a second heteroatom selected from the group consisting of oxygen and sulphur adjacent to the nitrogen; the ring being substituted by at least one group selected from the group consisting of halogen or C 1-4  alkyl optionally substituted by up to five halogen atoms, and optionally substituted by up to a further 4 groups independently selected from the group consisting of halogen, hydroxyl, and C 1-4  alkyl optionally substituted by up to five halogen atoms; 
 Q is CR 4 R 5  , where R 4  is hydrogen, fluorine or C 1-6  alkyl and R 5  is hydrogen, fluorine or hydroxy; 
 Ar is a 5- to 10-membered aromatic ring system in which up to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4  alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, -N(R 6 )R 7  , -(CH 2 )pN(R 8 )R 9  , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 ; or Ar is optionally substituted by a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; the 5 or 6 membered aromatic ring being optionally substituted by one or more substituents independently selected from the group consisting from C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano,- N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4  alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 ; 
 p is 1,2,3or4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; and 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; or 
 pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  is ethyl, propyl, butyl or cyclopropyl. 
     
     
         3 . The method of  claim 1 , wherein R 2  is methyl. 
     
     
         4 . The method of  claim 1 , wherein R 3  a group CO-G. 
     
     
         5 . The method of  claim 1 , wherein Q is CH 2 . 
     
     
         6 . The method of  claim 1 , wherein Ar is a 5-membered aromatic ring containing two heteroatoms optionally substituted as defined in  claim 1  or Ar is a 9- or 10- membered bicyclic ring containing one, two or three heteroatoms and optionally substituted as defined in  claim 1 , or phenyl, optionally substituted as defined in  claim 1 . 
     
     
         7 . The method of  claim 6 , wherein Ar is a thienyl, pyrazole or thiazole ring each substituted by two or three C 1-4 alkyl, halogen, trifluoromethyl substituents and/or also substituted by a 2-pyrimidinyl or 2-pyridyl group. 
     
     
         8 . The method of  claim 6 , wherein Ar is a group of sub-formula (i): 
       
         
           
           
               
               
           
         
       
       in which R 10  and R 11  are independently H, C 4 alkyl, or haloC 1-6 alkyl and R 12  is H, C 1-6 alkyl, haloC 1-6 alkyl, or a 5- to 6-membered aromatic ring system in which up to 3 ring atoms are heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, which ring are optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, nitro, cyano, -N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 , in which R 6 , R 7 , R 8 , R 9  and p are as defined in  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein R 10  and R 11  are methyl. 
     
     
         10 . The method of  claim 9 , wherein R 12  is H, C 1-3 alkyl or a 5- to 6- membered aromatic ring system in which up to 3 ring atoms are optionally heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, the ring system being optionally substituted by hydroxyl. 
     
     
         11 . The method of  claim 1 , wherein the compound of formula (1) is selected from the group consisting of:
 (S)-2-[[6-[(3,5-Dimethyl- 1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno [2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   1-Cyclopropyl-6-[(3,5-dimethyl- 1H-pyrazol-4-yl)methyl]-5- [[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (S)-2-[[6-[(1H-1,2,3-Benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6- [(4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-1-ethyl- 3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   (4S)-4-methyl-2-[[1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(4- quinolinylmethyl)thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol,   (4S)-2-[[6-[(2,4-Dichloro-5-thiazolyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (4S)-2-[[6- [(3-Bromo-2-thienyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)- 2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione,   6-[[3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   5-[[(4S)-4-Hydroxy-4-methyl-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-2-[[6-[[3,5-Dimethyl-1-(4-pyridinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3- methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d] pyrimidin-5-yl] carbonyl]-4-methyl-4- isoxazolidinol,   (4S)-2-[[6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl] methyl]-1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d] pyrimidin-5-yl] carbonyl]-4-methyl-4- isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl] carbonyl]-3-methyl-1-(1-methylethyl)-6- [(1-phenyl-1H-pyrazol-4-yl)methyl]-thieno[2,3-d] pyrimidine-2,4-(1H,3H)-dione,   6-[(8-Fluoroquinolin-4-yl)methyl]-5- {[(4S)-4-hydroxy-4-methylisoxazolidin-2- yl] carbonyl}-1-isopropyl-3-methylthieno[2,3-d] pyrimidine-2,4(1H,3H)-dione,   5-{[(4S)-4-Hydroxy-4-methylisoxazolidin-2-yl] carbonyl}-1-isopropyl-3-methyl-6-(4- pyrimidin-2-ylbenzyl)thieno[2,3-d] pyrimidine-2,4(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl] carbonyl]-3-methyl-1-(1-methylethyl)-6- [(5 -(2-pyridinyl)-2-thienyl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(1,3-Dimethyl-1H-5-pyrazolyl)methyl]-5- ]](4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   6-[(3,5-Dimethyl-4-isothiozolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(4-Fluorophenyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3- methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-1,2,3-triazol-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(6-Chloroimidazo[1,2-a]pyridin-3-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-hydroxy-4-methylisoxazolidin-2-yl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[4-(2-pyridinyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-4-Methyl-2-[[1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-6-[[5-methyl-1-(2- pyrimidinyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-5- yl]carbonyl]-4-isoxazolidinol,   (4S)-2- [[6- [[3,5-Dimethyl- 1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]- 1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5 -yl]carbonyl]-4-ethyl-4- isoxazolidinol,   (4S)-2- [[6-[[1-(2,3-Dihydro-2-oxo-4-pyrimidinyl)-3,5-dimethyl-1H-pyrazol-4- yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5- yl]carbonyl]-4-methyl-4-isoxazolidinol,   5- [[(4R)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione, and   pharmaceutically acceptable salts thereof.   
     
     
         12 . A method of effecting immunosuppression, comprising administering to a patient a therapeutically effective amount of a compound of formula (1): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-5 cycloalkylC 1-3 alkyl or C 36 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; 
 R 3  is a group CO-G or SO 2 -G, where G is a 5- or 6-membered ring containing a nitrogen atom and a second heteroatom selected from the group consisting of oxygen and sulphur adjacent to the nitrogen; the ring being substituted by at least one group selected from the group consisting of halogen or C 1-4  alkyl optionally substituted by up to five halogen atoms, and optionally substituted by up to a further 4 groups independently selected from the group consisting of halogen, hydroxyl, and C 1-4  alkyl optionally substituted by up to five halogen atoms; 
 Q is CR 4 R 5 , where R 4  is hydrogen, fluorine or C 1-6  alkyl and R 5  is hydrogen, fluorine or hydroxy; 
 Ar is a 5- to 10-membered aromatic ring system in which up to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4  alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4  alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, -N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 ; or Ar is optionally substituted by a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; the 5 or 6 membered aromatic ring being optionally substituted by one or more substituents independently selected from the group consisting from C 1-4 alkyl optionally substituted by 1,2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, - N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4  alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7    
 p is 1,2,3or4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; and R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; or 
 pharmaceutically acceptable salts thereof. 
 
     
     
         13 . The method of  claim 12 , wherein R 1  is ethyl, propyl, butyl or cyclopropyl. 
     
     
         14 . The method of  claim 12 , wherein R 2  is methyl. 
     
     
         15 . The method of  claim 12 , wherein R 3  is a group CO-G. 
     
     
         16 . The method of  claim 12 , wherein Q is CH 2.    
     
     
         17 . The method of  claim 12 , wherein Ar is a 5-membered aromatic ring containing two heteroatoms optionally substituted as defined in  claim 1  or Ar is a 9- or 10- membered bicyclic ring containing one, two or three heteroatoms and optionally substituted as defined in  claim 1 , or phenyl, optionally substituted as defined in  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein Ar is a thienyl, pyrazole or thiazole ring each substituted by two or three C 1-4 alkyl, halogen, trifluoromethyl substituents and/or also substituted by a 2-pyrimidinyl or 2-pyridyl group. 
     
     
         19 . The method of  claim 17 , wherein Ar is a group of sub-formula (i): 
       
         
           
           
               
               
           
         
       
       in which R 10  and R 11  are independently H, C 1-4 alkyl, or haloC 1-6 alkyl and R 12  is H,C 1-6 alkyl, haloC 1-6 alkyl, or a 5- to 6-membered aromatic ring system in which up to 3 ring atoms are heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, which ring are optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1,2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4  alkoxycarbonyl, C 24 alkanoyl, oxo, thioxo, nitro, cyano, -N(R 6 )R 7 , (CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2  N(R 6 )R 7 , in which R 6 , R 7 , R 8 , R 9  and p are as defined in  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein R 10  and R 11  are methyl. 
     
     
         21 . The method of  claim 20 , wherein R 12  is H, C 1-3 alkyl or a 5- to 6- membered aromatic ring system in which up to 3 ring atoms are optionally heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, the ring system being optionally substituted by hydroxyl. 
     
     
         22 . The method of  claim 12 , wherein the compound of formula (1) is selected from the group consisting of:
 (S)-2-[[6-[(3,5-Dimethyl- 1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5 -yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6-[(3,5-Dimethyl- 1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   1-Cyclopropyl-6-[(3,5 -dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (S)-2-[[6-](1H-1,2,3-Benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6- [(4,5-Dichloro-2-methyl-1H-imidazol- 1-yl)methyl]-1,2,3,4-tetrahydro- 1-ethyl- 3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   (4S)-4-methyl-2-[[1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(4- quinolinylmethyl)thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol,   (4S)-2-[[6-[(2,4-Dichloro-5-thiazolyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (4S)-2-[[6-[(3-Bromo-2-thienyl)methyl]-1,2,3,4-tetrahydro-3-methyl- 1-(2-methylpropyl)- 2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione,   6- [[3,5-Dimethyl- 1-(2-pyridinyl)- 1H-pyrazol-4-yl]methyl]-5- [[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   5-[[(4S)-4-Hydroxy-4-methyl-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-2-[[6- [[3,5-Dimethyl-1-(4-pyridinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3- methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4- isoxazolidinol,   (4S)-2-[[6- [[3,5-Dimethyl- 1-(2-pyrimidinyl)- 1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4- isoxazolidinol,   5- [[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [(1-phenyl-1H-pyrazol-4-yl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(8-Fluoroquinolin-4-yl)methyl]-5-{[(4S)-4-hydroxy-4-methylisoxazolidin-2- yl]carbonyl}-1-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   5-{[(4S)-4-Hydroxy-4-methylisoxazolidin-2-yl]carbonyl}-1-1-isopropyl-3-methyl-6-(4- pyrimidin-2-ylbenzyl)thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [(5-(2-pyridinyl)-2-thienyl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(1,3-Dimethyl-1H-5-pyrazolyl)methyl]-5- [[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   6-[(3,5-Dimethyl-4-isothiozolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno [2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5- [[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]thieno [2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(4-Fluorophenyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3- methyl-1-(1-methylethyl)thieno [2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-1,2,3-triazol-1-ylmethyl)thieno [2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(6-Chloroimidazo[1,2-a]pyridin-3-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno [2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-hydroxy-4-methylisoxazolidin-2-yl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[-(2-pyridinyl)phenyl]methyl]-thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-4-Methyl-2- [[1,2,3,4-tetrahydro-3-methyl-1-( 1-methylethyl)-6- [[5-methyl-1-(2- pyrimidinyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-5- yl]carbonyl]-4-isoxazolidinol,   (4S)-2-[[6- ]]3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]- 1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxothieno [2,3-d]pyrimidin-5-yl]carbonyl]-4-ethyl-4- isoxazolidinol,   (4S)-2- [[6-[[1-(2,3-Dihydro-2-oxo-4-pyrimidinyl)-3,5-dimethyl- 1H-pyrazol-4- yl]methyl]- 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno [2,3-d]pyrimidin-5- yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4R)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno [2,3-d]pyrimidine-2,4(1H,3H)- dione, and   pharmaceutically acceptable salts thereof.   
     
     
         23 . A method of treating a reversible obstructive airways disease in a patient suffering from the disease, comprising administering to the patient a therapeutically effective amount of a compound of formula (1): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-5 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; 
 R 3  is a group CO-G or SO 2 -G, where G is a 5- or 6-membered ring containing a nitrogen atom and a second heteroatom selected from the group consisting of oxygen and sulphur adjacent to the nitrogen; the ring being substituted by at least one group selected from the group consisting of halogen or C 1-4  alkyl optionally substituted by up to five halogen atoms, and optionally substituted by up to a further 4 groups independently selected from the group consisting of halogen, hydroxyl, and C 1-4  alkyl optionally substituted by up to five halogen atoms; 
 Q is CR 4 R 5 , where R 4  is hydrogen, fluorine or C 1-6  alkyl and R 5  is hydrogen, fluorine or hydroxy; 
 Ar is a 5- to 10-membered aromatic ring system in which up to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4  alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4  alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, -N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 ; or Ar is optionally substituted by a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; the 5 or 6 membered aromatic ring being optionally substituted by one or more substituents independently selected from the group consisting from C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, - N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 ; 
 p is 1,2,3or4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; and 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; and 
 pharmaceutically acceptable salts thereof. 
 
     
     
         24 . The method of  claim 23 , wherein the obstructive airways disease is chronic obstructive pulmonary disease. 
     
     
         25 . The method of  claim 23 , wherein R 1  is ethyl, propyl, butyl or cyclopropyl. 
     
     
         26 . The method of  claim 23 , wherein R 2  is methyl. 
     
     
         27 . The method of  claim 23 , wherein R 3  is a group CO-G. 
     
     
         28 . The method of  claim 23 , wherein Q is CH 2 . 
     
     
         29 . The method of  claim 23 , wherein Ar is a 5-membered aromatic ring containing two heteroatoms optionally substituted as defined in  claim 1  or Ar is a 9- or 10- membered bicyclic ring containing one, two or three heteroatoms and optionally substituted as defined in  claim 1 , or phenyl, optionally substituted as defined in  claim 1 . 
     
     
         30 . The method of  claim 29 , wherein Ar is a thienyl, pyrazole or thiazole ring each substituted by two or three C 1-4 alkyl, halogen, trifluoromethyl substituents and/or also substituted by a 2-pyrimidinyl or 2-pyridyl group. 
     
     
         31 . The method of  claim 29 , wherein Ar is a group of sub-formula (i): 
       
         
           
           
               
               
           
         
       
       in which R 10  and R 11  are independently H, C 1-4 alkyl, or haloC 1-6 alkyl and R 12  is H, C 1-6 alkyl, haloC 1-6 alkyl, or a 5- to 6-membered aromatic ring system in which up to 3 ring atoms are heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, which ring are optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, -N(R 6 )R 7 ,-(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2  N(R 6 )R 7 , in which R 6 , R 7 , R 8 , R 9  and p are as defined in  claim 1 . 
     
     
         32 . The method of  claim 31 , wherein R 10  and R 11  are methyl. 
     
     
         33 . The method of  claim 32 , wherein R 12  is H, C 1-3 alkyl or a 5- to 6- membered aromatic ring system in which up to 3 ring atoms are optionally heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, the ring system being optionally substituted by hydroxyl. 
     
     
         34 . The method of  claim 23 , wherein the compound of formula (1) is selected from the group consisting of:
 (S)-2-[[6-[(3,5-Dimethyl- 1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5 -yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   1-Cyclopropyl-6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (S)-2-[[6-](1H- 1,2,3-Benzotriazol- 1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6-](4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-1-ethyl- 3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   (4S)-4-methyl-2-[[1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(4- quinolinylmethyl)thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol,   (4S)-2-[[6-[(2,4-Dichloro-5-thiazolyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (4S)-2-[[6-[(3-Bromo-2-thienyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)- 2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione,   6-[[3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   5-[[(4S)-4-Hydroxy-4-methyl-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-2-[[6-[[3,5-Dimethyl-1-(4-pyridinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3- methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4- isoxazolidinol,   (4S)-2-[[6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]- 1,2,3 ,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4- isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [(1-phenyl-1H-pyrazol-4-yl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(8-Fluoroquinolin-4-yl)methyl]-5-{[(4S)-4-hydroxy-4-methylisoxazolidin-2- yl]carbonyl}-1-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   5-{[(4S)-4-Hydroxy-4-methylisoxazolidin-2-yl]carbonyl}-1-1-isopropyl-3-methyl-6-(4- pyrimidin-2-ylbenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [(5-(2-pyridinyl)-2-thienyl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(1,3-Dimethyl-1H-5-pyrazolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   6-[(3,5-Dimethyl-4-isothiozolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[1-(2-thiazolyl)- 1H-pyrazol-4-yl]methyl]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(4-Fluorophenyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3- methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-1,2,3-triazol-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(6-Chloroimidazo]1,2-a]pyridin-3-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-hydroxy-4-methylisoxazolidin-2-yl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[4-(2-pyridinyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-4-Methyl-2-[[1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-6-[[5-methyl-1-(2- pyrimidinyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-5 - yl]carbonyl]- 4-isoxazolidinol,   (4S)-2-[[6-[[3,5-Dimethyl- 1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-ethyl-4- isoxazolidinol,   (4S)-2-[[6-[[1-(2,3-Dihydro-2-oxo-4-pyrimidinyl)-3,5-dimethyl- 1H-pyrazol-4- yl]methyl]- 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5- yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4R)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione, and   pharmaceutically acceptable salts thereof.   
     
     
         35 . A method of treating cancer in a patient suffering from the cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (1): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-5 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; 
 R 3  is a group CO-G or SO 2 -G, where G is a 5- or 6-membered ring containing a nitrogen atom and a second heteroatom selected from the group consisting of oxygen and sulphur adjacent to the nitrogen; the ring being substituted by at least one group selected from the group consisting of halogen or C 4  alkyl optionally substituted by up to five halogen atoms, and optionally substituted by up to a further 4 groups independently selected from the group consisting of halogen, hydroxyl, and C 1-4  alkyl optionally substituted by up to five halogen atoms; 
 Q is CR 4 R 5 , where R 4  is hydrogen, fluorine or C 1-6  alkyl and R 5  is hydrogen, fluorine or hydroxy; 
 Ar is a 5- to 10-membered aromatic ring system in which up to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, -N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 ; or Ar is optionally substituted by a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; the 5 or 6 membered aromatic ring being optionally substituted by one or more substituents independently selected from the group consisting from C 1-4 alkyl optionally substituted by 1,2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, - N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2 N(R 6 )R 7 ; 
 p is 1,2,3or4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; and 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl 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; or 
 pharmaceutically acceptable salts thereof. 
 
     
     
         36 . The method of  claim 35 , wherein R 1  is ethyl, propyl, butyl or cyclopropyl. 
     
     
         37 . The method of  claim 35 , wherein R 2  is methyl. 
     
     
         38 . The method of  claim 35 , wherein R 3  is a group CO-G. 
     
     
         39 . The method of  claim 35 , wherein Q is CH 2 . 
     
     
         40 . The method of  claim 35 , wherein Ar is a 5-membered aromatic ring containing two heteroatoms optionally substituted as defined in  claim 1  or Ar is a 9- or 10- membered bicyclic ring containing one, two or three heteroatoms and optionally substituted as defined in  claim 1 , or phenyl, optionally substituted as defined in  claim 1 . 
     
     
         41 . The method of  claim 35 , wherein Ar is a thienyl, pyrazole or thiazole ring each substituted by two or three C 1-4 alkyl, halogen, trifluoromethyl substituents and/or also substituted by a 2-pyrimidinyl or 2-pyridyl group. 
     
     
         42 . The method of  claim 35 , wherein Ar is a group of sub-formula (i): 
       
         
           
           
               
               
           
         
       
       in which R 10  and R 11  are independently H, C 1-4 alkyl, or haloC 1-6 alkyl and R 12  is H, C 1-6 alkyl, haloC 1-6 alkyl, or a 5- to 6-membered aromatic ring system in which up to 3 ring atoms are heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, which ring are optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkly, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, -N(R 6 )R 7 , -(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbonyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbonyl, carboxy, and SO 2  N(R 6 )R 7 , in which R 6 , R 7 , R 8 , R 9  and p are as defined in  claim 1 . 
     
     
         43 . The method of  claim 42 , wherein R 10  and R 11  are methyl. 
     
     
         44 . The method of  claim 42 , wherein R 12  is H, C 1-3 alkyl or a 5- to 6- membered aromatic ring system in which up to 3 ring atoms are optionally heteroatoms independently selected from the group consisting of oxygen, sulphur and nitrogen, the ring system being optionally substituted by hydroxyl. 
     
     
         45 . The method of  claim 35 , wherein the compound of formula (1) is selected from the group consisting of:
 (S)-2-[[6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl- 1-(2- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   1-Cyclopropyl-6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (S)-2-[[6-](1H-1,2,3-Benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1- methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (S)-2-[[6-](4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-1-ethyl- 3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   (4S)-4-methyl-2-[[1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(4- quinolinylmethyl)thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol,   (4S)-2-[[6-[(2,4-Dichloro-5-thiazolyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2- methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   (4S)-2-[[6-[(3-Bromo-2-thienyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)- 2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione,   6-[[3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-4-methyl- 2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   5-[[(4S)-4-Hydroxy-4-methyl-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-2-[[6-[[3,5-Dimethyl-1-(4-pyridinyl)-1H-pyrazol-4-yl]methyl]- 1,2,3,4-tetrahydro-3- methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4- isoxazolidinol,   (4S)-2-[[6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4- isoxazolidinol,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [(1-phenyl-1H-pyrazol-4-yl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(8-Fluoroquinolin-4-yl)methyl]-5-{[(4S)-4-hydroxy-4-methylisoxazolidin-2- yl]carbonyl}-1-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   5-{[(4S)-4-Hydroxy-4-methylisoxazolidin-2-yl]carbonyl}-1-1-isopropyl-3-methyl-6-(4- pyrimidin-2-ylbenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-   (5-(2-pyridinyl)-2-thienyl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(1,3-Dimethyl-1H-5-pyrazolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-thieno[2,3-d]pyrimidine-2,4-(1H,3H)- dione,   6-[(3,5-Dimethyl-4-isothiozolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[1-(2-thiazolyl)- 1H-pyrazol-4-yl]methyl]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(4-Fluorophenyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3- methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- (1H-1,2,3-triazol-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   6-[(6-Chloroimidazo[1,2-a]pyridin-3-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,   5-[[(4S)-4-hydroxy-4-methylisoxazolidin-2-yl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[4-(2-pyridinyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,   (4S)-4-Methyl-2-[[1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-6-[[5-methyl-1-(2- pyrimidinyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-5 - yl]carbonyl]- 4-isoxazolidinol,   (4S)-2-[[6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-ethyl-4- isoxazolidinol,   (4S)-2-[[6-[[1-(2,3-Dihydro-2-oxo-4-pyrimidinyl)-3,5-dimethyl-1H-pyrazol-4- yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5- yl]carbonyl]-4-methyl-4-isoxazolidinol,   5-[[(4R)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6- [[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione, and   pharmaceutically acceptable salts thereof.