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(11) | EP 1 414 825 B9 |
(12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
Note: Bibliography reflects the latest situation |
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(54) |
THIENOPYRIMIDINEDIONES AND THEIR USE IN THE MODULATION OF AUTOIMMUNE DISEASE THIENOPYRIMIDINEDIONE UND DEREN VERWENDUNG IN DER BEHANDLUNG VON AUTOIMMUNERKRANKUNGEN THIENOPYRIMIDINEDIONES ET LEUR UTILISATION DANS LA MODULATION DE MALADIES AUTO-IMMUNES |
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Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
R1 and R2 each independently represent a C1-6alkyl, C3-6alkenyl, C3-6cycloalkylC1-3alkyl or C3-6cycloalkyl; each of which may be optionally substituted by 1 to 3 halogen atoms;
R3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group;
Q is -CO- or -C(R4)(R5)- (wherein R4 is a hydrogen atom or C1-4alkyl and R5 is a hydrogen atom or hydroxy group);
Ar is a 5- to 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 substituents independently selected from C1-4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, thioxo, nitro, cyano, -N(R6)R7 and -(CH2)pN(R8)R9, hydroxy, C1-4alkylsulphonyl, C1-4alkylsulphinyl, carbamoyl, C1-4alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, carboxy, or a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur;
p is 1 to 4
R6 and R7 each independently represent a hydrogen atom, C1-4alkanoyl or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom, C1-4alkanoyl or C1-4alkyl, 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 or a hydrolysable esther prodrug thereof.
R1 is C1-5alkyl or C3-6cycloalkylmethyl;
R2 is C1-5alkyl;
R3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group;
Q is -CO- or -CH2- (wherein R4 is a hydrogen atom or C1-4alkyl and R5 is a hydrogen atom or a hydroxy group);
Aris a 5- to 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 1, 2 or 3 substituents independently selected from C1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, nitro, cyano, NR6R7 and -CH2NR8R9;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.
R1 is C1-5alkyl or C3-6cycloalkylmethyl;
R2 is C1-5alkyl;
R3 is hydroxyisoxazin-2-ylcarbonyl, tetrahydroisoxazin-2-ylcarbonyl or hydroxytetrahydroisoxazin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Ar is a 5- to 10-membered aromatic ring system containing up to 4 ring heteroatoms selected from nitrogen, oxygen and sulphur providing that there is at least 1 ring nitrogen, the ring system being optionally substituted by one or more substituents independently selected from C1-4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4 alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, thioxo, nitro, cyano, -N(R6)R7 and-(CH2)pN(R8)R9, hydroxy, C1-4alkylsulphonyl, C1-4alkylsulphinyl, carbamoyl, C1-4 alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, carboxy and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.R1 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.
R2 is methyl;
R3 is hydroxytetrahydroisoxazin-2-ylcarbonyl, tetrahydroisoxazin-2-ylcarbonyl or hydroxytetrahydroisoxazin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Ar is a 5- to 10-membered aromatic ring system containing up to 4 ring heteroatoms selected from nitrogen, oxygen and sulphur providing that there is at least 1 ring nitrogen, the ring system being optionally substituted by one or more substituents independently selected from C1-4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, thioxo, nitro, cyano, - N(R6)R7 and -(CH2)pN(R8)R9, hydroxy, C1-4alkylsulphonyl, C1-4alkylsulphinyl, carbamoyl, C1-4alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.
R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl;
R2 is methyl;
R3 is hydroxyisoxazolidin-2-ylcarbonyl, tetrahydroisoxazin-2-ylcarbonyl or hydroxytetrahydroisoxazin-2-ylcarbonyl;
Q is -CH2-;
Ar is a 5- to 10-membered aromatic ring system containing up to 4 ring heteroatoms selected from nitrogen, oxygen and sulphur providing that there is at least 1 ring nitrogen, the ring system being optionally substituted by 1 or 2 substituents independently selected from C1-4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C1-4alkoxy, halogen, trihaloalkyl, C1-4alkylthio, C2-4alkanoyl, oxo, thioxo, cyano and -(CH2)pN(R8)R9 (wherein p is 1 or 2), hydroxy, C1-4alkylsulphonyl, carbamoyl, C1-4alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur;
or a pharmaceutically-acceptable salt thereof.
R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl;
R2 is methyl;
R3 is 4-hydroxytetrahydroisoxazin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl;
Q is -CH2-;
Ar is selected from 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, the ring system being optionally substituted by 1 or 2 substituents independently selected from methyl, ethyl, n-propyl, iso-propyl, tert-butyl, 1-methylethyl, trifluoromethyl, chloro, fluoro, bromo, hydroxymethyl, acetyl, methylthio, amino, methylamino, furanyl, thienyl, pyrimidyl, phenyl, cyano, thioxo and oxo;
or a pharmaceutically-acceptable salt thereof.R1 and R2 each independently represent a C1-6alkyl, C3-6alkenyl, C3-5cycloalkylC1-3alkyl or C3-6cycloalkyl; each of which may be optionally substituted by 1 to 3 halogen atoms;
R3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group;
Q is -CO- or -C(R4) (R5)- (wherein R4 is a hydrogen atom or C1-4alkyl and R5 is a hydrogen atom or hydroxy group);
Ar is a 5- to 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 substituents independently selected from C1-4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, thioxo, nitro, cyano, -N(R6)R7 and -(CH2)pN(R8)R9, hydroxy, C1-4alkylsulphonyl, C1-4alkylsulphinyl, carbamoyl, C1-4alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, carboxy;
p is 1 to 4
R6 and R7 each independently represent a hydrogen atom, C1-4alkanoyl or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom, C1-4alkanoyl or C1-4 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 or a hydrolysable ester prodrug thereof.R1 is C1-5alkyl or C3-6cycloalkylmethyl;
R2 is C1-5alkyl;
R3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group;
Ar is a 5- to 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 1,2 or 3 substituents independently selected from C1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, nitro, cyano, NR6R7 and -CH2NR8R9;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.R1 is C1-5alkyl or C3-6cycloalkylmethyl;
R2 is C1-5alkyl;
R3 is hydroxytetrahydroisoxazin-2-ylcarbonyl or hydroxytetrahydroisoxazin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Ar is a 5- to 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 1, 2 or 3 substituents independently selected from C1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, nitro, cyano, NR6R7 and -CH2NR8R9;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.R1 is C1-5alkyl or C3-6cycloalkylmethyl;
R2 is methyl;
R3 is hydroxyisoxazolidin-2-ylcarbonyl or hydroxytetrahydroisoxazin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Aris a 5- to 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 1, 2 or 3 substituents independently selected from C1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4 alkoxycarbonyl, C2-4alkanoyl, oxo, nitro, cyano, NR6R7 and -CH2NR8R9;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl;
R2 is methyl;
R3 is hydroxyisoxazolidin-2-ylcarbonyl or hydroxytetrahydroisoxazin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Ar is a 5- to 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 1,2 or 3 substituents independently selected from C1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl. C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, nitro, cyano, NR6R7 and -CH2NR8R9;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl;
R2 is methyl;
R3 is hydroxyisoxazolidin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Ar is a 5- to 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 1, 2 or 3 substituents independently selected from C1-4alkyl, (optionally substituted by 1,2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4 alkoxycarbonyl, C2-4alkanoyl, oxo, nitro, cyano, NR6R7 and -CH2NR8R9;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl;
R2 is methyl;
R3 is hydroxyisoxazolidin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Ar is selected from imidazolyl, pyrazolyl, 2,3-dihydrothiazolyl, quinolyl, indolyl, benzimidazolyl, indazolyl, pyrrolo[2,3-b]pyridinyl, 1H-1,2,3-benzotriazolyl, 2,3-dihydrobenzothiazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzoxazolyl and 1,3-thiazolo[5,4-b]pyridinyl, the ring system being optionally substituted by 1, 2 or 3 substituents independently selected from C1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy group), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4 alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, nitro, cyano, NR6R7 and -CH2NR8R9;
R6 and R7 each independently represent a hydrogen atom or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom or C1-4 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.R1 is n-propyl, 1-methylethyl or 2-methylpropyl;
R2 is methyl;
R3 is 4-hydroxyisoxazolidin-2-ylcarbonyl;
Q is -CO- or -CH2-;
Ar is selected from imidazolyl, pyrazolyl, 2,3-dihydrothiazolyl, quinolyl, indolyl, benzimidazolyl, pyrrolo[2,3-b]pyridinyl, 1H-1,2,3-benzotriazolyl, 2,3-dihydrobenzothiazolyl, 2,3-dihydrobenzoxazolyl and 1,3-thiazolo[5,4-b]pyridinyl, the ring system being optionally substituted by 1,2 or 3 substituents independently selected from methyl, ethyl, propyl, tert-butyl, chloro, fluoro, thioxo, hydroxymethyl, methylthio, amino, methylamino and oxo;
or a pharmaceutically-acceptable salt thereof.(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-pynolo[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(1 H,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-tetrabydro-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]tbieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-rnethyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)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-[2-(methylamino)-3H-imidazo[4,5-b]pyridtn-3-ylmethyl]-1-propyl-thteno[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-diethyl-1H-pyrazol-4-ylmethyl]-5-(4-hydroxyisoxazolidin-2-yl]arbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3-(1,1-dimethyletltyl)-5-ntethyl-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[2,3,b]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[2,3,b]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-ylcarnonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-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-hydroxyisoxazotidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-amino-1H-benzirnidazol-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-dmethyl-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-dmethylisoxazol-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-(triHuoromethyl)-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-[(4S)-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-[(4S)-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; and
(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;
and pharmaceutically-acceptable salts thereof.Synthesis of Compounds of the Formula (1)
(1) (the respiratory tract) airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
(2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis;
(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; and
(7) cancer.
Inhibition of PMA/ionomycin-stimulated peripheral blood mononuclear cell proliferation
Abbreviations
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone | DDQ |
Dimethylformamide | DMF |
m-Chloroperoxybenzoic acid | mCPBA |
Tetrahydrofuran | THF |
Example 1
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
a) (S) Methyl 2-[4-hydroxyisoxazolidin-2-yl]carbonylbenzoate
b) (S)-4-Isoxazolidinol hydrochloride
c) Ethyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
d) Ethyl 1,2,3,4-tetrahydro-6-[hydroxy (4-quinolinyl)methyl]-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
e) Ethyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(4-quinolinylmethyl)-thieno[2,3-d]pyrimidine-5-carboxylate
f) Sodium 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(4-quinolinylmethyl)-thieno[2,3-d]pyrimodine-5-carboxlyate
g) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Example 2
(R) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
a) (R) Methyl 2-[4-hydroxyisoxazolidin-2-ylcarbonyl]benzoate
b) (R)-4-Isoxazolidinol hydrochloride
c) (R) 5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-(isobutyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Example 3
(S) 6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3,6-dimethyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
b) Methyl 6-(bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
c) Methyl 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
d) 6-[(4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
e) 6-[(4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-(S)-hydroxy-2-isoxazolidinlycarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 4
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-quinolinylcarbonyl)thieno[2,3-d]pryimidine-2,4(1H,3H)-dione
Example 5
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate.
b) 1,2,3,4-Tetrahydro-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid.
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 6
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3-methyl-1(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3,b]pyridin-3-ylmethyl)thieno[2,3,d]pyrimidine-5-carboxylate
b) 1,2,3,4-Tetrahydro-3-methyl-1(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3,b]pyridin-3-ylmethyl)thieno[2,3,d]pyrimidine-5-carboxlic acid
c) (S) 5-[[4-hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-(isobutyl)-6-[(1H-pyrrolo[2,3,b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione
Example 7
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)carbonyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Example 8
(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
a) Ethyl methyl 2-methyl-5-(N,N-methylethylamino)-thiophene-3,4-dicarboxylate
b) Methyl 1,2,3,4-tetrahydro-3,6-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
c) 6-(Bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester
d) 1,2,3,4-Tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester
e) 1,2,3,4-Tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid
f) (S) 5-[[4-Hydroxyisoxazolidin-2-yl]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
Example 9
(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
a) 6-Mercapto-3-methyl-1-propyl-pyrimidine-2,4(1H,3H)-dione
b) Methyl 1,2,3,4-tetrahydro-3,6-dimethyl-2,4-dioxo-1-propylthieno[2,3-d]pyrimidine-5-carboxylate
c) 6-(Bromomethyl)-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propylthieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester
d) 1,2,3,4-Tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester
e) 1,2,3,4-Tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid
f) (S) 5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 10
(S)6-[4,5-Dichloro-2-oxo-(2H)-thiazol-3-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3,6-dimethyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
b) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3,6-dimethyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
c) (S) 5-[4-[(1,1-dimethylethyl)dimethylsilyloxylisoxazolidin-2-ylcarbonyl]-3,6-dimethyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
d) (S) 6-(Bromomethyl)-5-[4-[(1,1-dimethylethyl)dimethylsilyloxy]isoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
e) (S) 6-[(4,5-Dichloro-2-oxo-3(2H)-thiazolyl)methyl]-5-[4-[(1,1-dimethylethyl)dimethylsilyloxy]isoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
f) (S) 6-[(4,5-Dichloro-2-oxo-3(2H)-thiazolyl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 11
(S) 6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcarbon-yl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
a) 6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid.
b) (S) 6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-5-{[4-hydroxyisoxazolidin-2-yl]carbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Example 12
(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
a) (S) 6-(Bromomethyl)-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
b) (S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Example 13i)
(R) 6-[(4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13ii) ,
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13iii)
(S) 6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13iv)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl] -3-methyl-1-(isobutyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
Example 13 v)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione
Example 13 vi)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 vii)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a)1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 viii)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[(2-Amino-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-[(2-Amino-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-(2-amino-1H-benzinudazol-1-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 ix)
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-5-carboxylate
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13x)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-5-carboxylate
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-)-6-[(2-thioxo-3(2H)-benzothiazolyl)methyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-thioxo-3(2H)-benzothiazolyl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 xi)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 4-Chloro-2-fluorothiazole
b) 4-Chloro-2(3H)-thiazolone
c) Methyl 6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
d) 6-[4-Chloro-2-oxo-3(2H)-thiazolylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
e) (S) 6-[4-Chloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 xii)
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[(2-oxo-1,3-benzoxazol-3(2H)-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylate
b) Sodium 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo-1,3-benaoxazol-3(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylate
c) (S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 xiii)
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 3-Nitropyridine-2-thiol
b) 3-Aminonyridine-2-thiol
c) [1,3]Thiazolo[5,4-b]pyridin-2(1H)-one
d) Methyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylate
e) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo[1,3]thiazolo[5,4-b]pyridin-1(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid
f) (S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-oxo[1,3]thiazolo[5,4-b]pyridin-1(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 xiv)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-(1H-1,2,3-Benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-(1H-1,2,3-Benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 xv)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl-3-methyl-1-(isobutyl)-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 xvi)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidiue-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]-2,4-dioxo- thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione
Example 13xvii)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[5-cyano-(1H)-indol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[5-Cyano-1H-indol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-[5-Cyano-1H-indol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[5-cyano-(1H)-indol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13xviii
(S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-5-carboxylate
b) 1,2,3,4-Tetralyrdro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo-3(2H)-benzthiazolylmethyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 13 xix
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-oyraxin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate.
b) 1,2,3,4-Tetrahydro-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (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
Example 14i)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid,
c) (S) 5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 14ii)
(R) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 1,2,3,4-tetrahydro-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester.
b) 1,2,3,4-Tetrahydro-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid.
c) (R) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 14iii)
(S) 5-[4-Hydroxylsoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl 3-methyl-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate.
b) Sodium 3-methyl-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate.
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-d]pyridin-3-yl)methyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 15i)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-pronyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) (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
Example 15 ii)
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-Dropyl-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester.
b) 6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt.
c) (S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 15iii
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
a) 1,2,3,4-tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) Sodium 1,2,3,4-tetxahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylate
c) 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-yl methyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 15iv
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
a) 6-[2-amino-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-[2-amino-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) 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
Example 16 i)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbouyl]-3-methyl-6-[2-(methylamino)-1H-beuzimidazol-1-ylmethyl]-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
c) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 16 ii)
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-5-carboxamide
a) 6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt.
c) (S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimudine-5-carboxamide
Example 16iii
(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
a)1,2,3,4-tetrahydro-6-[2-(hydroxvmethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(isopropyl)-2,4-dioxo- thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) Sodium 1,2,3,4-tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
c) (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
Example 16iv
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[2-amino-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo- thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) Sodium 6-[2-amino-1H-benzimidazol-1-yl methyl]-1,2,3,4-tetrahydro-3-methyl-1-(isopronyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
c) (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
Example 16 v)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isoprouyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl methyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid.
b) (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
Example 17i)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[3,5-diethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[3,5-Diethyl-1H-pyrazol-4-ylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid.
b) (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[3,5-diethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 17 ii)
(S) 5-[4-Hydroxyisoaazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 18i)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-methyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) N-Methoxy-N,2-dimethyl-4-quinolinecarboxamide
b) 2-Methyl-4-quinolinecarboxaldehyde
c) 1,1-Dimethylethyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
d) 1,1-Dimethylethyl 1,2,3,4-tetrahydro-6-[hydroxy(2-methyl-4-quinolinyl)methyl]-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
e) 1,1-Dimethylethyl 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[(2-methyl-4-quinolinyl)methyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
f) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-methyl-4-quinolinylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
g) (S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-methyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 18 ii)
(S) 6-[6-Fluoro-4-quinolinyimethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[6-Fluoro-4-quinolinyl(hydroxy)methyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester.
b) 6-[6-Fluoro-4-quinolinylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic, acid ethyl ester.
c) 6-[6-Fluoro-4-quinolinylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt.
d) (S) 6-[6-Fluom-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 18iii)
(S) 6-[8-Fluoro-4-quiuolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[8-Fluoro-4-quinolinyl(hydroxy)methyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester.
b) 6-[8-Fluoro-4-quinolinylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester.
c) 6-[δ-Fluoro-4-quinolinylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt.
d) (S) 6-[8-Fluoro-4-quinolinylmethyl]-5-{4-hydroxylsoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 18iv
(S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione
a) 6-[Hydroxy(5-quinolinyl)methyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester.
b) 3-Methyl-1-(isobutyl)-2,4-dioxo-6-(5-quinolinylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester.
c) 3-Methyl-1-(isobutyl)-2,4-dioxo-6-(5-quinolinylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid sodium salt.
d) (S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 19
(S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-Chloro-3-methyl-1-propylpyrimidine-2,4(1H,3H)-dione
b) 3-Methyl-1-propyl-6-mercaptopyrimidine-2,4(1H,3H)-dione
c) Ethyl 3-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
d) Ethyl 6-[hydroxy(quinolin-4-yl)methyl]-3-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
f) Sodium 3-methyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
g) (S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)dione
Example 20
(S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isopropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Diethyl 2-((isopropyl)amino)thionhene-3,4-dicarboxylate
b) Ethyl 1,2,3,4-tetrahydro-3-methyl-1-(isopronyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
c) 6-[Hydroxy(4-quinolinyl)methyl]-3-methyl-1-(isopropyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester
d) 3-Methyl-1-(isopropyl)-2,4-dioxo-6-(4-quinolinylmethyl)-1,2,3,4-tetralydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl ester.
e) 3-Methyl-1-(isopropyl)-2,4-dioxo-6-(4-quinolinylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt.
f) (S) 5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isopropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 21i)
(S) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-methyl-1H-pyrrolo[2,3,b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3,b]pyridin-3-ylmethyl)thieno[2,3,d]pyrimidine-5-catboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3,b]pyridin-3-ylmethyl)thieno[2,3,d]pyrimidine-5-carboxylic acid
c) (S) 5-[[4-Hydroxyrisoxazolidin-2-yl]carbonyl]-3-methyl-1-(isobutyl)-6-[(2-methyl-1H-pyrrolo[2,3,b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione
Example 21ii)
(R) 5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-methyl-1H-pyrrolo[2,3,b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione
Example 22
(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
a) Methyl 6-(bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate.
b) Methyl 1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate.
c) 1,2,3,4-Tetrahydro-3-methyl-1-(isouropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl methyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
d) (S) 5-[4-Hydroxyrisoxazolidin-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
Example 23
(S)-6-[4,5-Dichloro-2-(hydrommethyl)-1H-imidazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 4,5-Dichloro-1H-imidazole-2-methanol
b) 6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester
c) 6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
d) 6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 24
(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
a) 6-[3,5-Dimethyl-1H-pyrazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester
b) 6-[3,5-Dimethyl-1H-pyrazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo- thieno[2,3-d]pyrimidine-5-carboxylic acid
c) 6-[3,5-Dimethyl-1H-pyrazol-1-yl methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 25
(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
a) 6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) 6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-(isobutyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 26
(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
a) 6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-3-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahvdrothieno[2,3-d]pyrimidine-5-carboxylic acid sodium salt.
b) (S) 6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 26i)
(S) 6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidia-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-1-isopropyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid sodium salt
b) (S) 6-[3,5-Dimethyl-1H-pyrazol-4-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 27
(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
a) Methyl 6-[3,5-dimethylisoxazol-4-ylmethyl]-1-(isobutyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate.
b) 6-[3,5-dimethylisoxazol-4-ylmethyl]-1-(isobutyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid.
c) 6-[3,5-dimethylisoxazol-4-yl methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-yl carbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 28
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
a) 1-Ethyl-3,6-dimethyl-2,4(1H,3H)-pyrrimidinedione
b) 1-Ethyl-6-mercapto-3-methyl-2,4(1H,3H)-pyrimidinedione
c) Methyl 1-ethyl-1,2,3,4-tetrahydro-3,6-dimethyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
d) Methyl 6-(bromomethyl)-1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
e) Methyl 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
f) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4,dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt
g) 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
Example 28i)
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
a) 1-Ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxlic acid, methyl ester
b) 1-Ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) 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
Example 28ii
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
a) Methyl 1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-propyl-1H-benzimidazol-1-yl methyl]-thieno[2,3-d]pyrimidine-5-carboxylate
b) 1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-prouyl-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt
c) 1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidiaylcarbonyl]-3-methyl-6-)[2-propyl-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 28iii
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
a) Methyl 1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-oxo-3(2H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylate
b) 1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-oxo-3(2H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt
c) 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
Example 28iv
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
a) Methyl 1-ethyl-1,2,3,4-tetrahydro-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo- thieno[2,3-d]pyrimidine-5-carboxylate
b) 1-ethyl-1,2,3,4-tetrahydro-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt
c) 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
Example 28v)
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
a) 6-[5-cyano-1H-indol-1-ylmethyl]-1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1-[1-Ethyl-1,2,3,4-tetrahydro-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]- 1H-indole-5-carbonitrile
Example 29i
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-(1-isopronyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 29ii
5-[(4S)-4-Hydroxyisoyazolidin-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
a) Methyl 1-isobutyl-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
b)1-Isobutyl-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
c) 5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-phenyl-1H-pymol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione
Example 29iii
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
a) Methyl 1-isobulyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate.
b) 1-Isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid.
c) 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
Example 29iv
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.
a) 1-Isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid.
b) 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.
Example 29(v)
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.
a) Methyl 6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
b) 6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxyrlic acid sodium salt.
c) 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.
Example 29(vi)
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
Example 30
6-(1H-1,2,3-Benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxvisoxazolidiuylcarbooyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione
a) 6-(1H-1,2,3-benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-(1H-1,2,3-benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) 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
Example 31
5-[(4S)-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
a) 1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-6-[2-oxothiazolo[5,4-b]pyridin-1(2H)-ylmethyl]-thienor[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-6-[2-oxothiazolo[5,4-b]pyridin-1(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic
c) 5-[(4S)-4-Hdroxisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-oxothiazolo[5,4-b]pyridin-1(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 32
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylearbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-1-(isopropyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-Tetrahydro-3-methyl-1-(isopropyl)-6-[2-(methylsulfonyl)-1H-benzimidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
c) 6-[2,3-Dihydro-2-oxo-1H-benzixnidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
d) 6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 33
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
a) 5,6-Difluoro-2-mercaptobenzimiazole
b) 5,6-Difluoro-2-(methylthio)benzimidazole
c) 6-[5,6-Difluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 34
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
a) Methyl 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
b) 6-(Imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
c) 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
Example 35
3-Methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-ylcarbonyl)-thieno[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
Example 36
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
a) 6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid,
c) 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
Example 37
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
a) 2-(methylthio)- 1H-imidazo[4,5-b]pyridine
b) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
c) Sodium 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
d) 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
Example 37i
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
a) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-2,4-dioxo- thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-2,4-dioxo- thieno[2,3-d]pyrimidine-5-carboxylic acid
c) 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
Example 38
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
a) 1,2,3,4-tetrahydro-6-methyl-1-(isonropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 3-Ethyl-1,2,3,4-tetrahydro-6-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
c) 6-(Bromomethyl)-3-ethyl-1,2,3,4-tetrahydro-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
d) 6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-1,2,3,4-tetrahydro-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
e) 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
Example 39
5-[(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) 1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid
b) 5-[(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl-6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Example 40
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
a) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
b) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
c) 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
R1 and R2 each independently represent a C1-6alkyl, C3-6alkenyl, C3-6cycloalkylC1-3alkyl or C3-6cycloalkyl; each of which may be optionally substituted by 1 to 3 halogen atoms;
R3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group;
Q is -CO- or -C(R4)(R5)- (wherein R4 is a hydrogen atom or C1-4alkyl and R5 is a hydrogen atom or hydroxy group);
Ar is a 5- to 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 substituents independently selected from C1-4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C1-4alkoxyC1-4alkyl, C1-4alkylthio, C1-4alkoxycarbonyl, C2-4alkanoyl, oxo, thioxo, nitro, cyano, -N(R6)R7 and -(CH2)pN(R8)R9, hydroxy, C1-4alkylsulphonyl, C1-4alkylsulphinyl, carbamoyl, C1-4alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, carboxy, or a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur;
p is 1 to 4
R6 and R7 each independently represent a hydrogen atom, C1-4alkanoyl or C1-4alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring;
R8 and R9 each independently represent a hydrogen atom, C1-4alkanoyl or C1-4alkyl, 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 or a hydrolysable ester prodrug thereof.(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]pytimidine-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]pyrinydine-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-[(32-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-(hydroxyrnethyl)-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-hydroxyisoxnzolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[3,3-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-hydmxyisoxazolidin-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-diethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl]arbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1 H,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-guinolinylmethyl]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[2,3,b]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[2,3,b]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-yl)methyl]-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]pyrintidine-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-dmethyl-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-dmethylisoxazol-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-etliyl-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]pyrinudine-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-imdazol-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[3,3-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-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;
or a pharmaceutically-acceptable salt thereof.a) reacting a compound of the formula (10):
with isoxazolidine or tetrahydroisoxazine (each being optionally substituted by a
hydroxy group);
b) when Q is methylene, reacting a compound of the formula (11):
with a compound of the formula Ar;
c) when Q is methylene, reducing a compound of the formula (12):
d) reacting a compound of the formula (11) or (13) to form Ar by primary ring synthesis:
e) reacting a compound of the formula (14) with R1-L2:
R1 und R2 jeweils unabhängig voneinander für C1-6-Alkyl, C3-6-Alkenyl, C3-6-Cycloalkyl-C1-3-alkyl oder C3-6-Cycloalkyl stehen, die jeweils gegebenenfalls durch 1 bis 3 Halogenatome substituiert sein können;
R3 für Isoxazolidin-2-ylcarbonyl oder Tetrahydroisoxazin-2-ylcarbonyl steht, wobei jeder Ring gegebenenfalls durch eine Hydroxylgruppe substituiert ist;
Q für -CO- oder -C(R4) (R5)- steht (wobei R4 für ein Wasserstoffatom oder C1-4-Alkyl steht und R5 für ein Wasserstoffatom oder eine Hydroxylgruppe steht);
Ar für ein 5- bis 10gliedriges aromatisches Ringsystem steht, wobei bis zu vier Ringatome unabhängig voneinander aus Stickstoff, Sauerstoff und Schwefel ausgewählte Heteroatome sein können, wobei das Ringsystem gegebenenfalls durch einen oder mehrere Substituenten unabhängig voneinander ausgewählt aus C1-4-Alkyl (gegebenenfalls substituiert durch 1, 2 oder 3 Hydroxylgruppen), C1-4-Alkoxy, Halogen, Halogenalkyl, Dihalogenalkyl, Trihalogenalkyl, C1-4-Alkoxy-C1-4-alkyl, C1-4-Alkyl-thio, C1-4-Alkoxycarbonyl, C2-4-Alkanoyl, Oxo, Thioxo, Nitro, Cyano, -N(R6)R7 und -(CH2)pN(R8)R9, Hydroxy, C1-4-Alkylsulfonyl, C1-4-Alkylsulfinyl, Carbamoyl, C1-4-Alkylcarbamoyl, Di-(C1-4-alkyl)carbamoyl, Carboxy oder einen 5- oder 6gliedrigen aromatischen Ring mit bis zu 4 Heteroatomen unabhängig voneinander ausgewählt aus Stickstoff, Sauerstoff und Schwefel substituiert;
p für 1 bis 4 steht;
R6 und R7 jeweils unabhängig voneinander für ein Wasserstoffatom, C1-4-Alkanoyl oder C1-4-Alkyl stehen oder zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 7gliedrigen gesättigten heterocyclischen Ring bilden;
R8 und R9 jeweils unabhängig voneinander für ein Wasserstoffatom, C1-4-Alkanoyl oder C1-4-Alkyl stehen oder zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 7gliedrigen gesättigten heterocyclischen Ring bilden;
und deren pharmazeutisch annehmbare Salze und hydrolysierbare Ester und Prodrugs.(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-chinolinylmethyl)-thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(R)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-chinolinylmethyl)-thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[4,5-Dichlor-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3,d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-chinolinyl-carbonyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(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]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[4,5-Dichlor-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trimethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(R)-6-[(4,5-Dichlor-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2,9,5-trichlor-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[4-chlor-2-oxo-3(2H)-thiazolylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(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]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl) thieno[2,3-d]pyrimidin-2,4(1H, 3H) - dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-pyrrolo[2,3-b]-pyridin-1-ylmethyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(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]pyrimidin-2,4(1H,3H)-dion;
(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-indol-5-carbonsäurenitril;
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pylimidin-2,4(1H,3H)-dion;
(R)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[4,5-Dichlor-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxlazolidinylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[4,5-Dichlor-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(1-methylethyl)[2,3-d]pyrimidin-5-carbonsäureamid;
(S)-6-[3,5-Diethyl-1H-pyrazol-4-ylmethyl}-5-{4-hydroxyisoxazolidin-2-yl]carbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[3-(1,1-Dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoiazolidin-2-ylcarbonyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-chinolinylmethyl]thieno[2,3-d]pyrimidin-2, 4 (1H, 3H) -dion;
(S)-6-[6-Fluor-4-chinolinylmethyl]-5-(4-hydroxy-isoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl) thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[8-Fluor-4-chinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-chinolinylmethyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(chinolin-9-ylmethyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-chinolinylmethyl)-thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(R)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(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]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-1-propylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-propylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(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]pyrimidin-2,4(1H,3H)-dion;
(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]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[4,5-Dichlor-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[3,5-Dimethyl-1H-pyrazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
(S)-6-[3,5-Dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
6-[4,5-Dichlor-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methylthieno[2,3-d]pyrimidin-2,4 (1H,3H)-dion;
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinyl-carbonyl]-3-methyl-6-(1H-pyrrolo-[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-2, 4(1H,3H)-dion;
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinyl-carbonyl]-3-methyl-6-[2-propyl-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H)-benzothiazolyl-methyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
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]pyrimidin-2,4(1H,3H)-dion;
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano-1H-indol-1-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-9-ylmethyl]-3-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-(trifluormethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidin-2,9(1H,3H)-dion;
6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
6-(1H-1,2,3-Benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4H)-4-Hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxothiazolo[5,4-b]pyridin-1(2H)-yl)methyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
6-[5,6-Difluor-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxy-2-isoxazolidinyl-carbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]-pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
3-Methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-ylcarbonyl)-thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
6-[2-Brom-4,5-dichlor-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
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]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]-pyridin-3-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1-(iso-propyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(trifluormethyl)phenylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion;
5-[(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion; oder
(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]pyrimidin-2,9(1H,3H)-dion;
und deren pharmazeutisch annehmbare Salze handelt.a) Umsetzung einer Verbindung der Formel (10):
mit Isoxazolidin oder Tetrahydroisoxazin (jeweils gegebenenfalls substituiert durch
eine Hydroxylgruppe);
b) wenn Q für Methylen steht, Umsetzung einer Verbindung der Formel (11):
mit einer Verbindung der Formel Ar;
c) wenn Q für Methylen steht, Reduktion einer Verbindung der Formel (12):
d) Umsetzung einer Verbindung der Formel (11) oder (13) zur Bildung von Ar durch Primärringsynthese:
e) Umsetzung einer Verbindung der Formel (14) mit R1-L2:
R1 et R2 représentent chacun indépendamment C1-6alkyle, C3-6alcényle, C3-6cycloalkylC1-3alkyle ou C3-6cycloalkyle, dont chacun peut être éventuellement substitué par 1 à 3 atomes d'halogène ;
R3 est isoxazolidin-2-ylcarbonyle ou tétrahydroisoxazin-2-ylcarbonyle où chaque cycle est éventuellement substitué par un groupement hydroxy ;
Q est -CO- ou -C(R4)(R5)- (où R4 est un atome d'hydrogène ou C1-4alkyle et
R5 est un atome d'hydrogène ou un groupement hydroxy) ;
Ar est un système de cycle aromatique à 5 à 10 chaînons où jusqu'à 4 atomes du cycle peuvent être des hétéroatomes choisis indépendamment parmi azote, oxygène et soufre, le système de cycle étant éventuellement substitué par un ou plusieurs substituants choisis indépendamment parmi C1-4alkyle (éventuellement substitué par 1, 2 ou 3 groupements hydroxy), C1-4alcoxy, halogène, halogénoalkyle, dihalogénoalkyle, trihalogénoalkyle, C1-4alcoxyC1-4alkyle, C1-4alkylthio, C1-4alcoxycarbonyle, C2-4Calcanoyle, oxo, thioxo, nitro, cyano, -N(R6)R7 et - (CH2)pN(R8)R9, hydroxy, C1-4alkylsulfonyle, C1-4alkylsulfinyle, carbamoyle, C1-4alkylcarbamoyle, di-(C1-4alkyl)carbamoyle, carboxy, ou un cycle aromatique à 5 ou 6 chaînons contenant jusqu'à 4 hétéroatomes choisis indépendamment parmi azote, oxygène et soufre ;
p est 1 à 4
R6 et R7 représentent chacun indépendamment un atome d'hydrogène, C1-4alcanoyle ou C1-4alkyle, ou conjointement avec l'atome d'azote auquel ils sont attachés forment un cycle hétérocyclique saturé à 5 à 7 chaînons ;
R8 et R9 représentent chacun indépendamment un atome d'hydrogène, C1-4alcanoyle ou C1-4alkyle, ou conjointement avec l'atome d'azote auquel ils sont attachés forment un cycle hétérocyclique saturé à 5 à 7 chaînons ;
ou un sel pharmaceutiquement acceptable ou une prodrogue ester hydrolysable de celui-ci.(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-(4-quinoléinylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(R)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-(4-quinoléinylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[4,5-dichloro-2-méthyl-1H-imidazol-1-ylméthyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-1-(2-méthylpropyl)thiéno[2,3,d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-(4-quinoléinylcarbonyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[(2-méthyl-1H-indol-3-yl)méthyl]-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)méthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[(2-méthyl-1H-indol-3-yl)carbonyl]-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(1-méthyléthyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[4,5-dichloro-2-oxo-3(2H)-thiazolylméthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[(3,5-diméthyl-1H-pyrazol-4-yl)méthyl]-5-(4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-méthylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-méthyl-6-[1,3,5-triméthyl-1H-pyrazol-4-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(R)6-[(9,5-dichloro-2-méthyl-1H-imidazol-1-yl)méthyl]-5-[4-hydroxy-isoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[(2méthyl-1H-benzimidazol-1-yl)méthyl]-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 6-[(2-éthyl-1H-benzimidazol-1-yl)méthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)méthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[2-(méthylthio)-1H-benzimidazol-1-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxyméthyl)-1H-benzimidazol-1-ylméthyl]-3-méthyl-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[2-(méthylamino)-1H-benzimidazol-1-ylméthyl]-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[2-amino-1H-benzimidazol-1-ylméthyl]-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[2,4,5-trichloro-1H-imidazol-1-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[4-chloro-2-oxo-3(2H)-thiazolylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-méthyl-1-(2-méthylpropyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-méthyl-1-(2-méthylpropyl)-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)méthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-(1H-1,2,3-benzotriazol-1-ylméthyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-(1H-pyrrolo[2,3-b]pyridin-1-ylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[(2-méthyl-1H-pyrrolo[2,3-b]pyridin-1-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)1-[1,2,3,4-tétrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-2,4-dioxothiéno[2,3-d]pyrimidin-6-ylméthyl)-5-carbonitrile ;
(S)5-(4-hydroxyisoxazolidin-2-ylcarbonyl)-3-méthyl-1-(2-méthylpropyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(R)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[2-méthyl-1H-indol-3-ylméthyl]-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[7-méthyl-1H-indol-3-ylméthyl]-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[2-(méthylamino)-3H-imidazo[4,5-b]pyridin-3-ylméthyl]-1-propyl-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[4,5-dichloro-2-méthyl-1H-imidazol-1-ylméthyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-1-propyl-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[2-(méthylamino)-1H-benzimidazol-1-ylméthyl]-1-(1-méthyléthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[4,5-dichloro-2-méthyl-1H-imidazol-1-ylméthyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-1-(1-méthyléthyl)thiéno[2,3-d]pyrimidine-5-carboxamide ;
(S)6-[3,5-diéthyl-1H-pyrazol-4-ylméthyl]-5-{4-hydroxyisoxazolidin-2-yl]carbonyl}-3-méthyl-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[3-(1,1-diméthyléthyl)-5-méthyl-1H-pyrazol-4-ylméthyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl-3-méthyl-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[2-méthyl-4-quinoléinylméthyl]thiéno[2,3-d]pyrimidine-2,9(1H,3H)-dione ;
(S)6-[6-fluoro-4-quinoléinylméthyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl)-3-méthyl-1-(2-méthylpropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[8-fluoro-4-quinoléinylméthyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-méthyl-1-(2-méthylpropyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-méthyl-1-(2-méthylpropyl)-6-(5-quinoléinylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-méthyl-1-propyl-6-(quinoléin-4-ylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-méthyl-1-(1-méthyléthyl)-6-(4-quinoléinylméthyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[(2-méthyl-1H-pyrrolo[2,3-b]pyridin-3-yl)méthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(R)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(2-méthylpropyl)-6-[(2-méthyl-1H-pyrrolo[2,3-b]pyridin-3-yl)méthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isobutyl)-6-[2,3-dihydro-6-méthyl-3-oxo-pyrazin-2-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-6-[(2-méthyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)méthyl]-1-propyl-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxyméthyl)-1H-benzimidazol-1-ylméthyl]-3-méthyl-1-propyl-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-propyl-6-[2-amino-1H-benzimidazol-1-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxyméthyl)-1H-benzimidazol-1-ylméthyl]-3-méthyl-1-(isopropyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isopropyl)-6-[2-méthyl-1H-pyrrolo[2,3-b]pyridin-1-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isopropyl)-6-[2-méthyl-1H-pyrrolo[2,3-b]pyridin-3-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-6-[4,5-dichloro-2-(hydroxyméthyl)-1H-imidazol-1-ylméthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isobutyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-6-[3,5-diméthyl-1H-pyrazol-1-ylméthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isobutyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylméthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isobutyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)6-[3,5-diméthyl-1H-pyrazol-4-ylméthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-propylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)6-[3,5-diméthyl-1H-pyrazol-4-ylméthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-méthylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
(S)-6-[3,5-diméthylisoxazol-4-ylméthyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-méthylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-[4,5-dichloro-2-méthyl-1H-imidazol-1-ylméthyl]-1-éthyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
1-éthyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-6-(1H-pyrrolo-[2,3-b]pyridin-3-ylméthyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
1-éthyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-6-[2-propyl-1H-benzimidazol-1-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
1-éthyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-6-[2-oxo-3(2H)-benzothiazolylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
1-éthyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-6-[2-méthyl-1H-pyrrolo[2,3-b]pyridin-3-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
1-éthyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-6-[5-cyano-1H-indol-1-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-diméthyl-1H-pyrazol-4-ylméthyl]-3-méthylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-méthyl-6-[5-méthyl-3-phényl-1H-pyrazol-4-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-méthyl-6-[5-méthyl-3-(trifluorométhyl)-1H-pyrazol-4-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-méthyl-1H-pyrazol-4-ylméthyl]-3-méthylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-[3,5-diméthyl-1-phényl-1H-pyrazol-4-ylméthyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-méthylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-[3,5-diméthyl-1-phényl-1H-pyrazol-4-ylméthyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-propylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-(1H-1,2,3-benzotriazol-1-ylméthyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-méthyl-1-(isopropyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-méthyl-1-(isopropyl)-6-[(2-oxothiazolo[5,4-b]pyridin-1(2H)-yl)méthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylméthyl]-5-[(S)-4-hydroxyisoxazolidinylcarbonyl]-3-méthyl-1-(isopropyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylméthyl]-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-1-(isobutyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylméthyl)-1-isobutyl-3-méthylthiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
3-méthyl-6-[2-méthylindol-3-ylméthyl]-1-(isobutyl)-5-(tétrahydroisoxazin-2-ylcarbonyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylméthyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-méthyl-1-(isobutyl)thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isobutyl)-6-[2-(méthylthio)-1H-imidazo[4,5-b]pyridin-1-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-méthyl-1-(isobutyl)-6-[2-(méthylthio)-3H-imidazo[4,5-b]pyridin-3-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
6-[3,5-diméthyl-1H-pyrazol-4-ylméthyl]-3-éthyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1-(isopropyl)-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-1-(isobutyl)-6-[2-(trifluorométhyl)phénylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-méthyl-1-(isobutyl)-6-[2-(méthylthio)-1H-imidazol-1-ylméthyl]-thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ; ou
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-méthyl-1-(isopropyl)-6-[2-méthyl-1H-pyrrolo[2,3-b]pyridin-3-ylméthyl]thiéno[2,3-d]pyrimidine-2,4(1H,3H)-dione ;
ou un sel pharmaceutiquement acceptable de celui-ci.a) la réaction d'un composé de formule (10) :
avec une isoxazolidine ou une tétrahydroisoxazine (chacune étant éventuellement substituée
par un groupement hydroxy) ;
b) lorsque Q est méthylène, la réaction d'un composé de formule (11) :
avec un composé de formule Ar ;
c) lorsque Q est méthylène, la réduction d'un composé de formule (12) :
d) la réaction d'un composé de formule (11) ou (13) pour former Ar par synthèse de
cycle primaire :
e) la réaction d'un composé de formule (14) avec R1-L2 :
REFERENCES CITED IN THE DESCRIPTION
Patent documents cited in the description
Non-patent literature cited in the description