MXPA99010911A

MXPA99010911A - Novel compounds

Info

Publication number: MXPA99010911A
Application number: MXPA/A/1999/010911A
Authority: MX
Inventors: Furber Mark; Cooper Martin; Cheshire David; Perry Matthew; Thorne Philip; Donald David; Cooke Andrew
Original assignee: Astra Pharmaceuticals Ltd
Priority date: 1997-05-28
Filing date: 1999-11-25
Publication date: 2000-09-04

Abstract

A compound of formula (I), wherein R, R1, R2 and R3 have the meanings given in the description. Compound (I) is useful in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).

Description

NOVEL COMPOUNDS DESCRIPTION OF THE INVENTION This invention relates to pharmaceutically useful compounds, to processes for their production, to pharmaceutical compositions containing them and to methods of treatment involving their use. T cells play an important role in the immune response, however, in autoimmune diseases, T cells are activated against particular tissues, for example causing inflammation associated with rheumatoid arthritis. Interleukin-2 (IL-2) is an essential autocrine growth factor for cells. T and therefore the inhibition of transcription of IL-2 is beneficial in the modulation of autoimmune diseases. The formation of a nuclear factor transcriptional complex of activated T-cell protein 1 (NFTA-1) in the IL-2 promoter is essential for the transcription of IL-2. The mediated transcription of NFTA-I has hitherto been proposed as an appropriate molecular target for immunomodulation, Y. Baine eü al. , I munol. , 1995, 154, 3667-3677. W "~ F. Michne et al., In J. Med. Chem. (1995) 38, 2557-2569 describes numerous quinazoline-2,4-diones and pyrrolo [3,4- REF. 32030 d] pyrimidine-2,4-diones which inhibit transcription regulated by the region of DNA bound by the NFTA-I protein. We have now found novel thieno [2,3-d] pyrimidinediones which show pharmacological activity, and in particular immunosuppressive activity. In a first aspect, the invention therefore provides a compound of formula (I): (I) wherein R is -C (0) Ar \ -C (R4) (R ^ Ar1 or Ar2; Ar1 is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each of which may be optionally substituted by one or more substituents which are selected from C 1 alkyl, C 1 alkoxy, halogen or trifluoromethyl, or Ar 1 is phenyl optionally substituted by one or more substituents which are selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl, amino, nitro, cyano, t ri f luor orne t oxy, phenoxy, -CH2N (R6) 2, • NHS02CF3 alkylsulfonylamino of C?, NHC (0) RSa, C02R7 or -C (0) NR8R8a; R4 represents H or C 1-4 alkyl, R s represents H or OH, each R 6 independently represents H or C 1-4 alkyl, preferably methyl or ethyl, R 6 a represents H, C 1-6 alkyl, aryl or C 4 alkyl, wherein the aryl group or the aryl portion in the aralkyl group is phenyl or pyridyl, each of which may be optionally substituted by one or more substituents that are selected Examples of C 1-4 alkyl, C 1 alkoxy, C 1-4 alkylcarbonylamino, halogen or trifluoromethyl, - R 7 represents H or C 1-4 alkyl, preferably methyl or ethyl, - R 8 and R a and p independently each, H C 1-4 alkyl, preferably methyl or ethyl, phenyl or pyridyl, acenaphtenyl indanyl iminodihydrobenzofuranyl or fluorenyl, each of which may be optionally substituted by one or more substituents which are selected from OH, C 1 alkyl, -C1-4 alkoxy, halogen or trifluoromethyl; R1 and R2 are independently H, alkyl of C ^ g, alkenyl of C3_s, CH2, cycloalkyl of C3-B or cycloalkyl of R3 represent H, X-R9 or X-Ar3; X represents S (0) n, C (0) NR10, C (0) 0, NH (CO) NR10, NH (CO) 0 or S02NR10; n is 0, 1 or 2; R9 represents a methyl group optionally substituted by one or more substituents that are selected from CN, C02H, C 1-5 alkoxycarbonyl, 5-tetrazolyl, S02NH2 or C (0) NR1: LR12 OR R9 represents C2_6 alkyl or C3- alkenyl 6, each of which may be optionally substituted by one or more substituents selected from OH, CN, C02H, C1-s alkoxy, C1-s alkoxycarbonyl, 5-tetrazolyl, azide, phthalimido, S02NH2, C. { 0) RX1R12, NR13R14, NHC (0) R1S or NHS02R16 where R11, R12, R13 and R14, each independently, represent H or C1-4 alkyl, R15 represents C1-4 alkyl, C1-4 alkoxy, and (C1-4 dialkyl) amino or alkoxyalkylene containing up to 6 carbon atoms, and R1S represents C1.4 alkyl or trifluoromethyl; or additionally, in the case where X represents C (0) NRXO, NH (CO) NR10 or S02NR10, R9 and R10 together with the nitrogen atom to which they are attached, can form a 4- to 7-membered heterocyclic ring on the which may be optionally substituted by one or more OH groups; R10 represents H, C1-s alkyl or is attached to R9 as defined above; and Ar3 is phenyl, pyridyl or pyridine N-oxide, each of which may be optionally substituted by one or more substituents which are selected from OH, N02, NH2, NHS02CF3, C1-4 alkoxy, C1-bis-alkanesulfonylamino 4, C1-4 alkylcarbonylamino or C1-4 alkoxycarbonylamino; or a pharmaceutically acceptable salt or solvate thereof. In the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl portion in a substituent group may be linear or branched. When a substituent on an alkenyl group is OH, phthalimido, NR13R14 or NHC (0) R15, the substituent does not bind to an unsaturated carbon atom. The alkyl portions in a di (C1-4 alkyl) amino group may be the same or different. The group R is -C (0) Ar \ -C (R4) (RE) Arx or Ar2. The group R 4 represents H or C 1-4 alkyl, preferably methyl or ethyl, and the group R 5 represents H or OH. Preferably, Ar 1 is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each of which may be optionally substituted by one to four, particularly one or two substituents which are selected from C 1-4 alkyl (eg methyl or ethyl) ), C 1-4 alkoxy (for example methoxy or ethoxy), halogen (for example fluorine, chlorine or bromine) or trifluoromethyl or Ar 1 e phenyl optionally substituted by one to four, particularly one or two substituents which are selected from C 1 alkyl -4 (for example methyl or ethyl), C1-4 alkoxy (for example methoxy or ethoxy), halogen (for example fluorine, chlorine or bromine), trifluoromethyl, amino, nitro, cyano, trifluoro ethoxy, phenoxy, -CH2N ( RS) 2, -NHS02CF3, C1-4 alkylsulfonylamino, -NHC (0) R6a, C02R7 or -C (0) NR8R8a. More preferably, Ar 1 is a naphthyl, quinolyl or benzofuranyl group, or a phenyl group optionally substituted by one or two substituents that are selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl, nitro, amino, cyano, phenoxy or -NHC (0) RS. The group Ar2 is preferably acenaphthenyl, indanyl, iminodihydrobenzofuranyl or fluorenyl, each of which may be optionally substituted by one to four, particularly one or two substituents which are selected from OH, C1-4alkyl (for example methyl or ethyl) , C 1-4 alkoxy (for example methoxy or ethoxy), halogen (for example fluorine, chlorine or bromine) or trifluoromethyl. Especially preferred are indanyl, iminodihydrobenzofuranyl and indanyl groups substituted with hydroxy. Preferably R6a is H, C1-S alkyl, particularly C1-4 alkyl, aryl or aralkyl of 1? , wherein the aryl group or the aryl moiety in the aralkyl group is phenyl or pyridyl, each of which may be optionally substituted by one to four, especially one or two substituents which are selected from C 1-4 alkyl, (per example methyl or ethyl), C x 4 alkoxy (for example methoxy or ethoxy), C 1-4 alkylcarbonylamino (for example methyl- or ethylcarbonylamino), halogen (for example fluorine, chlorine or bromine) or trifluoromethyl. Most preferably, RS represents a phenyl or phenylalkyl group substituted on the aromatic ring by one or two substituents which are selected from methoxy and methylcarbonylamino. Preferably, R1 and R2 are independently H, C1-4 alkyl, C3-4 alkenyl or C3-6 cycloalkyl. It is preferred that R1 is C3.4 alkyl or C4 alkenyl, in particular 1-methylethyl, 2-methylpropyl or 2-methylpropenyl. It is preferred that R2 is H or, especially, methyl. R3 represents H, X-R9 or X-Ar3. X represents S (0) n where n is 0, 1 or 2, C (0) NR10, C (0) 0, NH (C0) NR10, NH (C0) 0 or S02NR10. Preferably, R9 represents a methyl group optionally substituted by CN, C02H, C1-5 alkoxycarbonyl, 5-tetrazolyl, S02NH2 or C (O) NR1XR12, or R9 preferably represents C2-6 alkyl or C3-alkenyl, each of which may be optionally substituted by one to four, particularly one or two substituents which are selected from OH, CN, C02H, C1-S alkoxy, C ^, 5-tetrazolyl alkoxycarbonyl, azide, phthalimido, S02NH2, CIOJNR ^ R12 , R13R14, NHC (0) R15 or NHS02R16 wherein R11, R12, R13 and R14 each independently represents H or Ci-n alkyl particularly methyl or ethyl, R15 represents C ^ alkyl, particularly methyl or ethyl, C-alkoxy; ^, particularly methoxy or ethoxy, di (C1-4 alkyl) amino, particularly dimethylamino or diethylamino or alkoxyalkylene containing from 2 to 4 carbon atoms, and R1S represents C1-4 alkyl, preferably methyl or ethyl, or trifluoromethyl; or else, in the case where X represents C (0) NR10, NH (C0) NR10 or S02NR10, R9 and R10 together with the nitrogen atom to which they are attached, can form a 5- or 6-membered heterocyclic ring which may be optionally substituted by one or two OH groups. More preferably, R9 represents a methyl group optionally substituted by C02H or C (O) NR13-R12, or a C2-4 alkyl group (for example ethyl, propyl or butyl) which optionally may be substituted by one or two substituents selected from OH, C02H, C1-s alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl), azide, phthalimido, NR13R14, NHC (0) R15 or NHS02R16; or R9 and R10, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring which may be optionally substituted by an OH group. Preferably, R10 represents H, C1-2 alkyl, especially methyl, or is attached to R9 as defined above.

More preferably, each of R11, R12, R13 and R14 represents hydrogen. More preferably, R1S represents methyl, methoxy, dimethylamino or methoxymethylene. More preferably, R16 represents methyl or trifluoromethyl. Preferably, Ar3 is phenyl, pyridyl or pyridine N-oxide, each of which may optionally be substituted by one to four, particularly one or two substituents which are selected from OH, N02, NH2, NHS02CF3. C 1-4 alkoxy (particularly methoxy or ethoxy), C 1-4 bis-alkanesulfonylamino (particularly C 1-2 bis-alkanesulfonylamino), C 1-4 alkylcarbonylamino (particularly C1-2 alkylcarbonylamino) or C1-4 alkoxycarbonylamino (particularly C1-2 alkoxycarbonylamino). The group Ar3 is most preferably phenyl, pyridyl or pyridine N-oxide, each of which may be optionally substituted by one or two substituents which are selected from OH, N? 2, NH2, methoxy, bis-methanesulfonylamino , methylcarbonylamino or methoxycarbonylamino. Particularly preferred compounds of the invention include: 6- (4-methoxyphenylmethyl) -3-methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 6- (4-methoxy-phenylmethyl) -3 -methyl-l- (2-methyl-2-propenyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 1- (2-methylpropyl) -6- (1-naphthalenylmethyl) ) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2, 3-d] pyrimidin-2, 4 (1H, 3H) -dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(2-pyridinyl) thio] thieno [2, 3 d] pyrimidin-2, 4 (1H, 3H) -dione, 5- [(3-Hydroxypropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1 -naf such enylmethyl) thieno [2 , 3-d] pyrimidin-2, 4 (1H, 3H) -dione, 4- [(1,2,3, 4-tet) rahydro-3-methyl-1- (2-methylpropyl) -6- (1 - naph talenylmethyl) 2,4-dioxothieno [2,3-d] pyrimidin-5-yl) thio] butanoate methyl, 4- [(1,2,4,4-tetrahydro-3-methyl-1- (2 -methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-t-ene (2,3-d) pyrimidin-5-yl) thio) uta noico, 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine -5-yl) sulfonyl] butanoate, 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2, 4 -dioxothieno [2,3-d] pyrimidin-5-yl) sulfonyl] butanoate methyl, 4- [(1, 2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6] - (1-naphthalenylmethyl) -2,4-di-oxo-t-ene [2,3-d] pyrimidin-5-yl) sulf onyl] butanoic acid, 6-benzyl-3-methyl-1- (2-methylpropyl) thieno [2,3-d] -pyrimidin-2,4 (1H, 3H) -dione, 3-methyl-1- (1-methylethyl) -6- (f -methylmethyl) thieno [2,3-d] pyrimidin-2 4 (1H, 3H) -dione, 6- [(1-hydroxy-1-phenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2, 4 ( 1H, 3H) -dione,. { ±.) 5- [(2-hydroxypropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl]) thieno [2,3-d] pyrimidine -2,4 (1H , 3H) -dione, 1,2, 3,4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2, 4- dioxothieno [2,3-d] pyrimidin-5-carboxamide, (3R) -1-. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methyl-ylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] carbonyl} pirrol idin- 3 -ol, l-. { [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2, -di oxo-t-ene [2, 3-d] irimidin- 5 - il carbonil} piperidin-4-ol, (3R) -1 -. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphylenylethyl) -2, -dioxothieno [2,3-d) pyrimidin-5-yl] carbonyl} piperidin-3-ol, 1,2,3, 4-tetrahydro-N- (2-hydroxyethyl) -3, N-dimethyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2, 4-dioxothieno [2,3-d] pyrimidin-5-carboxamide, 2- acid. { [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-ti-ene [2,3-d] pyrimidine-5 -yl] carboxamido} acetic, acid 3-. { [1, 2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2, 4-di-oxo-ene-ene [2,3-d] pyrimidin-5-yl] -carboxamido} propanoic, 2-. { [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] ] carboxamido} acetamide, l-. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] carbonyl) pyrrolidine, 1,2,3,4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothiene [2, 3-d] pyrimidin-5-sulfonamide, 5- [(3-methoxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1 -naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, - (1H, 3H) -dione, 5- [(3-hydroxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1 -naphthalenylmethyl) thieno [2, 3 d] pyrimidin-2, 4- (1H, 3H) -dione, 5- [(3-hydroxyphenyl) sulfinyl] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2 , 3-d] pyrimidin-2, 4- (1H, 3H) -dione, 5- [(3-hydroxyphenyl) sulfonyl] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5- [(3-nitrophenyl) thio] thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H) -dione, 5- [(3-aminophenyl) thio] -3-methyl- 1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 5-1 [3-. { (bis-methanesulfonyl) amino) phenyl] thio} -3-me il- 1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4- (1H, 3H) -dione, 5 - [(3-ethoxycarbonylaminophenyl) ) thio] -3-methyl-l- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 5- [(3 -acetamidophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(4-nitrophenyl) thio] thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) - dione, 5- [(4-aminophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 3-Methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(5-nitropyridin-2-yl) thio] thieno [2,3-d] pyrimidine-2 , 4- (1H, 3H) -dione, - 2-N-oxide. { [1, 2, 3, 4-tetrahydro-3-methyl-l- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] thio] pyridine, 5- [(3-azidopropyl) thiol-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4 (1H, 3H ) -dione, 5- [(3-aminopropyl) thiol-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2, 4 (1H , 3H) -dione, N-. { 3- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) • 6 - (1-naphthalenylmethyl) -2,4-di-oxo-ti-ene [2, 3-d] pyrimidin-5 • yl) thio] propyl} acetamide, N-. { 3- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-ti-ene [2, 3-d] pyrimidin-5-yl) thio] ropil} -N1, N '-dimethylurea, N-. { 3- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-ti-ene [2, 3-d] pyrimidin-5-yl) thio] propyl} -methoxyacetamide, N-. { 3- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-ti-ene [2, 3-d] pyrimidin-5-yl) thio] propyl} methyl carbamate, N-. { 3- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-ti-ene [2, 3-d] pyrimidin-5-yl) thio] propyl) methanesul fonamide, N-. { 3 - [(1, 2,3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-t-ene [2,3-d] pyrimidine - 5-yl) thio] propyl} trif luorometanosul fonamida, 5-. { [3- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) propyl] thio} -3-methyl7l- (2-methylpropyl) -6- (1 naphthalenylmethyl) thieno [2,3-d] pyrimidine- 2,4 (1H, 3H) -dione, N- (2-hydroxyethyl) -N1- [1, 2, 3, 4 -tetrahydro-3-met il-1- (2-methylpropyl) -6- (l-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl ) urea, 2-hydroxy-oxyethyl [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-ti-ene [2] 3-d] pyrimidin-5-yl] carbamate, N- (2-hydroxyethyl) -N-methyl-N 1 - [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) - 6 (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl) urea, 6- [(1-hydroxy-1- (3-fluorophenyl)) methyl] -3-methyl -l- (2-methylpropyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 6- [(3-fluorophenyl) methyl] -3-methyl-1- (2 - methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (2-bromofinyl)) methyl] -3-methyl-1- ( 2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (2-methylphenyl)) methyl] -3-methyl-1-methyl (2-methylpr pil) thieno [2, 3-d} pyrimidin-2, 4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (3-cyanofenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3 d] pyrimidine-2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (3-trifluoromethylphenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3 -d] irimidin-2, 4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (3-phenyloxyphenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione , 6- [(1-hydroxy-1- (1-naphthalenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3-d} pyrimidin-2, 4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (6-quinolinyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3-d] ] pyrimidin-2, 4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (4-quinolinyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3] d] pyrimidin-2, 4 (1H, 3H) -dione, (±) 6- [1- (benzo [b] furan-2-yl) -l-hydroxymethyl]] -3-methyl-1- (2 - methylpropyl) thieno [2, 3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- [(l-hydroxy-l- (2-chloro-6-f luorofenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno- [2,3-d] pyrimidine- 2, 4 (1H, 3H) -dione, 6- [(l-hydroxy-l-phenyl) ethyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- [ (l-hydroxy-1- (4-trifluoromethylphenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, (±) 6- (2,3-dihydro-1-hydroxy-lH-indenyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (2-quinolinyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione, 6- (l-hydroxy-l- [3-quinolinyl] methyl) -3-methyl-1- (2-methylpropyl) thieno [2, 3-d] -pyrimidin-2, (1H, 3H) -dione, 6- (2-bromophenylmethyl) -3-methyl-1- (2-methylpropyl) thieno (2,3-d) pyrimidin-2,4 (1H, 3H) -dione, 6- (2-methylphenylmethi) ) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- (3-cyano-phenylmethyl) -3-methyl-1- (2 -methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- (3-trifluoromethyl-f-enylmethyl) -3-methyl-1- (2-methylpropyl) -iene (2, 3-d] -pyrimidin-2, 4 (1H, 3H) -dione, 6- (3-phenyloxyphenylmethyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2, 4 (1H, 3H) -dione, 3-methyl-1- (2-methylpropyl) -6- (4-quinolinylmethyl) -thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 3 -methyl-l- (2-methylpropyl) -6- (6-quinolinylmethyl) -thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, Trifluoroacetic acid salt of 3-methyl-1- (2-methylpropyl) ) -6- (2-quinolinylmethyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione, 6- (2-benzo [b] furanylmethyl) -3-methyl-1- (2 -methylpropyl) -thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- (2-chloro-6-fluorophenylmethyl) -3-methyl-1- (2-methylpropyl) thieno (2,3-d) pyrimidin-2,4 (1H, 3H) -dione, 6- (1-f-enylethyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) dione, 6- (4-trifluoromethyl-f-enylmethyl) -3-methyl-1- (2-methylpropyl) thieno (2,3-d) -pyrimidin-2,4 (1H, 3H) ) -dione, (±) 6- (2, 3-dihydro-lH-inden-l-yl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] -pyrimidin-2, 4 (1 H, 3 H) -dione, 6- (3-imino-l, 3-dihydro-benzo [c] furan-1-i]) - 3-methyl-1- (2-methylpropyl) thieno- [2, 3-d] pyrimidin-2, 4 (1H, 3H) -dione, 2- [(1, 2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -2,4-dioxothien [2 , 3-d] - pyrimidin-6-yl) methyl] benzamide, 6- (l-hydroxy-l- [l-naphthalenyl] methyl) -5- ([3-hydroxypropyl] thio) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2, 4 (1 H, 3 H) -dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenyl-carbonyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione, (±) -5- [(3-idroxybutyl) -io] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2 , 3-d] pyrimidine -2,4 (1H, 3H) -dione, 6- (3-f luorofenyl) methyl-5- [(3-hydroxypropyl) thiol-3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, - [(5-amino-2-pyridinyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione, 1,2,3, 4- tetrahydro-3-methyl-1- (2-methylpropyl) -6-p-enylmethyl-2,4-dioxothieno [2,3-d] pyrimidin-5-carboxylate ethyl, 1,2,3,4-tetrahydro-3, N, N-trimethyl-1- (2-methylpropyl) -6-f-enylmethyl -2,4-dioxothieno [2,3-d] pyrimidine- 5 - carboxamide, 6- [l-hydroxy- (4-nitrophenyl) met il] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione , 6 - (4-nitro-enylmethyl) -3-methyl-] - (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6 - (4-aminofenylmethyl) - 3 -methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 4- (3,4-dimethoxyphenyl) -N-. { 4- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -2,4-dioxothieno [2,3-d] pyrimidin-6-yl) methyl] phenyl} -butanamide, and 3-acetamido-N- (4- [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropi]) -2, -dioxothieno [2,3-d] pyrimidine- 6-yl) methyl] phenyl) benzamide. According to the invention, there is also provided a process for the preparation of a compound of formula (I) which comprises: (a) the preparation of a compound of formula (I), wherein X is S02, by oxidation of a compound of formula (I) wherein X is S (O) n and n is 0 or 1, in the presence of an appropriate oxidizing agent (for example 3-chloroperoxybenzoic acid) and a suitable solvent (for example dichloromethane) for example at 0 ° C up to room temperature (20 ° C); or (b) the preparation of a compound of formula (I) wherein X is SO, by oxidation of a compound of formula (I) wherein X is S, in the presence of an appropriate amount of a suitable oxidizing agent (per example potassium peroxymonosulfate, sold commercially under the tradename "OXONE") in a suitable solvent (for example aqueous methanol), for example at room temperature; or (c) the preparation of a compound of a formula (I) wherein X is S by reacting a compound of the general formula: (ID wherein R, R1 and R2 are as defined above, with a compound of general formula (III), R17-SS-R17, wherein both R17 groups represent R9 or Ar3, as previously defined, or with a compound of general formula IV, LS-R17, wherein L represents a group such as an arylsulfinate group and R17 is as defined above, in the presence of lithium diisopropylamide at a temperature from -78 ° C to 50 ° C, or (d) the preparation of a compound of formula (I) in the that R3 represents H, by reaction of a compound of the general formula: (V) wherein R18 and R19 - each independently represents an alkyl group (eg ethyl) or aryl and R and R1 are as defined above, with a compound of general formula (VI), R2NH2, wherein R2 is as defined above, in the presence of a suitable solvent (for example ethanol), for example at elevated temperature and pressure; O well (e) preparing a compound of formula (I) wherein X is C (0) NR10, by reacting a compound of general formula (VII) wherein R, R1 and R2 are as defined in the above, with a compound of general formula: R / HN Vo (VIII) wherein R9 and R10 are as defined above, in the presence of 1 (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole hydrate; (f) preparation of a compound of formula (I) wherein X is NH (CO) NR10, by reacting a compound of the general formula: wherein R, R1 and R2 are as defined above, with a compound of formula (VIII) as described above in the presence of a solvent such as toluene, or (g) the preparation of a compound of formula (I), wherein X is NH (CO) 0, by reacting a compound of the formula (IX) as defined above, with a compound of the general formula (X), R9OH wherein R9 is as defined in the foregoing, in the presence of a solvent such as toluene; or (h) the preparation of a compound of formula (I), wherein X is S02NR10, by reacting a compound of the general formula: (??: wherein L1 represents a leaving group such as a halogen atom (for example chlorine) and R, R1 and R2 are as defined above, with a compound of formula (VIII) as defined above in the presence of a solvent such as dichloromethane; or (i) the preparation of a compound of formula (I) wherein X is C (0) 0, by reacting a compound of the general formula: (Va) wherein R3 'represents C02R9 or C02Ar3 and R, R1, R18 and R19 are as defined above, with a compound of the general formula (VI) as defined above, in the presence of a suitable solvent (for example ethanol), for example, at elevated temperature and pressure; and optionally, after (a), (b), (c), (d), (e), (f), (g), (h) or (i) converting the compound of formula (I) obtained to an additional compound of formula (I) and / or forming a pharmaceutically acceptable salt or solvate thereof. The compounds of formula (II) in which R is -C (= 0) Ar "- can be conveniently prepared by reacting a compound of the general formula (XII) wherein R1 and R2 are as defined above, with a compound of general formula (XIII), A ^ COCl, in the presence of aluminum chloride (III) and a solvent such as 1,2-dichloroethane under the conditions of reflux, - or alternatively, by oxidising a compound of the general formula wherein R 4 represents H, R 5 represents OH and R 1 and R 2 are as previously defined, in the presence of potassium permanganate, and 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (sold commercially as "18 -Crown- 6") in a solvent such as dichloromethane at room temperature. The compounds of formula (XIV) in which Rs is OH and R1, R, R4 and Ar1 are as defined above, can be prepared by reacting a compound of formula (XII) as defined above with a composed of the general formula: (XV) in which R4 is as defined above, in the presence of lithium diisopropylamide at a temperature from -78 ° C to 50 ° C. The compounds of formula (XIV) in which Rs is H and R1, R2, R4 and Ar1 are as defined above, can be easily prepared by reducing a corresponding compound of formula (XIV) in which Rs is OH, in the presence of triethylsilane and trifluoroacetic acid at room temperature. Compounds of formula (II) in which R is Ar 2 can be prepared by reacting a compound of formula (XII) as defined above with 1-indanone, 2-indanone, 9-fluorenone or 1-acenaphtenone in the presence of lithium diisopropylamide - and optionally cerium (III) chloride at a temperature from -78 ° C to 50 ° C, followed by a reduction reaction, for example, in the presence of triethylsilane and trifluoroacetic acid. The compounds of formula (V) can be conveniently prepared by reacting a compound of the general formula: (XVI: wherein R, R1 and R18 are as defined in the foregoing, with a compound of the general formula 19 R -o Hal (XVII) wherein R19 is as defined above and Hal is a halogen atom (for example chlorine) in the presence of a suitable base, (for example triethylamine) and a solvent such as dichloromethane. The compounds of formula (XVI) in which R1 is H can be prepared by reacting a compound of general formula (XVIII), R-CH2-CH0, wherein R is as previously defined, with a compound of the formula general: (XIX) wherein R18 is as previously defined, and with elemental sulfur, in a suitable solvent, for example, dimethylformamide. The compounds of formula (XVI) in which R1 is CH2 alkyl of C1-s, CH2 alkenyl of C2.5 or CH2 cycloalkyl of C3-s can be suitably prepared by reacting a corresponding compound of formula (XVI) in which R1 is H, with a compound of general formula (XX), R20C02H, wherein R20 represents C1-s alkyl, C2_5 alkenyl or C3-5 cycloalkyl, and with a reducing agent such as sodium borohydride in the absence of a solvent. The compounds of formula (XVI) in which R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, can be conveniently prepared by reacting a corresponding compound of formula (XVI) in which R 1 - is H, in the presence of a solvent such as toluene and a catalytic toluenesulfonic acid under reflux conditions, with a compound of the general formula: (???; wherein the R21 groups are both methyl or ethyl groups, and R22 and R23, each independently, represent a hydrogen atom or an alkyl group, or together form a hydrocarbyl ring, the total number of carbon atoms in R22 and R23 , taken together, does not exceed five, followed by the reaction with a reducing agent such as sodium borohydride. The compounds of formula (Va) can be prepared in a manner similar to the compounds of formula (V) but using instead of the compound of formula (XVI), a compound of the general formula: wherein R, R1, R3 'and R18 are as previously defined. The compounds of formula (XXII) in which R1 is H can be prepared by reacting a compound of general formula (XXIII), RCH2C (0) R3 'wherein R and R3' are as previously defined, with a compound of formula (XIX) as defined above, and also with elemental sulfur in a suitable solvent.

The compounds of formula (XXII) in which R1 is different from hydrogen, can be prepared by a process analogous to that described above for the preparation of compounds of formula (XVI) in which R1 is different from hydrogen. "The compounds of formula (VII) can be suitably prepared by reacting a compound of formula (II) above with carbon dioxide in the presence of lithium diisopropylamide, for example in tetrahydrofuran at room temperature, from -78 ° C to 50 °. C, under pressure The compounds of formula (IX) can be easily prepared by reacting a compound of formula (VII) as described above with diphenylphosphorylazide, (C6H50) 2P (O) N3 in the presence of a solvent, for example a mixture of triethylamine and toluene Compounds of formula (XI) in which L1 represents a halogen atom such as chlorine, can be prepared by reacting a compound of formula (II) as defined above with lithium diisopropylamide and Sulfur dioxide to form an intermediate which is then reacted with N-chlorosuccinimide and aqueous hydrochloric acid in the presence of a solvent such as dichloromethane The compounds of formula (I) they can be converted to additional compounds of formula (I) using standard or conventional procedures. For example, compounds of formula (I) wherein Ar 3 is nitrophenyl can be converted to compounds of formula (I) wherein Ar 3 is aminophenyl by reduction using iron powder and ammonium chloride in ethanol under reflux conditions; or the compounds of formula (I) wherein Ar 3 is pyridyl can be converted to compounds of formula (I) wherein Ar 3 is pyridine N-oxide by reaction with 3-chloroperoxybenzoic acid in a solvent such as dichloromethane. The compounds of formula (III), (IV), (VI), (VIII), (X), (XII), (XIII), (XV), (XVII), (XVIII) (XIX), (XX) , (XXI) and (XXIII) are commercially available, are well known in the literature or can be easily prepared using known techniques. It will be appreciated by those familiar with the art that in the processes described above, functional groups (eg, hydroxy, amino or carboxyl groups) or intermediate compounds may require that they be protected by protecting groups. The final step in the preparation of the compounds of the invention may involve the removal of one or more protecting groups. The protection and deprotection of functional groups is fully described in "Protective Groups in Organic Chemistry", edited by J. F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", second edition, T.. Greene & P. G. M. uts, iley-Interscience (1991).

The compounds of formula (I) above can be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate, or an alkali metal salt such as sodium or potassium salt. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof, including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. The isomers can be resolved or separated by conventional techniques, for example by chromatography or fractional crystallization. The enantiomers can be isolated by separation of a racemic mixture or other mixture of the compounds using conventional techniques (eg chiral CLAP). Alternatively, the desired optical isomers can be produced by reaction of the appropriate optically active starting materials under conditions which do not cause racemization, or by derivatization (formation of derivatives), for example with homochiral acid followed by separation of the diastereomeric derivatives by conventional means (for example CLAP, chromatography on silica) or it can be made with chiral and chiral reagents with initial materials. All stereoisomers are included within the scope of the invention. The compounds of the invention can be isolated from their reaction mixtures using conventional techniques. The compounds of the invention are useful because they possess pharmacological activity in human and non-human animals. Therefore, they are indicated as pharmaceutical substances for use in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases, and in immunologically mediated diseases that include rejection of transplanted organs or tissues or acquired immunodeficiency syndrome (AIDS). The examples of these conditions are: (1) (the respiratory tract) reversible obstructive diseases in the airways that include asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (eg delayed asthma and hyperresponsiveness of the tract) aerial); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca and rhinitis medicamentosa; Membranous rhinitis including croupy, fibrinous and pseudomembranous rhinitis as well as scrupulous 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) (bones and joints) rheumatoid rhinitis, seronegative spondioarthropathies (including ankylosing spondylitis, psoriatic rhinitis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis; (3) (skin) psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigus bullosum, epidermolysis bullosa, urticaria, angioderma, vasculitides, erythema, eosinophilia, uveitis, alopecia areata and conjunctivitis vernal; (4) (gastrointestinal tract) coeliaca disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Cron's disease, ulcerative colitis, food-related allergies which have remote effects on the intestine, for example migraine, rhinitis and eczema, (5) (other tissues and systemic diseases) multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosis, Hashimoto's thyroiditis, severe myiastemia, type I diabetes, nephrotic syndrome, fasciitis eosinophilia, syndrome of hyper IgE, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenic purpura; (6) (allograft rejection) acute and chronic posterior, for example, to transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.

The compounds of the invention are also indicated for use as antimicrobial agents and can therefore be used in the treatment of diseases caused by pathogenic microorganisms. Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined above, for use in therapy. In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined above, in the manufacture of a medicament for use in therapy. The invention further provides a method for carrying out immunosuppression, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined above. The invention further provides a method for treating or reducing the risk of reversible obstructive airway disease in patients suffering from, or at risk of, such a disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined above. For the therapeutic uses mentioned above, the dosage administered will of course vary with the compound used, the mode of administration, the treatment desired and the indicated disorder. "The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof can be used per se, but will generally be administered in the form of a pharmaceutical composition in which the compound / salt / solvate (active ingredient) of Formula (I) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight (percent by weight), more preferably less than 80% by weight, for example from 0.10 to 70% by weight, and even more preferably less than 50% by weight of the active ingredient, all percentages by weight are based on the total composition.Therefore, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined above, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined above, with an adjuvant, diluent or pharmaceutically acceptable carrier. The pharmaceutical composition of the invention can be administered topically (for example, to the lung and / or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and as dry powder formulations; or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.

The invention will be illustrated in the following examples in which the following abbreviations are used: p.f. = melting point, NMR = nuclear magnetic resonance, EM = mass spectrometry and h = hour or hours.

EXAMPLE 1 6- (4-methoxyphenylmethyl) -3-ptethylthieno [2 3-d] pyrin idin-2,4 (1H, 3H) -dione a) 3- (4-methoxypheniDpropanal) A solution of 3- (4-methoxyphenyl) propan-1-ol (15.02 g) in dichloromethane (100 ml) is added to a stirred suspension of pyridinium chlorochromate (29 g) in dichloromethane (250 ml).

The mixture is stirred for 2 hours and then filtered through a pad of kieselguhr. The residue is washed with ether (3 x 500 ml) and the combined water is evaporated under reduced pressure. The residual oil is purified by vacuum distillation to provide the subtitle compound (6.81 g) as an oil. MS (El) 164 [M +], 121 (PB) XH NMR (CDC13) d 2.75 (2H, t); 2.91 (2H, t); 3.79 (3H, s); 6.84 (2H, d); 7.12 (2H, d); 9.81 (1H, s). b) Ethyl 2-amino-5- (4-methoxyphenylmethyl) -3-thiophenecarboxylate 3- (4-Methoxyphenyl) propanal (5.17 g) is added in portions over 20 minutes to a stirred solution of ethyl cyanoacetate (3.4 g), sulfur (0.975 g) and triethylamine. (3.00 ml) in dimethylformamide (10 ml). After an additional 3 hours, the mixture is diluted with water (400 ml) and extracted with ethyl acetate (2 x 250 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with ethyl acetate: petroleum ether (1: 3) to give the subtitle compound (7.08 g). MS (El) 291 (M +) X H NMR (CDCl 3) d 1.33 (3 H, t); 3.79 (3H, s); 3.85 (2H, s); 4.24 (2H, c); 5.79 (2H,? Broad); 6.68 (1H, s); 6.84 (2H, d); 7.13 (2H, d). c) N- [3-ethoxycarboni 1 - 5 - (-methoxyphenylmethyl) -2-thienyl] -O-ethyl carbamate Ethyl chloroformate (1.00 ml) is added to a stirred solution of ethyl 2-amino-5- (4-methoxyphenylmethyl) -3-thiophenecarboxylate (3.00 g) and pyridine (4.00 ml) in dichloromethane (30 ml) at 0- 5 ° C. After 45 minutes, the mixture is washed with hydrochloric acid (10%, 50 ml). The aqueous phase is extracted with additional dichloromethane (30 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with an elution gradient of ethanol: dichloromethane (1:19 to 1: 3) to give the subtitle compound (5.61 g) - "? NMR (CDC13) d 1.29-1.37 (6H, m), 3.79 (3H, s), 3.95 (2H, s), 4.22-4.32 (4H, m), 6.82-6.85 (3H, m), 7.15 (2H, d), 10.13 (1H, s) , large) . d) 6 - (4-ethoxy-enylmethyl) -3-ethylthio- or [2 .3 -d] pyrimidine- 2,4 (1H, 3H) -dione Methylamine (8 ml) is condensed in a cooled solution of N- [3-ethoxycarbonyl-5- (4-methoxyphenylmethyl) -2-thienyl] -O-ethyl carbamate (0.93 g) in ethanol (15 ml). The resulting solution is heated to 120 ° C and sealed in a pump for 16 hours. The solvent is evaporated under reduced pressure and the residue is triturated with ether to give the title compound (0.41 g) as a solid. MS (El) 291 (M +) "-H NMR (DMS0-d6) d 3.17 (3H, s); 3.73 (3H, s); 4.01 (2H, s), 6.87-6.91 (3H, m); 7.19 ( 2H, d); 12.10 (1H, s, broad).

Example 2 6- (4-methoxyphenylmethyl) -3-methyl-1- (2-methyl-2-propenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione 1-Bromo-2-methyl-2-propene (0.055 ml) is added to a stirred suspension of potassium carbonate (0.203 g) and 6- (4-methoxyphenylmethyl) -3-methylthieno [2,3-d] pyrimidine. 2, 4 (1H, 3H) -dione (0.15 g) in acetone (5 ml). After 16 hours at room temperature, the mixture is diluted with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica, eluting with ethyl acetate: petroleum ether (1: 3, then 3: 7, then 7:13) to give the title compound (0.11 g) -p.f. 111 ° C MS (El) 356 (M +) X H NMR (CDC13) d 1.75 (3H, s); 3.43 (3-H, s); 3.81 (3H, s); 4.00 (2H,?); 4.48 (2H, s); 4.83 (1H, s); 4.98 (1H, s); 6.86 (2H, d), - 7.02 (1H, s); 7.14 (2H, d).

EXAMPLE 3 1- (2-methylpropyl) -6-81-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione a) 3- (l-naphthiDpropanoic acid % palladium on carbon (1.00 g) is added to a suspension of 3- (l-naphthyl) acrylic acid (50.0 g) in tetrahydrofuran (500 ml). The mixture is hydrogenated at 6 atmospheres for 18 hours and then filtered through a kieselguhr pad by washing with ethyl acetate (3 x 100 ml). The filtrate is evaporated under reduced pressure to provide the title compound (50.0 g) as a solid. ? E NMR (DMSO-D6) d 2.65 (2H, t); 3.30 (2H, t); 7.37-7.46 (2H, m); 7.49-7.60 (2H, m); 7.79 (1H, d); 7.93 (1H, d); 8.07 (1H, d), - 12.10 (1H, s, broad). b) 2-amino-5- (1-naphthalenylmethyl) -3-thiophenecarboxylate from ethyl A solution of oxalyl chloride (7.40 ml) in anhydrous dichloromethane (50 ml) is added dropwise to a stirred suspension of 3- (1- Naphthyl) propanoic (8.50 g) in anhydrous dichloromethane (100 ml) and dimethylformamide (0.1 ml). After 2 hours, the resulting solution is evaporated under reduced pressure and the residual oil is dried in vacuo at 50 ° C during ° C. The oil is redissolved in anhydrous tetrahydrofuran (45 ml) and added to a mixture of 10% palladium on carbon (0.50 g) and anhydrous 2,6-lutidine (5.82 ml) in anhydrous tetrahydrofuran (30 ml). The mixture is hydrogenated at 2 atmospheres for 4 days and then filtered through a pad of kieselguhr. The filtrate is evaporated under reduced pressure and the residual oil is dried in vacuo to give a solid. This solid is redissolved in anhydrous dimethylformamide (20 ml). Ethyl cyanoacetate (4.53 ml) and sulfur (1.36 ml) are added, and the mixture is stirred at 50 ° C, under nitrogen for 2 hours. Water (300 ml) is added, followed by a saturated solution of sodium chloride (50 ml) and the mixture is extracted with ether (3 x 100 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with ether: hexane (2: 3) to give the subtitle compound (11.00 g). MS (APCI) 312.1 ((M + H) +), XH NMR (DMSO-D6) d 1.20 (3H, t); 4.12 (2H, c); 4.35 (2H, S); 6.56 (1H, s); 7.08 (2H, s, broad); 7.41-7.56 (4H, m); 7.84 (1H, d); 7.90-7.96 (1H, m); 8.09-8.13 ((1H, m). c) ethyl 2- (2-methylpropyl) amino- 5- (l-naphthalenylmethyl) -3-thiophenecarboxylate Sodium borohydride (1.3 g) is added in 10 portions over 5 hours to a stirred solution of ethyl 2-amino-5- (1-naphthalenylmethyl) -3-thiophenecarboxylate (5.50 g) in 2-methylpropanoic acid (40 ml). at 0 ° C. The mixture is stirred at room temperature for 16 hours and then additional sodium borohydride (1.8 g) is added in 10 portions over 8 hours and stirring is continued for an additional 16 hours. The solution is poured into water (1000 ml), neutralized with sodium bicarbonate and extracted with ethyl acetate (2 x 500 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with ether: hexane (1: 3) to give the sub-title compound (6.20 g): m.p. 57-59 ° C MS (APCI) 368.1 ((M + H) +), XH NMR (DMSO-D d 0.86 (6H, d); 1.22 (3H, t); 1.66-1.92 (1H, m); 2.91 (2H, dd), 4.14 (2H, c), 4.40 (2H, s), 6.70 (1H, s), 7-43-7.57 (4H, m), 7.84 (1H, dd), 7.92-7.95 (1H , m); 8.11-8.14 (1H, m). d) N '-acetyl-N- (2-methylpropyl) -N- [3-ethoxycarbonyl-5- (1-naphthalenylmethyl) -2-thienyl] urea Acetyl chloride (1.08 ml) is added to a stirred suspension of silver cyanate (2.37 g) in anhydrous toluene (50 ml). After 1 hour, ethyl 2- (2-methylpropyl) amino-5- (1-naphthalenylmethyl) -3-thiophenecarboxylate (4,646 g) is added and stirring is continued for 16 hours. The mixture is filtered and the solid residue is washed with ether (50 ml). The combined water is evaporated under reduced pressure and the residue is purified by column chromatography on silica, eluting with ether: hexane (1: 1) to give the subtitle compound (5.05 g) as an oil. MS (APCI) 453.1 ((M + H) +). X H NMR (CDC13) d 0.87 (6H, d); 1.29 (3H, t); 1.78-1.92 (1H, m); 2.44 (3H, s); 3.06-3.80 (2H, broad); 4.24 (2H, c); 4.53 (2H, s); 7.09 (1H, s); 7.30 (1H, s, broad); 7.41-7.58 (4H, m); 7.84 (1H, d); 7.90 (1H, dd); 7.99 (1H, dd). e) 1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione Sodium ethoxide (0.036 g) is added to a solution of N '-acetyl-N- (2-methylpropyl) -N- [3-ethoxycarbonyl-5- (1-naphthalenylmethyl) -2-thienyl] urea (0.20 g) in ethanol (4 ml). The mixture is stirred for 3 hours and then additional sodium ethoxide (0.036 g) is added. After an additional 3 hours, the mixture is poured into hydrochloric acid (2M, 20 ml) and extracted with ethyl acetate (2 x 20 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual solid recrystallizes from ethyl acetate / hexane to give the title compound (0.105 g). p.f. 189-190 ° C MS (APCI) 365.1 ((M + H) +),? E NMR (DMSO-D d 0.84 (6H, d); 2.02-2.18 (2H, m); 3.57 (2H, d); 4.60 (2H, s); 7.01 (1H, s); 7.48-7.59 (4H, m); 7.87 (1H, dd), - 7.95 (1H, dd), - 8.16 (1H, dd), - 11.34 (1H, s, broad).

EXAMPLE 4 3-methyl-1- (2- (methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2, 3 (1H, 3H) -dione Sodium ethoxide (0.18 g) is added to a stirred solution of N 1 -acetyl-N- (2-methylpropyl) -N- [3-ethoxycarbonyl-5- (1-naphthalenylmethyl) -2-thienyl] urea (Example 3, step c), (0.30 g) in ethanol (6 ml). After 6 hours, iodomethane (0.165 ml) is added. After an additional 16 hours, iodomethane (0.165 ml) is added. After a further 24 hours, the reaction mixture is poured into hydrochloric acid (2M, 30 ml) and extracted with ethyl acetate (2 x 30 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with ether: hexane (1: 1) and then triturated with ether to give the title compound (0.24 g) m.p. 137-138 ° C MS (APCI) 379.1 ((M + H) +), X H NMR (CDCl 3) d 0.93 (6H, d); 2.18-2.32 (1H, m); 3.38 (3H, s); 3.68 (2H, d); 4.52 (2H, s); 7.04 (1H, t); 7.40-7.52 (4H, m); 7.82 (1H, d); 7.86-7.90 (1H, m); 7.95-8.02 (1H, m).

EXAMPLE 5 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(2-pyridinyl) thio] thieno [2, 3-d] pyrimidin-2, 4 (1H, 3H) - diona N-Butyllithium (2.0M solution in hexanes, 0.32 ml) is added dropwise to a solution of diisopropylamine (0.093 ml) in anhydrous tetrahydrofuran (5 ml) at 0 ° C, under nitrogen. The solution is stirred for 5 minutes and then cooled to -78 ° C, and a solution of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] is added. pyrimidin-2, 4 (1H, 3H) -dione (0.20 g) in anhydrous tetrahydrofuran (5 ml). After 15 minutes, a solution of 2,2'-dipyridyl disulfide (0.145 g) in anhydrous tetrahydrofuran (2 ml) is added. The mixture is stirred for an additional 1 hour at -78 ° C, and then allowed to warm to room temperature. The reaction mixture is poured into a saturated aqueous solution of sodium bicarbonate (30 ml) and then extracted with ether (2 x 30 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with acetone: hexane (1: 2) and then recrystallized from ethyl acetate / hexane to give the title compound (0.172 g). p.f. 148-149 ° C MS (APCI) 488.1 ((M + H) +), 2 H NMR (CDC13) d 0.89 (6H, d); 2.10-2.25 (1H, m); 3.31 (3H, s); 3.63 (2H, d); 4.73 (2H, s); 7.05 (1H, dd); 7.17 (1H, d); 7.36 (1H, td); 7.40-7.58 (4H, m); 7.81 (1H, dd); 7.85 (1H, d); 7.98 (1H, d); 8.42-8.45 (1H, m).

EXAMPLE 6 - . 5 - [(3-Hydroxypropyl) io] -3-methyl-1- (2-methoxypropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione It is prepared according to the procedure described in example 5 from n-butyllithium (2.0 M solution in hexanes, 0.32 ml) and diisopropylamine (0.093 ml) in anhydrous tetrahydrofuran (5 ml), 3-methyl-1- (2 -methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] irimidin-2,4 (1H, 3H) -dione (0.20 g) in anhydrous tetrahydrofuran (5 ml) and 3-. { [dimethyl (1,1-dimethylethyl) silyl] oxy} propyl-4-methylphenylthiosulfonate (0.19 g, J. Med. Chem. 1995, 38, 2557) in anhydrous tetrahydrofuran (2 ml). The crude adduct is dissolved in tetrahydrofuran (6 ml) and treated with tetrabutylammonium fluoride hydrate. (0.20 g). After 16 hours, the solution is diluted with water (30 ml) and extracted with ether (2 x 30 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with ether and then recrystallized from ethyl acetate / hexane to give the title compound (0.098 g). p.f. 130-131 ° C MS (APCI) 469 ((M + H) +), XH NMR (CDC13) d 0.88 (6H, d); 1.90 (2H, quin); 2-10-2.24 (1H, m); 2.84 (1H, t); 3.17 (2H, t); 3.42 (2H, s), 3.63 (2H, d); 3.89 (2H, C); 4.78 (2H, s); 7.35 (1H, d); 7.44 (1H, t); 7.45-7.56 (2H, m); 7.82 (1H, d); 7.84-7.92 (1H, m); 8.01-8.07 (1H, m).

EXAMPLE 7 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] irimidin-5 -il) thio] methyl utanoate a) 4,4,4-trimethoxybutyl para-toluentiosulfonate A suspension of the para-toluenesulfonic potassium salt (8.77 g), trimethyl 4-bromoortobutyrate (8.00 g) and 18 -corone-6 (10.24 g) in anhydrous tetrahydrofuran (60 ml) is sonicated for 5 minutes and then it is stirred at room temperature for 3 days. The mixture is poured into a saturated aqueous solution of sodium bicarbonate (200 ml) and extracted with ether (2 x 200 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide the subtitle compound (10 -.52 g) as an oil. E NMR (CSD6) d 1.57-1.62 (2H, m); 1.64-1.75 (2H, m), - 1.86 (3H, S); 2.88 (2H, t); 3.06 (9H, s); 6.73 (2H, d); 7.84 (2H, d). b) 4- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine- 5 -yl) thio] methyl butanoate The procedure described in example 5 is prepared according to coX from n-butyllithium (2.5M solution in hexanes, 0.77 ml) and diisopropylamine (0.277 ml) in anhydrous tetrahydrofuran (5 ml), 3-methyl-1- (2 -methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] pyrimidin-2, 4 (1H, 3H) -dione (0.20 g) in anhydrous tetrahydrofuran (10 ml) and para-toluentiosulfonate of 4, 4 , 4-trimethoxybutyl (0.799 g) in anhydrous tetrahydrofuran (5 ml). The reaction is suspended with hydrochloric acid (0.5M, 20 ml), diluted with ether (20 ml) and stirred for 10 minutes. The phases are separated and the aqueous phase is extracted with additional ether (20 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with ether: hexane (1: 1) to give the title compound (0.365 g) as a solid, m.p. 111-112 ° C MS (APCI) 511.0 ((M + H) *), XH NMR (CDC13) d 0.87 (6H, d); 1.98 (2H, quin); 2.10-2.20 (1H, m); 2.52 (2H, t); 3.10 (2H, t); 3.42 (3H, s); 3.62 (2H, d), -3.67 (3H,?); 4.76 (2H, s); 7.35 (1H, d); 7.45 (1H, t); 7.48-7.55 (2H, m); 7.81 (1H, d); 7.86-7.92 (1H, m); 7.99-8.04 (1H, m).

EXAMPLE 8 4- [(1, 2,3,4-Tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine-5] -il) thio] butanoic An aqueous solution of sodium hydroxide (1M, 4 ml) is added to a solution of 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (l- methyl naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl) thio] butanoate (0.382 g) in methanol (8 ml) and tetrahydrofuran (4 ml). The mixture is stirred at room temperature for 4 hours, diluted with water (50 ml), acidified with hydrochloric acid (2 M) and extracted with a mixture of ether / ethyl acetate (5: 3, 80 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual solid is recrystallized from ethyl acetate / hexane to give the title compound (0.19 g).

P.f. 172-173 ° C MS (APCI) 497 ((M + H) +), "NMR (MDSO-D d 0.80 (6H, d), 1.78 (2H, quin), 1.97-2.15 (1H, m), 2.37 (2H, t), 3.04 (2H, t), 3.24 (3H, s), 3.58 (2H, d), 4.76 (2H, s), 7.42 (1H, d), 7.49 (1H, t), 7.53 -7.59 (2H, m), 7.88 (1H, d), 7.96 (1H, dd), 8.06 (1H, d), 12.12 (1H, broad s).

Example 9 4- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] irimidin-5 methyl) sulfonyl] butanoate Potassium peroxymonosulfate (0.163 g) is added to a stirred suspension of 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2, Methyl 4-dioxothieno [2,3-d] pyrimidin-5-yl) thio] butanoate (0.246 g) in methanol (3 ml), tetrahydrofuran (3 ml) and water (3 ml). After 1 hourThe reaction mixture is poured into a saturated aqueous solution of sodium bicarbonate (20 ml) and extracted with ethyl acetate (2 x 20 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography eluting with hexane: ethyl acetate (1: 1) followed by trituration with ethyl acetate / hexane to give the title compound (0.80 g). P.f. 160-161 ° C MS (APCI) 527.1 (M + H) +),? E NMR (DMS0-D6) d 0.77. (3H, d), 0.79 (3H, d), 1. 95-2.09 (2H, m), 2.10-2.25 (1H, m), 2.56 (2H, t), 3.19 (3H, s), 3.20-3.33 22H, m), 3.46 (1H, dd), 3.58-3.64 (4H, m), 4.74 (1H, d), 5.58 (1H, d), 7.50-7.59 (4H, m), 7.90 (1H, d), 7.97 (1H, d), 8.21 (1H, d).

Example 10 4- [(1, 2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naph-alenyl-1-yl) -2,4-dioxothieno [2, 3-d] irimidin- Methyl 5 -yl) sulfonyl] butanoate 3-Chloroperoxybenzoic acid (57-86%, 0.366 g) is added to a solution of 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-) methyl naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl) thio] butanoate (0.36 g) in dichloromethane (20 ml). After 1 hour, the solution is diluted with ethyl acetate (40 ml) and then washed with a saturated aqueous solution of sodium metabisulfite (20 ml) followed by a saturated aqueous solution of sodium bicarbonate (20 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is crystallized from ethyl acetate / hexane to give the title compound (0.182 g). P.f. 122-124 ° C MS (APCI) 543.0 (M + H) +),? NMR (DMS0-D6) d 0.81 (6H, d), 1.98-2.15 (1H, m), 2.30 (2H, quin), 2.61 (2H, t), 3.40 (3H, s), 3.54 (2H, d) , 3.71 (3H, s), 3.94 (2H, t), 5 ~ 10 (2H, s), 7.43-7.58 (4H, m), 7.86-7.94 (3H, m).

Example 11 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (l-naph-alenyl-yl) -2,4-dioxo-ene [2,3-d] pyrimidine] -5-yl) sulfonyl] butanoic A solution of sodium hydroxide (1 M, 1 ml) is added to a stirred suspension of 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (l -naphthalenylmethyl) -2,4-dioxothieno- [2,3-d] pyrimidin-5-yl) sulfonyl] butanoate (0.10 g) in methanol (3 ml) and tetrahydrofuran (3 ml). After 4 hours, the reaction mixture is diluted with water (20 ml), acidified with hydrochloric acid (2 M) and extracted with ethyl acetate (2 x 30 ml). The organic extracts are evaporated under reduced pressure. The residue is partitioned between ether (30 ml) and an aqueous solution of sodium hydroxide (0.1 M, 30 ml). The aqueous phase is acidified with hydrochloric acid (2 M) and extracted with ethyl acetate (2 x 30 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is triturated with ethyl acetate / hexane to give the title compound (0.028 g). Mp .. 174-175 ° C MS (APCI) 529.0 (M + H) +), XH NMR (DMSO-D6) d 0.77 (6H, d), 1.92-2.05 (3H, m), 2.43 (2H, t ), 3.24 (3H, s), 3.55 (2H, d), 3.85 (2H, t), 5.10 (2H, s), 7.46-7.61 (4H, m), 7.95 (1H, d), 7.97-8.04 ( 2H, m), 12.22 (1H, broad s).

Example 12 6 -. 6-benzyl-3-methyl-l- (methylpropyl) ieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione a) Ethyl 2-amino-5- (phenylmethyl) thiophene-3-carboxylate.

Triethylamine (10.40 ml) is added to a solution of 3-phenylpropanal (10.0 g), ethyl cyanoacetate (7.95 ml) and sulfur (2.40 g) in dimethylformamide (30 ml). The mixture is heated at 50 ° C under nitrogen for 3 hours, then diluted with water (350 ml) and extracted four times with diethyl ether. The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography eluting with diethyl ether: isohexane (1: 3) to give the subtitle compound (14.2 g). MS (APCI) 262 (M + H) +), XH NMR (CDC13) d 1.33 (3H, t), 3.91 (2H, s), 4.25 (2H, c), 5.78 (2H, broad s), 6.70 ( 1H, s), 7.20-7.33 (5H,). b) ethyl 2- (2-methylpropylamino) -5- (phenylmethyl) -iophene-3-carboxylate.

Sodium borohydride (3.0 g) is added in 6 portions over 3 hours to a stirred solution of ethyl 2-amino-5- (phenylmethyl) thiophene-3-carboxylate in 2-methylpropanoic acid under nitrogen. The mixture is stirred at room temperature for 20 hours and then diluted with water, neutralized with sodium bicarbonate and extracted with ethyl acetate 4 times. The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography eluting with diethyl ether: isohexane (1:19) to give the subtitle compound (2.80 g). MS (APCI) 318 (M + H) +), XH NMR (CDCl 3) d 0.96 (6H, d), 1.32 (3H, t), 1.93 (1H, m), 2.97 (2H, dd), 3.92 (2H , s), 4.23 (2H, c), 6.75 (1H, s), 7.20-7.34 (5H, m), 7.46 (1H, m). c) N1-Acetyl-N- (2-methylpropyl) -N- [3-ethoxycarbonyl-5- (phenylmethyl) -2-thienyl] urea.

Acetyl chloride (0.69 ml) is added to a stirred suspension of silver cyanate (1.51 g) in anhydrous toluene (30 ml) under nitrogen. After 1 hour, 2- (2-methylpropylamino) -5- (phenylmethyl) thiophene-3-ethyl carboxylate (2.55 g) is added and stirring is continued for 20 hours. The mixture is filtered and the solid residue is washed with diethyl ether. The combined water is evaporated under reduced pressure and the residue is purified by column chromatography eluting with diethyl ether: isohexane (1: 1) to give the subtitle compound (3.08 g). MS (APCI) 403 (M + H) +), XH NMR (CDC13) d 0.88 (6H, d), 1.31 (3H, t), 1.92. (1H, m), 2.46 (3H, s), 2.80-3.90 (2x 1H, 2 vbs), 4.08 (2H, s), 4.27 (2H, c), 7.08 (1H, s), 7.25-7.39 (5H , m), 7.46 (1H, m). d) 3-methyl-1- (2-methylpropyl) -6- (phenylmethyl) thieno- [2,3-d] pyrimidin-2,4- (1H, 3) -dione.

Sodium ethoxide (1.96 g) is added to a solution of N-acetyl-N- (2-methyl-propyl) -N- [3-ethoxycarbonyl-5- (phenylmethyl) -2-thienyl] -urea (2.90 g) in ethanol (40 ml) under nitrogen. The mixture is stirred for 20 hours, and then iodomethane (1.80 ml) is added. The mixture is refluxed for 3 hours and then allowed to cool to room temperature, and evaporated under reduced pressure. The residue is diluted with water and extracted with ethyl acetate twice. The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography eluting with diethyl ether: isohexane (1: 1) to provide an oil which recrystallizes from diethyl ether / isohexane to give the title compound (1.70 g). P.f. 72-3 ° C MS (APCI) 329 (M + H) +), 1"-H NMR (CDC13) d 0.95 (6H, d), 2.28 (1H, m), 3.41 (3H, s), 3.72 ( 2H, d), 4.07 (2H, s), 7.05 (1H, s), 7.23-7.37 (5H, m).

Example 13 3-methyl-1- (1-methylethyl) -6- (phenylmethyl) ieno- [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione. a) 2- (1-Methylethylamino) -5- (phenylmethyl) thiophene-3-carboxylic acid ethyl ester.

To a solution of the ethyl ester of 2-amino-5- (phenylmethyl) thiophene-3-carboxylic acid (2.61 g) and 4-methylbenzenesulfonic acid (30 mg) in dry toluene (50 ml) is added 2, 2-dimethoxypropane. The solution is refluxed for 5 hours and then allowed to cool to room temperature. A solution of sodium borohydride (800 mg) in ethanol (100 ml) is added to the solution, and the mixture is stirred at room temperature under nitrogen for 24 hours. The mixture is diluted with water and then extracted three times with ethyl acetate. The combined organic extracts are washed with brine and then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide an oil. The residue is purified by column chromatography on silica, eluting with diethyl ether: isohexane (1:19) to give the subtitle compound (550 mg). MS (APCI) 304 (M + H) +),? NMR (CDC13) d 1.25 (6H, d), 1.31 (3H, t), 3.41 (1H, m), 3.93 (2H, s), 4.22 (2H, c), 6.74 (1H, s), 7.20-7.33 '(5H, m). b) N '-acetyl-N- (1-methylethyl) -N-] 3-ethoxycarbonyl-5- (phenylmethyl) -2-thienyl] urea. _- It is prepared from the 2- (1-methylethylamino) -5- (phenylmethyl) thiophene-3-carboxylic acid ethyl ester (550 mg), silver cyanate (340 mg) and acetyl chloride (0.155 ml) following the method of example 12, step c) to provide the subtitle compound. MS (APCI) 389 (M + H) +), c) 3-methyl-1- (1-methylethyl) -6- (phenylmethyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione.

It is prepared from N '-acetyl-N- (1-methylethyl) -N-] 3-ethoxycarbonyl-5- (phenylmethyl) -2-thienyl] urea (700 mg), sodium ethoxide (400 mg) and iodomethane (0.45 ml) following the method of. example 12, step d) to provide the title compound. P.f. 91-3 ° C MS (APCI) 315 (M + H) +), H NMR (CDC13) d 1.55 (6H, d), 3.38 (3H, s), 4.07 (2H, s), 4.60 (1H, s broad), 7.07 (1H, s), 7.23-7.37 (5H, m).

Example 14 6- [(1-hydroxy-l-phenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2, - (1H, 3H) -dione A solution of 3-methyl-1- (1-methylethyl) -6- (phenylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (Example 12, 0.150 g) and N- Bromosuccinimide (0.090 g) in anhydrous chloroform (5 ml) is heated to reflux under nitrogen for 2 hours. The mixture is evaporated under reduced pressure and the residue is purified by column chromatography eluting with diethyl ether: isohexane (1: 1) to give the title compound (0.085 g). P.f. 140-2 ° C MS (APCI) 345 (M + H) +), XH NMR (CDC13) d 0.97 (6H, d), 2.31 (1H, m), 2.57 (1H, d), 3.39 (3H, s ), 3.77 (2H, ddd), 5.97 (1H, d), 7.03 (1H, s), 7.33-7.46 (5H, m).

Example 15 (+) 5- [(2-hydroxypropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenyl-methyl) thieno [2,3-d] pyrimidin-2, 4- ( 1H, 3H) -dione a) Bis-2-hydroxypropyl disulfide (+) and meso L-mercaptopropan-2-ol (2 ml) is dissolved in dichloromethane (10 ml). Sodium bicarbonate (2.67 g) and water (10 ml) are added. The suspension is stirred vigorously and cooled in an ice bath. A solution of bromine (0.59 ml) in dichloromethane (5 ml) is added dropwise to the suspension. The mixture is stirred for 10 minutes after the addition is complete, and then the phases are separated. The aqueous phase is extracted with dichloromethane, the dichloromethane phases are combined, and then dried, filtered and evaporated to give the subtitle compound (2.56 g) • SH NMR (CDC13) d 1.29 (6H, d) , 2.33 (2H, broad), 2.67-2.75 (2H, m), 2.83-2.92 (2H, m), 4.05-4.12 (2H, m). b) Bis-2- [(1,1-dimethylethyl) - (dimethyl) -silyloxy] ropildisulfide (+) and meso It is dissolved in bis-2-hydroxypropyl disulfide (+.) And meso (2.56 g) in dimethylformamide (20 ml). Imidazole (1.60 g) and dimethyl (1,1-dimethylethyl) silyl chloride are added (3.46 g), and the resulting solution is stirred overnight. The reaction mixture is poured into water (100 ml) and extracted three times with ether. The ether extracts are combined, washed with brine, dried, filtered and evaporated. Chromatography, eluting with isohexane: ether (99: 1) gives the subtitle compound (3.90 g). XH NMR (CDC13) d 0.08 (6H, s), 0.09 (6H, s), 0.89 (18H, s), 1.24 (6H, d), 2.63-2.70 (2H, m), 2.79-2.87 (2H, m ), 4.00-4.07 (2H, m). c) (+) 5- [(2-hydroxypropyl) io] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- ( 1H, 3H) -dione 3-Methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (Example 2) (220 mg) is dissolved in tetrahydrofuran (1 ml) and cooled to -78 ° C. LDA (1 M solution in tetrahydrofuran / hexane) is added dropwise until a red color persists. The solution is stirred for 1 h, and then a solution of bis-2- [dimethyl (1,1-dimethylethyl) -silyloxy] propyldisulfide is added. { ±) and meso (298 mg) in tetrahydrofuran (3 ml) and the solution allowed to warm to 0 ° C. After 65 minutes, sodium bicarbonate (aqueous) is added and the mixture is extracted three times with ethyl acetate. The ethyl acetate phases are combined, washed with brine, dried, filtered and evaporated, chromatography eluting with isohexane: ethyl acetate (9: 1 to 4: 1) yields the silylether of the title compound (MS (+ ve APCI) 583 (M + H) +) Silyl ether is dissolved in acetonitrile (3 ml), hydrofluoric acid (40% aqueous, 0.6 ml) is added and the solution is stirred for 40 minutes. sodium bicarbonate (aqueous) and the reaction mixture is extracted three times with ethyl acetate.The ethyl acetate phases are combined, washed with brine, dried, filtered and evaporated.Chromatography, eluting with isohexane: acetate of ethyl (3: 1) changing to ethyl acetate followed by CLAP (isohexane: ethyl acetate, 50:50 to 0: 100) yields the title compound (28 mg), mp 126-128 ° C MS (+ ve APCI) 469 (M + H) +), XH-NMR (DMSO-ds) d 0.81 (6H, d), 1.17 (3H, d), 1.98-2.11 (1H, m), 2.89 (1H, m), 3.00-3.06 (1H, m), 3.25 (3H, s), 3.59 (2H, d), 3.70-3.81 (1H, m), 4.79 (2H, s), 4.84 (1H, d), 7.41 (1H, d), 7.49 (1H, t), 7.52-7.58 (2H, m), 7.88 (1H, d), 7.93-7.98 (1H, m) and 8.08-8.11 (1H, m).

Example 16 1,2,3, 4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-methylpropyl) -6- (l-naph-alenyl-yl) -2,4-dioxo-ene [2,3 -d] irimidine-5-carboxamide a) 1, 2, 3, 4-Hydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethi) -2,4-dioxothieno [2,3-d] pyrimidine-5-carboxylic acid .

N-Butyllithium (2.0 M solution in hexanes, 1.90 ml) is added dropwise to a solution of diisopropylamine (0.069 ml) in anhydrous tetrahydrofuran (30 ml) at 0 ° C, under nitrogen. The solution is stirred for 5 minutes and then cooled to -78 ° C and a solution of 3-met il-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-] is added dropwise. d] pyrimidin-2,4 (1H, 3H) -dione (1.50 g) in anhydrous tetrahydrofuran (15 ml). After 15 minutes, the flask is transferred to a sealed pump having carbon dioxide granules (2 g) and heated at 50 ° C for 18 hours. The reaction mixture is cooled to room temperature and then added to an aqueous solution of sodium hydroxide (0.25 M, 75 ml) and washed with ether (2 x 75 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether (2 x 75 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with isohexane: ethyl acetate (3: 1) containing 1% acetic acid, to give the subtitle compound (0.337 g) as a solid. MS (+ ve APCI) 432 (M + H) +) MS. 'H NMR (DMSO-de) d 0.79 (6H, d), 1.96-2.10 (1H, m), 3.25 (3H, s), 3.58 (2H, d), 4.75 (2H, d), 7.49-7.55 ( 4H, m), 7.88-7.91 (1H, m), 7.95-7.98 (1H, m), 8.09-8.12 (1H, m). b) 1,2,3,4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothien [2, 3 d] pyrimidine-5-carboxamide To a solution of 1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine- 5-carboxylic acid (50 mg) and 2-aminoethanol (14 μl) in dichloromethane (2 ml) is added l-hydroxybenzotriazole hydrate (48 mg) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (45 mg) ). The reaction mixture is stirred at room temperature for 18 hours and then hydrochloric acid (1 M, 20 ml) is added and the mixture is extracted with ether (30 ml). The organic extracts are washed with water, then with a 1 M sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue recrystallizes from ethyl acetate: isohexane to give the title compound (28 mg). P.f. 193-194 ° C MS (+ ve APCI) 466 (M + H) +), "-H NMR (CDC13) d 0.84 (6H, d), 2.05-2.20 (1H, m), 3.41 (3H, s) , 3.57-3.70 (5H, m), 3.91 (2H, c), 4.92 (2H, s), 7.42-7.52 (4H, m), 7.82-7.90 (2H, m), 8.04-8.08 (1H, m) , 8.38 (1H, broad t).

The following compounds are prepared according to the method of example 16 using 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (l-naph-alenylmethyl) -2, 4- dioxotiene [2, 3-d] pyrimidine-5-carboxylic acid (example 15a) and the appropriate amine. l-. { [1,2,3,4- 210-506 (CDC1,) 0.89- tetrahydrs-3- 211 0.92 (6H, m), methyl-1- (2- 1.08-1.19 + methylpropyl) -6- 1.39-1.56 + (1- 1.70-1.90 + . y- * Q. r < Xl naf alenylmethyl) - 2.00-2.25 (5H, . X K. 2,4-m), 3.36 (3 H, dioxot ieno [2,3-s), 2.70-2.80 d] pyrimidin-5- + 3.06-3.31 + il] -carbonyl} - 3.38-3.59 +? Iperidin-4-ol 3.66-3.83 + 3.85-3.99 (7H, m), 4.16-4.37 (1H, m), 4.40- .58 (2H, m), 7.38-7.57 (4H, m ), 7.79-7.92 (2H, m), 8.02- 8.08 (1H, m).

E j Emplo Compues or p.f./ EM (+ ve XH NMR 6 ° c APCI) (M + H) *) 19 (3R) -l-. { [1,2,3,4-506 (DMSO d 0.81- tetrahydro-3- 0.88 (6H, m), methyl-1- (2- 1.20-1.59 + methylpropyl) -6- 1.67-1.97 (4H, X (1- m), 2.00-2.15 naph alenylmethyl) - (1H, m), 2.57- X 2.4- 2.95 + 2.99- dioxotiene [2,3- 3.19 (2H), d] pyrimidine-5- 3.11- 3.74 (7H, il] -carbonyl.} - m), 3.90-4.08 piperidin-3-ol + 4.18-4.58 (3H), 4.72-4.96 (1H, m), 7.49-7.55 (4H, m), 7.85 -7.91 (1H, m), 7.93- 7.98 (1H, m), 8.12-8.19 (1H, m).

Example 21 Acid 2-. { [1, 2, 3, -tetrahydro-3-methyl-l- (2-methylpropyl) -6- (l-naf talenylme il) -2,4-dioxo-ene [2, 3-d] • pyrimidine- 5-yl] carboxamido} acetic Oxalyl chloride (0.092 ml) is added to a solution of 1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxotiene acid [ 2,3-d] -pyrimidine-5-carboxylic acid (example 15a, 222 mg) and dimethylformamide (0.01 ml) in anhydrous dichloromethane (5 ml) at room temperature. After 2 hours, the solution is evaporated under reduced pressure to provide the 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,5 chloride. -dioxothieno [2,3-d] pyrimidin-5-carbonyl as an oil. A solution of this oil (58 mg) in anhydrous dichloromethane (2 ml) is added to a stirred mixture of glycine methyl ester hydrochloride (29 mg) and triethylamine (0.037 ml) in anhydrous dichloromethane (1 ml) at room temperature. After 1 hour, ethyl acetate (25 ml) and 2M hydrochloric acid are added. The organic layer is washed with water and then with a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and it evaporates under reduced pressure. The residue is dissolved in a mixture of tetrahydrofuran (4 ml), methanol (2 ml) and a solution of 1 M sodium hydroxide (1 ml). After 2 hours, water (20 ml) is added and the solution is extracted with ether (20 ml). The aqueous layer is acidified with hydrochloric acid and then extracted with ethyl acetate (3 x 20 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is recrystallized from ethyl acetate: isohexane to give the title compound (42 mg). P.f. 218-219 ° C MS (+ ve APCI) 480 * (M + H) *),? E NMR (CDCL3 / DMSO d6) d 0.83 (6H, d), 2.06-2.15 (1H, m), 3.41 (3H , s), 3.59 (2H, d), 4.23 (2H, d), 5.00 (2H, s), 7.43-7.54 (4H, m), 7.80-7.90 (2H, m), 8.01-8.06 (1H, m ), 9.73 (1H, t).

The following examples are prepared according to the method of Example 21"using 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalerylmethyl) -2- chloride. -dioxothieno [2,3-d] -pyrimidine-5-carbonyl (prepared in example 19) and the appropriate amine (excluding the hydrolysis step for examples 23 and 24).

Example 25 1,2,3,4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-methylpropyl) -6- (1-naphomethylmethyl) -2,4-di-oxo-ieno [2, 3-d] -pyrimidin-5-sulf on amide a) 1, 2, 3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naph-alenylme-il) -2,4-dioxo-ene [2, 3-d] -pyrimidine- 5-lithium sulphinate.

A solution of "lithium diisopropylamide (3.52 mmol) in anhydrous tetrahydrofuran (10 ml) is added dropwise to a solution of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenyl-methyl) thieno [2]. , 3-d] pyrimidin-2, 4 (1H, 3H) -dione (1.00 g) in anhydrous tetrahydrofuran (20 ml) at -78 ° C under nitrogen.After 15 minutes, sulfur dioxide was bubbled through. the reaction mixture which is heated at room temperature for 30 minutes, then nitrogen is bubbled through the solution for 10 minutes.The precipitated solid is filtered, washed with ether and dried in vacuo at 50 ° C to provide the composed of the subtitle (1.20 g) EM (+ ve APCI) 425 (M + H-HOLi) *), 'H NMR (DMSO-d6) d 0.75 (6H, d), 1.85-2.06 (1H, m), 3.21 (3H, s), 3.50 (2H, d), 5.22 (1H, s), 7.43-7.51 (3H, m), 7.55 (1H, d), 7.83 (1H, d), 7.90 (1H, dd) , 8.54 (1H, dd). b) 1,2,3,4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothien [2, 3 d] -pyrimidine-5-sulfonamide N-Chlorosuccinimide (52 mg) is added to a rapidly stirred suspension of 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothiene [2,3-d] -pyrimidin-5-sulfinate lithium (200 mg) in dichloromethane (8 ml) and 0.22 M hydrochloric acid (9 ml). After 1 hour, additional N-chlorosuccinimide (26 mg) is added. After 1 hour, water (30 ml) and dichloromethane (30 ml) are added and the phases are separated. The aqueous phase is extracted with dichloromethane (2 x 10 ml). The combined organic extracts are treated with ethanolamine (0.071 ml). After 30 minutes, the solution is washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with ether to provide the title compound (120 mg) as a foam. MS (+ ve APCI) 502 (M + H) *), XH NMR (CDC13) 6 0.82 (6H, d), 2.01-2.16 (1H, m), 3.32 (2H, c), 3.41 (3H, s) , 3.79-3.85 (2H,), 5.05 (2H, s), 7.41-7.56 (4H, m), 7.59 (1H, t), 7.83-7.98 (3H, m).

Example 26 - [(3-methoxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -iene [2,3-d] irimidin-2, 4- (1H, 3H) - diona A solution of lithium diisopropylamide (3.09 mmole) in anhydrous tetrahydrofuran (10 ml) is added dropwise to a solution of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenyl-methyl) thieno [2, 3-d] pyrimidin-2,4 (1H, 3H) -dione (1.00 g) in anhydrous tetrahydrofuran (25 ml) at -78 ° C under nitrogen. After 15 minutes, bis- (3-methoxyphenyl) disulfide (J. Amer. Chem. Soc., 75; 1953; 5736) (0.88 g) is added and the mixture allowed to warm to room temperature. The mixture is added to a saturated solution of sodium hydrogen carbonate (100 ml) and extracted with ether (2 x 100 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with isohexane: ether (1: 1) to give the title compound (1.00 g) as an oil. MS (+ ve APCI) 517 (M + H) *), XH NMR (CDC13) d 0.88 (6H, d), 2.13-2.22 (1H, m), 3.34 (3H, s), 3.62 (2H, d) , 3.76 (3H, s), 4.71 (2H, s), 6.71 (1H, dt), 6.79 (1H, t), 6.81 (1H, d), 7.20 (1H, t), 7.37-7.52 (4H, m ), 7.81 (1H, d), 7.86 (1H, d), 7.89 (1H, d).

Example 27 5- [(3-hydroxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione Boron tribromide (1M solution in dichloromethane, 5.63 ml) is added to a stirred solution of 5 - [(3-methoxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6-naphthalenylmethyl) thieno [2 , 3-d] pyrimidin-2, 4- (1H, 3H) -dione (example 26, 0.97 g) in anhydrous dichloromethane (50 ml) at 0 ° C under nitrogen. After 1 hour, a saturated sodium hydrogen carbonate solution (100 ml) is added and the mixture is extracted with ethyl acetate (2 x 100 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with ethyl acetate: isohexane (3: 2) and then recrystallized from ethyl acetate: isohexane to give the title compound (0.468 g). P.f. 200-201 ° C MS (+ ve APCI) 503 (M + H) *), 1 H NMR (DMSO d 6) 6 0.82 (6H, d), 2.00-2.11 (1H, m), 3.17 (3H, s), 3.61 (2H, d), 4.73 (2H, s), 6.56 (1H, t), 6.58 (1H, dt), 6.64 (1H, dt), 7.11 (1H, t), 7.35 (1H, dt), 7.45 -7.52 (3H, m), 7.86-7.90 (2H, m), 7.94 (1H, d), 9.49 (1H, s).

Example 28 - [(3-hydroxyphenyl) sulfinyl] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H) - diona 3-Chloroperoxybenzoic acid (0.12 g) is added to a solution of 5- [(3-hydroxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3 d] pyrimidin-2, 4- (1H, 3H) -dione (example 27, 0.20 g) in dichloromethane (5 ml).

After 2 hours, ethyl acetate (50 ml) is added and the solution is washed with a saturated solution of sodium bisulfite (25 ml), and then with a saturated solution of sodium hydrogen carbonate (25 ml), and subsequently with brine (25 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.

The residue is purified by preparative CLAP in normal phase, with an elution gradient of dichloromethane: ethanol and then recrystallized from ethyl acetate: isohexane to give the title compound (0.05 g). P.f. 242-243 ° C MS (+ ve APCI) 519 (M + H) *) X H NMR (DMSO d 6) 6 0.74 (3 H, d), 0.75 (3 H, d), 1. 88-2.02 (1H, m), 3.25 (3H, s), 3.49 (2H, d), 4.58 (1H, d), 5.37 (1H, d), 6.95 (1H, dt), 7.24-7.36 (3H, m), 7.42 (1H, t), 7.45-7.55 (3H, m), 7.67 (1H, d), 7.89 (1H, d), 7.94 (1H, d).

Example 29 - [(3-hydroxyphenyl) sulfonyl] -3-methyl-1 - (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H ) -dione 3-Chloroperoxybenzoic acid (50 mg) is added to a solution of 5- [(3-hydroxyphenyl) sulfinyl] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3 d] pyrimidin-2, 4- (1H, 3H) -dione (example 28, 80 mg) in dichloromethane (2 ml).

After 2 hours, ethyl acetate (25 ml) is added and the solution is washed with a saturated solution of sodium bisulfite (10 ml), then with a saturated solution of sodium hydrogen carbonate (10 ml) and subsequently with brine. (10 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is recrystallized from ethyl acetate: isohexane to give the title compound (24 mg). P.f. 209-210 ° C EM (+ ve APCI) 535 (M + H) *) 7E? NMR (DMSO d6) d 0.76 (6H, d), 1.89-2.01 (1H, m), 3.11 (3H, s) 7 3.52 (2H, d), 5.25"(2H, s), 7.05 (1H," dt ), 7.38-7.68 (7H, m), 7.94 (1H, dd), 7.99-8.07 (2H, m). .

Example 30 ~ 3-methyl-l- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(3-nitrophenyl) thio] thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H) -diona A solution of lithium diisopropylamide (3.63 mmol) in anhydrous tetrahydrofuran (5.5 ml) is added dropwise to a solution of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenyl-methyl) thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H) -dione (1.00 g) in anhydrous tetrahydrofuran (20 ml) at -78 ° C under nitrogen. After 15 minutes, bis (3-nitrophenyl) disulfide (0.90 g) is added and the mixture is heated at room temperature for 1 hour. A saturated solution of sodium hydrogen carbonate (100 ml) is added, and the mixture is extracted with ether (2 x 100 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with ethyl acetate: isohexane (1: 1) to give a partially purified material (1.40 g). A portion of this material (0.20 g) is further purified by preparative CLAP in normal phase with an elution gradient of dichloromethane: ethanol and then recrystallized from ethyl acetate: isohexane to give the title compound (22 mg). P.f. 144-145 ° C MS (+ ve APCI) 523 (M + H) *) "? NMR (CDC13) 6 0.91 (6H, s), 2.12-2.28 (1H,), 3.31 (3H, s), 3.66 ( 2H, d), 4.75 (2H, s), 7.36-7.53 (5H, m), 7.56 (1H, dt), 7.82 (1H, d), 7.88 (1H, d), 7.92 (1H, d), 7.95 (1H, t), 8.00 (1H, dt).

Example 31 - [(3-aminophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -diona A suspension of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenyl-methyl) -5 - [(3-nitrophenyl) thio] thieno [2,3-d] pyriraidin-2, 4- ( 1H, 3H) -dione partially purified (example 30, 1.20 g), iron powder (0.59 g) and ammonium chloride (0.56 g) in ethanol (5 ml) and water (5 ml) is heated at reflux for 2 hours , and then cooled to room temperature. A solution of 2 M sodium hydroxide (50 ml) is added and the mixture is stirred for 30 minutes. The resulting solution is decanted from the insoluble solid. The solid and the solution are then extracted with ethyl acetate (3 x 50 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with ether: isohexane (2: 1) followed by recrystallization from ethyl acetate: isohexane to give the title compound (0.41 g). P.f. 149-150 ° C MS (+ ve APCI) 502 (M + H) *) H NMR (CDC13) 6 0.88 (6H, d), 2.10-2.23 (1H, m), 3.35 (3H, s), 3.62 ( 2H, d), 3.63 (2H, s), 4.71 (2H, s), 6.48 (1H, dt), 6.59 (1H, t), 6.64 (1H, dt), 7.06 (1H, t), 7.37-7.50 (4H, m), 7.80-7.92 (3H, m).

Example 32 -. { [3-. { (bis-methanesulfonyl) amino} phenyl] thio} -3-methyl-1- (2-methylpropyl) -6- (1 -naphthalimethyl) -thieno [2,3-d]? Irimidin-2,4- (1H, 3H) -dione Methanesulfonyl chloride (0.028 ml) is added to a solution of 5- [(3-aminophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2, 3 d] pyrimidin-2, 4- (1H, 3H) -dione (60 mg) and triethylamine (0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature. After 1 houra saturated solution of sodium hydrogen carbonate (10 ml) is added and the mixture is extracted with ether (2 x 10 ml) The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by preparative CLAP in a normal phase, with an elution gradient of isohexane: ethyl acetate and then recrystallized from ethyl acetate: isohexane to give the title compound (28 mg) .Pf 216-217 ° C MS (+ ve APCI) 658 (M + H) *) XH NMR (CDC13) d 0.88 (6H, d), 2.10-2.24 (1H, m), 3.29 (3H, s), 3.34 (6H, s), 3.63 (2H, d), 4.27 (2H, s), 7.15-7.18 (2H, m), 7.34-7.51 (6H, m), 7.82 (1H, d), 7.87 (1H, d), 7.95 (1H, d).

Example 33 - [(3-methoxycarbonylaminophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naph-alenylmethyl) -thieno [2,3-d] pyrimidin-2, 4- (1H, 3H ) -dione Methyl chloroformate (0.028 ml) is added to a solution of 5- [(3-aminophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (l-naphthalenylmethyl) -thieno [2, 3- d] pyrimidin-2, 4- (1H, 3H) -dione (60 mg) and triethylamine (0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature. Additional triethylamine (0.067 ml) and methyl chloroformate (0.028 ml) are added after 4 hours and 24 hours. A saturated solution of sodium hydrogen carbonate (10 ml) is added and the mixture is extracted with ether (2 x 10 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by preparative CLAP in the normal phase with an elution gradient of dichloromethane: ethanol and then recrystallized from ethyl acetate: isohexane to give the title compound (15 mg). P.f. 167-168 ° C MS (+ ve APCI) 560 (M + H) *) XH NMR (CDC13) d 0.89 (6H, d), 2.11-2.24 (1H, m), 3.34 (3H, s), 3.63 ( 2H, d), 3.74 (3H, s), 4.73 (2H, s), 6.52 (1H, broad s), 6.93 (1H, d), 7.17 -7.35 (3H, m), 7.35-7.50 (4H, m), 7.80-7.91 (3H, m).

Example 34 - [(3-Acetamidophenyl) io] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidine-2,4- (1H, 3H ) -dione Acetic anhydride (0.034 ml) is added to a solution of 5- [(3-aminophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2, 3-d] ] pyrimidin-2, 4- (1H, 3H) -dione (60 mg) and 'triethylamine (0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature. After 1 hour, treatment and purification as in Example 32 provide the title compound (15 mg). P.f. 173-174 ° C MS (+ ve APCI) 544 (M + H) *) Trl NMR (CDC13) d 0.88 (6H, d), 2.08-2.24 (1H, m), 2.14 (3H, s), 3.34 ( 3H, s), 3.63 (2H, d), 4.73 (2H, s), 6.97 (1H, d), 7.08 (1H, broad s), 7.22 (1H, t), 7.35-7.50 (6H, m), 7.81 (1H, d), 7.86 (1H, d), 7.91 (1H, d).

Example 35 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(4-nitrophenyl) io] ieno [2, 3-d] pyrimidin-2, 4- (1H, 3H) - diona A solution of lithium diisopropylamide (2.6 mmol) in anhydrous tetrahydrofuran (7.5 ml) is added dropwise to a solution of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3 d] pyrimidin-2, 4- (1H, 3H) -dione (1.00 g) in anhydrous tetrahydrofuran (20 ml) at -78 ° C under nitrogen. After 15 minutes, bis (4-nitrophenyl) isulfide (0.90 g) is added and the mixture is heated at room temperature for 16 hours. A saturated solution of sodium hydrogen carbonate (100 ml) is added and the mixture is extracted with ether (2 x 100 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered through a pad of silica and evaporated under reduced pressure to give the crude product (1.4 g). A portion of this material (0.14 g) is purified by preparative CLAP in the normal phase with an elution gradient of dichloromethane: ethanol and then recrystallized from ethyl acetate: isohexane to give the title compound (28 mg). P.f. 184-185 ° C MS (+ ve APCI) 532 (M + H) *) XH NMR (CDC13) d 0.91 (6H, s), 2.15-2.28 (1H, m), 3.32 (3H, s), 3.66 ( 2H, d), 4.73 (2H, s), 7.25 (2H, d), 7.33-7.51 (4H, m), 7.82-8.11 (3H, m), 8.12 (2H, d).

Example 36 - [(4-aminophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-na talenylmethyl) -thieno [2,3-d] pyrimidin-2, 4- (1H, 3H ) -dione A suspension of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(4-nitrophenyl) thio] thieno [2,3-d] irimidin-2, 4- ( 1H, 3H) -dione crude (example 35, 1.26 g), iron powder (0.59 g) and ammonium chloride (0.56 g) in ethanol (5 ml) and water (5 ml) is refluxed for 4 hours , and then cooled to room temperature. A solution of sodium hydroxide (10%, 50 ml) is added and the mixture is stirred for 1 hour. The resulting solution is decanted from an insoluble solid. The solid and the solution in turn are extracted with dichloromethane (3 x 50 ml) and then ethyl acetate (3 x 50 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, they are filtered and evaporated under reduced pressure. The residue is partially purified by column chromatography on silica, eluting with ethyl acetate: isohexane (1: 1). Part of the pure material is recrystallized from isohexane: ethyl acetate to give the title compound (0.065 g). The remaining material is purified by preparative CLAP in normal phase with an elution gradient of dichloromethane: ethanol to provide the title compound (0.163 g). P.f. 177-178 ° C MS (+ ve APCI) 502 (M + H) *) XH NMR (CDC13) d 0.86 (6H, d), 2.07-2.20 (1H, m), 3.37 (3H, s), 3.59 ( 2H, d), 3.68 (2H, broad s), - 4.74 (2H, s), 6.61 (2H, d), 7.28 (2H, d), 7.34-7.51 (4H, m), 7.81 (1H, d) , 7.87 (1H, d), 7.90 (1H, d).

Example 37 3-Methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5- [(5-n-ropyridin-2-yl) thio] thieno [2, 3-d] pyrimidin-2, 4- ( 1H, 3H) -dione A solution of lithium diisopropylamide (6.2 mmol) in anhydrous tetrahydrofuran (20 ml) is added dropwise to a solution of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2, 3 -d] pyrimidin-2, 4 - (1H, 3H) -dione (2.00 g) in anhydrous tetrahydrofuran (40 ml) at -78 ° C under nitrogen. After 20 minutes, 2,2 '-dithiobis (5-nitropyridine) (1.97 g) is added and the mixture is heated at room temperature for 1 hour. A saturated solution of sodium hydrogen carbonate (200 ml) is added and the mixture is extracted with ethyl acetate (200 ml). A suspended solid is collected in the organic extracts, by filtration, washed with ethyl acetate and dried in vacuo at 40 ° C to provide the title compound (2.14 g).

P.f. 200-201 ° C MS (+ ve APCI) 533 (M + H) *) XE NMR (CDCl 3) d 0.91 (6H, d), 2.15-2.29 (1H, m), • 3.30 (3H, S), 3.66 (2H, d), 4.72 (2H, s), 7.28 (1H, d), 7.35-7.51 (4H, m), 7.81 (1H, d), 7.87 (1H, d), 7.93 (1H, d), 8.27 (1H, dd), 9.20 (1H, d).

Example 38 2-. { [1, 2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] thio ) - pyridine N-oxide A solution of lithium diisopropylamide (1.55 mmole) in anhydrous tetrahydrofuran (5 ml) is added dropwise to a solution of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3 d] pyrimidin-2, 4- (1H, 3H) -dione (0.50 g) in anhydrous tetrahydrofuran (10 ml) at -78 ° C under nitrogen. After 20 minutes, 2,2'-dithiobis (pyridine N-oxide) (0.40 g) is added and the mixture is warmed to room temperature. After 2 hours, a saturated solution of sodium hydrogen carbonate (100 ml) is added and the mixture is extracted with ethyl acetate (3 x 50 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica eluting with ethyl acetate: methanol (19: 1) and then recrystallized from ethyl acetate to give the title compound (0.18 g). P.f. 228-229 ° C MS (+ ve APCI) 504 (M + H) *) H NMR (DMSO ds) d 0.86 (6H, d), 2.03-2.16 (1H, m), 3.15 (3H, s), 3.64 (2H, d), 4.74 (2H, s), 6.86 (1H, dd), 7.17-7.27 (2H, d), 7.34 (1H, td), 7.42-7.53 (3H, m), 7.86 (1H, dd ), 7.91 (1H, d), 7.93 (1H, d), 8.36 (1H, dd).

EXAMPLE '39 5- [(3-Azidopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (l-naph-alenylmethyl) -iene [2, 3-d] pyrimidine-2, 4- (1H , 3H) -dione a) 3- [(1, 2, 3, 4-tetrahydro-3-methyl-1 - (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxotiene methansulphone [2, 3] -d] pyrimidin-5-yl) thio] propyl Dissolve 5- [(3-hydroxypropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H ) -dione (example 4) (403 mg) in dichloromethane (6 ml).

Triethylamine (300 μl) is added followed by methanesulfonyl chloride (150 μl) and the mixture is stirred overnight. Sodium bicarbonate (aqueous) is added and the phases are separated. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, washed with brine, dried, filtered and evaporated to give the subtitle compound (0.57 g). MS (+ ve APCI) 547 (M + H) *) XH NMR (CDC13) d 0.89 (6H, d), 2.09 (2H, quintet), 2.09-2.24 (1H, m), 3.16 (2H, t), 3.00 (3H, s), 3.42 (3H, s), 3.64 (2H, d), 4.37 (2H, t), 4.77 (2H, s), 7.34 (1H, d), 7.45 (1H, t), 7.51 -7.54 (2H, m), 7.82 (1H, d), 7.87-7.90 (1H, m), 7.99-8.02 (1H, m). b) 5- [(3-azidopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H ) -dione 3 - [(1,2,3,4-Tetrahydro-3-methyl-1- (2-methylpropyl) -6- (l-naph-alenylmethyl) -2,4-dioxothieno [2, 3-d] methanesulfonate is suspended. ] pyrimidin-5-yl) thio] propyl (0.57 g) and sodium azide (501 mg) in dimethylformamide (7 ml). The suspension is subjected to sonication (cleaning bath) for 3 hours. Water is added and the suspension is extracted three times with ethyl acetate. The extracts are combined and washed successively with brine, water and brine, then -Dry, filter and evaporate. Chromatography (isohexane: ethyl acetate 4: 1 to 3: 1) gives a yellow oil which is triturated with cyclohexane to give the title compound (118 mg). P.f. 94-96 ° C MS (+ ve APCI) 494 (M + H) *) XH NMR (DMSO d6) 6 0.81 (6H, d), 1.79 (2H, quintet), 1.98-2.10 (1H, m), 3.05 (2H, t), 3.25 (3H, s), 3.46 (2H, t), 3.60 (2H, d), 4.78 (2H, s), 7.41 (1H, d), 7.50 (1H, t), 7.52- 7.59 (2H, m), 7.88 (1H, d), 7.95-7.98 (1H, m), 8.06-8.09 (1H, m).

Example 40 - [(3-aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione Dissolve 5- [(3-azidopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H ) -dione (656 mg), 1,3-propanedithiol (100 μl) and triethylamine (400 μl), in a mixture of dichloromethane (3 ml) and isopropanol (5 ml). Sodium borohydride (78 mg) is added and the mixture is stirred overnight. The solvents are removed by evaporation, and then diluted hydrochloric acid is added dropwise until the effervescence ceases. The solution is made alkaline with aqueous sodium hydroxide and then extracted with dichloromethane (4 times). The extracts are dried, filtered and evaporated. Purification by CLAP (ethanol: dichloromethane 5-40: 95-60) followed by trituration With ether-cyclohexane, to provide the title compound (280 mg). MS (+ ve APCI) 468 (M + H) *) * H NMR (CDC13) d 0.88 (6H, d), 1.82 (2H, quintet), 2.11-2.22 (1H, m), 2.88 (2H, t) , 3.12 (2H, t); 3.42 (3H, s), 3.63 (2H, d), 4.78 (2H, s), 7.35 (1H, d), 7.45 (1H, t), 7.49-7.52 (2H, m), 7.82 '(1H, d) ), 7.87-7.89 (1H, m) and 8.02-8.04 (1H, m).

Dissolve 5- [(3-aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidin-2, 4 (1H, 3H ) -dione (142 mg) in dichloromethane-ethanol and 1M HCl in ether (1 ml) is added. The solution is evaporated, and then the solid is triturated with ethyl acetate to give the title compound as the monohydrate of the hydrochloride salt (62 mg). P.f. 200-205 ° C ~ Elemental analysis: found: C 57.42%, H 6.02%, N 7.87%, S 11.90% theoretical for C2SH32C1N3022: C 57.51%, H 6.18%, N 8.05%, S 12.28% EM (+ ve APCI ) 468 (M + H) *) * -H NMR (DMSO d,) 0.82 (6H, 1.83 (2H, quintet), 1.99-2.12 (1H, m), 2.94 (2H, t), 3.05 (2H, t ), 3. 26 (3H, e), 3.61 (2H, d), 4.78 (2H, s), 7.40 (1H, d), 7.50 (1H, t), 7.53-7.62 (2H, m), 7.78 (3H, broad), 7.89 (1H, d), 7.96-7.99 (1H, m) and 8.06 (1H, d).

Example 41 N-. { 3- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine-5 -il) thio] propyl} acetamide Dissolve 5- [(3-aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidin-2, 4 (1H, 3H ) -dione (51 mg) and triethylamine (100 μl) in dichloromethane (2 ml) and acetyl chloride (25 μl) is added. The reaction is stirred overnight, then water is added and the phases are separated. The aqueous phase is extracted with dichloromethane, and then the organic phases are combined, dried, filtered and evaporated. Purification by CLAP (ethanol: dichloromethane 1-10: 99-90) gives the title compound (36 mg). P.f. 114-117 ° C MS (+ ve APCI) 510 (M + H) *) X H NMR (DMSO d 6) d 0.81 (6H, d), 1.67 (2H, quintet), 1.78 (3H, s), 1.99-2.11 (1H, m), 2.99 (2H, t), 3. 14 (2H, c), 3.25 (3H, s), 3.59 (2H, d), 4.77 (2H, e), 7.41 (1H, d), 7.49 (1H, t), 7.52-7.58 (2H, m), 7.84-7.89 (2H, m), 7.95-7.98 (1H, m) and 8.06-8.09 (1H,).

Example 42 N-. { 3- [(1, 2, 3, 4-tetrahydro-3-yl-l- (2'-methylpropyl-6- (l-naphthalenylmethyl) -2, -di oxo] ene [2,3-d] pyrimidin-5-yl) thio] propyl.} - N ', N' -dimethylurea Prepared from 5- [(3-aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione (10 mg) and dimethylcarbamoyl chloride (24.8 mg) following the example method 41 to provide the title compound (8 mg). MS (+ ve APCI) 539 (M + H) *) "-H NMR (CDC1,) d 0.88 (6H, d), 1.89 (2H, quintet), 2. 10-2.24 (1H, m), 2.94 (6H, s), 3.12-3.17 (2H, m), 3.40 (3H, s), 3.51 (2H, c), 3.64 (2H, d), 4.78 (2H, s), 5.44 (1H, t), 7.35 (1H, d), 7.44 (1H, t), 7.48-7.53 (2H, m), 7.81 (1H, d), 7.87-7.90 (1H, m) and 8.02 -8.05 (1H, m).

Example 43 N-. { 3- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-na talenylmethyl) -2,4-di-oxo-ti in o [2,3-d] ] pyrimidin-5-yl) thio] ropil} -metoxiacetami da Prepared from 5- [(3-aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione (10 mg) and methoxyacetyl chloride (53 mg) following the method of example 41 to provide the title compound (6 mg).

MS (+ ve APCI) 540 (M + H) *) X H NMR (CDCl 3) d 0.88 (6H, d), 1.90 (2H, quintet), 2. 10-2.24 (1H, m), 3.07-3.14 (2H, m), 3.41 (3H, s), 3.43 (3H, s), 3.52 (2H, c), 3.63 (2H, d), 3.89 (2H, s), 4.78 (2H, s), 7.02 (1H, t), 7.35 (1H, d), 7.44 ( 1H, t), 7.48-7.54 (2H, m), 7.81 (1H, d), 7.87-7.90 (1H, m), and 8.00-8.04 (1H, m).

Example 44 N-. { 3- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2, 3-d] irimidin-5 -il) thio] propyl} methyl carbamate Prepared from 5- [(3-aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidin-2, (1H , 3H) -dione (10 mg) and methyl chloroformate (34 mg) following the method of example 41 to provide the title compound (4 mg). MS (+ ve APCI) 526 (M + H) *) NMR (CDC13) d 0.88 (6H, d), 1.87 (2H, quintet), 2.10-2.24 (1H, m), 3.08 (2H, t), 3.39 (2H, c), 3.43 (3H, s), 3.63 (2H, d), 3.66 (3H, s), 4.77 (2H, s), 5.51 (1H, broad), 7.34 (1H, d), 7.44 ( 1H, t), 7.48-7.53 (2H, m), 7.82 (1H, d), 7.87-7.90 (1H, m) and 8.01-8.04 (1H, m).

Example 45 N-. { 3- [(1, 2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5- il) thio] propyl} methanesulfonamide - 5- [(3-Aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (50 mg) and triethylamine (100 μl) in dichloromethane (5 ml) and then cooled in ice. Methanesulfonyl chloride (25 μl) is added dropwise and the solution is stirred for 1 hour. Aqueous ammonia (dilute) is added and the phases separated. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, dried, filtered and evaporated. Purification by CLAP (ethyl acetate: isohexane 20-100: 80-0) followed by trituration with methanol gives the title compound (43 mg). MS (+ ve APCI) 546 (M + H) *) X H NMR (DMSO dβ) d 0.81 (6H, d), 1.76 (2H, quintet), 2.00-2.11 (1H, m), 2.87 (3H, s) , 3.00-3.09 _ (4H, m), 3.25 (3H, s), 3.59 (2H, d), 4.77 (2H, s), 7.03 (1H, t), 7.41 (1H, d), 7.50 (1H, t), 7.52-7.60 (2H, m), 7.88 (1H, d), 7.95-7.98 (1H, m), and 8.07 (1H, d).

Example 46 N-. { 3- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-di-oxo-ti in o [2,3-] d] pyrimidin-5-yl) thio] propyl} trif luorometansulf onamide - [(3-Aminopropyl) thio] -3-methyl-1- (2-methyl-propyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (48 mg) and triethylamine (100 μl) in 5 ml of dichloromethane and after cooling to -78 °. Trifluoromethanesulfonic anhydride (50 μl) in dichloromethane (2 ml) is added dropwise and the solution is stirred for 5 minutes. Ammonia in ethanol (1 M, 0.5 ml) is added and the reaction mixture is allowed to warm to room temperature. Water is added and the phases are separated. The aqueous phase is extracted twice with dichloromethane, the phases, organic are combined and dried, filtered and evaporated. Purification by CLAP (ethyl acetate: isohexane 5-40: 95-60) gives the title compound (23 mg). MS (+ ve APCI) 600 (M + H) *) XH NMR (DMSO dβ) d 0.82 (6H, d), 1.76 (2H, quintet), 2.00--2.11 (1H, m), 3.03 (2H, t) , 3.25 (3H, s), 3. 27 (2H, t), 3.60 (2H, d), 4.76 (2H, s), 7.39. (1H, d), 7.49 (1H, t), 7.54-7.57 (2H, m), 7.88 (1H, d), 7.96 (1H, d), 8.04 (1H, d), 9.36 (1H, s).

Example 47 - . { [3- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) pro? Il] thio} -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione Dissolve 5- [(3-hydroxypropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (example 4, 470 mg), triphenylphosphine (290 mg) and phthalimide (162 mg) in tetrahydrofuran (7 ml). A solution of diethyl azodicarboxylate is added dropwise (170 μl) in tetrahydrofuran (2 ml) and the mixture is stirred overnight. Water and ether are added, and the phases are separated. The aqueous phase is extracted with dichloromethane twice. The organic extracts are washed with brine, dried, filtered and evaporated. Column chromatography (Ether 2: 1: isohexane) gives a solid which is hot-triturated with isohexane: ethyl acetate (4: 1) and then recrystallized from isohexane: ethyl acetate (2: 1) to give the compound of the title (12 mg). MS (+ ve APCI) 598 (M + H) *) H NMR (DMSO d6) d 0.81 (6H, d), 1.87 (2H, quintet), 1.98-2.10 (1H, m), 3.01 (2H, t ), 3.05 (3H, s), 3.57 (2H, d), 3.67 (2H, t), 4.77 (2H, s), 7.38 (1H, d), 7.46 (1H, t), 7.49-7.56 (2H, m), 7.82 (4H, s), 7.85 (1H, d), 7.93-7.96 (1H, m), and 8.06-8.09 (1H, m).

Example 48 N- (2-hydroxyethyl) -N '- [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2, -dioxo-ieno [2, 3-d] pyrimidin-5-yl)] urea Diphenylphosphoryl azide (0.27 ml) is added to a solution of 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothiene [2]. 3-d] irimidine-5-carboxylic acid (example 16, step a), 400 mg) and triethylamine (0.18 ml) in anhydrous toluene (12 ml). The mixture is heated at 90 ° C under nitrogen for 3 hours, then cooled to room temperature to provide a 0.088 M solution of N- [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) ) - 6 - (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] irimidin-5-yl)] isocyanate. Part of this solution (3 ml) is treated with ethanolamine (0.019 ml) and after 1 hour, 1 M hydrochloric acid (50 ml) is added. Methanol (20 ml) is added and the mixture is extracted with ethyl acetate (5 x 100 ml).

The combined organic extracts are washed with water (50 ml) and then with a saturated solution of sodium hydrogen carbonate (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a volume of about 30. ml. After 16 hours, the precipitated solid is collected by filtration and dried in vacuo to provide the title compound (0.058 g). p.f. 227-228 ° C MS (+ ve APCI) 481 (M + H) *) 'H NMR (DMSO d6) d 0.77 (6H, d), 1.97-2.07 (1H, m), 3.19 (2H, c), 3.21 (3H, s), 3.46 (2H, c), 3.51 (2H, d), 4.43 (2H, s), 4.72 (1H, t) 7 7.01 (1H, t), 7.45-7.54 (4H, m) , 7.86 (1H, dd), 7.92-7.95 '(1H, m), 8.01-8.04 (1H, m), 8.26 (1H, s).

Example 49 [1, 2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl) ] 2-hydroxyethyl carbamate Ethylene glycol (1 ml) is added to a solution 0. 088 M N- [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine- 5-yl)] isocyanate in toluene (example 48, 3 ml). The mixture is heated at 90 ° C for 1 hour and then added to 1 M hydrochloric acid (50 ml) and extracted with ether (100 ml). The organic extracts are washed with water (50 ml) and then with a saturated solution of sodium hydrogen carbonate (50 ml), then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with ether: isohexane (3: 2) and then recrystallized from ethyl acetate: isohexane to give the title compound (0.023 g) 7 P.f. 201-202 ° C MS (+ ve APCI) 482- (M + H) *) NMR (CDC13) d 0.84 (6H, d), 2.06-1.99 (lH, "m), 2. 27 (1H, t), 3.38 (3H, s), 3.55 (2H, d), 3.87-3.92 (2H, m), 4.33-4.37 (2H, m), 4.57 (2H, s), 7.42-7.51 ( 4H, m), 7.80-7.84 (1H, m), 7.86-7.89 (1H, m), 7.93-7.97 (1H, m), 8.16 (1H, broad s).

Example 50 N- (2-hydroxyethyl) -N-methyl-N '- [1,2,3,4-tetrahydro-3-methyl-1- (2-methylphenyl) -6- (1 -naph talen ilme ti 1 ) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl)] urea 2- (Methylamino) ethanol (0.026 ml) is added to a solution of 0.088 M N- [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) - 6 - (1 - Naphthalenylmethyl) -2,4-dioxothieno [2,3-d] irimidin-5-yl)] isocyanate in toluene (Example 48.3 ml). After 16 hours, ethyl acetate (50 ml) is added and the mixture is washed with 1 M hydrochloric acid (50 ml), water (50 ml) and after a saturated sodium hydrogen carbonate solution (50 ml), after Dry over anhydrous magnesium sulfate, filter and evaporate under reduced pressure. The residue is purified by column chromatography on silica, eluting with ether and then recrystallized from ethyl acetate: isohexane to give the title compound (0.061 g). P.f. 151-152 ° C MS (+ ve APCI) 495 (M + H) *) -H NMR (CDC13) d 0.84 (6H, d), 2.08-2.21 (1H, m), 3.18 (3H, s), 3.23 (1H, t), 3.37 (3H, s), 3.55-3.60 (4H, m), 3.87 (2H, c), 4.54 (2H, s), 7.43-7.49 (4H, m), 7.79-7.82 (1H , m), 7.85-7.88 (1H, m), 7.95-7.99 (1H, m), 8.37 (1H, s).

Example 51 6- [(hydroxy-1- (3-fluorophenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione a) 6-chloro-3-methyl-l- (2-methylpropyl) -lH-pyrimidine-2,4 (1H, 3H) -dione A mixture of 6-chloro-3-methyl-lH-pyrimidin-2,4 (1H, 3H) -dione (J. A., Chem. Soc., 1980, 102, 5036) (27.85 g), l-iodo-2-methylpropane (21.9 ml) and potassium carbonate (26.36 g) in anhydrous dimethylformamide (110 ml) is stirred at 90 ° C under nitrogen for 40 h. The reaction mixture is cooled to room temperature and diluted with water (800 ml). Aggregate (100 ml) is added and the mixture extracted with ether (2 x 500 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude oil is triturated with ether and the resulting crystals are filtered, washed with ether and dried in vacuo to give the title compound (7.38 g). The mother liquors are evaporated under reduced pressure and purified by column chromatography on silica eluting with isohexane: ether (1: 1) to further provide the title compound (6.90 g). * H NMR (CDC13) d 0.96 (6H, d), 2.10-2.24 (1H, m), 3. 34 (3H, s), 3.90 (2H, d), 5.92 (1H, e). b) 3-methyl-l- (2-methyl? ropil) -6-thioxo-pyrimidine-2,4 (1H, 3H) -dione To a stirred solution of 6-chloro-3-methyl-1- (2-methylpropyl) -lH-pyrimidin-2,4 (1H, 3H) -dione (31.5 g) in ethanol (120 ml) is added sulfur hydrate. of sodium acid (11.83 g). After 16 hours, additional sodium acid sulfide hydrate (5.92 g) is added and stirring is continued for 5 hours. The reaction mixture is diluted with water and then extracted with ethyl acetate (2 x 200 ml). The aqueous layer is acidified by the addition of. concentrated hydrochloric acid and extracted with ethyl acetate (3 x 500 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide the subtitle compound as a solid (25.44 g) MS (+ ve APCI) 215 (M + H) *) "-H NMR (CDC13) d 0.94 (6H, d), 2.23-2.38 (1H, m), 3.32 (3H, s), 4.16 (2H, s), 4.30 (2H, d). c) 3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione Sodium acetate (38.9 g) is added to a stirred suspension of 3-methyl-1- (2-methylpropyl) -6-thioxo-pyrimidin-2,4 (1H, 3H) -dione (25.42 g) in water (1 g). 1). After 5 hours, the mixture is filtered. An aqueous solution of chloroacetaldehyde (50% by weight, 142 ml) is added to the filtrate and the mixture is stirred for 16 hours. The mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 500 ml). The combined organic extracts are washed with a saturated solution of sodium hydrogen carbonate, they are dried on anhydrous magnesium eulfate, filtered and evaporated under reduced pressure. The residual oil is purified by column chromatography on silica eluting with isohexane: ether (1: 1) to give the title compound (26.78 g) as a solid. MS (+ ve APCI) 239 (M + H) *) XH NMR (CDC13) d 1.00 (6H, d), 2.26-2.42 (1H, m), 3.43 (3H, s), 3.81 (2H, d), 6.84 (1H, d), 7.36 (1H, d). d) 6- [(1-hydroxy-1- (3-fluorophenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) - diona To a solution of 3-methyl-1- (2-methyl-propyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (1 g) in tetrahydrofuran (20 ml) at -78 ° Add lithium diisopropylamide (1M, 6.3 ml). After 5 minutes, a solution of m-fluorobenzaldehyde in tetrahydrofuran (2 ml) is added and the reaction is stirred for 2 hours at -78 ° C. Water (10 mL) is added and the reaction is allowed to warm to room temperature and then extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate and concentrated in vacuo. The resulting oil is subjected to "chromatography (silica), eluting with 1: 1 isohexane: ethyl acetate to give the title compound (461 mg) .Pf 54 ° C MS (+ ve APCI) 363 (M + H) *) 'H NMR (DMSO ds) d 0.90 (6H, d), 2.17 (1H,), 3.22 (3H, e), 3.60-3.78 (2H, dm), 5.98 (1H, d), 6.66 (1H, d), 7.03 (1H, e), 7.11 (1H, m), 7.28 (2H, m), 7.41 (1H, m).

Example 52 6- [(3-fluorophenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione To a solution of 6- (1-hydroxy- (3-fluorophenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (Example 51) (957 mg) in trifluoroacetic acid (7 ml) is added triethyleilane (4 ml) and the reaction is allowed to stir for 16 hours.The mixture is then poured into 10% eodium hydroxide and extracted with acetate The organic layer is dried over magnesium sulfate and then concentrated in vacuo to a viscous oil.The oil is purified by CLAP in normal manner to give the title compound (82 mg) .Pf 76-8 ° C (+ e APCI 347 (M + H) *) H NMR (DMSO d6) d 0.88 (6H, d), 2.16 (1H, m), 3.23 (3H, s), 3.67 (2H, d), 4.16 (2H , e), 7.04-7.18 (4H, m), 7.37 (H, m) 7 ~ "" The following compounds are prepared from 3-methyl-1- (2-methylpropyl ") thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione and the appropriate aldehyde following the method of Example 51 : The following compounds were prepared from the corresponding alcohols (see above) by the method of Example 52: 74 3-methyl-l- (2- 115- 380 0.86 (6H, d), methylpropyl) -142 2.14 (1H, m), 6- (6-3.23 (3H, s), quinolinyl- 3.66 (2H, d) ), or methyl) - 4.35 (2H, s), "i" '? X - --- - thieno [2,3- 7.16 (1H, s), d] pyrimidin- 7.53 (1H, dd), 2, 4- (1H, 3H) - 7.70 (1H, dd ), dione 7.99 (1H, d), 8.33 (1H, d), 8.88 (1H, dd). 75 salt of 143- 380 0.88 (6H, d), acid 148 2.18 (1H, m), trifluorodesc 3.22 (3H, s), acetic of 3- 3.68 (2H, d), methyl-l- (2- 4.50 (2H, s), ,, •, 'e ~ - * _ methylpropyl) - 7.20 (1H, s), 6- (2-7.58 (1H, d), quinolinyl- 7.61 (1H, t), methyl) - 7.80 (1H, t) , thieno [2,3-8.00 (2H, t), d] pyrimidine- 8.40 (1H, d). 2,4- (1H, 3H) -dione Example 81 6- (3-imino-l, 3-dihydro-benzo [c] furan-1-yl) -3-methyl- - (2-methylpropyl) thieno [2,3-d] pyrimidin-2, (1H, 3H ) -dione To a solution of 3-methyl-1- (2-methylpropyl) -thieno [2,3-d] irmidin-2, 4- (1H, 3H) -dione (500 mg) in tetrahydrofuran (10 ml) at -78 ° C is added lithium diieopropylamide (1 M, 3.1 ml). After 5 minutes, a solution of o-cyanobenzaldehyde in tetrahydrofuran (2 ml) is added and the reaction is allowed to stir for 2 hours. Water (10 ml) is added and the mixture is allowed to warm to room temperature. The mixture is extracted with ethyl acetate. The organic layer is separated and dried over magnesium sulfate, then concentrated in vacuo and purified by normal phase CLAP to give the title compound (15 mg). P.f. 152 ° C MS (+ ve APCI) 370 (M + H).

Example 82 2- [(1, 2,3,4-Tetrahydro-3-methyl-1- (2-methylpropyl) -2,4-dioxothieno [2,3-d] pyrmidin-6-yl) methyl] -enoxamide It is prepared from 6- (3-imino-1,3-dihydro-enzo [c] furan-1-yl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine- 2, 4 (1H, 3H) -dione following the method of example 52. Pf 183 ° C MS (+ ve APCI) 372 (M + H) 7 H NMR DMSO-d 6 d 0.88 (6H, d), 2.16 (1H, m), 3.32 (3H, s), 3.65 (2H, d), 4.31 (2H, s), 7.03 (1H, s), 7.27-7.49 (5H, m), 7.88 (1H, broad s).

Example 83 (+) 6- (l-hydroxy-l- [l-naphthalenyl] methyl) -5- (3-hydroxypropyl] thio) -3-methyl-l- (2-methylpropyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione a) (+) 6- (1- [dimethyl- (1,1-dimethylethyl) silyloxy] -1- [l-naphthalenyl] methyl) -3-methyl-1- (2-methylpropyl) thieno [2,3- d] pyrimidin-2,4 (1H, 3H) -dione.

Dimethyl- (1,1-dimethylethyl) silyl chloride (230 mg) and imidazole (130 mg) are added to a solution of (±) 6- (l-hydroxy-l- [l-naphthalenyl] methyl) -3- methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (500 mg) in dimethylformamide (10 ml). The solution is stirred at room temperature for 3 days. The reaction mixture is suspended with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is separated and washed twice with dilute hydrochloric acid and once with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica eluting with isohexane: ethyl acetate (4: 1 to 2: 1) yields the subtitle product (0.47 g). MS (APCI) 509 (M + H) *) b) (+) 6- (l-hydroxy-l- [l-naphthalenyl] methyl) -5- ([3-hydroxypropyl] io) -3-methyl-l- (2-ylp-opyl) thieno [2, 3-d] pyrimidine-2, 4 (1H, 3H) -dione A solution of lithium diisopropylamide (1.40 mmol) in tetrahydrofuran (5 ml) is added to a solution of '(+ _) 6- (1- [dimethyl-1, l-dimethylethylsilyloxy] -1- tinaphthalenyl] methyl) -3 methyl-1 - (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (450 mg) and 4-methylphenylthiosulfonate of 3-. { [dimethyl- (1,1-dimethylethyl) silyl] oxy} propyl (J. Med. Chem. 1995, 38, 2557, 500 mg) in tetrahydrofuran (15 ml) at -78 ° C. After 1 hour at -78 ° C, the reaction mixture is allowed to warm to room temperature. The reaction mixture is suspended with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is separated and washed twice with dilute hydrochloric acid, twice with a saturated solution of sodium hydrogen carbonate and once with brine, then dried over magnesium sulfate and concentrated in vacuo. The residue is dissolved in acetonitrile (3 ml) and hydrofluoric acid (40% aqueous, 0.1 ml) is added. After 24 hours, the reaction mixture is suspended by the addition of a saturated solution of sodium hydrogencarbonate and extracted into ethyl acetate. The organic phase is separated and washed twice with a saturated sodium hydrogen carbonate solution and once with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel eluting with ethyl acetate gives the title compound (0.012 g) - P.f. 100-105 ° X MS (APCI) 467 (M + H-H20) *) 1 H NMR (DMSO) d 0.3 (6H, t), 1.58 (2H, luintet), 2.10 (1H, m), 2.87 (1H , m), 2.95 (1H, m), 3.24 (3H, s), 3.30 (2H, dt), 3.50 (1H, dd), 3.70 (1H, dd), 4.41 (1H, t), 7.14 (1H,), 7.38 (1H,), 7.49 (1H, t); 7.55-7.65 (2H, m), 7.93 (1H, d), 8.00-8.05 (2H, m).

Example 84 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylcarbonyl) -thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione L-naphthoyl chloride (1.25 ml) is added under nitrogen to a stirred suspension of aluminum chloride (1.1 g) in 1,2-dichloroethane (10 ml). A solution of 3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (2.0 g) in 1,2-dichloroethane (10 g) is added dropwise. ml) and the resulting mixture is stirred under reflux for 24 hours and then allowed to cool to room temperature. The reaction mixture is suspended by careful addition of water (2 ml) and then concentrated in vacuo. The residue is dissolved in ethyl acetate and washed three times with dilute hydrochloric acid, twice with a saturated sodium hydrogen carbonate solution and once with brine, and then dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel eluting with toluene: ethyl acetate (9: 1) gives the title compound (0.78 g). P.f. ~ 150 ° C MS (APCI) 393 (M + H) *) X H NMR (DMSO dβ) d 1.00 (6H, d), 2.25 (1H, m), 3.22 (3H, s), 3.80 (2H, d) , 7.47 (1H, e), 7.55-7.65 (2H, m), 7.70 (1H, t), 7.85 (1H, d), 8.05 (1H, dd), 8.10 (1H, dd), 8.20 (1H, d ).

Example 85 (+) 5- [(3-hydroxybutyl] thio) -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -diona A solution of dimethyl sulfoxide (0.113 ml) in anhydrous dichloromethane (1 ml) is added to a solution of oxalyl chloride (0.093 ml) in anhydrous dichloromethane (5 ml) at -78 ° C under nitrogen. After 5 min, a solution of 5- [(3-hydroxypropyl] thio) -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] is added dropwise. pyrimidi -2,4 (1H, 3H) -dione (0.25 g) in anhydrous dichloromethane (4 ml). After 10 min, triethylamine (0.372 ml) is added and the mixture is warmed to room temperature, ether (30 ml) is added and the mixture is washed with 2 M hydrochloric acid (10 ml) and then with a saturated solution of Sodium carbonate acid (10 ml), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is dissolved in anhydrous tetrahydrofuran (10 ml), cooled to -78 ° C under nitrogen and treated with methylmagnesium chloride (3.0 M solution in tetrahydrofuran, 0.265 ml). The mixture is heated to room temperature, and then added to a saturated sodium carbonate solution (30 ml) and then extracted with ethyl acetate (2 x 30 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered through a small pad of silica and evaporated. The residue is purified by preparative CLAP in normal phase with an elution gradient of ethyl acetate / isohexane followed by recrystallization from ethyl acetate / isohexane to give the title compound (58 mg). P.f. 162-163 ° C MS (+ ve APCI) 483 (M + H) *) XH NMR (CDC13) d 0.88 (6H, d), 1.25 (3H, d), 1.76-1.82 (2H, m), 2.10- 2.25 (1H, m), 3.10-3.23 (3H, m), 3.42 (3H, s), 3.57-3.75 (2H, m), 4.14-4.26 (1H, m), 4.77 (2H, Abe), 7.35 (1H, d), 7.45 (1H, t), 7.50-7.56 (2H , m), 7.82 (1H, d), 7.87-7.90 (1H, m), 8.02-8.06 (1H, m).

Example 86 6- (3-fluorophenyl) methyl-5- [(3-hydroxypropyl] thio) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) - diona A tetrahydrofuran solution of lithium diisopropylamide (5.0 mL, 0.72 mmol) is added to a solution of 6- (3-fluorophenyl) -methyl-3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2, 4 (1H, 3H) -dione (example 52, 0.24 g) in anhydrous tetrahydrofuran (5 ml) at -78 ° C under nitrogen. After 15 min, an additional solution of lithium diisopropylamide (2.5 ml, 0.36 mmol) is added. The reaction mixture is maintained at -78 ° C for an additional 3 hours. 4-Methylphenylthiosulfonate of "3- {[dimethyl- (1, 1-dimethylethyl) silyl] oxypropyl (J. Med. Chem. 1995, 38, 2557, 0.286 g) is added and the mixture is heated to 50 ° C. The reaction mixture is added to a saturated solution of sodium hydrogen carbonate (50 ml) and extracted with ether (50 ml) The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is dissolved in acetonitrile (10 ml) and then treated with 40% hydrochloric acid (1 ml) After 1 hour, the mixture is added to a saturated solution of sodium hydrogen carbonate (100 ml) and extracted with ether. (2 x 50 ml) The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated The residue is purified by column chromatography on silica eluting with ethyl acetate: isohexane (1: 1) followed by recrystallization from of ethyl acetate / isohexane to give the title compound (0.058 g) .Pf 99-100 ° C MS (+ ve APCI) 437 (M + H) *) 'H NMR (CDC13) d 0.96 (6H, d), 1.84 (2H, quintet), 2.19-2.34 (1H, m), 2.76 (1H, t), 3.06 (2H, t), 3.43 (3H, s), 3.74 (2H, d), 3.85 (2H, c), 4.32 (2H, s); 6.90-7.02 (3H, m), 7.25-7.32 (1H, m).

Example 87 - [(5-amino-2-? Iridinyl] thio) -3-methyl-1 - (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4 ( 1H, 3H) -dione Iron powder (0.85 g) and ammonium chloride (0.81 g) are added to a stirred suspension of 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5- [(5-nitropyridine. -2 -il) -thieno [2, 3-d] irimidin-2,4 (1H, 3H) -dione (example 37, 2.02 g) in ethanol (10 ml) and water (10 ml). The mixture is refluxed for 3 hours, and then cooled to room temperature. A solution of 2 M sodium hydroxide (50 ml) is added and the mixture is stirred vigorously for 1 hour, ethyl acetate (100 ml) is added and the 2-phase mixture is filtered. The solid and the aqueous layer are in turn washed with ethyl acetate (100 ml), 2 M hydrochloric acid (25 ml) is added to the solid and the mixture is stirred for 1 hour, and then added to a hydroxide solution. of sodium and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is recrystallized from ethyl acetate to give the title compound (1.07 g). The mother liquors are evaporated and purified by column chromatography on silica eluting with ethyl acetate and then recrystallized from ethyl acetate to provide the additional title compound (0.665 g). P.f. 208-209 ° C MS (+ ve APCI) 503 (M + H) *) 'H NMR (DMSO ds) d 0.81 (6H, d), 1.97-2.02 (lH, "m), 3.15 (3H, s) , 3.58 (2H, d), 4.72 (2H, s), 5.26 (2H, broad s), 6.89 (2H, Abe), 7.38 (1H, td), 7.45-7.55 (3H, m), 7.83 (1H, t), 7.85-7.90 (1H, m), 7.93 (1H, d), 8.02 (1H, d).

Example 88 1,2,3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6-phenylmethyl-2,4-dioxothieno [2,3-d] pyrimidine-5-carboxylic acid ethyl ester a) 2-amino-5-phenylmethylthiophen-3,4-dicarboxylate diethyl ester It is prepared from sulfur (0.85 g), triethylamine (3.69 ml) ethyl 2-oxo-4-phenylbutyrate (5.00 ml) and ethyl cyanoacetate (2.81 ml) in dimethylformamide (15 ml) following the method of example 1, step b to provide the subtitle compound (4.13 g) as an oil. MS (+ ve APCI) 334 (M + H) *)? E NMR (CDC13) d 1.30 (3H, t), 1.33 (3H, t), 3.94 (2H, s), 4.24 (2H, c), 4.30. (2H, c), 5.88 (2H, broad s), 7.20-7.35 (5H, m). b) Diethyl 2- (2-methylpropyl) amino-5-phenylmethylthiophen-3,4-dicarboxylate It is prepared from sodium borohydride (2.2 g) and diethyl 2-amino-5-phenylmethylthiophen-3,4-dicarboxylate (4.10 g) in 2-methylpropanoic acid (20 ml) following the method of example 3 step b to provide the subtitle compound (2.39 g) as an oil. MS (+ ve APCI) 390 (M + H) *) X H NMR (CDCl 3) d 0.94 (6 H, d), 1.29 (3 H, t), 1.33 (3 H, t), 1.84-1.98 (1 H, m), 2.95 (2H, t), 3.94 (2H, s), 4.20 (2H, c), 4.30 (2H, c), 7.19-7.35 (5H, m), 7.66 (1H, broad t). c) 1, 2, 3, -tetrahydro-3-methyl-l- (2-methylpropyl) -6-phenylmethyl-2,4-dioxothieno [2,3-d] pyrimidine-5-carboxylic acid ethyl ester It is prepared from acetyl chloride (0.60 ml), silver cyanate (1.35 g) and 2 - (2-methylpropyl) amino-5-phenylmethylthiophen-3,4-dicarboxylate diethyl ester (2.38 g), following the method of Example 3, step c and treating the residue with sodium ethoxide (1.24 g) and iodomethane (1.14 ml) in ethanol (24 ml) following the method of example 4, to provide the title compound (1.58 g). MS (+ ve APCI) 401 (M + H) *) a H NMR (CDCl 3) d 0.93 (6H, d), 1.39 (3H, t), 2.17-2.30 (1H, m), 3.39 (3H, s), 3.69 (2H, d), 4.12 (2H, s), 4.44 (2H, c), 7.24-7.36 (5H, m).

Example 89 l, 2,3,4-tetrahydro-3-N, N-trimethyl-1- (2-methylpropyl) -6-phenylmethyl-2,4-dioxothieno [2,3-d] pyrimidine-5-carboxamide a) 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6-phenylmethyl-2, -dioxothieno [2,3-d] pyrimidine-5-carboxylic acid A 1 M sodium hydroxide solution is added (7.5 ml) to a stirred solution of 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6-phenylmethyl-2,4-dioxothieno [2,3-d] pyrimidine-5 ethyl carboxylate (1.50 g) in methanol (7.5 ml) and tetrahydrofuran (15 ml). After 16 hours, an additional 1M sodium hydroxide solution (7.5 ml) is added and the solution is stirred at 50 ° C for an additional 8 hours. Water (100 ml) is added and the solution is washed with ether (100 ml). The aqueous phase is acidified by the addition of concentrated hydrochloric acid and then extracted with ethyl acetate (2 x 100 ml). The solid not dissolved in the organic extracts is filtered and dried in vacuo at 50 ° C to provide the title compound (1.00 g). P.f. 238 ° C (decomposition) MS (+ ve APCI) 373 (M + H) *) 'H NMR (DMSO d6) 8 0.87 (6H, d), 2.05-2.20 (1H, m), 3.25 (3H, s) , 3.68 (2H, d), 4.25 (2H, s), 7.24-7.36 (5H,), 13.92 (1H, broad s). b) 1,2,3,4-tetrahydro-3, N, N-trimethyl-1- (2-methylpropyl) -6-phenylmethyl-2,4-dioxothieno [2,3-d] pyrimidine-5-carboxamide Oxalyl chloride (0.087 ml) is added to a stirred solution of 1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6-phenylmethyl -2,4-dioxothien [2, 3 -d] pyrimidine-5-carboxylic acid (0.37 g) and dimethylformamide (0.01 ml) in anhydrous dichloromethane (20 ml). After 1 hour, the solution evaporates. The residue is dissolved in anhydrous tetrahydrofuran (7 ml) and 1 ml of ethanol is added to a stirred mixture of a 40% dimethylamine aqueous solution (1 ml) and a saturated sodium hydrogen carbonate solution (2 ml). After 30 minutes, water (10 ml) is added and the mixture is extracted with ethyl acetate (10 ml). The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is recrystallized from ethyl acetate / isohexane to give the title compound (0.025 g). P.f. 144-146 ° C MS (+ ve APCI) 400 (M + H) *) XH NMR (DMSO d6) d 0.89 (6H, d), 2.08-2.21 (1H, m), 2.64 (3H, s), 2.97 (3H, s), 3.21 (3H, s), 3.59-3.76 (2H, m), 3.97 (2H, Abe), 7.21-7.35 (5H, m).

Example 90 6- [1-hydroxy- (4-nitrophenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione It is prepared from 3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (example 51, step c) and 4-nitrobenzaldehyde following the method of example 51, step d. P.f. 156 ° C * -H NMR (DMSO d6) d 0.89 (6H, d), 2.17 (1H, m), 3.21 (3H, s), 3.61-3.79 (2H, m), 6.14 (1H, d), 6.84 (1H, d), 7.10 (1H, s), 7.73 (2H, d), 8.24 (2H, d).

Example 91 6- (4-nitrofenylmethyl) -3-methyl-1 - (2-methylpropyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione Prepared from 6- [1-hydroxy- (4-nitrophenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) - dione following the method of Example 52. "Mp 127 ° C MS (+ ve APCI) 372 (M + H) *) XH NMR (DMSO d6) d 0.88 (6H, d), 2.18 (1H, m), 3.23 ( 3H, s), 3.67 (2H, d), 4.31 (2H, s), 7.15 (1H, s), 7.59 (2H, d), 8.20 (2H, 'd) 7 Example 92 6- (4-Amino-enylmethyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione To a solution of 6- (4-nitrophenylmethyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione in ethanol (15 ml) and water (1 ml) is added iron powder (82 mg) and ammonium chloride (78 mg). The mixture is heated at 90 ° C for 6 hours, and then allowed to cool to room temperature. The reaction is filtered and then evaporated before being partitioned between ethyl acetate and water. The organic layer is collected, dried over magnesium sulfate and then evaporated. The resulting oil is purified by normal phase CLAP (isohexane: ethyl acetate 80-0: 20-100) to give the title compound (20 mg). P.f. 104 ° C MS (+ ve APCI) 344 (M + H) *) "-H NMR (DMSO d6) d 0.87 (6H, d), 2.15 (1H, m), 3.22 (3H, s), 3.66 (2H , d), 3.91 (2H, s), 4.98 (2H, s), 6.51 (2H, d), 6.91 (1H, s), 6.94 (2H, d).

Example 93 4- (3,4-dimethoxy-enyl) -N-. { 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -2, -dioxothieno [2,3-d] irimidin-6-yl) -methyl] phenyl} -butanamide To a solution of N-ethyl-N '- [3 - (dimethylamino) -propyl] carbodiimide (37 mg), l-hydroxybenzotriazole (26 mg) and 4- (3,4-dimethylphenoxyphenyl) butanoic acid (36 mg) in dichloromethane (6 ml) is added 6- (4-aminophenylmethyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (45 mg) in dichloromethane (2 ml). The reaction mixture is stirred overnight and then washed with half-saturated sodium hydrogen carbonate and extracted into ethyl acetate. The organic layer is dried over magnesium sulfate, evaporated and the residue is purified by CLAP in a normal phase. (isohexane: ethyl acetate 50-0: 50-100) to give the title compound (19 mg) as a foam. MS (+ ve APCI) 550 (M + H) *) X H NMR (DMSO d 6) d 0.87 (6H, d), 1.88 (2H, m), 2.01 (1H, m), 2.29 (2H, t), 2.51 (2H, t), 3.32 (3H, s), 3.66 (2H, d), 3.73 (3H, s), 3.75 (3H, s), 4.06 ( 2H, s), 6.70 (lH, 'm), 6.72 (1H, m), 6.84 (1H, m), 7.03 (1H, s), 7.19 (2H, d), 7.53 (2H, d), 9.85 (1H, s).

EXAMPLE 94 3-Acetamido-N- (4- [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-mepropro) -2,4-dioxothieno [2,3-d] pyrimidine- 6-yl) -methyl] enyl} -benzamide- It is prepared following the method of Example 93 starting from 6 - (4-ai no f eni lme ti 1) -3-me ti 1 -1 - (2-methylpropyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione and 3-acetamidobenzoic acid. P. f. 230 ° C MS (+ ve APCI) 505 (M + H) *) aH NMR (DMSO d6) d 0.88 (6H, d), 2.19 (1H, m), 3.23 (3H, s), 3.32 (3H, s ), 3.67 (2H, d), 4.10 (2H, s), 7.06 (1H, S), 7.23 (2H, d), 7.43 (1H, t), 7.59 (1H, d), 7.71 (2H, d) , 7.81 (1H, d), 8.06 (1H, s), 10.13 (1H, s), 10.24 (1H, s).

Example 95 Inhibition of the Mixed Human Lymphocyte Reaction (MLR) The MLR test is performed in 96 well flat bottom microtiter plates. The compounds are prepared as a 10 mM concentrated solution in dimethyl sulfoxide. A 50-fold dilution of this is prepared in RPMI. Serial dilutions are prepared from this solution. 10 μl of the 50-fold diluted concentrate or dilutions thereof are added to the wells to provide concentrations in the assay that start at 9.5 μM and decrease. In each well, 1.5 x 105 cells are placed from each of the two donors that respond, in a final volume of 0.2 ml of RPMI 1640 medium supplemented with 10% human serum, 2 mM L-glutamine and penicillin / streptomycin. The cells are incubated at 37 ° C in a humidified atmosphere at 5% carbon dioxide for 120 hours. 3H-thymidine (0.5 μCi) is added for the final six hours of incubation. The level of radioactivity incorporated by the cells is then determined, which is a measure of the proliferation of T cells. It is found that the title compounds of Examples 1 to 94 show an AI50 value of less than 1 x 10.6 M in the previous test. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of formula (I): (I! characterized in that R is -C (0) Ar? -C (R4) (R5) Arx or Ar2; Ar 1 is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each of which may be optionally substituted by one or more substituents which are selected from C 1-4 alkyl, C 1-4 alkoxy, halogen or trifluoromethyl, or Ar 1 is phenyl optionally substituted by one or more solvents which are selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy, -CH 2 N (R 6) 2 / -NHS02CF 3, alkylsulfonylamino of C1-4, NHC (0) R a, C02R7 or -C (O) NR8R8a; R4 represents H or C1-4 alkyl, - Rs represents H or OH; each R6 independently represents H or C1-4 alkyl; RS a represents H, C 1-6 alkyl, aryl or C 1-4 alkyl, wherein the aryl group or the aryl moiety in the aralkyl group is phenyl or pyridyl, each of which may be optionally substituted by one or more substituents which are selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonylamino, halogen or trifluoromethyl; R7 represents H or C1-4 alkyl; R8 and R8a independently represent each, H, C1-4 alkyl, phenyl or pyridyl; The acenaphthenyl indanyl iminodihydrobenzofuranyl or fluorenyl, each of which may be optionally substituted by one or more substituents selected from OH, C 1 alkyl, C 1-4 alkoxy, halogen or trifluoromethyl, - R 1 and R 2 are independently H , C1.6alkyl, C3s alkenyl, CH2, C3 cycloalkyl or cycloalkyl R3 represents H, X-R9 or X-Ar3; X represents S (0) n, C (0) NR10, C (0) 0, NH (CO) NR10, NH (CO) 0 or S02NR10; n is 0, 1 or 2; R9 represents a methyl group optionally substituted by one or more substituents selected from CN, C02H, C1-s alkoxycarboxylic acid, 5-tetrazolyl, S02NH2 or C (O) NR11! 12 or R9 represents C2-6 alkyl or alkenyl C3.6, each of which may be optionally substituted by one or more substituents which are selected from OH, CN, C02H, C1-5 alkoxy, C1-s alkoxycarbonyl, 5-tetrazolyl, azide, phthalimido, S02NH2, CÍOJNR ^ R12, NR13R14, NHC (0) R1S or NHS02R? E wherein R11, R12, R13 and R14, each independently, represent H or C1-4 alkyl, R15 represents C1-4 alkyl, C1-6 alkoxy 4, (C 1-4 alkylamino or "alkoxyalkylene" containing up to 6 carbon atoms, and R * 6 represents Cl-4 alkyl or trifluoromethyl, or additionally, in the case where X represents C (0) NR 10 , NH (CO) NR10 or SO-NR10, R9 and R10 together with the nitrogen atom to which they are attached, can form a 4- to 7-membered heterocyclic ring which can optionally be e substituted by one or more OH groups; R10 represents H, C: -e alkyl or is linked to R9 as defined above; and Ar3 is phenyl, pyridyl or pyridine N-oxide, each of which may be optionally substituted by one or more substituents which are selected from OH, N02, NH2, NHS02CF3, C1-4 alkoxy, C1-bis-alkane-sulfonylamino 4, 'C 1-4 alkylcarbonylamino or C 1-4 alkoxycarbonylamino; or a pharmaceutically acceptable salt or solvate thereof.

2. The composition according to claim 1, characterized in that Ar 1 is naphthyl, quinolyl or benzofuranyl, or a phenyl group which is optionally substituted by one or two solvents which are selected from C 1 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl, nitro, amino, cyano, phenoxy or -NHC (0) R6a.

3. The compound according to claim 1 or 2, characterized in that R 4 represents H, methyl or ethyl.

4. The compound according to any of * X '' i claims 1 to 3, characterized in that Ar2 is inundale, iminodihydrobenzofuranyl or indanyl substituted with hydroxy.

5. The compound according to any one of claims 1 to 4, characterized in that R 1 and R 2 are independently H, C 1-4 alkyl, C 3-4 alkenyl or C 3-6 cycloalkyl.

6. The compound according to any of the preceding claims, characterized in that R9 represents a methyl group optionally substituted by C02H or C (O) NR ?: LR12, or a C2_4 alkyl group which may be optionally substituted by one or two substituents which are selected from OH, C02H, C4 alkoxycarbonyl, < azide, phthalimido, NR13R14, NHC (0) R15 or NHS02R16, - or R9 and R10, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring which can be optionally substituted by an OH group .

7 *. The compound according to any of the preceding claims, characterized in that R 10 represents H, methyl, or is linked to R 9, according to claim 1.

8. The compound according to any of the preceding claims, characterized in that R11, R12, R13 and R14 represent hydrogen.

9. The compound according to any of the preceding claims, characterized in that R15 represents methyl, methoxy, dimethylamino or methoxymethylene.

10. The compound according to any of the preceding claims, characterized in that R1S represents methyl or trifluoromethyl.

11. The compound according to any of the preceding claims, characterized in that Ar3 is phenyl, pyridyl or pyridine N-oxide, each of which may optionally be substituted by one or two substituents which are selected from OH, N02, NH2, methoxy, bis-et anulul oni 1 amino, me ti 1 c arboni 1 amino or methoxycarbonylamino.

12. A compound, according to claim 1, characterized in that it is selected from: 6- (4-methoxyphenylmethyl) -3-methylthieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- (4-methoxyphenylmethyl) -3-methyl-1- (2 -methyl-2-propenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] ] irimidin-2, 4 (1H, 3H) dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidine-2, 4 (1H, 3H ) -dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(2-pyridinyl) thio] thieno [2,3-d] irimidin-2,4 (1H, 3H) -dione, 5- [(3-hydroxypropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2, 4 (1H) , 3 H) -dione, "~ 4- [(1,2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) 2,4-dioxothien [2]. Methyl 3-d] pyrimidin-5-yl] thio] butanoate, 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl)] ) -2, 4-dioxothieno (2,3-d] pyrimidin-5-yl) thio) butanoic, 4- [(1, 2,3, 4-tetra methyl-3-methyl-1- (2-methylpropyl) -6- (1 -naf talenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl) sulphonyl] butanoate, 4- [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1 -naf, t to enylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine- Methyl 5-yl) eulphonyl] butanoate, 4- [(1, 2, 3, 4-tet, rahydro-3-met-il-1 - (2-methylprpr) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] irimidin-5-yl) sulfonyl] utanoic acid, 6-benzyl-3-methyl-1- (2-methylpropyl) thieno [2,3-d] -pyrimidin- 2, 4 (1H, 3H) -dione, 3-methyl-1- (1-methylethyl) -6- (phenylmethyl) thieno [2,3-d] irimidin- 2,4 (1H, 3H) -dione, 6 - [(1-hydroxy-1-phenyl) -methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3-d] pyrimidin-2, 4 (1H, 3H) -dione, (±. ) 5- [(2-hydroxypropyl) thio] -3-methyl-1- (2-methylprpr) -6- (1-naphthalenylmethyl)) thieno [2,3-d] pyrimidine-2,4 (1H) , 3H) -dione, 1,2,3, 4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-ethyl-propyl) -6- (1- naph talenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-carboxamide, (3R) -l-. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) 2,4-dioxothieno [2,3-d] pyrimidin-5-yl] carbonyl } irrol idin- 3 -ol, l-. { [1, 2, 3, 4-tetrahydro-3-met il-1- (2-methylpropyl) -6- (l-naphthalenylmethyl) -2, 4-dioxothieno [2,3-d] pyrimidin-5-carbonyl} piper idin- 4 -ol, (3R) -l-. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylethyl) -2,4-dioxothieno [2,3-d) irimidin-5-yl] carbonyl} piper idin -3 -ol, 1,2,3,4-tetrahydro-N- (2-hydroxyethyl) -3, N-dimethyl-1- (2-methylpropyl) -6- (l-naphthalenylmethyl) -2, 4-dioxothieno [2,3-d] pyrimidine-5-carboxamide, 2 - acid. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methyl-ylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl ] carboxamido} acetic, acid 3 -. { [1, 2, 3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] carboxamido} propanoic, 2-. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] carboxamido} acetamide, l-. { [1,2,3,4-tetrahydro-3-met-il-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] ] carbonyl) pyrrolidine, 1,2,3,4-tetrahydro-N- (2-hydroxyethyl) -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothiene [2, 3-d] pyrimidin-5-eulphonamide, 5- [(3-methoxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H) -dione, 5- [(3-Hydroxyphenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -Diona, 5- [(3-hydroxyphenyl) sulf inyl] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2, 3-d] pyrimidin-2, 4- (1H, 3H ) -dione, 5- [(3-hydroxyphenyl) sulfonyl] -3-methyl-1 - (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- ( 1H, 3H) -dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5- [(3-nitrophenyl) thio] thieno [2,3-d] pyrimidine- 2 4- (1H, 3H) -dione, 5- [(3-aminofenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine -2,4- (1H, 3H ) -diona, 5 - . 5 - . { [3 - . { (bie-methanoeulf onyl) amino) phenyl] thio} -3- ethyl -1- (2-methylphenyl) -6- (1 -naf talenylmethyl) thieno [2,3- • d] pyrimidin-2, 4- (1H, 3H) -dione, 5 - [( 3 -me oxycarbonyl aminofenyl) io] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4- * (1H, 3H ) -dione, 5- [(3-acetamidophenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2, 4- ( 1 H, 3 H) -dione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5- [(4-nitrophenyl) thio] thieno [2, 3-d] pyrimidine- 2 4- (1H, 3H) -dione, 5- [(4-aminofenyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 3-Methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -5 - [(5-nitropyridin-2-yl) thio] thieno [2,3-d] pyrimidine-2, 4- ( 1H, 3H) -dione, 2-N-oxide. { [1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpro-yl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5-yl] ] thio] pyridine, 5- [(3-azidopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2, 4 ( 1H, 3H) -dione, 5- [(3-aminopropyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidin-2, 4 (1 H, 3H) -dione, N-. { 3 - [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine-5 -il) thio] propyl} acetamide, N-. { 3 - [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine- 5 -il) thio] propyl} -N ', N' -dimethylurea, N-. { 3 - [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine- 5 -il) thio] propyl} -me toxiacet amide, N-. { 3 - [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidin-5] -il) thio] propyl} methyl carbamate, N-. { 3 - [(1, 2, 3, 4-tetrahydro-3-methyl-1- (2-methylphenyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine] -5-yl) thio] propyl) methanesulfonamide, N-. { 3 - [(1, 2, 3, 4-tetrahydro-3-methyl-l- (2-methylpropyl) -6- (1 -naf talenylme il) -2,4-dioxo-ene [2,3-d] irimidin - 5 -yl) thio] propyl} trif luorometanosul fonamida, 5 -. { [3- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) propyl] thio} 3-methyl-1- (2-methylpropyl) -6- (1 naphthalenylmethyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, N- (2-hydroxyethyl) - N1 - [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) -2,4-dioxothieno [2,3-d] pyrimidine- 5 - il) urea, 2-hydroxy oxyethyl [1,2,3,4-tetrahydro-3-methyl-1- (2-methylphenyl) -6- (1-naphthalenylmethyl) -2,4-dioxothiene [2, 3-d] irimidin-5-yl] carbamate, N- (2-hydroxyethyl) -N-methyl-N * - [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6 (1-naphthalenylmethyl) -2,4-dioxo-thieno [2,3-d] pyrimidin-5-yl) urea, 6- [(1-hydroxy-1- (3-f luorofenyl)) methyl] - 3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2, 4- (1H, 3H) -dione, 6- [(3-fluorophenyl) methyl] -3-methyl-l- (2-methylpropyl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (2-bromofinyl)] methyl] -3-methyl- l- (2-methylprp) thieno [2, 3-d] pyrimidine- 2, 4 (1H, 3 H) -dione, 6- [(1-hydroxy-1- (2-methyl phenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3-d} pyrimidin-2, 4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (3-cyanofenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3 - d] pyrimidine-2, 4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (3-trifluoromethylphenyl)) methyl] -3-me ti 1 -1- (2-methyl-propyl) ) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (3-f-enyloxy-enyl) -methyl] -3-methyl-1 - ( 2-methylpropyl) thieno [2,3-d] pyrimidine -2, 4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (1-naphthalenyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3 -d} pyrimidin-2, 4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (6-quinolinyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3-d] ] pyrimidin-2,4 (1H, 3H) -dione, 6- [(l-hydroxy-1- (4-quinolinyl)) methyl] -3-methyl-1- (2-methylpropyl) thieno [2, 3] d] pyrimidin-2, 4 (1H, 3H) -dione, (+ _) 6- [i- (benzo [b] furan-2-yl) -1-hydroxymethyl]] -3 • methyl-1- (2 -methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (2-chloro-6-fluorophenyl)) methyl] -3-methyl 1- (2-methylpropyl) thieno- [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1-phenyl) ethyl] -3-methyl-1 - (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (4-trifluoromethylphenyl)) methyl] -3-methyl- 1- (2-methylpropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, (±) 6- (2,3-dihydro-l-hydroxy-lH-indenyl) -3 -methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- [(1-hydroxy-1- (2-quinolinyl)) methyl] - 3-methyl-1- (2-methylpropyl) ieno [2, 3-d] pyrimidin-2, 4 (1H, 3H) -dione, 6- (l-hydroxy-l- [3-quinolinyl] methyl) -3-methyl-1- (2-methylpropyl) thieno [2, 3 -d] -pyrimidin-2, 4 (1H, 3H) -dione, 6- (2-bromophenylmethyl) -3-methyl-1- (2-aramethylpropyl) thieno (2,3-d) irimidin-2, 4 ( 1H, 3H) -dione, 6- (2-methylphenylmethyl)) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine- 2,4 (1H, 3H) -dione, 6- (3-cyanofenylmethyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6- (3-trifluoromethyl-phenylmethyl) -3 -methyl-1- (2-methylpropyl) thieno (2,3-d) -pyrimidin-2,4 (1H, 3H) -dione, 6- (3-phenyloxyphenylmethyl) -3-methyl-1- (2, - methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 3-methyl-1- (2-methylpropyl) -6- (4-quinolinylmethyl) -thieno [2, 3-d] ] irimidin-2, 4 (1H, 3H) -dione, 3-methyl-1- (2-methylpropyl) -6- (6-quinolinylmethyl) -thieno [2,3-d] irimidin-2,4 (1H, 3H) -dione, Trifluoroacetic acid salt of 3-methyl-1- (2-methylprp) -6- (2-quinolinylmethyl) thieno [2, 3-d] pyrimidine -2,4 (1 H, 3 H) -dione, 6- (2-benzo [b] furanylmethyl) -3-methyl-1- (2-methylphenyl) -thieno [2, 3-d] pyrimidin-2, 4 (1 H, 3 H) -dione, 6- (2-chloro-6-f luorofenylmethyl) -3-methyl-1- (2-methylpropyl) thieno (2,3-d) pyrimidin-2, 4 (1H, 3H) -dione, 6- (1-f-phenylethyl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2, 4 (1H, 3H ) dione, 6- (4-trifluoromethylphenylmethyl) -3-methyl-1- (2-methylpropyl) thieno (2,3-d) -pyrimidin-2,4 (1H, 3H) -dione, (±) 6 - (2,3-dihydro-lH-inden-l-yl) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] -pyrimidin-2,4 (1H, 3H) -dione, 6- (3-imino-l, 3-dihydro-benzo [c] furan-1-i]) -3-methyl-1- (2-methylpropyl) thieno- [2,3-d] pyrimidine- 2, 4 (1H, 3H) -dione, 2 - [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -2,4-dioxothieno [2,3-d] -pyrimidin-6] -yl) ethyl] benzamide, (±) 6- (l-hydroxy-l- [l-naphthalenyl] methyl) -5- ([3-hydroxypropyl] thio) -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidine- 2, 4 (1H, 3H) -d ione, 3-methyl-1- (2-methylpropyl) -6- (1-naphthalenyl-carbonyl) thieno [2, 3-d] pyrimidine-2, 4 (1H, 3H) -dione, (±) -5 - [(3-hydroxybutyl) thio] -3-methyl-1- (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione 6- (3-f luorofenyl) methyl-5 - [(3-hydroxypropyl) thiol -3-methyl-1- (2-methylpropyl) thieno [2,3-d] irimidin -2,4 (1H, 3H ) -dione, 5 - [(5-amino-2-pyridinyl) thio] -3-methyl-1 - (2-methylpropyl) -6- (1-naphthalenylmethyl) thieno [2,3-d] pyrimidine -2, 4 ( 1 H, 3 H) -dione, 1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -6-phenylmethyl -2,4-dioxothieno [2,3-d] pyrimidin-5-carboxylate of ethyl, 1, 2, 3, 4-tetrahydro-3, N, N-trimethyl-1- (2-methylpropyl) -6-f-enylmethyl -2,4-dioxothieno [2,3-d] pyrimidin- 5- carboxamide, 6- [1-hydroxy- (4-nitrophenyl) methyl] -3-methyl-1- (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6 - (4-Nitropinylmethyl) -3-methyl-] - (2-methylpropyl) thieno [2,3-d] pyrimidin-2,4 (1H, 3H) -dione, 6 - (4-aminofenylmethyl) - 3-methyl-1 - (2-methylpropyl) thieno [2, 3-d] pyrimidin-2, 4 (1H, 3H) -dione, 4- (3, 4-dimethoxyifenyl) -N-. { 4- [(1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropyl) -2,4-dioxothieno [2,3-d] pyrimidin-6-yl) methyl] phenyl} -butanamide, and 3-acetamido-N- (4- [1,2,3,4-tetrahydro-3-methyl-1- (2-methylpropi]) -2,4-dioxothieno [2,3-d] pyrimidine -6-yl) methyl] phenyl) benzamide.

13. A process for the preparation of a compound of formula (I), according to claim 1, characterized in that it comprises .- (a) the preparation of a compound of formula (I), wherein X is SO or SO by oxidation of a compound of formula (I) wherein X is S (0) n and n is 0 or 1; or (b) the preparation of a compound of formula (I) wherein X is S, by reacting a compound of the general formula: (II) wherein R, R1 and R2 are as defined according to claim 1, with a compound of general formula (III), R17-SS-R17, wherein both R17 groups represent R9 or Ar3, as defined according to claim 1, or with a compound of general formula (IV), LS-R17, wherein L represents a leaving group and R17 is as defined above, -or (c) the preparation of a compound of Formula (I) in which R3 represents H, by reaction of a compound of the general formula: wherein R1 and R19 each independently represents an alkyl or aryl group and R and R1 are as defined according to claim 1, with a compound of general formula (VI), R2NH2, wherein R2 is as defined in accordance with claim 1; or (d) preparation of a compound of formula (I) wherein X is C (= 0) NR10, by reacting a compound of general formula (vil) wherein R, R1 and R2 are as defined in accordance with claim 1, with a compound of general formula: (VIII) wherein R9 and R10 are as defined in the foregoing, in accordance with claim 1; or (e) preparation of a compound of formula (I) wherein X is NH (C0) NR10, by reacting a compound of the general formula: (IX) wherein R, R1 and R2 are as defined in accordance with claim 1, with a compound of formula (VIII) as described above; or (f) the preparation of a compound of formula (I), wherein X is NH (C0) 0, by reacting a compound of the formula (IX) as defined above, with a compound of the general formula (X), R90H wherein R9 is as defined according to claim 1; or (g) the preparation of a compound of formula (I), wherein X is S02NR10, by reacting a compound of the general formula: (??: wherein L1 represents a leaving group and R, R1 and R2 are as defined according to claim 1, with a compound of formula (VIII) as defined in the above; or (h) ~ the preparation of a compound of formula (I) wherein X is C (0) 0, by reacting a compound of the general formula: (Goes) wherein R3 'represents C02R9 or C02Ar3 and R, R1, R1S and R19 are as defined above, with a compound of the general formula (VI) as defined above; and optionally, after (a), (b), (c), (d), (e), (f), (g) or (h) converting the compound of formula (I) obtained to an additional compound of formula (I) and / or form a pharmaceutically acceptable salt or solvate thereof.

14. A pharmaceutical composition, characterized in that it comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 12, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

15. A process for the preparation of a pharmaceutical composition, according to claim 14, characterized in that it comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 12, with a pharmaceutically acceptable adjuvant, diluent or carrier.

16. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 12, for use in therapy.

17. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 12, characterized in that it is used in the manufacture of a medicament for use in therapy.

18. A method for carrying out immunosuppression, characterized in that it comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 12.

19. A method for treating, or reducing the risk of, a reversible obective airway disease in a patient suffering from, or at risk of, such a disease, characterized in that it comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 12.