Thienopyrimidinediones and their use in modulation of autoimmune disease

Abstract

The invention relates to thienopyrimidinediones of formula (I): in which R 1 , R 2 , Q are as defined in the specification, and Ar and Ar 2 are selected from certain aromatic ring systems which may be optionally substituted, as defined in the specification. Processes for the preparation of compounds of formula (I), pharmaceutical compositions containing them and their use in therapy are also described.

1 . A method of inhibiting the proliferation of T cells, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent 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; 
 Q is CR 4 R 5 , in which 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 optionally 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 or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 Ar 2  is a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, sulphur or oxygen, and which is optionally substituted by one or more groups independently selected from the group consisting of C 1-4 alkyl (optionally substituted by 1, 2 or 3 hydroxy or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 or a pharmaceutically acceptable salt thereof, provided that the compound is other than 5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  is C 1-6  alkyl. 
     
     
         3 . The method of  claim 1 , wherein R 2  is methyl. 
     
     
         4 . The method of  claim 1 , wherein Q is CH 2 . 
     
     
         5 . The method of  claim 1 , wherein Ar is a 5 or 6-membered aromatic ring system wherein up to 2 ring atoms are optionally 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, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         6 . The method of  claim 5 , wherein Ar is a group of sub-formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 10  and R 11  are independently selected from H, C 1-4 alkyl, or haloC 1-4 alkyl. 
     
     
         7 . The method of  claim 1 , wherein Ar 2  is other than phenyl. 
     
     
         8 . The method of  claim 7 , wherein Ar 2  contains at least one heteroatom. 
     
     
         9 . The method of  claim 1 , wherein Ar 2  is a 5 or 6-membered aromatic ring system wherein up to 3 ring atoms are optionally 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 C 1-4 alkyl, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         10 . The method of  claim 9 , wherein Ar 2  is pyridinyl or pyrimidinyl. 
     
     
         11 . The method of  claim 9 , wherein Ar 2  is thiazolyl. 
     
     
         12 . The method of  claim 1 , wherein the compound is selected from the group consisting of (S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-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-isoxazolidinol and pharmaceutically acceptable salts thereof. 
     
     
         13 . A method of effecting immunosuppression, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent 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; 
 Q is CR 4 R 5 , in which 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 optionally 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 or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 Ar 2  is a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, sulphur or oxygen, and which is optionally substituted by one or more groups independently selected from the group consisting of C 1-4 alkyl (optionally substituted by 1, 2 or 3 hydroxy or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 or a pharmaceutically acceptable salt thereof, provided that the compound is other than 5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof. 
 
     
     
         14 . The method of  claim 13 , wherein R 1  is C 1-6  alkyl. 
     
     
         15 . The method of  claim 13 , wherein R 2  is methyl. 
     
     
         16 . The method of  claim 13 , wherein Q is CH 2 . 
     
     
         17 . The method of  claim 13 , wherein Ar is a 5 or 6-membered aromatic ring system wherein up to 2 ring atoms are optionally 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, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         18 . The method of  claim 17 , wherein Ar is a group of sub-formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 10  and R 11  are independently selected from H, C 1-4 alkyl, or haloC 1-4 alkyl. 
     
     
         19 . The method of  claim 13 , wherein Ar 2  is other than phenyl. 
     
     
         20 . The method of  claim 19 , wherein Ar 2  contains at least one heteroatom. 
     
     
         21 . The method of  claim 13 , wherein Ar 2  is a 5 or 6-membered aromatic ring system wherein up to 3 ring atoms are optionally 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 C 1-4 alkyl, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         22 . The method of  claim 21 , wherein Ar 2  is pyridinyl or pyrimidinyl. 
     
     
         23 . The method of  claim 21 , wherein Ar 2  is thiazolyl. 
     
     
         24 . The method of  claim 13 , wherein the compound is selected from the group consisting of (S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-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-isoxazolidinol and pharmaceutically acceptable salts thereof. 
     
     
         25 . 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 (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent 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; 
 Q is CR 4 R 5 , in which 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 optionally 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 or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 Ar 2  is a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, sulphur or oxygen, and which is optionally substituted by one or more groups independently selected from the group consisting of C 1-4 alkyl (optionally substituted by 1, 2 or 3 hydroxy or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 or a pharmaceutically acceptable salt thereof, provided that the compound is other than 5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof. 
 
     
     
         26 . The method of  claim 25 , wherein the obstructive airways disease is chronic obstructive pulmonary disease. 
     
     
         27 . The method of  claim 25 , wherein R 1  is C 1-6  alkyl. 
     
     
         28 . The method of  claim 25 , wherein R 2  is methyl. 
     
     
         29 . The method of  claim 25 , wherein Q is CH 2 . 
     
     
         30 . The method of  claim 25 , wherein Ar is a 5 or 6-membered aromatic ring system wherein up to 2 ring atoms are optionally 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, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         31 . The method of  claim 30 , wherein Ar is a group of sub-formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 10  and R 11  are independently selected from H, C 1-4 alkyl, or haloC 1-4 alkyl. 
     
     
         32 . The method of  claim 25 , wherein Ar 2  is other than phenyl. 
     
     
         33 . The method of  claim 32 , wherein Ar 2  contains at least one heteroatom. 
     
     
         34 . The method of  claim 25 , wherein Ar 2  is a 5 or 6-membered aromatic ring system wherein up to 3 ring atoms are optionally 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 C 1-4 alkyl, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         35 . The method of  claim 34 , wherein Ar 2  is pyridinyl or pyrimidinyl. 
     
     
         36 . The method of  claim 34 , wherein Ar 2  is thiazolyl. 
     
     
         37 . The method of  claim 25 , wherein the compound is selected from the group consisting of (S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-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-isoxazolidinol and pharmaceutically acceptable salts thereof. 
     
     
         38 . A method of treating cancer in a patient suffering from the cancer, comprising administering to the patient a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent 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; 
 Q is CR 4 R 5 , in which 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 optionally 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 or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 Ar 2  is a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, sulphur or oxygen, and which is optionally substituted by one or more groups independently selected from the group consisting of C 1-4 alkyl (optionally substituted by 1, 2 or 3 hydroxy or halo groups), C 1-4 alkoxy, halogen, 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 ) p N(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, SO 2 N(R 8 )R 9 ; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring optionally containing a further O, S, NH or N-alkyl group; 
 or a pharmaceutically acceptable salt thereof, provided that the compound is other than 5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or 
 6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof. 
 
     
     
         39 . The method of  claim 38 , wherein R 1  is C 1-6  alkyl. 
     
     
         40 . The method of  claim 38 , wherein R 2  is methyl. 
     
     
         41 . The method of  claim 38 , wherein Q is CH 2 . 
     
     
         42 . The method of  claim 38 , wherein Ar is a 5 or 6-membered aromatic ring system wherein up to 2 ring atoms are optionally 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, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         43 . The method of  claim 42 , wherein Ar is a group of sub-formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 10  and R 11  are independently selected from H, C 1-4 alkyl, or haloC 1-4 alkyl. 
     
     
         44 . The method of  claim 38 , wherein Ar 2  is other than phenyl. 
     
     
         45 . The method of  claim 44 , wherein Ar 2  contains at least one heteroatom. 
     
     
         46 . The method of  claim 38 , wherein Ar 2  is a 5 or 6-membered aromatic ring system wherein up to 3 ring atoms are optionally 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 C 1-4 alkyl, C 1-4 alkoxy, halogen, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, oxo, thioxo, cyano and C 1-4 alkylsulphonyl. 
     
     
         47 . The method of  claim 46 , wherein Ar 2  is pyridinyl or pyrimidinyl. 
     
     
         48 . The method of  claim 46 , wherein Ar 2  is thiazolyl. 
     
     
         49 . The method of  claim 38 , wherein the compound is selected from the group consisting of (S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-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-isoxazolidinol and pharmaceutically acceptable salts thereof.