Thienopyriminediones and their use in the modulation of autoimmune disease
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Abstract
The invention relates to thienopyrimidinediones of formula (1) wherein R1 and R2 each independently represent a C1-6akyl, C3-6alkyl, C3-6alkenyl, C3-5cycloalkylC1-3alkyl or C3-6cycloalkyl; each of which may be optionally substituted by 1 to 3 halogen atoms R3 is a group CO-G or SO2-G where G is a 5- or 6-membered ring containing a nitrogen atom and a second heteroatom selected from oxygen and sulphur adjacent to the nitrogen; the ring being substituted by at least one group as defined in the specification, Q is CR4R5 where R4 is hydrogen, fluorine or C1-6 alkyl and R5 is hydrogen, fluorine or hydroxy; and Ar is a 5-10-membered aromatic ring system wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more groups defined in the specification; as well as pharmaccutically acceptable salts and solvates thereof. Processes for their preparation of the compounds, pharmaceutical compositions containing them and their use in therapy, in particular in immunosuppressive therapy are also described.
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Citations
17 Claims
- 1. A compound of formula (I):
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11. A compound of formula (I) selected from:
- (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,1H)-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,3H1)-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.
- (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,
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12. (canceled)
Specification