US2008207642A1PendingUtilityA1
Thienopyrimidinediones and Their Use in the Modulation of Autoimmune Disease
Est. expiryJul 28, 2021(expired)· nominal 20-yr term from priority
A61P 9/10A61P 35/00A61P 31/18A61P 37/00A61P 37/08A61P 37/06A61P 3/10A61P 43/00A61P 37/02A61P 27/16A61P 29/00A61P 25/00A61P 19/02A61P 11/06A61P 21/04A61P 11/00A61P 17/00C07D 495/04A61P 17/08A61P 13/12A61P 1/00A61P 21/00
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Claims
Abstract
The invention relates to a compound of formula (1): in which R 1 and R 2 each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; R 3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group; Q is —CO— or —C(R 4 )(R 5 )— in which R 4 is a hydrogen atom or C 1-4 alkyl and R 5 is a hydrogen atom or hydroxy group; and Ar is a 5- to 10-membered aromatic ring system in which up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents as defined in the specification. It also relates to methods of preparing, pharmaceutical compositions containing and methods of using the compound of the formula (1), particularly in the modulation of autoimmune disease.
Claims
exact text as granted — not AI-modified1 . 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 3-6 cycloalkylC 1-3 alkyl, or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms;
R 3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl, in which each ring is optionally substituted by one hydroxy group;
Q is —CO— or —C(R 4 )(R 5 )—; in which R 4 is a hydrogen atom or C 1-4 alkyl and
R 5 is a hydrogen atom or hydroxy group;
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 substitutes 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 ) 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, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur;
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, 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 a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein R 2 is methyl or ethyl.
3 . The method of claim 1 , wherein R 1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl, or 3,3,3-trifluoropropyl.
4 . The method of claim 1 , wherein Q is —CO— or —CH 2 —.
5 . The method of claim 1 , wherein Ar contains at least 1 ring nitrogen.
6 . The method of claim 1 , wherein Ar contains at least 2 ring nitrogens.
7 . The method of claim 1 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl, and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 1 .
8 . The method of claim 1 , wherein Ar is substituted by 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 2-4 alkanoyl, oxo, thioxo, cyano and —(CH 2 ) p N(R 8 )R 9 wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur.
9 . The method of claim 1 , wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trimethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-pyrrolo[2,3-h]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-carbonitrile;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxamide;
(S) 6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-yl methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl-1H-benzimidazol-1-yl methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
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;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxothiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; or
(S) 5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
or a pharmaceutically acceptable salt thereof.
10 . 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 3-6 cycloalkylC 1-3 alkyl, or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms;
R 3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl, in which each ring is optionally substituted by one hydroxy group;
Q is —CO— or —C(R 4 )(R 5 )—; in which R 4 is a hydrogen atom or C 1-4 alkyl and
R 5 is a hydrogen atom or hydroxy group;
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 substitutes 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 ) 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, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur;
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, 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, 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 a pharmaceutically acceptable salt thereof.
11 . The method of claim 10 , wherein R 2 is methyl or ethyl.
12 . The method of claim 10 , wherein R 1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl, or 3,3,3-trifluoropropyl.
13 . The method of claim 10 , wherein Q is —CO— or —CH 2 —.
14 . The method of claim 10 , wherein Ar contains at least 1 ring nitrogen.
15 . The method of claim 10 , wherein Ar contains at least 2 ring nitrogens.
16 . The method of claim 10 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl, and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 1 .
17 . The method of claim 10 , wherein Ar is substituted by 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 2-4 alkanoyl, oxo, thioxo, cyano and —(CH 2 ) p N(R)R 9 wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur.
18 . The method of claim 10 , wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trimethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-carbonitrile;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxamide;
(S) 6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyridine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-yl methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-t1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl-1H-benzimidazol-1-yl methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
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;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-[1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxothiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; or
(S) 5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
or a pharmaceutically acceptable salt thereof.
19 . 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 3-6 cycloalkylC 1-3 alkyl, or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms;
R 3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl, in which each ring is optionally substituted by one hydroxy group;
Q is —CO— or —C(R 4 )(R 5 )—; in which R 4 is a hydrogen atom or C 1-4 alkyl and
R 5 is a hydrogen atom or hydroxy group;
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 substitutes 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 ) 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, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur;
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, 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, 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 a pharmaceutically acceptable salt thereof.
20 . The method of claim 19 , wherein the obstructive airways disease is chronic obstructive pulmonary disease (COPD).
21 . The method of claim 19 , wherein R 2 is methyl or ethyl.
22 . The method of claim 19 , wherein R 1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl, or 3,3,3-trifluoropropyl.
23 . The method of claim 19 , wherein Q is —CO— or —CH 2 —.
24 . The method of claim 19 , wherein Ar contains at least 1 ring nitrogen.
25 . The method of claim 19 , wherein Ar contains at least 2 ring nitrogens.
26 . The method of claim 19 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl, and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 1 .
27 . The method of claim 19 , wherein Ar is substituted by 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 2-4 alkanoyl, oxo, thioxo, cyano and —(CH 2 ) p N(R 8 )R 9 wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur.
28 . The method of claim 19 , wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trimethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1 ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-carbonitrile;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxamide;
(S) 6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-1{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione-(S) 6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-yl methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl-1H-benzimidazol-1-yl methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
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;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxothiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; or
(S) 5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
or a pharmaceutically acceptable salt thereof.
29 . 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 3-6 cycloalkylC 1-3 alkyl, or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms;
R 3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl, in which each ring is optionally substituted by one hydroxy group;
Q is —CO— or —C(R 4 )(R 5 )—; in which R 4 is a hydrogen atom or C 1-4 alkyl and
R 5 is a hydrogen atom or hydroxy group;
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 substitutes 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 ) 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, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur;
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, 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, 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 a pharmaceutically acceptable salt thereof.
30 . The method of claim 29 , wherein R 2 is methyl or ethyl.
31 . The method of claim 29 , wherein R 1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl, or 3,3,3-trifluoropropyl.
32 . The method of claim 29 , wherein Q is —CO— or —CH 2 —.
33 . The method of claim 29 , wherein Ar contains at least 1 ring nitrogen.
34 . The method of claim 29 , wherein Ar contains at least 2 ring nitrogens.
35 . The method of claim 29 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl, and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 1 .
36 . The method of claim 29 , wherein Ar is substituted by 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 2-4 alkanoyl, oxo, thioxo, cyano and —(CH 2 ) p N(R 8 )R 9 wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulphur.
37 . The method of claim 29 , wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trimethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyri idine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-carbonitrile;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxamide;
(S) 6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyridine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-yl methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyhsoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydroxy-2-isoxazohdinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H-dione-1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl-1H-benzimidazol-1-yl methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
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;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxothiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; or
(S) 5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
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