PatentDe  


Dokumentenidentifikation EP1697394 03.05.2007
EP-Veröffentlichungsnummer 0001697394
Titel COMT-INHIBITOREN
Anmelder F. Hoffmann-La Roche AG, Basel, CH
Erfinder DIEDERICH, Francois, CH-8953 Dietikon, CH;
JAKOB-ROETNE, Roland, 79594 Inzlingen, DE;
LERNER, Christian, 4102 Binningen, CH;
PAULINI, Ralph, CH-8051 Zuerich, CH
Vertreter derzeit kein Vertreter bestellt
DE-Aktenzeichen 602004005502
Vertragsstaaten AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LI, LT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR
Sprache des Dokument EN
EP-Anmeldetag 13.12.2004
EP-Aktenzeichen 048038160
WO-Anmeldetag 13.12.2004
PCT-Aktenzeichen PCT/EP2004/014186
WO-Veröffentlichungsnummer 2005058228
WO-Veröffentlichungsdatum 30.06.2005
EP-Offenlegungsdatum 06.09.2006
EP date of grant 21.03.2007
Veröffentlichungstag im Patentblatt 03.05.2007
IPC-Hauptklasse C07H 19/22(2006.01)A, F, I, 20060808, B, H, EP
IPC-Nebenklasse A61K 31/7076(2006.01)A, L, I, 20060808, B, H, EP   A61K 31/52(2006.01)A, L, I, 20060808, B, H, EP   

Beschreibung[en]

The invention relates to purine derivatives of formula wherein

R1
is H, CN, halogen, -COR2, -S(O)xR2, C1-12-alkyl, C2-12-alkenyl, C3-8-cycloalkyl, a heterocyclyl group, an aryl group, a heteroaryl group, C3-8-cycloalkyl-(C1-3)-alkyl, a heterocyclyl-(C1-3)-alkyl group, an aryl-(C1-3)-alkyl or a heteroaryl-(C1-3)-alkyl group; the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclyl group, aryl and heteroaryl groups may all be optionally substituted;
R2
is -N(R3, R3'), C1-6-alkyl, C3-8-cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8-cycloalkyl-(C1-3)-alkyl, a heterocyclyl-(C1-3)-alkyl group, an aryl-(C1-3)-alkyl or a heteroaryl-(C1-3)-alkyl group, the C1-6-alkyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl may all be optionally substituted;
R3 and R3'
are independently hydrogen or (C1-3)-alkyl;
x
is 0, 1 or 2;
and to the ester thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof.

Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, related to the COMT inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of diseases such as depression, schizophrenia, Parkinson's disease, and to improve cognition.

The compounds of formula I possess valuable pharmacological properties. In particular, these compounds inhibit the enzyme catechol-O-methyltransferase (COMT), a magnesium-dependent enzyme which catalyzes the transfer of the methyl group of S-adenosylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuronal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure.

The compounds of formula I above can accordingly be used in the prevention or control of illnesses in which a deactivation of extraneuronal catecholamines by COMT plays a role, for example, in the prevention or control of depressions. In this case the compounds of formula I above can be used as individual compounds or in combination with other therapeutically active substances which favorably influence the course of the illness. The compounds of formula I can, however, also be used as co-medications with other therapeutically active substances. In addition the compounds of formula I are COMT inhibitors that lack the potential toxicity associated with nitrocatechol containing compounds (K. S. Smith, P. L. Smith, T. N. Heady, J. M. Trugman, W. D. Harman, T. L. Macdonald, Chem. Res. Toxicol. 2003, 16, 123-128; M. d'Ischia, C. Costantini, Bioorganic & Medicinal Chemistry 1995, 3, 923-927).

The compounds of formula I can also be used for the control of illnesses with therapeutically active substances which have a catechol structure. The treatment of Parkinson's disease and of parkinsonism with L-dopa, a therapeutically active substance having the catechol structure, can be mentioned as an example. In such cases the compounds of formula I can be used in the form of a co-medication or as combination preparations.

Numerous documents describe the current knowledge on COMT- inhibition, for example - in the field of depression Fava, M., J. F. Rosenbaum, A. R. Kolsky, J. E. Alpert, A. A. Nierenberg, M. Spillmann, C. Moore, P. Renshaw, T. Bottiglieri, G. Moroz, and G. Magni. Open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder. J Clin Psychopharmacol 1999, 19, 329.

  • in the field of schizophrenia:
    • Weickert, C. S., and D. R. Weinberger. A candidate molecule approach to defining developmental pathology in schizophrenia. Schizophr Bull 1998, 24, 303 .
    • Weinberger, D. R., M. F. Egan, A. Bertolino, J. H. Callicott, V. S. Mattay, B. K. Lipska, K. F. Berman, and T. E. Goldberg. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001, 50, 825.


    Egan, M. F., T. E. Goldberg, B. S. Kolachana, J. H. Callicott, C. M. Mazzanti, R. E. Straub, D. Goldman, and D. R. Weinberger. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001, 98, 6917
  • in the field of Parkinson's Disease

    Two COMT inhibitors are marketed for improvement of levodopa therapy,

    Tasmar/Tolcapone

    M. C. Kurth, C. H. Adler, M. St. Hilaire, C. Singer, C. Waters, P. LeWitt, D. A. Chernik, E. E. Dorflinger, K. Yoo,; Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson's disease experiencing motor fluctuations: A multicenter, double-blind, randomized, placebo-controlled trial. Neurology, 1997,48,81-87; V. V. Myllylä, M. Jackson, J. P. Larsen, H; Baas, Eur. J Neurol., 1997, 4, 333-341); Pfeiffer, Ronald F. Catechol-O-methyltransferase in Parkinson's disease. Neurological Disease and Therapy (2003), 59(Handbook of Parkinson's Disease (3rd Edition)), 437-451;

    and Entacapone

    Gershanik, Oscar; Emre, Murat; Bernhard, Gudrun; Sauer, Dirk. Efficacy and safety of levodopa with entacapone in Parkinson's disease patients suboptimally controlled with levodopa alone, in daily clinical practice: an international, multicentre, open-label study. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2003, 27(6), 963-971.
  • in the field of cognition improvement

    Lachman, H. M., D. F. Papolos, T. Saito, Y. M. Yu, C. L. Szumlanski, and R. M. Weinshilboum. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996, 6, 243.

    Malhotra, A. K., L. J. Kestler, C. Mazzanti, J. A. Bates, T. Goldberg, and D. Goldman. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002, 159, 652.

The following definitions of the terms used in the present description shall apply irrespective whether these terms are used alone or in combination.

The term "C1-12-alkyl" denotes a straight or branched chain hydrocarbon group with 1 to 12 carbon atoms, especially with 1 to 6 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl; the alkyl groups may optionally be substituted by halogen, hydroxy, alkoxy, especially by halogen. Examples of such substituted alkyl groups are, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl, and the like.

The term "C1-12-alkoxy" represent an alkyl-O- group, where the alkyl part is as defined above.

The term "C3-8-cycloalkyl" represents a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; the cycoalkyl group may optionally be substituted by an alkyl group as defined above. Examples of such substituted groups are methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methyl-2-cyclopentenyl, methyl-3-cyclopentenyl or methylcyclohexyl.

The term "heterocyclyl" represents 3- to 7-membered non-aromatic heterocyclic group containing 1 or 2 hetero atoms selected from nitrogen, oxygen and sulfur or sulfur oxidized to sulfones or sulfoxides. Examples of such groups are oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl. Preferred heterocycles are piperidyl and morpholinyl. Such heterocyclic groups may optionally be substituted by alkyl or alkoxy.

The term "aryl" represents an mono- or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms, examples of such groups are phenyl or naphthyl, a preferred aryl group is phenyl. These aryl groups may optionally be further substituted by one or several substituents chosen from halogen, alkyl or alkoxy groups as defined above. Examples of such substituted aryl groups are, 2, 3 or 4-fluorophenyl, 2, 3 or 4-bromophenyl, 2, 3 or 4-chlorophenyl, 2, 3 or 4-methylphenyl, 2,6- or 3,5-difluorophenyl, 2,6- or 3,5-dichlorophenyl, 2,6- or 3,5-dibromophenyl or 2,6- or 3,5-dimethylphenyl, and the like.

The term "heteroaryl group" represents 5- or 6- membered aromatic mono- or bicyclic heterocyclic group having 1 to 4 heteroatoms chosen from N, O and S. Examples of such aromatic heterocyclic groups include pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl,1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,3-triazolyl and tetrazolyl; examples of bicyclic heteroaryl groups are benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzodioxolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl or phthalazinyl.

The "heteroaryl groups" may be further substituted by halogen or an alkyl group as defined above.

"Halogen" stand for fluorine, chlorine, bromine or iodine.

Preferred compounds of formula I are compounds

wherein R1 is a hydrogen, cyano, halogen, -COR2, -S(O)2R2, C1-6-alkyl, C1-6-alkyl substituted with halogen, C2-6-alkenyl substituted with COR2, phenyl or phenyl substituted with C1-6-alkyl or halogen, benzyl or benzyl substituted with C1-6-alkyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl and

wherein R2 is C1-6-alkyl, C1-6-alkyl substituted with halogen or -N(R3,R3') and R3 and R3' are C1-3-alkyl, furthermore wherein R2 is phenyl or phenyl substituted with C1-6-alkyl or halogen, cyclohexyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl.

Preferred compounds are the compounds of formula I wherein R1 is hydrogen cyano or halogen, such as for example

N-{3- [5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl] -allyl}-2,3-dihydroxy-benzamide (Example 1)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyano-2,3-dihydroxy-benzamide (Example 3)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-bromo-2,3-dihydroxy-benzamide (Example 2)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-chloro-2,3-dihydroxy-benzamide (Example 7)

Further preferred compounds are the compounds of formula I wherein R1 is C1-6-alkyl, C1-6-alkyl substituted with halogen, C2-6-alkenyl substituted with COR2, and wherein R2 is -NR3,R3' and R3 and R3' are C1-3-alkyl, such as for example

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-alkyl}-2,3-dihydroxy-5-isopropyl-benzamide (Example 17)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-alkyl}-5-(2-dimethylcarbamoyl-vinyl)-2,3-dihydroxy-benzamide (Example 15) N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoromethyl-benzamide (Example 16)

A further group of preferred compounds of formula I are the compounds wherein R1 is - COR2 and R2 is C1-6-alkyl, C1-6-alkyl substituted with halogen, -N(R3,R3') and R3 and R3' are C1-3 -alkyl, such compounds are for example

N-{3-[5-(6 Amino-purin-9-yl)-3,4-dihydroxy tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy 5-trifluoroacetyl-benzamide (Example 4)

N3-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy tetrahydro-furan-2-yl]-allyl}-4,5-dihydroxy-N1,N1-dimethyl-isophthalamide (Example 14)

A further group of preferred compounds of formula I are the compounds wherein R1 is -COR2, and wherein R2 is phenyl, phenyl substituted with C1-6-alkyl or halogen, C3-8-cyclohexyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl, for example

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzoyl)-benzamide (Example 18)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamide (Example 6)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(pyridine-4-carbonyl)-benzamide (Example 5)

A further preferred group of compounds are the compounds of formula I wherein R1 is - S(O)2R2, and wherein R2 is C1-6alkyl, C1-6-alkyl substituted with halogen, -N(R3,R3') and R3 and R3' are C1-3-alkyl, furthermore wherein R2 is phenyl, phenyl substituted with C1-6-alkyl or halogen, cyclohexyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl, for example

N-{3-[5-(6-Amino-puria-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzamide (Example 18)

A further preferred group of compounds are the compounds of formula I wherein R1 is phenyl or phenyl substituted with C1-6-alkyl or halogen, pyridinyl, thiazolyl, benzthiazolyl, benzyl or benzyl substituted with C1-6-alkyl, such as for example

4'-Fluoro-4,5-dihydroxy-biphenyl-3-carboxylic acid {3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide (Example 8)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-thiazol-2-yl-benzamide(Example 10)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-pyridin-4-yl-benzamide (Example 12)

4,5-Dihydroxy-4'-methyl-biphenyl-3-carboxylic acid {3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide (Example 9)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamide (Example 11)

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzyl)-benzamide (Example 13)

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by process described below, which process comprises

  1. a) reacting 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine of furmula II with a optionally protected 2,3-dihydroxy-benzoic acid derivative substituted by R1 in position 5 wherein R1 is as defined above

    in the presence of (3-dimethylamino-propyl)-ethyl-carbodiimide (EDC), triethyl amine and N-hydroxy-succinimide (HOSu) in a suitable solvent such as dichloroethylene and
  2. b) subsequent deprotection of the hydroxy groups where necessary with trifluoroacetic acid in an aqueous solution to form the compounds of formula I.

The amino-purin derivative of formula II can be prepared according to Scheme 1 starting from 2-(6-Amino-purin-9-yl)-5-hydroxymethyl-tetrahydro-furan-3,4-diol (1) which is protected and subsequently reacted with (triphenyl-phosphanylidene)-acetic acid ethyl ester to the ester (4). The ester group in compound (4) is reduced to the alcohol (5) and transformed into the amide of formula II wherein TsOH stand for tosylchloride, IBX for 1-hydroxy-1,2-benziodoxol-3(1H)-1-oxide, DMSO for dimethylsulfoxide, PPh3 for triphenylphosphine, DEAD for diethyl azodicarboxylate and THF for tetrahydrofurane, Angew. Chem. (2001) 113, 4164.

The optionally protected 2,3-dihydroxy-benzoic acid derivatives substituted by R1 in position 5 (IIIa and IIIb) are prepared according to reaction schemes 2 to 6.

A method for the preparation of compounds of formula IIIb, wherein R1 is hydrogen or bromine is given in scheme 2.

  • step a) esterification of 2,3-dihydroxy-benzoic acid dissolved in a suitable solvent for example an alcohol such as methanol in the presense of thionylchloride to form the ester (8);
  • step b) protection of the ester (8) by ketalisation of the two hydroxy groups with a suitable ketone, e.g. with dichlorodiphenylmethane;
  • step c) hydrolysation of the ester group in the presence of a strong base such a LiOH. step d) 2,3-dihydroxy-benzoic acid is brominated in acetic acid and in the following steps e) to g) the carboxylic group is esterified to form the ester (11), the two hydroxy groups are protected to form the ketal (12) and the ester group is cleaved as described for steps a) to c).

The compounds of formula IIIb wherein R1 is chlorine can be prepared as depicted in

  • step a) 2-hydroxy-3-methoxy-benzoic acid (13) is chlorinated for example with N-chlorosuccinimide in acetic acid to yield 5-chloro-2-hydroxy-3-methoxy benzoic acid (14);
  • step b) the methoxy group of compound (14) is reacted with hydrobromic acid in acetic acid to yield 5-chloro-2,3-dihydroxy benzoic acid (15);

5-chloro-2,3-dihydroxy benzoic acid is then transformed into the protected compounds IIIb, wherein R1 is chlorine by esterification of the carboxylic group, ketalisation of the two hydroxy groups and subsequent cleavage of the ester group (steps c) to e)) as described above.

In Scheme 4 the preparation of derivatives of formula IIIb, wherein R1 is -COR2 and R2 is trifluoromethyl, cyclohexyl or pyridin-4-yl. The protected 5-bromo-benzoic acid derivative (the compound of formula IIIb, wherein R1 is bromine) is converted to its lithium salt. Lithium-halogen exchange and reaction with ethyl-trifluoroacetate, cyclohexane carboxylic acid methoxymethylamide, or pyridine-4-carbaldehyde followed by oxidation with IBX yielded the corresponding derivatives of formula IIIb.

In Scheme 5 the preparation of further derivatives of formula IIIb starting from protected 5-bromo benzoic acid ester (9) is shown. The nitrile is obtained by Pd catalysed cyanation. Arylsubstitutents were introduced using a Pd catalysed Suzuki-coupling with arylboronic acids.

In Scheme 6 the preparation of several derivatives of formula IIIb starting from protected 5-bromo benzoic acid derivative (9) is shown. 5-Bromo benzoic acid ester (9) is first converted to the dioxaborolane (10) which is subsequently reacted with benzylbromides, bromo aryl or bromo heteroaryl compounds in a palladium catalysed Suzuki reaction to yield the corresponding derivatives IIIb.

The various compounds which are used as starting materials are known or can be prepared according to known methods.

As mentioned earlier, the compounds of formula I inhibit the enzyme COMT. The inhibitory activity can be determined in vitro with COMT obtained from rat liver. Rat liver homogenate is incubated in the presence of a suitable substrate as described by Zürcher et al. in J. Neurochem. 1982, 38, 191-195 and the COMT activity is measured.

The IC 50 values (concentration of the inhibitor at which 50% activity of the enzyme is observed) were determined in a radiochemical assay described by Zürcher et al. (see above) and are listed in Table 1.

IC50 values were determined as follows: The inhibitors were dissolved in Me2SO as 1.2 mM stock solution and further diluted with Me2SO. The reactions were performed in standard polypropylene vials. 25 µl of the inhibitor in varying concentrations from 10-4 to 10-9 mol L-1 were mixed with 215 µl freshly prepared buffer-substrate mixture consisting of 170 µl potassium phosphate buffer (0.1 mol L-1, pH 7.6), 10 µl MgCl2, (0.1 mol L-1), 10 µl dithiothreitol (0.065 mol L-1) and 25 µl of tissue extract. The enzyme preparations were preincubated for 15 min at 37°C. The reaction was started by adding 30 µl substrate (benzene-1,2-diol, 0.025 mol L-1), 10 µl [3H] SAM (5.5 mmol L-1, specific activity: 13.36 Bq mol-1 (3.61 Cimol-1) and 20 µl deionized H2O, reaching a final substrate concentration of 2.5 mM and a final [1H]/[3H]SAM concentration of 183 µM. The reaction was stopped after incubating the vials in a water-bath at 37°C for 15 min by addition of 200 µl HOAc (5.7%) containing guaiacol (0.1 g L-1). The reaction vessels were transferred into polyethylene scintillation vials and 3 ml of scintillation fluid (5 g butyl-PBD, dissolved in 200 ml toluene, made up to 1 L with n-hexane) was added. The vials were capped and more than 98% (3H] guajacol formed was extracted into the organic phase by vigorous shaking for 3 min. The samples were counted in a Beckmann LS 6000 TA scintillation counter. Table 1 Example IC50 [nM] comparative example N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-d.ihydroxy-5-nitro-benzamide 9 1 N-13-[5-(6-Aniino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl] -allyl} -2,3-dihydroxy-benzamide 2600 2 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-bromo-2,3-dihydroxy-benzamide 28 3 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyano-2,3-dihydroxy-benzamide 29 4 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoroacetyl-benzamide 39 5 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl] -allyl}-2,3-dihydroxy-5-(pyridine-4-carbonyl)-benzamide 42 6 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamide 83 7 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-chloro-2,3-dihydroxy-benzamide 44 8 4'-Fluoro-4,5-dihydroxy-biphenyl-3-carboxylic acid {3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl] -allyl}-amide 21 9 4,5-Dihydroxy-4'-methyl-biphenyl-3-carboxylic acid {3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide 23 10 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-thiazol-2-yl-benzamide 27 11 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamide 29 12 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-pyridin-4-yl-benzamide 23 13 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzyl)-benzamide 608 14 N3-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-4,5-dihydroxy-N1,N1-dimethyl-isophthalamide 2000 15 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-(2-dimethyl-carbamoyl-vinyl)-2,3-dihydroxy-benzamide 97 16 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoromethyl-benzamide 35 17 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-isopropyl-benzamide 1370 18 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzamide 213 19 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy 5-(4-methyl-benzoyl)-benzamide 34

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The compounds of formula I, ester or ether derivatives thereof, and salts thereof can be used as medicaments, for example, in the form of pharmaceutical preparations for enteral or parenteral administration. The compounds of formula Ia can be administered, for example, perorally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.

The manufacture of the pharmaceutical preparations can be effected in a manner which is familiar to any person skilled in the art by bringing the compounds of formula I, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.

As carrier materials there are suitable not only inorganic carrier materials, but also organic carrier materials. Thus, for tablets, coated tablets, dragees and hard gelatine capsules there can be used as carrier materials, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols. Depending on the nature of the active substances no carriers are, however, required in the case of soft gelatine capsules. Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carrier materials for suppositories are, for example natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.

As pharmaceutical adjuvants there come into consideration the usual preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, flavor-improving agents such as sweetening agents and flavoring agents, coloring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.

The dosage of the compounds of formula I, or ester derivatives thereof and salts thereof can vary within wide limits depending on the illness to be treated, the age and the individual condition of the patient and on the mode of administration and will, of course, be fitted to the individual requirements in each particular case. For example in the improvement of the treatment of Parkinson's disease and of parkinsonism with or without L-dopa a daily dosage of 25 mg to about 1000 mg, especially about 100 mg to about 300 mg, comes into consideration. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.

The pharmaceutical preparations in accordance with the invention conveniently contain about 25 mg to about 300 mg, preferably about 50 mg to about 150 mg, of a compound of formula I or of an ester derivative thereof which is hydrolyzable under physiological conditions or of a pharmaceutically acceptable salt thereof.

The Examples which follow will further illustrate the invention and contain detailed information concerning the preparation of compounds of formula I and the used starting materials.

Experimental Materials and Methods

Solvents for extractions and chromatography were of technical grade and were distilled prior to usage. Reactions were performed using solvents of p.a. grade purchased from Fluka or j. T. Baker or solvents of comparable quality. THF (tetrahydrofuran) was distilled from sodium benzophenone ketyl and CH2Cl2 from CaH2.

Thin layer chromatography was performed on aluminum-backed sheets coated with SiO2. 60 F254 from Macherey-Nagel using UV-light (254 nm) for detection.

Column chromatography was perfomed using Fluka SiO2 60, 40-63 mesh, at r.t. (room temperature) and at a pressure of 1·106 to 4·106 Pa (0.1 - 0.4 bar)

Analytical HPLC was performed on a Merck LiChrospher® 100 RP-18 (250 x 4 mm, 5µm, 100Å) column, using a linear gradient of CH3CN in H2O with 0.1% TFA (trifluoro acetic acid), 5 → 55% in 20 min, a flow of 1 mL / min, and UV-detection at 254 nm.

Preparative HPLC was performed on a Merck LiChrosorb® RP-18 (250 x 25 mm, 7µm) column, using a linear gradient of CH3CN in H2O with 0.1% TFA, a flow of 10 mL / min and UV-detection at 254 nm.

Melting points were determined on a Büchi-510 apparatus and are uncorrected.

Infrared spectra were recorded on a Perkin-Elmer 1600-FT spectrometer.

NMR spectra (1H and 13C) were recorded at r.t. on Varian-Mercury 300 or Bruker AMX-500 instruments.

Mass Spectra were recorded by the MS service of the Labortorium für Organische Chemie at ETH Zürich using IonSpec Ultima (MALDI, with 2,5-dihydroxybenzoic acid or 2,4,6-trihy-droxyacetophenone / diammonium citrate 2:1 as matrix) and VG-TRIBID (EI) spectrometers.

Elemental analyses were performed by the Mikrolabor of the Laboratorium für Organische Chemie at ETH Zürich.

General Procedures (GP) General procedure 1 (GP1) for the synthesis of methyl 2,3-dihydroxybenzoate derivatives from the corresponding 2,3-dihydroxybenzoic acids

To a solution of the 2,3-dihydroxy-benzoic acid (1 eq.) in MeOH was slowly added SOCl2 (3 eq.) via a syringe and the reaction mixture was then refluxed overnight. After evaporation of the solvent under reduced pressure the grayish solid was redissolved in EtOAc and washed twice with saturated K2CO3 solution, then saturated NaCl solution before being dried over MgSO4 and the solvent evaporated in vacuo. Drying under high vacuum yielded the product as a grayish solid.

General procedure (GP2) for the protection of catechols as diarylmethylketals General procedure 2.1 (GP2.1) Protection as diphenylmethylketal.

Method A. A suspension of the corresponding methyl 2,3-dihydroxybenzoate (1 eq.) in dichlorodiphenylmethane (1.5 eq.) was stirred at 160°C for 40 min. After cooling to 50°C, 30 mL MeOH was added to the viscous brown oil leading to the formation of a precipitate. The precipitate was filtered, washed with MeOH (3 x 20 mL) and dried under high vacuum to yield the desired compound as a colorless solid.

Method B. A suspension of the corresponding methyl 2,3-dihydroxybenzoate (1 eq.) in 3.7 mL dichlorodiphenylmethane (1.5 eq.) was stirred at 160°C for 40 min. After cooling, EtOAc was added to the viscous mixture and the solution was washed with saturated NaCl solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified using flash chromatography (silica gel, hexane / Et2O 10:1) to yield the desired compound as a colorless solid.

General procedure 2.2 (GP2.2) Protection as 4,4'-dimethoxy-diphenylmethylketal.

4,4'-Dimethoxybenzophenone (1.5 eq.) and oxalyl chloride (8 eq.) were stirred at 60°C for 30 min., then the temperature was raised to 110°C to remove the excess oxalyl chloride and the corresponding methyl 2,3-dihydroxy-benzoate (1 eq.) was added to the reaction mixture. The dark red solution was stirred at 160°C for 40 min. After cooling, EtOAc was added to the viscous mixture and the solution was washed with saturated NaCl solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified using flash chromatography (silica gel, hexane / Et2O 10:1 or hexane / EtOAc 20:1).

General procedure 3 (GP3) for the synthesis of catechol carboxylic acids from the corresponding ester precursors

The biphasic mixture of a solution of the methyl catechol carboxylate (1 eq.) in 5 mL THF and a solution of LiOH·H2O (3 eq.) in 5 mL H2O was refluxed for 3 h. After cooling to r.t. the reaction mixture was acidified by addition of 4 mL 10% AcOH - solution and poured into a separatory funnel containing 50 mL H2O and 50 mL EtOAc. The layers were separated and the aqueous layer was extracted twice with 20 mL EtOAc. The pooled organic fractions were washed twice with saturated NaCl-solution before being dried over MgSO4 and evaporated in vacuo to yield the desired compound as a colorless solid.

General procedure 4 (GP4) for the synthesis of functionalized catechol carboxylic acids starting from 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Method A. To a suspension of 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1 eq.) in 3 mL MeOH, LiOMe (2 eq.) was added leading to the formation of a clear solution, which was stirred 20 min. at r.t. Following evaporation of the solvent under reduced pressure, the resulting white foam was dried overnight under vacuum. The residue was then redissolved in 10 mL dry THF and cooled to -78°C. To this solution t-BuLi (1.5M solution in pentane, 2.5 eq.) was added dropwise via a syringe and the resulting dark yellow solution was stirred 30 min. at -78°C. The desired electrophile was added to the reaction mixture and the stirring continued 30 min. at low temperature. The cooling bath was removed and the reaction was stirred another 2 h at r.t., followed by acidification with 10% AcOH-solution and extraction with EtOAc (2 x 30 mL). The organic fractions were pooled, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH) to give the title compound as a yellowish to colorless solid.

Method B. To a solution of 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1 eq.) in 8 mL dry THF, LiH (2 eq.) was added. The reaction mixture was stirred 15 min. at r.t., then cooled to -78°C. To this solution t-BuLi (1.5M solution in pentane, 2.5 eq.) was added dropwise via a syringe and the resulting yellow solution was stirred 30 min. at -78°C. The desired electrophile was added to the reaction mixture and the stirring continued 30 min. at low temperature. The cooling bath was removed and the reaction was stirred another 2 h at r.t., followed by acidification with 10% AcOH-solution and extraction with EtOAc (2 x 30 mL). The organic fractions were pooled, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane / EtOAc / AcOH) to give the desired compound as a colorless solid.

General procedure 5 (GP5) for the synthesis of biaryl catechol carboxylic esters via Suzuki reaction between methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate and the corresponding aryl boronic acid

To a solution of methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (1 eq.) and Pd(PPh3)4 (0.05 eq.) in 10 mL toluene, a solution of the desired aryl boronic acid (4 eq.) in 1.5 mL EtOH and a solution of K2CO3 (6 eq.) in 1 mL H2O were added. This mixture was refluxed 2 h - 4 h. After cooling to r.t. the mixture was partitioned between EtOAc and H2O. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was further purified using flash chromatography (silica gel, hexane/EtOAc 20:1 → 5:1) to yield the desired compound as a colorless solid.

General procedure 6 (GP6) for the preparation of biaryl catechol carboxylic esters via one-pot arylboronate - Suzuki biaryl synthesis

To a solution of methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (1 eq.) in 20 mL dry toluene, Pd(PPh3)4 (0.05 eq.), bis(pinacolato)diboron (1.3 eq.) and KOAc (1.5 eq.) were added and the mixture refluxed for 4 h. After cooling to r.t. the reaction mixture was filtered over Celite, which was washed with an additional 30 mL of toluene. The combined toluene fractions were concentrated in vacuo to ca.10-15 mL. To this yellowish solution Pd(PPh3)4 (0.05 eq.), 1.2 eq. of the desired arylbromide, e.g. 2-bromo-1,3-benzothiazole and a solution of K2CO3 (5 eq.) in 3 mL H2O were added and the reaction was refluxed for 16 h. After cooling to r.t., the mixture was partitioned between H2O and EtOAc and the organic fraction was washed twice with 20 mL saturated NaCl solution, before being dried over MgSO4 and evaporated under reduced pressure. The crude product was further purified using flash column chromatography (silica gel, hexane/EtOAc 20:1 → 9:1) to yield the desired compound as a colorless solid.

General procedure 7 (GP7) for the amide coupling of catechol carboxylic acids and 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]dioxol-4-yl}-9H-purin-6-amine

To a solution of the catechol carboxylic acid (1 eq.) in 5 mL CH2Cl2, EDC·HCl (1-(dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride) (1.5 eq.) and N-hydroxysuccinimide (1.3 eq.) were added and the solution was stirred 2 h at r.t. After addition of 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine (0.7 eq. - 1 eq.) and Et3N (0.1 mL, 0.68 mmol) stirring was continued another 3 h, then the solution was poured into a separatory funnel containing CH2Cl2 and H2O and the phases were separated. The aqueous phase was extracted with CH2Cl2 (3 x 15 mL), then the combined organic fractions were washed with saturated aqueous NaCl solution, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2 → CH2Cl2/MeOH = 20:1) to yield the desired compound as a colorless foam.

General procedure 8 (GP8) for the synthesis of target molecules by deprotection of the acetonide and the diarylmethylketal protecting groups

The protected precusor was treated with 3 mL of a mixture of TFA and H2O (1:1) at r.t. for 20-60 min. The reaction mixture was then lyophilized. The crude product was redissolved in 3 mL DMSO and purified using preparative HPLC chromatography. The product fractions were subsequently lyophilized to yield the desired compound as a fluffy solid.

Example 1 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-2,3-dihydroxy-benzamide a) 2,2-Diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo [3,4-d] [1,3] dioxol-4-yl] -prop-2-enyl} - amide

2,2-Diphenyl-1,3-benzodioxole-4-carboxylic acid (150 mg, 0.471 mmol, eq.), EDC·HCl (136 mg, 0.71 mmol,1.5 eq.), N-hydroxy-succinimide (65 mg, 0.565 mmol,1.2 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3]dioxol-4-yl}-9H-purin-6-amine (150 mg, 0.451 mmol, eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 189 mg (67 %). Colorless foam. Mp.:105°C. [&agr;]D 20: -14.3 (c=1.0, MeOH). IR (KBr): 3424m; 3175m; 2987w; 1651s; 1532s; 1455s; 1373m; 1246s; 1082s; 867m; 748m. 1H-NMR (300 MHz, CDCl3): 1.37 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.05 (m, 2 H, H-C(7'), H-C(7")); 4.69 (m, H, H-C(4')); 4.95 (dd; J= 6.5, 3.7, 1H, H-C(3')); 5.46 (dd, J= 6.5, 2.2,1 H, H-C(2')); 5.61 (bs, 2H, NH2); 5.86 (m, 2 H, H-C(5'), H-C(6')); 6.08 (d, J = 2.2,1 H, H-C(1')); 6.95 (t, J= 8.1, 1H, Harom, Cat.); 7.02 (dd, J = 8.1, 1.2, 1H, Harom, Cat.); 7.14 (t, J = 5.6, 1H, NHCO); 7.35-7.39 (m, 6 H, Harom, Ketal), 7.48-7.53 (m, 4 H, Harom, Ketal); 7.58 (dd, J = 8.7,1.2, Harom, Cat.); 7.84 (s, 1 H, H-C(8)); 8.20 (s,1H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.5; 27.2; 40.7; 84.0; 84.5; 87.1; 90.2; 111.8; 114.6; 115.5; 118.1; 120.1; 122.0; 122.4; 126.3; 128.2; 128.3; 129.5; 130.6; 138.8; 139.6; 144.5; 147.0; 149.3; 153.0; 155.3; 163.2. HR-MS (MALDI): calcd. for C35H33N6O6 ([M+H]+): 633.2461, found 633.2442.

b) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-2,3-dihydroxy-benzamide

The protected precursor (120 mg, 0.19 mmol) was treated with 3.5 mL of a mixture of TFA and H2O (5:2) at 0°C for 60 min. The solvents were evaporated under reduced pressure, then the residue was dissolved in 5% NH4OH in H2O and extracted with CHCl3 (3 x 15 mL). The aqueous phase was then evaporated under reduced pressure and coevaporated with H2O (3×10 mL). The crude product was redissolved in 8 mL DMF and purified using HPLC chromatography to yield the title compound as a colorless solid.

Yield: 60 mg (74%). Mp.: 134°C (dec.). tR, analyt.: 10.9 min. IR (KBr): 3424 br, s; 1641s; 1604s; 1460w; 1420w; 1340w; 1278m; 1129w; 1050w; 1H-NMR (500 MHz, (CD3)2SO): 3.95 (m, 2 H, H-C(7'), H-C(7")); 4.11 (t, J= 4.8,1 H, H-C(4')); 4.37 (m; 1H, H-C(3')); 4.65 (t, J= 5.1,1H, H-C(2')); 5.82-5.93 (m, 2 H-C(5'), H-C(6')); 5.93 (d, J = 5.1,1H, H-C(1')); 6.69 (t, J = 7.9,1 H, Harom, Cat.); 6.92 (dd, J = 7.9, 1.1, 1H, Harom, Cat.); 7.31 (dd, J = 7.9,1 H, Harom, Cat.); 8.23 (s,1H, H-C(8)); 8.49 (s,1 H, H-C(2)); 8.97 (t, J = 5.4,1H, H-NHCO); 12.64 (bs,1H, OH). 13C-NMR (125 MHz, (CD3)2SO): 40.1; 73.1; 73.9; 84.3; 87.8; 115.0; 117.2; 118.0; 118.9; 119.1; 129.2; 129.6; 141.3; 146.2; 148.9; 149.0; 149.6; 153.2; 169.5. HR-MS (MALDI): calcd. for C19H21N6O6 ([M+H]+): 429.1522, found 429.1513.

Example 2 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-bromo-2,3-dihydroxy-benzamide a) Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 5-bromo-2,3-dihydroxybenzoate (3 g, 12.87 mmol, 1 eq.) was reacted with dichlorodiphenylmethane (3.7 mL, 4.58 g, 19.31 mmol, 1.5 eq.) according to GP2, Method A.

Yield: 4 g (76 %). Colorless powder. Mp.:146-148°C. IR (KBr): 3079w; 2950w; 1718s (CO); 1467s; 1355s; 1238s; 1204s; 1043s; 1013s; 944m; 867m; 780s. 1H-NMR (300 MHz, CDCl3): 3.94 (s, 3 H, CH3); 7.14 (d, J = 1.9, 1 H. Harom, cat); 7.38-7.41 (m, 6 H, Harom, Ketal); 7.55-7.59 (m, 5 H, Harom, Cat, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 52.4; 112.6; 113.7; 115.6; 119.1; 125.0; 126.2; 128.3; 129.4; 139.0; 147.5; 149.1; 163.7. HR-MS (MALDI): calcd. for C21H16BrO4 ([M+H]+): 411.0231, found 411.0220.

b) 6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (0.5 g, 1.216 mmol, 1 eq.) and LiOH·H2O (204 mg, 4.86 mmol, 4 eq.) were reacted according to GP3.

Yield: 437 mg (91%). Colorless solid. Mp.: 215°C. IR (KBr): 3063m; 2873 br, In; 2538m; 1695s (CO); 1598w; 1468s; 1406m; 1350m; 1287s; 1234s; 1202s; 1045s; 1023s; 949m; 858m; 784m; 698s. 1H-NMR (300 MHz, CDCl3): 7.19 (d, J = 2.1,1 H, Harom, Cat.); 7.40-7.42 (m, 6 H, Harom, Ketal); 7.58-7.62 (m, 5 H, Harom, Cat., Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 112.7; 112.8; 116.4; 119.5;125.4; 126.3; 128.4; 129.5; 138.9; 148.3; 149.3; 167.9. HR-MS (MALDI): calcd. for C20H14BrO4 ([M+H]+): 397.0075, found 397.0078. Anal. calcd. for C20H13BrO4: C 60.47, H 3.30; found C 60.40, H 3.35.

c) 6-Bromo-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3] dioxol-4-yl]-prop-2-enyl}-amide

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.503 mmol, 1.4 eq.), EDC·HCl (145 mg, 0.755 mmol, 2.1 eq.), N-hydroxy-succinimide (76 mg, 0.654 mmol, 1.8 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3] di-oxol-4-yl}-9H-purin-6-amine (120 mg, 0.361 mmol, 1 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 166 mg (65 %). Colorless foam. Mp.: 116°C. IR (KBr): 3424m; 3170 br, w; 2985w; 1636s; 1594s; 1531m; 1495s; 1423w; 1373w; 1236s; 1207s; 1156w; 1082s; 1016m; 867w; 778w; 698m. 1H-NMR (300 MHz, CDCl3):1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.04 (m, 2 H, H-C(7'), H-C(7")); 4.69 (m, 1 H, H-C(4')); 4.95 (dd; J= 6.3, 3.6, 1H, H-C(3')); 5.45 (dd, j = 6.3, 2.3, 1H, H-C(2')); 5.84 (m, 2 H, H-C(5'), H-C(6')); 5.96 (bs, 2 H, NH2); 6.09 (d, J = 2.3, 1H, H-C(1')); 7.05 (t, J = 5.6, 1H, NHCO); 7.15 (d, J = 2.0, 1 H, Harom, Cat.); 7.35-7.40 (m, 6 H, Harom, Ketal); 7.44-7.50 (m, 4 H, H-C(6), Harom, Ketal); 7.72 (d, J = 2.0,1 H, Harom, Cat.); 7.87 (s, 1H, H-C(8)); 8.20 (s, 1H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.5; 27.3; 40.9; 84.1; 84.5; 87.1; 90.3; 114.0; 114.7; 115.2; 116.3; 119.5; 120.1; 125.0; 126.3; 128.4; 129.8; 130.5; 138.3; 140.1; 144.1; 148.1; 149.2; 151.7; 154.7; 162.0. HR-MS (MALDI): calcd. for C35H32BrN6O6 ([M+H]+): 711.1567, found 711.1553. Anal. calcd. for C35H31BrN6O6: C 59.08, H 4.39, N 11.81 found C 59.06, H 4.54, N 11.62.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-bromo-2,3-dihydroxy-benzamide

The protected precusor (50 mg, 0.07 mmol) was deprotected according to GPB.

Yield: 18 mg (52%). Colorless solid. tR, analyt.: 13.4 min. Mp.:123°C (dec.). IR (KBr): 3396 br, m; 1699s; 1637m; 1467w; 1426w; 1325w; 1203s; 1135m; 1050w. 1H-NMR (500 MHz, CD3OD): 4.03 (m, 2 H, H-C(7'), H-C(7")); 4.23 (t, J= 5.0, 1 H, H-C(4')); 4.52 (m; 1 H, H-C(3')); 4.72 (t, J= 4.8,1 H, H-C(2')); 5.92-5.94 (m, 2 H, H-C(5'); H-C(6')); 6.06 (d, J = 4.8, H-C(1')); 7.05 (d, J= 2.3, 1H, Harom, Cat.); 7.43 (d, J= 2.3, 1 H, H-Carom, Cat.); 8.27 (s, 1 H, H-C(8)); 8.39 (s, 1H, H-C(2)). 13C-NMR (125 MHz, CD3OD): 41.6; 75.2; 75.6; 86.1; 90.6; 111.2; 118.2; 120.7; 121.3; 122.3; 130.3; 130.9; 143.4; 147.8; 148.8; 149.6; 150.2; 153.5; 169.9. HR-MS (MALDI): calcd. for C19H20BrN6O6 ([M+H]+): 507.0628, found 507.0627.

Example 3 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-cyano-2,3-dihydroxy-benzamide a) Methyl 6-cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

To a solution of methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (800 mg, 1.95 mmol, 1 eq.) in a mixture of 15 mL benzene and 5 mL DMF, Pd(PPh3)4 (225 mg, 0.195 mmol, 0.1 eq.), KCN (127 mg, 1.95 mmol, 1 eq.) and 18-crown-6 (415 mg, 1.56 mmol, 0.8 eq.) was added and the reaction mixture was stirred at 100°C overnight. Then the reaction mixture was poured into a separatory funnel containing EtOAc and H2O and the aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with H2O, then saturated aqueous NaCl solution, dried over MgSO4, and evaporated under reduced pressure. Flash chromatography on silica gel (hexane / EtOAc = 20:1 → 9:1) afforded the desired compound as a colorless solid.

Yield: 530 mg (76%). Mp.:141°C. IR (KBr): 3051w; 2951w; 2228m (CN); 1713s (CO); 1470s; 1375m; 1264s; 1225s; 1045s; 917m; 786s. 1H-NMR (300 MHz, CDCl3):3.97 (s, 3 H, CH3); 7.20 (d, J = 1.9, 1 H, Harom, Cat.); 7.39-7.43 (m, 6 H, Harom, Ketal); 7.55-7.58 (m, 4 H, Harom, Ketal); 7.82 (d, J = 1.9, 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 52.67; 104.8; 113.4; 113.9; 118.0; 120.4; 126.2; 128.4; 129.2; 129.7; 138.4; 148.9; 151.5; 163.1. HR-MS (MALDI): calcd. for C22H16NO4 ([M+H]+): 358.1079, found 358.1071.

b) 6-Cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

To a solution of methyl 6-cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (60 mg, 0.168 mmol, 1 eq.) in a mixture of 3 mL MeOH and 0.5 mL CH2Cl2, a solution of LiOH·H2O (21 mg, 0.5 mmol, 3 eq.) in 3 mL H2O was added. The reaction mixture was vigorously stirred 16 h at r.t., then acidified with 10% AcOH in H2O and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, and the solvents evaporated under reduced pressure to yield the desired compound as a colorless solid.

Yield: 53 mg (92%). Mp.: 221°C. IR (KBr): 2925m; 2229m; 1696s; 1449s; 1267s; 1213s; 1048s; 949m; 922m; 756m; 694s; 641m; 617w. 1H-NMR (300 MHz, CDCl3): 7.25 (d, J= 1.7, 1H, Harom, Cat.); 7.41 (m, 6 H, Harom, Ketal); 7.58 (m, 4 H, Harom,Ketal); 7.87 (d, J= 1.7, 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 105.0; 112.6;114.4; 117.8; 120.7; 126.1; 128.5; 129.6; 129.8; 138.2; 149.0; 152.1; 167.1. HR-MS (MALDI): calcd. for C21H14NO4 ([M+H]+): 344.0923, found 344.0910.

c) 6-Cyano-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-Cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (80 mg, 0.23 mmol, 1.5 eq.), EDC·HCl (73 mg, 0.38 mmol, 2.5 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine (50 mg, 0.15 mmol, 1 eq.) and Et3N (0.05 mL, 0.34 mmol) were reacted according to GP7.

Yield: 67 mg (68%). Colorless foam. Mp.: 125°C. IR (KBr): 3428s; 3171w; 2986w; 2227w; 1635s; 1597m; 1528m; 1466s; 1374m; 1262s; 1209s; 1082m; 1017m; 867w; 762w; 699m; 641w. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.05 (m, 2 H, H-C(7'), H-C(7")); 4.70 (m, 1H, H-C(4')); 4.96 (dd; J= 6.3, 3.9, 1H, H-C(3')); 5.46 (dd, J = 6.3, 2.0, 1H, H-C(2')); 5.79 (bs, 2 H, NH2); 5.83 (m, 2 H, H-C(5'), H-C(6')); 6.08 (d, J = 2.0, 1H, H-C(1')); 7.00 (t, J = 5.7,1H, NHCO); 7.22 (d, J = 1.7,1H, Harom, Cat.); 7.38-7.49 (m, 10 H, Harom, Ketal); 7.86 (s, 1 H, H-C(8)); 7.99 (d, = 1.7, Harom, Cat.); 8.19 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.5; 27.3; 41.0; 84.1; 84.5; 87.2; 90.3; 105.9; 113.7; 114.7; 116.1; 118.0; 120.2; 120.7; 126.3; 128.6; 128.8; 129.1; 130.1; 130.2; 137.6; 140.0; 147.8; 148.0; 149.2; 152.3; 155.0; 161.2. HR-MS (MALDI): calcd. for C36H32N7O6 ([M+H]+): 658.2414, found 658.2403.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-cyano-2,3-dihydroxy-benzamide

The protected precusor (70 mg, 0.11 mmol) was deprotected according to GP8.

Yield: 20 mg (42%). tR, analyt.: 9.0 min. IR (KBr): 3396 br, s; 2233w; 1703s; 1639s; 1477w; 1441w, 1303m; 1195s; 1137m; 1050w. 1H-NMR (500 MHz, CD3OD): 4.06 (d, J = 3.7, 2 H, H-C(7'), H-C(7")); 4.24 (t, j = 4.9, 1H, H-C(4')); 4.51 (t; J = 4.9, 1H, H-C(3')); 4.73 (t, J = 4.6, 1H, H-C(2')); 5.94 (m, 2 H, H-C(5'), H-C(6')); 6.04 (d, J= 4.6, 1H, H-C(1')); 7.17 (d, J = 1.8, 1 H, Harom, Cat.); 7.70 (d,J = 1.8, 1 H, Harom, Cat.); 8.23 (s, 1 H, H-C(8)); 8.33 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, (CD3OD + 2 drops of DMSO-d6): 41.7; 75.2; 75.4; 85.9; 90.2; 102.6; 117.3; 119.8; 120.5; 121.1; 124.2; 130.5; 130.6; 143.6; 146.3; 148.4; 149.9; 154.6; 169.3 (1 peak missing). HR-MS (MALDI): calcd. for C20H20N7O6 ([M+H]+): 454.1475, found 454.1466.

Example 4 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl] prop-2-enyl}-5-(2,2,2-triffuoro-acetyl)-2,3-dihydroxy benzamide a) 2,2-Diphenyl-6-(trifluoroacetyl)-1,3-benzodioxole-4-carboxylic acid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.503 mmol, 1 eq.), LiOMe (40 mg, 1 mmol, 2 eq.) and ethyl trifluoroacetate (0.6 mL, 5.03 mmol, 10 eq.) as the electrophile were reacted according to GP4, Method A. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH 77:20:3) to give the title compound as a yellowish solid.

Yield: 79 mg (38%). Mp.: 187°C. IR (KBr): 2925m; 2555m; 1692s; 1635m; 1482s; 1254s; 1213s; 1131s; 1048m; 1013m; 987m; 945m; 802m; 760s; 699s. 1H-NMR (300 MHz, CDCl3): 7.40-7.44 (m, 6 H, Harom, Ketal); 7.59-7.62 (m, 4 H, Harom, Ketal); 7.74 (d, J = 1.2,1 H, Harom, Cat); 8.35 (m, 1 H, Harom, Cat). 13C-NMR (75 MHz, CDCl3): 111.7; 112.4;116.5 (q, J = 289); 121.0; 124.0; 126.2; 128.5; 128.9; 129.8; 138.3; 149.6; 154.3; 167.7; 178.1 (q, J = 35.2). 19F-NMR (282 MHz, CDCl3): -70.72 (s). HR-MS (MALDI): calcd. for C22H14F3O5 ([M+H]+): 415.0793, found 415.0784. Anal. calcd. for C22H13F3O5: C 63.77, H 3.16; found C 63.81, H 3.29.

b) 2,2-Diphenyl-6-(2,2,2-troffuoro-acetyl)-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo [3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

GP7, starting from 2,2-diphenyl-6-(trifluoroacetyl)-1,3-benzodioxole-4-carboxylic acid (250 mg, 0.603 mmol, 1 eq.), EDC·HCl (175 mg, 0.91 mmol, 1.5 eq.), N-hydroxy-succinimide (90 mg, 0.784 mmol, 1.3 eq.) and 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethyl-perhydrofuro[3,4-d][1,3]di-oxol-4-yl]-9H-purin-6-amine (120 mg, 0.361 mmol, 0.6 eq.) provided the title compound as a colorless foam.

Yield: 174 mg (66%). Mp.: 108-110°C. IR (KBr): 3426m; 3199m; 2986w; 2227w; 1644s; 1599m; 1534m; 1476m; 1442m; 1378w; 1253s; 1207s; 1151m; 1082m; 1017w; 866w; 761w; 699m; 642w. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.07 (m, 2 H, H-C(7'), H-C(7")); 4.68 (m, 1 H, H-C(4')); 4.97 (dd; J= 6.3, 3.6, 1H, H-C(3')); 5.47 (dd, J = 6.3, 2.1, 1H, H-C(2')); 5.85 (m, 4 H, H-C(5'), H-C(6'), NH2); 6.08 (d, J= 2.1, 1H, H-C(1')); 7.03 (t, J= 5.7, 1H, NHCO); 7.38-7.45 (m, 6 H, Harom,Ketal); 7.47-7.52 (m, 4 H, Harom, Ketal); 7.69 (d, J=1.7, 1H, Harom, Cat.); 7.86 (s, 1 H, H-C(8)); 8.21 (s, 1H, H-C(2)); 8.43 (d, J = 1.7, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 25.5; 27.3; 41.1; 84.1; 84.5; 87.1; 90.2; 111.5; 114.7;115.5; 116.6 (q, J= 281); 120.1; 120.9; 124.8; 126.3; 128.2; 128.6; 128.8; 130.2; 137.6; 137.7; 139.9; 148.4; 149.2; 150.2; 152.3; 155.0; 161.6; 178.5 (q, J= 35.5). 19F-NMR (282 MHz, CDCl3): -71.24 (s). HR-MS (MALDI): calcd. for C37H32F3N6O7 ([M+H]+): 729.2285, found 729.2291.

c) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(2,2,2-trifluoro-acetyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (100 mg, 0.137 mmol) gave the desired product as a colorless solid.

Yield: 40 mg (56%). tR, analyt.: 11.1 min. IR (KBr): 3370 br, s; 1699s; 1640s; 1545w; 1439w; 1326m; 1283m; 1202s; 1142s; 1052w; 724w. 1H-NMR (500 MHz, CD3OD) 4.05 (d, J= 2.2, 2 H, H-C(7'), H-C(7")); 4.23 (t, J = 5.0, 1 H, H-C(4')); 4.52 (m, 1 H, H-C(3')); 4.72 (t, J= 4.9, 1 H, H-C(2')); 5.94 (m, 2 H, H-C(5'), H-C(6')); 6.05 (d, J= 4.9, 1 H, H-C(1')); 7.18 (s, 1 H, H-C(8)); 7.57 (m, 1 H, Harom, Cat.); 8.26 (d, j = 4.2, 1 H, Harom, Cat.); 8.38 (s,1 H, H-C(2)). 13C-NMR (125 MHz, (CD3OD): 41.6; 75.2; 75.6; 86.1; 90.5;116.4; 119.2; 119.3; 120.7; 124.4 (q, J= 286); 126.4; 130.2; 131.1; 143.1; 147.2; 148.6; 150.3; 151.0; 154.0; 170.9 (1 peak missing). HR-MS (MALDI): calcd. for C21H20F3N6O7 ([M+H]+): 525.1346, found 525.1345.

Example 5 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl] prop-2-enyl}-5-(pyridine-4-carbonyl)-2,3-dihydroxy benzamide a) 6-(Hydroxy-pyridin-4-yl-methyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1 g, 2.52 mmol, 1 eq.), LiOMe (192 mg, 5.04 mmol, 2 eq.) and pyridine-4-carbaldehyde (0.48 mL, 5.03 mmol, 2 eq.) as the electrophile were reacted according to GP4, Method A. The crude product was purified using flash chromatography (silica gel, CH2Cl2MeOH 92:8 → 80:20) to give the title compound as a yellow solid.

Yield 350 mg (33%). Mp.: 213-217°C (dec.). IR (KBr): 3381 br, s; 1565s; 1473m; 1410s; 1257s; 1205s; 1047s; 1026m; 948w; 806w; 777m; 698m; 642m. 1H-NMR (300 MHz, (CD3)2SO): 5.63 (s, 1 H, Hbenz.); 6.11 (bs, H, OH); 7.04 (s, 1H, Harom, Cat.); 7.36 (d, J= 5.7, 2 H, Harom, Pyr.); 7.40-7.42 (m, 7 H, Harom, Cat., Harom, Ketal); 7.50-7.54 (m, 4 H, Harom, Ketal); 8.46 (d, J = 5.7, 1 H, Harom, Pyr.). 13C-NMR (75 MHz, (CD3)2SO): 62.6; 108.2; 116.1; 120.9; 121.4; 125.7; 128.2; 129.1; 137.3; 139.5; 139.6; 145.3; 147.0; 149.2; 153.6; 189.8. HR-MS (MALDI): calcd. for C26H20NO5 ([M+H]+): 426.1341, found 426.1332.

b) 2,2-Diphenyl-6-(pyridine-4-carbonyl)-1,3-benzodioxole-4-carboxylic acid

To a solution of 6-(hydroxy-pyridin-4-yl-methyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (128 mg, 0.324 mmol, 1 eq.) in a mixture of 10 mL acetone and 3 mL DMSO, IBX (273 mg, 0.973 mmol, 3 eq.) was added and the reaction mixture was stirred 3 h at 50°C. The mixture was partitioned between H2O and EtOAc, and the organic layer was washed with saturated NaCl solution before being dried over MgSO4 and evaporated under reduced pressure to yield the title compound as a yellowish solid.

Yield: 130 mg (95%). Mp.: 256-257°C. IR (KBr): 3447 br, w; 3062w; 2426w; 1709m; 1669m; 1624m; 1475m; 1440s; 1408w; 1323w; 1270s; 1211s; 1048s; 1017m; 910w; 801w; 759m; 698m; 642m. 1H-NMR (300 MHz, (CD3)2SO): 7.45-7.48 (m, 7 H, Harom, Cat., Harom, Ketal); 7.54-7.58 (m, 6 H, Harom, Ketal, Harom, Pyr.); 7.73 (s, 1H, Harom, Cat.); 8.77 (d, J = 4.5, 2 H, Harom,Pyr.). 13C-NMR (75 MHz, (CD3)2SO): 111.8;112.9; 118.9; 122.4; 125.8; 127.9; 128.6; 129.5; 129.8; 138.2; 144.2; 148.4; 149.8; 151.1; 163.9; 192.1. HR-MS (MALDI): calcd. for C26H19NO5 ([M+2H]+): 425.1263, found 425.1254.

c) 2,2. Diphenyl-6-(pyridine-4-carbonyl)-benzo [1,3] dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Diphenyl-6-(pyridine-4-carbonyl)-1,3-benzodioxole-4-carboxylic acid (100 mg, 0.236 mmol, 1 eq.), EDC·HCl (68 mg, 0.354 mmol, 1.5 eq.), N-hydroxy-succinimid (36 mg, 0.307 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro [3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (72 mg, 0.215 mmol, 0.9 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 98 mg (62%). Colorless foam. Mp.: 122-126°C. IR (KBr): 3427m; 1661s; 1596m; 1528m; 1472m; 1435m; 1374w; 1266s; 1208s; 1019w; 867w, 780w; 759w; 700w; 647w. 1H-NMR (300 MHz, CDCl3):1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.07 (m, 2 H, H-C(7'), H-C(7")); 4.72 (m, 1 H, H-C(4')); 4.93 (dd; J= 6.3, 3.6, 1H, H-C(3')); 5.40 (dd, J = 6.3, 2.0, 1H, H-C(2')); 5.83 (m, 2 H, H-C(5'), H-C(6')); 6.10 (d, J= 2.0, 1H, H-C(1')); 6.55 (bs, 2 H, NH2); 7.10 (t, J= 5.4, 1 H, NHCO); 7.39-7.45 (m, 6 H, Harom, Ketal); 7.51-7.55 (m, 6 H, H-Carom, Ketal, Harom, pyridyl); 7.65 (d, J = 1.8, 1 H, Harom, Cat.); 7.92 (s, 1 H, H-C(8)); 8.03 (d, J =1.8, Harom,Cat.); 8.29 (s, 1 H, H-C(2)); 8.79 (dd, J= 4.5, 1.8, 2 H, Harom, pyridyl). 13C-NMR (75 MHz, CDCl3): 25.5; 27.2; 41.0; 84.2; 84.4; 87.2; 90.4; 111.8; 114.6; 114.7; 120.0; 120.4; 122.6; 126.3; 128.0; 128.6; 130.1; 130.3; 130.8; 137.9; 138.0; 140.2; 144.3; 148.4; 148.9; 149.1; 150.3; 151.0; 154.4;162.1; 193.0. HR-MS (MALDI): calcd. for C41H36N7O7 ([M+H]+): 738.2676, found 738.2677.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(pyridine-4-carbonyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (50 mg, 0.068 mmol) afforded the desired product as a yellowish solid.

Yield: 18 mg (50%). tR,analyt.: 10.9 min. IR (KBr): 3385 br, s; 1678s; 1637s; 1432w; 1307m; 1201s; 1132m; 1051w; 835w; 723w. 1H-NMR (500 MHz, CD3OD): 3.94 (d, J = 3.7,2 H, H-C(7'), H-C(7")); 4.13 (t, J= 5.3, 1H, H-C(4')); 4.39 (t, J= 5.3, 1H, H-C(3')); 4.64 (t, J = 4.8,1 H, H-C(2')); 5.82 (m, 2 H, H-C(5'), H-C(6')); 5.93 (d, J= 4.8, 1H, H-C(1')); 7.37 (d, J = 2.1,1 H, Harom, Cat.); 7.57 (dd, J = 4.6,1.6,2 H, Harom, Pyr.); 7.71 (d, J = 2.1, 1H, Harom, cat.); 8.12 (s, 1H, H-C(8)); 8.22 (s, 1 H, H-C(2)); 8.65 (dd, J= 4.6,1.6,2 H, Harom, Pyr.). 13C-NMR (125 MHz, CD3OD): 41.7; 75.1; 75.6; 85.9; 90.5; 116.7; 119.6; 120.7; 123.5; 124.5; 127.9; 130.5; 130.7; 142.5; 147.7; 148.1; 150.3; 150.4; 150.5; 155.1; 155.7; 170.2; 194.7. HR-MS (MALDI): calcd. for C25H24N7O7 ([M+H]+): 534.1737, found 534.1729.

Example 6 Preparation of N1-{(E)-3-((3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-cydohexanecarbonyl-2,3-dihydroxy-benzamide a) 6-Cyclohexanecarbonyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1.26 g, 3.16 mmol, 1 eq.), LiOMe (240 mg, 6.32 mmol, 2 eq.) and cyclohexanecarboxylic acid methoxy-methylamide (650 mg, 3.8 mmol, 1.2 eq.) as the electrophile were reacted according to GP4, Method A. The crude product was purified using flash chromatography (silica gel, hexane/Et2O/AcOH 5:1:0.1) and subsequent recrystallization from CH2Cl2 / hexane to give the title compound as a yellowish solid.

Yield: 338 mg (25%). Mp.: 212-214°C. IR (KBr): 3062w; 2932m; 2854m; 1693s; 1628w; 1448s; 1250s; 1205s; 1155m; 1042m; 1020m; 988m; 948m; 875w; 752m; 695s. 1H-NMR (300 MHz, CDCl3): 1.26-1.52 (m, 6 H, CH2,cyclohexyl); 1.72-1.86 (m, 4H, CH2,cyclohexyl); 3.24 (m, 1 H, CHCO); 7.38-7.45 (m, 6 H, Harom, Ketal); 7.59-7.65 (m, 4H, Harom,Ketal); 7.70 (d, J = 1.7, 1H, Harom, Cat.); 8.16 (d, J = 1.7,1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 25.9; 26.0; 29.7; 45.4; 110.9; 112.1; 119.8; 125.4; 126.3; 128.4; 129.6; 130.7; 138.8; 149.3; 152.4; 168.8; 201.2. HR-MS (MALDI): calcd. for C27H25O5 ([M+H]+): 429.1702, found 429.1693.

b) 6-Cyclohexanecarbonyl-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Diphenyl-6-cyclohexanecarbonyl-1,3-benzodioxole-4-carboxylic acid (197 mg, 0.46 mmol, 1 eq.), EDC·HCl (133 mg, 0.69 mmol,1.5 eq.), N-hydroxy-succinimide (70 mg, 0.6 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro [3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine (130 mg, 0.391 mmol, 0.85 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 145 mg (50%). Colorless foam. Mp.: 120-122°C. IR (KBr): 3428 br, m; 2931m; 2853w; 1667s; 1636s; 1596m; 1529m; 1473m; 1433m; 1376w; 1252s; 1209s; 1154w; 1082m; 1049m; 1018w; 867w; 777w; 699w. 1H-NMR (300 MHz, CDCl3): 1.24-1.52 (m, 9 H, CH3-exo, CH2,cyclohexyl); 1.62 (s, 3 H, CH3-endo); 1.70-1.86 (m, 4 H, CH2,cyclohexyl); 3.70 (m, 1 H, CHCO); 4.07 (m, 2 H, H-C(7'), H-C(7")); 4.70 (m, 1 H, H-C(4')); 4.96 (dd; J= 6.5, 3.9, 1 H, H-C(3')); 5.45 (dd, j= 6.5, 2.1, 1H, H-C(2')); 5.86 (m, 2 H, H-C(5'), H-C(6')); 5.92 (bs, 2 H, NH2); 6.09 (d, J= 2.1, 1H, H-C(1')); 7.11 (t, J= 5.4, 1H, NHCO); 7.36-7.41 (m, 6 H, Harom, Ketal); 7.48-7.52 (m, 4 H, H-Carom, Ketal,); 7.65 (d, J = 1.5, 1 H, H-Carom, Cat); 7.87 (s, 1H, H-C(8)); 8.22 (s,1 H, H-C(2)); 8.24 (d, J = 1.5, H-Carom, Cat).13C-NMR (75 MHz, CDCl3): 25.4; 25.8; 26.0; 27.2; 29.6; 40.9; 45.3; 84.1; 84.4; 87.1; 90.2; 110.9; 114.4; 114.7; 119.7; 120.1; 124.6; 126.3; 128.4; 129.8; 130.4; 131.5; 138.1; 138.2; 139.9; 148.0; 148.1; 149.2; 152.0;154.8; 162.5; 201.8. HR-MS (MALDI): calcd. for C42H43N6O7 ([M+H]+): 743.3193, found 743.3195. Anal. calcd. for C42H42N6O5: C 67.91, H 5.70, N 11.31 found C 67.77, H 5.85, N 11.05.

c) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (60 mg, 0.081 mmol) afforded the desired product as a colorless solid.

Yield: 25 mg (59%). tR, analyt.: 14.5 min (linear gradient of CH3CN in H2O with 0.1% TFA 15 → 55% in 20 min.) IR (KBr): 3388 br, s; 2933m; 1700s; 1638s; 1543w; 1430w; 1326m; 1295m; 1202s; 1130m; 1048w; 837w; 801w; 724w. 1H-NMR (500 MHz, CD3OD): 1.23-1.29 (m, 1 H, 3.94 CH2,cyclohexyl); 1.38-1.50 (m, 4 H, CH2,cyclohexyl); 1.72-1.83 (m, 5 H, CH2,cyclohexyl); 3.35 (t, J = 1.6, 1 H, CHCO); 4.08 (d, J = 3.3, 2 H, H-C(7'), H-C(7")); 4.25 (t, J = 5.0, 1 H, H-C(4')); 4.52 (t, J = 5.0, 1 H, H-C(3')); 4.74 (t, J= 4.7,1 H, H-C(2')); 5.96 (m, 2 H, H-C(5'), H-C(6')); 6.04 (d, J= 4.7, 1 H, H-C(1')); 7.53 (d, J = 2.0, 1 H, H-Carom, Cat.); 8.02 (d, J = 2.0, 1 H, Harom, Cat.); 8.23 (s, 1 H, H-C(8)); 8.34 (s, 1 H, H-C(2)). 13C-NMR (125 MHz, CD3OD): 26.8; 27.1; 30.8; 41.7; 46.0; 75.1; 75.6; 86.0; 90.5; 116.4; 118.5; 120.7; 128.6; 130.5; 130.9; 142.8; 147.8; 149.7; 150.3; 154.7; 154.9; 170.7; 204.6. HR-MS (MALDI): calcd. for C26H31N6O7 ([M+H]+): 539.2254, found 539.2244.

Example 7 Preparation of N1-[(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-chloro-2,3-dihydroxy-benzamide a) Methyl 5-chloro-2,3-dihydroxy-benzoate

5-Chloro-2,3-dihydroxybenzoic acid (290 mg, 1.54 mmol, 1 eq.) and SOCl2 (550 mg, 4.61 mmol, 3 eq.) were reacted according to GP1.

Yield: 250 mg (80%). Gray powder. IR (KBr): 3453s; 3096m; 2960m; 1700s; 1673s; 1471s; 1437s; 1316s; 1233s; 1202s; 1152s; 1013m; 932m; 863m; 788m; 723m. 1H-NMR (300 MHz, CDCl3): 3.96 (s, 3 H, OCH3); 5.73 (bs, 1 H, OH); 7.10 (d, J= 2.1, 1H, Harom, Cat.); 7.35 (d, J = 2.1, 1H, Harom, Cat); 10.84 (s, 1H, OH). 13C-NMR (75 MHz, CDCl3): 52.8; 112.7; 119.7; 120.0; 124.1; 145.7; 147.6; 169.7. HR-MS (EI): calcd. for C8H7ClO4 ([M+H]+): 202.0033, found 201.9774.

b) Methyl 6-chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 5-chloro-2,3-dihydroxy-benzoate (330 mg,1.63 mmol, 1 eq.) and dichlorodiphenyl-methane (470 mg, 1.96 mmol,1.2 eq.) were reacted according to GP2, Method B.

Yield: 310 mg (52%). Colorless solid. Mp.: 151-152°C. IR (KBr): 3086w; 2947w; 1719s (CO); 1595w; 1468s 1445m; 1360m; 1277m; 1245s; 1202s; 1166m; 1042m; 1014m; 905w; 866w; 806m; 781m; 762m; 696m. 1H-NMR (300 MHz, CDCl3): 3.94 (s, 3 H, CH3); 7.00 (d,j = 2.1, 1H, Harom, Cat.); 7.38-7.40 (m, 6 H, Harom, Ketal, Harom, Cat.); 7.56-7.59 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 52.6; 111.1;113.3;119.4; 122.3;126.3;126.6; 128.6; 129.7; 139.4; 147.4; 149.3; 164.2. HR-MS (MALDI): calcd. for C21H16ClO4 ((M+H]+): 367.0737, found 367.0731. Anal. calcd. for C21H15ClO4: C 68.77, H 4.12, found C 68.64, H 4.29.

c) 6-Chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (150 mg, 0.408 mmol, 1 eq.) and LiOH·H2O (52 mg, 1.23 mmol, 3 eq.) were reacted according to GP3.

Yield: 117 mg (82%). Colorless solid. Mp.: 206-207°C. IR (KBr):. 3071m; 2868m; 2616w; 1704s (CO); 1599w; 1469s; 1450m; 1407w; 1350w; 1284m; 1267m; 1238s; 1200s; 1044m; 1022m; 949w; 908w; 859w; 799m; 761m; 698m; 642w. 1H-NMR (300 MHz, CDCl3): 7.05 (d, J = 2.1, 1H, Harom, Cat.); 7.39-7.42 (m, 6 H, Harom, Ketal); 7.46 (d, J = 2.1, 1 H, Harom, Cat.); 7.58-7.61 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 112.3; 114.1; 119.9; 122.6; 126.5; 126.6; 128.7; 129.8; 139.2; 148.1; 149.5; 168.5. HR-MS (MALDI): calcd. for C20H14ClO4 ([M+H]+): 353.0581, found 353.0576.

d) 6-Chloro-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3] dioxol-4-yl]-prop-2-enyl}-amide

6-Cloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (90 mg, 0.255 mmol, 1 eq.), EDC-HCl (75 mg, 0.383 mmol, 1.5 eq.), N-hydroxy-succinimide (40 mg, 0.332 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3] di-oxol-4-yl}-9H-purin-6-amine (85 mg, 0.255 mmol, 1 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 123 mg (73%). Colorless foam. Mp.: 111-113°C. IR (KBr):. 3424m; 3176m; 2986m; 1638s; 1595s; 1530m; 1462s; 1374m; 1329m; 1240s; 1208s; 1156w; 1083m; 1047m; 1017m; 971w; 867w; 778w, 698m. 1H-NMR (300 MHz, CDCl3): 1.37 (s, 3 H, CH3-exo); 1.61 (s, 3 H, CH3-end); 4.04 (m, 2 H, H-C(7'), H-C(7")); 4.69 (m, 1H, H-C(4')); 4.94 (dd; J= 6.3, 3.6, 1H, H-C(3')); 5.44 (dd, J=6.3, 2.1, 1H, H-C(2')); 5.83 (m, 2 H, H-C(5'), H-C(6')); 6.05 (bs, 2 H, NH2); 6.08 (d, J = 2.1, 1H, H-C(1')); 7.00 (d, J = 2.1, 1 H, Harom, Cat.); 7.06 (t, J = 5.7, 1 H, NHCO); 7.35-7.40 (m, 6 H, Harom, Ketal); 7.44-7.50 (m, 4 H, H-C(6), Harom, Ketal); 7.56 (d, J = 2.1, 1 H, Harom, Cat.); 7.87 (s, 1 H, H-C(8)); 8.19 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.6; 27.4; 41.0; 84.4; 84.7; 87.4; 90.5; 112.8; 115.0;116.1; 119.8; 120.2; 122.3; 126.6; 127.6; 128.6; 128.8; 130.2; 130.8; 138.7; 140.4; 143.9; 148.3; 149.5; 152.2; 155.1; 162.5. HR-MS (MALDI): calcd. for C35H32ClN6O6 ([M+H]+): 667.2072, found 667.2065.

e) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-chloro-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (70 mg, 0.105 mmol) afforded the desired product as a colorless solid.

Yield: 35 mg (73%). tR, analyt : 13.1 min. IR (KBr): 3396 br, s; 1700s; 1636m; 1542w; 1469w, 1429w; 1326w, 1203s; 1135m; 1050w; 972w; 800w; 725w. 1H-NMR (500 MHz, (CD3)2SO): 3.93 (m, 2 H, H-C(7'), H-C(7")); 4.09 (t, J = 4.9, 1 H, H-C(4')); 4.35 (m; 1 H, H-C(3')); 4.64 (t, J = 5.1,1 H, H-C(2')); 5.78-5.89 (m, 2 H, H-C(5'), H-C(6')); 5.91 (d, J = 5.1, H-C(1')); 6.92 (d,J= 2.5,1 H, Harom, Cat.); 7.41 (d, J= 2.5,1 H, Harom, Cat); 8:12 (bs, 1 H, OH); 8.23 (s, 1 H, H-C(8)); 8.46 (s, H, H-C(2)); 9.02 (t, J = 5.4,1 H, H-NHCO); 12.62 (bs, 1 H, OH). 13C-NMR (125 MHz, CD3OD): 40.1; 73.0; 73.9; 84.3; 87.8; 115.7; 116.5; 118.3; 119.1; 121.7; 129.3; 129.4; 141.1; 147.6; 148.8; 148.9; 149.3; 153.4; 168.3. HR-MS (MALDI): calcd. for C19H20ClN6O6 ([M+H]+): 463.1132, found 463.1133.

Example 8 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-fluoro-phenyl)-2,3-dihydroxybenzamide a) Methyl 6-(4-fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (100 mg, 0.243 mmol, 1 eq.), Pd(PPh3)4 (15 mg, 0.012 mmol, 0.05 eq.), 4-fluorophenylboronic acid (135 mg, 0.972 mmol, 4 eq.) and K2CO3 (202g, 1.46 mmol, 6 eq.) were reacted according to GP5.

Yield: 80 mg (78%). Colorless solid. Mp.: 125-127°C. IR (KBr): 3061m; 2950m; 1723s (CO); 1634w; 1603m; 1517m; 1472s; 1364m; 1257s; 1215s; 1053s; 947m; 833s; 780m; 698s; 640m. 1H-NMR (300 MHz, CDCl3): 3.97 (s, 3 H, CH3); 7.10 (tt, J = 8.7, 2.0, 2 H, Harom, p-F-phenyl); 7.20 (d, J= 2.0, 1 H, Harom,cat); 7.39-7.42 (m, 6 H, Harom, Ketal); 7.45-7.50 (m, 2 H, Harom, p-F-phenyl); 7.59 (d, J = 2.0, 1H), Harom, Cat); 7.62-7.65 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 52.2;111.1; 112.7; 115.6 (d, J = 21.2);118.4; 121.1; 126.3; 128.2; 128.3; 129.2; 134.0; 136.0; 139.4; 147.4; 148.8; 162.2 (d, J= 244.7); 164.8. 19F-NMR (282 MHz, CDCl3): -115.9 (tt, J = 9.6, 5.4). HR-MS (MALDI): calcd. for C27H19FO4 ([M]+): 426.1267, found 426.1258.

b) 6-(4-Fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-(4-fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (250 mg, 0.586 mmol, 1 eq.) and LiOH·H2O (74 mg, 1.76 mmol, 3 eq.) were reacted according to GP3.

Yield: 214 mg (89%). Colorless solid. Mp.: 215-217°C. IR (KBr): 3032m; 2625w; 1687s (CO); 1635w; 1604m; 1519m; 1473s; 1422m; 1355w; 1281s; 1219s; 1179m; 1055s; 1022s; 948m; 918w; 832s; 784m; 756m; 699s; 641m. 1H-NMR (300 MHz, CDCl3): 7.10 (t, J = 8.7, 2 H, Harom, p-F-phenyl); 7.26 (d, J = 1.0, 1 H, Harom, Cat.); 7.39-7.43 (m, 6 H, Harom, Ketal); 7.46-7.51 (m, 2 H, Harom, p-F-phenyl); 7.63-7.66 (m, 5 H, Harom, Ketal, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 111.7; 112.0; 115.7 (d, J = 21.2); 118.9; 121.6; 126.3; 128.3; 128.4; 129.4; 134.3; 135.9 (d, J= 3.1); 139.3; 148.1; 149.0; 162.3 (d, J= 245.3); 169.0. 19F-NMR (282 MHz, CDCl3): -115.7 (tt, J= 8.5, 5.4). HR-MS (MALDI): calcd. for C27H19FO4Na ([M+Na]+): 435.1009, found 435.1000.

c) 6-(4-Fluoro-phenyl)-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3] dioxol-4-yl]-prop-2-enyl}-amide

6-(4-Fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (130 mg, 0.315 mmol, 1 eq.), EDC·HCl (91 mg, 0.473 mmol,1.5 eq.), N-hydroxy-succinimide (48 mg, 0.409 mmol, 1.3 eq.), 9-1(3aR,4R,6R,6a.R)-6-[(E)-3-aminoprop-1-enyll-2,2-dimethylperhydrofuro[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (90 mg, 0.271 mmol, 0.86 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 130 mg (66%). Colorless foam. Mp.: 123-125°C. IR (KBr): 3425m; 3175w; 2987w; 1636s; 1598m; 1517m; 1469s; 1373w; 1274m; 1213s; 1158w; 1082m; 1052m; 1016w; 867w; 834w; 777w; 699m. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.08 (m, 2 H, H-C(7'), H-C(7")); 4.71 (m, 1 H, H-C(4')); 4.95 (dd; J= 6.6, 3.6,1 H, H-C(3')); 5.44 (dd, J= 6.6, 2.3, 1H, H-C(2')); 5.87 (m, 2 H, H-C(5'), H-C(6')); 5.93 (bs, 2 H, NH2); 6.09 (d, J = 2.3, 1 H, H-C(1')); 7.10 (tt, J = 8.7, 2.1, 2 H, Harom, p-F-phenyl); 7.12 (t, J = 5.6, 1 H, NHCO); 7.22 (d, J = 1.8, 1 H, H-Carom, Cat.); 7.37-7.41 (m, 6 H, Harom, Ketal); 7.47-7.56 (m, 6 H, Harom, Ketal, Harom, p-F-phenyl); 7.77 (d, J = 1.8, Harom, Cat.); 7.87 (s, 1 H, H-C(8)); 8.19 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.5; 27.3; 40.9; 84.1; 84.5; 87.1; 90.3; 110.6; 114.7; 115.3; 115.6 (d, J = 21.2); 118.8; 120.1; 121.0; 126.4; 128.2; 128.4; 128.5; 129.7; 130.7; 135.0; 136.1; 138.7; 139.9;144.1; 147.8; 149.2; 152.0; 154.8; 162.3 (d, J = 244.7); 163.1. 19F-NMR (282 MHz, CDCl3): -115.9 (tt, J = 8.5, 5.4). HR-MS (MALDI): calcd. for C41H35FN6O6Na ([M+Na]+): 749.2500, found 749.2501.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-fluoro-phenyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (70 mg, 0.096 mmol) afforded the desired product as a colorless solid.

Yield: 28 mg (56%). tR, analyt.: 17.8 min. IR (KBr): 3407 br, s; 1700s; 1641m; 1542w, 1479w; 1314w; 1204s; 1137m; 1050w; 835w; 801w; 725w. 1H-NMR (500 MHz, CD3OD): 4.07 (m, 2 H, H-C(7'), H-C(7")); 4.24 (t, J = 5.3, 1H, H-C(4')); 4.52 (t, J = 5.3, 1H, H-C(3')); 4.73 (t, J = 4.8, 1H, H-C(2')); 5.96 (bd, J = 3.3, 2 H, H-C(5'), H-C(6')); 6.05 (d, J = 4.8,1 H, H-C(1')); 7.13 (t, J = 8.8, 2 H, Harom, p-F-phenyl); 7.20 (d, J = 2.0, 1H, H-Carom,Cat.); 7.51 (d, J = 2.0, 1H, Harom, Cat.); 7.58 (dd, J = 8.8, 5.4, 2 H, Harom, p-F-phenyl); 8.23 (s, 1H, H-C(8)); 8.37 (s, 1 H, H-C(2)). 13C-NMR (125 MHz, CD3OD): 41.7; 75.2; 75.6; 86.1; 90.5; 116.4 (d, J = 21.3); 117.0; 117.1; 118.2; 129.3; 129.4; 130.3; 131.0; 132.3; 138.1; 143.0; 147.8; 149.0; 152.6; 149.8; 163.6 (d, J = 242.5); 171.2. HR-MS (MALDI): calcd. for C25H24FN6O6 ([M+H]+): 523.1741, found 523.1731.

Example 9 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-p-tolyl-2,3-dihydroxy-benzamide a) Methyl 2,2-diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (500 mg, 1.215 mmol, 1 eq.) Pd(PPh3)4 (70 mg, 0.06 mmol, 0.05 eq.), p-tolylboronic acid (330 mg, 2.43 mmol, 2 eq.) and K2CO3 (1g, 7.29 mmol, 6 eq.) were reacted according to GP5.

Yield: 403 mg (79%). Colorless solid. Mp.: 159-160°C. IR (KBr): 3034w; 2941w; 1719s; 1470s; 1450s; 1429m; 1363w; 1255s; 1209s; 1161m; 1053s; 1028s 944w; 817m; 775m; 702s; 640m. 1H-NMR (300 MHz, CDCl3): 2.38 (s, 3 H, CH3); 3.97 (s, 3 H, OCH3); 7.22 (d, J = 7.8, 2 H, Harom, p-tolyl); 7.26 (d, J = 1.8, 1H, Harom, Cat.); 7.38-7.44 (m, 8 H, Harom, p-tolyl, Harom, Ketal); 7.62-7.66 (m, 5 H, Harom, Cat., Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 21.2; 52.2; 111.1; 112.7; 118.2; 121.0; 126.3; 126.6; 128.2; 129.2; 129.4; 135.0; 136.9; 137.0; 139.6; 147.3; 148.7; 164.9. HR-MS (MALDI): calcd. for C28H22O4Na ([M+Na]+: 445.1416, found 445.1406.

b) 2,2-Diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylate (280 mg, 0.662 mmol, 1 eq.) and LiOH·H2O (84 mg, 2 mmol, 3 eq.) were reacted according to GP3.

Yield: 251 mg (93%). Colorless solid. Mp.: 223-224°C. IR (KBr): 3030m; 2624m; 1684s (CO); 1634m; 1602w; 1473s; 1421m; 1355w; 1282s; 1213s; 1055s; 1023s; 947m; 918w; 871w; 814m; 784m; 758m; 699s; 640m. 1H-NMR (300 MHz, CDCl3): 2.39 (s, 3 H, CH3); 7.23 (d, J= 7.8, 2 H, Harom, p-tolyl); 7.31 (d, J = 1.8, 1 H, Harom, Cat.); 7.39-7.45 (m, 8 H, Harom, Ketal, Harom, p-tolyl); 7.64-7.67 (m, 4 H, Harom, Ketal); 7.71 (d, J = 1.8, 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 21.1; 111.8; 112.0; 118.7; 121.5; 126.4; 126.7; 128.4; 129.4; 129.5; 135.3; 136.9; 137.2; 139.5; 148.0; 149.0; 169.4. HR-MS (MALDI): calcd. for C27H20O4Na ([M+Na]+): 431.1259, found 431.1259.

c) 2,2-diphenyl-6-p-tolyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylic acid (164 mg, 0.4 mmol, 1 eq.), EDC·HCl (115 mg, 0.6 mmol, 1.5 eq.), N-hydroxy-succinimide (60 mg, 0.52 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (90 mg, 0.271 mmol, 0.68 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 111 mg (57%). Colorless foam. Mp.: 124-126°C. IR (KBr): 3423m; 3176m; 2986w; 1638s; 1597s; 1531m; 1469s; 1434m; 1373w; 1329w; 1276s; 1207s; 1156w; 1081m; 1052s; 1016m; 970w; 867m; 818m; 777m; 699m; 641m. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 2.37 (s, 3 H, CH3); 4.09 (m, 2 H, H-C(7'), H-C(7")); 4.71 (m, 1 H, H-C(4')); 4.94 (dd; J= 6.5, 3.6, 1 H, H-C(3')); 5.42 (dd, J= 6.5, 2.6, 1 H, H-C(2')); 5.86 (m, 2 H, H-C(5'), H-C(6')); 6.06 (bs, 2 H, NH2); 6.09 (d, J = 2.6, 1 H, H-C(1')); 7.17 (t, J = 5.6, 1 H, NHCO); 7.21 (d, J = 8.3, 2 H, Harom, p-tolyl); 7.26 (d, J = 1.8, 1 H, Harom, Cat.); 7.36-7.42 (m, 6 H, Harom, Ketal); 7.46 (d, J = 8.3, 2 H, Harom, p-tolyl); 7.51-7.56 (m, 4 H, Harom, Ketal); 7.82 (d, J = 1.8, H-Carom, Cat.); 7.88 (s, 1 H, H-C(8)); 8.19 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.2; 25.5; 27.2; 40.8; 84.1; 84.4; 87.1; 90.3; 110.5; 114.7; 115.2; 118.6; 120.0; 120.8; 126.4; 126.6; 128.0; 128.3; 129.4; 129.6; 130.8; 135.9; 136.0; 137.0; 138.8; 140.0; 143.8; 147.7; 149.1; 151.5;154.6; 163.2. HR-MS (MALDI): calcd. for C42H38N6O6Na ([M+Na]+): 745.2751, found 745.2750. Anal. calcd. for C42H38N6O6: C 69.79, H 5.30, N 11.63, found C 69.61, H 5.56, N 11.93.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-p-tolyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (70 mg, 0.097 mmol) afforded the desired product as a colorless solid.

Yield: 28 mg (56%). tR, analyt.: 18.3 min. IR (KBr): 3397 br, s; 1700s; 1640m; 1541w; 1478w; 1430w; 1319w; 1203s; 1137m; 1050w; 973w; 799w; 725w. 1H-NMR (500 MHz, (CD3)2SO): 3.97 (m, 2 H, H-C(7'), H-C(7")); 4.10 (t, J= 4.9,1 H, H-C(4')); 4.37 (t; J= 4.9, 1H, H-C(3')); 4.64 (t, J= 5.1,1 H, H-C(2')); 5.83-5.90 (m, 2 H, H-C(5'), H-C(6')); 5.91 (d, J = 5.1, H-C(1')); 7.20 (d, J= 1.9,1 H, Harom,Cat.); 7.22 (d, J= 8.0, 1 H, Harom, p-tolyl); 7.51 (d, J= 8.0, 1 H, Harom, p-tolyl); 7.63 (d, J = 1.9, 1 H, Harom,Cat.); 8.12 (bs, 1 H, OH); 8.23 (s, 1 H, H-C(8)); 8.47 (s, 1H, H-C(2)); 9.16 (t, J = 5.5, 1H, H-NHCO); 12.79 (bs, 1 H, OH). 13 C-NMR (125 MHz, (CD3)2SO): 20.6; 40.1; 73.0; 73.9; 84.2; 87.7; 114.8; 114.9; 116.8; 119.0; 125.9; 129.3; 129.5; 130.1; 136.0; 136.7; 141.0; 146.5; 148.9; 149.2; 149.4; 153.5; 169.6. HR-MS (MALDI): calcd. for C26H26N6O6Na ([M+Na]+): 541.1812, found 541.1810.

Example 10 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-thiazol-2-yl-2,3-dihydroxy-benzamide a) Methyl 2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (250 mg, 0.608 mmol, 1 eq.) Pd(PPh3)4 (70 mg, 0.06 mmol, 0.1 eq.), bis(pinacolato)diboron (200 mg, 0.79 mmol, 1.3 eq.) and KOAc (90 mg, 0.912 mmol, 1.5 eq.), then Pd(PPh3)4 (70 mg, 0.06 mmol, 0.1 eq.), 2-bromo-thiazole (110 mg, 0.67 mmol, 1.1 eq.) and K2CO3 (420 mg, 3.04 mmol, 5 eq.) were used according to GP6 to yield the title product as a colorless solid.

Yield: 166 mg (66%). Mp.: 154-155°C. IR (KBr): 3054w; 2947w, 1712s (CO); 1627w; 1497w, 1468s; 1447s; 1359m; 1321w, 1286m; 1254s; 1212s; 1047s; 1017s; 944w; 929w, 883w; 801m; 781m; 760m; 699s; 641m. 1H-NMR (300 MHz, CDCl3): 3.97 (s, 3 H, OCH3); 7.28 (d, J = 3.2, 2 H, Harom, thiazolyl); 7.37-7.42 (m, 6 H, Harom, Ketal); 7.60-7.63 (m, 4 H, Harom, Ketal); 7.71 (d, J = 2.3, 1H, Harom, Cat.); 7.81 (d, J = 3.2, 2 H, Harom, thiazolyl); 8.01 (d, J = 2.3, 1H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 52.5; 110.4; 113.1; 118.9; 119.4; 122.2; 126.6; 127.8; 128.6; 129.7; 139.5; 143.5; 149.4; 149.9; 164.6; 167.4. HR-MS (MALDI): calcd. for C24H18NO4S ([M+H]+): 416.0957, found 416.0947.

b) 2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylate (300 mg, 0.722 mmol, 1 eq.) and LiOH·H2O (91 mg, 2.17 mmol, 3 eq.) were reacted according to GP3.

Yield: 280 mg (96%). Colorless solid. Mp.: 226-227°C. IR (KBr): 3122w; 2924w; 1702m (CO); 1629w; 1477s; 1446s; 1319w; 1266s; 1235m; 1213s; 1133s; 1048m; 1018m; 948w; 909w; 851w; 792m; 762w; 720w; 699m; 641w. 1H-NMR (300 MHz, (CD3)2SO): 7.46-7.50 (m, 6 H, Harom, Ketal); 7.34-7.57 (m, 4 H, Harom, Ketal); 7.76 (d, J= 3.0, 2 H, Harom, thiazolyl); 7.78 (d. J = 1.8, 1 H, Harom, Cat.); 7.89 (d, J = 3.0, 2 H, Harom, thiazolyl); 7.92 (d, J = 1.8, 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 109.7; 113.8; 118.3; 120.4; 121.3; 125.9; 127.3; 128.7; 129.7; 138.7; 143.7; 148.4; 148.5; 164.4; 165.7. HR-MS (MALDI): calcd. for C23H16NO4S ([M+H]+): 402.0800, found 402.0794.

c) 2,2-diphenyl-6-thiazol-2-yl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylic acid (160 mg, 0.4 mmol, 1 eq.), EDC·HCl (115 mg, 0.6 mmol, 1.5 eq.), N-hydroxy-succinimide (60 mg, 0.52 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (100 mg, 0.3 mmol, 0.75 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 158 mg (74%). Colorless foam. Mp.: 132°C. IR (KBr): 3424m; 3199w; 2987w; 1639s; 1598m; 1532m; 1471m; 1440m; 1374w; 1329w; 1263m; 1212s; 1156w; 1081m; 1050m; 1015m; 867w; 779w; 700m; 643w. 1H-NMR (300 MHz, CDCl3):1.39 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.08 (m, 2 H, H-C(7'), H-C(7")); 4.76 (m, 1H, H-C(4')); 4.93 (dd; J = 6.2, 3.0, 1 H, H-C(3')); 5.42 (dd, J = 6.2, 2.0,1 H, H-C(2')); 5.82 (m, 2 H, H-C(5'), H-C(6')); 6.10 (d, J= 2.0,1 H, H-C(1')); 6.63 (bs, 2 H, NH2); 7.12 (t, J= 5.7, 1 H, NHCO); 7.30 (d, J = 3.5, 2 H, Harom, thiazolyl); 7.37-7.43 (m, 6 H, H-Carom, Ketal); 7.50-7.54 (m, 4 H, Harom, Ketal); 7.73 (d, J = 1.7, 1 H, H-Carom, Cat.); 7.81 (d, J = 3.5, 2 H, Harom, thiazolyl); 7.92 (s, 1 H, H-C(8)); 8.14 (d, J = 1.7, H-Carom, Cat.); 8.20 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.4; 27.1; 40.9; 84.3; 84.4; 87.3; 90.7; 109.7; 114.6; 115.4; 119.0; 119.3; 119.9; 121.9; 126.4; 127.9; 128.4; 128.6; 129.8; 130.8; 138.4; 140.5; 143.3; 145.9; 148.0; 148.9; 149.5; 153.8; 162.6; 167.2. HR-MS (MALDI): calcd. for C38H33N7O6SNa ([M+Na]+): 738.2111, found 738.2095. Anal. calcd. for C42H38N6O6: C 63.76, H 4.65, N 13.70, found C 63.55, H 4.70, N 13.68.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-thiazol-2-yl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (80 mg, 0.112 mmol) afforded the desired product as a colorless solid.

Yield: 43 mg (75%). tR, analyt.: 13.1 min. IR (KBr): 3402 br, s; 1700s; 1642m; 1597m; 1552w; 1428w; 1318w; 1293w; 1200s; 1136m; 1050w; 837w; 800w; 723m. 1H-NMR (500 MHz, (CD3)2SO): 3.97 (m, 2 H, H-C(7'), H-C(7")); 4.10 (t, J= 4.9, 1H, H-C(4')); 4.37 (dd; J= 5.0, 4.9, 1H, H-C(3')); 4.63 (t, J= 5.0, 1H, H-C(2')); 5.82-5.91 (m, 2 H, H-C(5'), H-C(6')); 5.92 (d, J= 5.0, H-C(1')); 7.53 (d, J= 1.7, 1H, Harom, Cat.); 7.68 (d, J= 3.3, 1H, Harom, thiazolyl); 7.83 (d, J = 3.3, 1 H, Harom, thiazolyl); 7.92 (d, J = 1.7,1 H, Harom, Cat.); 8.52 (s, 1 H, H-C(8)); 8.56 (bs, 1 H, OH); 9.27 (t, J= 5.7,1 H, H-NHCO); 9.71 (s, 1 H, H-C(2)); 12.98 (bs, 1 H, OH). 13C-NMR (125 MHz, (CD3)2SO): 40.1; 73.2; 73.9; 84.3; 87.8; 115.5; 115.8; 115.9; 119.0; 119.6; 123.8; 129.3; 129.6; 141.4; 143.4; 146.8; 148.4; 148.8; 151.5; 152.7; 167.0; 168.9. HR-MS (MALDI): calcd. for C22H21N7O6SNa ([M+Na]+): 534.1172, found 534.1173.

Example 11 Preparation of N1-{(E)-3-[(3aR,4R,6Ri,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-benzothiazol-2-yl-2,3-dihydroxy benzamide a) Methyl 6-benzothiazol-2-yl-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (600 mg, 1.459 mmol,1 eq.), Pd(PPh3)4 (85 mg, 0.073 mmol, 0.05 eq.), bis(pinacolato)diboron (480 mg, 1.9 mmol, 1.3 eq.) and KOAc (216 mg, 2.2 mmol, 1.5 eq.), then Pd(PPh3)4 (85 mg, 0.073 mmol, 0.05 eq.), 2-bromo-1,3-benzothiazole (375 mg, 1.75 mmol, 1.2 eq.) and K2CO3 (1 g, 7.3 mmol, 5 eq.) were used according to GP6 to yield the title product as a colorless solid.

Yield: 274 mg (41%). Mp.: 184-185°C. IR (KBr): 3055w; 2950w; 1718s; 1635w; 1502w; 1446s; 1368m; 1297m; 1239s; 1212s; 1163m; 1047s; 1015s; 945m; 921m; 874m; 795m; 776s; 759s; 723w, 701s; 640m. 1H-NMR (300 MHz, CDCl3): 4.00 (s, 3 H, OCH3); 7.38-7.51 (m, 8 H, Harom, benzothiazole, Harom, Ketal); 7.62-7.64 (m, 4 H, Harom, Ketal); 7.86 (d, J= 1.7, 1 H, Harom, Cat.); 7.88 (d, J = 9.3, 1 H, Harom, benzothiazole); 8.04 (d, J = 9.3, 1 H, Harom, benzothiazole); 8.13 (d, J = 1.7, 1 H, Harom, Cat). 13C-NMR (75 MHz, CDCl3): 52.4; 110.6; 112.8; 119.3; 121.5; 122.9; 123.2; 125.1; 126.3; 127.5; 128.3; 129.4; 134.8; 139.1; 149.1; 150.2; 153.7; 164.1; 166.5. HR-MS (MALDI): calcd. for C28H20NO4S ([M+H]+): 466.1113, found 466.1113. Anal. calcd. for C28H19NO4S: C 72.24, H 4.11, N 3.01, found C 72.15, H 4.03, N 3.19.

b) 2,2-diphenyl-6-benzothiazol-2-yl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-benzothiazol-2-yl-1,3-benzodioxole-4-carboxylate (210 mg, 0.451 mmol, 1 eq.) and LiOH·H2O (57 mg, 1.35 mmol, 3 eq.) were reacted according to GP3.

Yield: 201 mg (99%). Colorless solid. Mp.: 227°C. IR (KBr): 3437w; 2965w; 2610w; 1738m; 1688s; 1634w; 1460s; 1427m; 1360w; 1256s; 1237s; 1211s; 1047s; 1048m; 1015m; 999m; 928w; 878w; 788m; 760m; 726m; 699m; 641w. 1H-NMR (300 MHz, CDCl3):7.36-7.44 (m, 7 H, Harom, benzothiazole, Harom, Ketal); 7.46-7.53 (m, 1 H, Harom, benzothiazole); 7.53-7.67 (m, 4 H, Harom, Ketal); 7.88 (d, J = 1.8, 1 H, Harom, Cat.); 7.89 (d, J = 8.7, 1 H, Harom, benzothiazole); 8.15 (d, J = 8.7, 1 H, Harom, benzothiazole); 8.28 (d, J = 1.8, 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 111.4; 112.2; 119.7; 121.5; 123.1; 123.7; 125.2; 126.3; 126.4; 127.5; 128.3; 129.5; 134.6; 138.9; 149.3; 150.9; 153.6; 166.6; 167.8. HR-MS (MALDI): calcd. for C27H18NO4S ((M+H]+): 452.0957, found 452.0955.

c) 6-Benzothiazol-2-yl-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo [3,4-d] [1,3] dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-benzothiazol-2-yl-1,3-benzodioxole-4-carboxylic acid (170 mg, 0.38 mmol, 1 eq.), EDC·HCl (110 mg, 0.565 mmol, 1.5 eq.), N-hydroxy-succinimide (57 mg, 0.49 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (100 mg, 0.3 mmol, 0.8 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 151 mg (66%). Colorless foam. Mp.: 138-140°C. IR (KBr): 3424m; 2982w; 1635s; 1596m; 1533m; 1463m; 1436s; 1373w; 1259m; 1208s; 1155w; 1081m; 1048m; 1011m; 867w; 759w; 699w; 641w. 1H-NMR (300 MHz, CDCl3):1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 4.07 (m, 2 H, H-C(7'), H-C(7")); 4.72 (m, 1 H, H-C(4')); 4.95 (dd; J = 6.3, 3.6, 1H, H-C(3')); 5.44 (dd, J = 6.3, 2.3, 1H, H-C(2')); 5.85 (m, 2 H, H-C(5'), H-C(6')); 6.09 (d. J = 2.3, 1 H, H-C(1')); 6.17 (bs, 2 H, NH2); 7.13 (t, J = 5.7, 1 H, NHCO); 7.34-7.49 (m, 8 H, Harom, Ketal, Harom, benzoth.); 7.49-7.55 (m, 4 H, Harom, Ketal); 7.87 (s, 1 H, H-C(8)); 7.88 (d, J = 7.8, 2 H, Harom, benzoth.); 7.91 (d, J= 1.9, 1 H, Harom, Cat.); 7.81 (d, J= 7.8, 2 H, Harom, benzoth.); 8.20 (s, 1 H, H-C(2)); 8.22 (d, J = 1.9, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 25.4; 27.2; 40.9; 84.1; 84.4; 87.2; 90.3; 110.1;114.6; 115.4; 119.5; 120.0; 121.5; 122.9; 123.2; 125.1; 126.2; 126.4; 128.3; 128.4; 128.6; 129.8; 130.5; 135.0; 138.3; 140.0; 146.7; 148.1; 149.1; 151.5; 153.7; 154.7; 162.4; 166.7. HR-MS (MALDI): calcd. for C42H35N7O6SNa ([M+Na]+): 788.2267, found 788.2266.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-benzothiazol-2-yl-2,3-dihydroxy benzamide

GP8, starting from the protected precursor (83 mg, 0.108 mmol) afforded the desired product as a yellowish solid.

Yield: 38 mg (64%). tR, analyt.: 17.7 min. IR (KBr): 3377 br, s; 1685s; 1645m; 1544w; 1436m; 1303m; 1202s; 1137m; 834w; 800w; 759w; 724w. 1H-NMR (500 MHz, (CD3)2SO: 4.01 (m, 2 H, H-C(7'), H-C(7")); 4.13 (t, J= 4.9, 1H, H-C(4')); 4.39 (dd; J= 6.7, 4.9, 1H, H-C(3')); 4.66 (t, J= 5.0, 1H, H-C(2')); 5.80-5.96 (m, 2 H, H-C(5'), H-C(6')); 5.93 (d, J= 5.0, H-C(1')); 7.43 (t, J=8.0, 1H, Harom,benzoth.); 7.53. (t, J= 8.0, 1H, Harom,benzoth.); 7.65. (d, J= 2.0, 1 H, Harom, Cat); 8.00 (d, J= 8.0, 1 H, Harom, benzoth.); 8.09 (d, J= 2.0, 1 H, Harom, Cat.); 8.12 (d, J = 8.0, 1H, Harom, benzoth.); 8.27 (s,1 H, H-C(8)); 9.37 (t, J= 5.3,1 H, H-NHCO); 9.86 (s,1 H, H-C(2));13.19 (bs, 1H, OH). 13C-NMR (125 MHz, (CD3)2SO): 40.1; 73.0; 73.9; 84.2; 87.7; 115.4; 115.5; 116.4; 119.1; 122.3; 122.4; 123.3; 125.2; 126.6; 129.4; 129.5; 134.4; 141.0; 147.0; 149.0; 149.1; 152.6; 153.3; 153.5; 167.0; 168.7. HR-MS (MALDI): calcd. for C26H23N7O6SNa ([M+Na]+): 584.1328, found 584.1330.

Example 12 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl{-5-pyridin-4-yl-2,3-dihydroxy-benzamide a) Methyl 2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (400 mg, 0.973 mmol, 1 eq.), Pd(PPh3)4 (100 mg, 0.087 mmol, 0.09 eq.), bis(pinacolato)diboron (320 mg, 1.26 mmol, 1.3 eq.) and KOAc (150 mg, 1.5 mmol, 1.5 eq.), then Pd(PPh3)4 (112 mg, 0.097 mmol, 0.1 eq.), 2-bromo-pyridine hydrochloride (265 mg, 1.36 mmol, 1.4 eq.) and K2CO3 (680 mg, 4.9 mmol, 5 eq.) were used according to GP6 to yield the title product as a colorless solid.

Yield: 264 mg (67%). Mp.: 151-152°C. IR (KBr): 3030w; 2954w; 1718s; 1635w; 1594m; 1475s; 1439s; 1418m; 1325m; 1291m; 1269s; 1225s; 1180m; 1054s; 1038m; 1018m; 947w; 927w; 886w; 815m; 782m; 753w; 703m; 693m; 641m. 1H-NMR (300 MHz, CDCl3): 3.98 (s, 3 H, OCH3); 7.31 (d, J=1.8,1 H, Harom, Cat.); 7.39-7.41 (m, 6 H, Harom, Ketal); 7.48 (dd, J = 4.7, 1.8, 1H, Harom, pyridyl); 7.61-7.64 (m, 4 H, Harom, Ketal); 7.75 (d, J = 1.7, 1H, Harom, Cat.); 8.63 (dd, J= 4.7, 1.8,1 H, Harom,pyridyl). 13C-NMR (75 MHz, CDCl3): 52.6; 110.9; 113.4; 119.4; 121.6; 122.3; 126.6; 128.6; 129.8; 131.7; 139.5; 148.0; 149.4; 149.7; 149.8 164.9. HR-MS (MALDI): calcd. for C26H20NO4 ([M+H]+): 410.1392, found 410.1383.

b) 2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylate (250 mg, 0.61 mmol,1 eq.) and LiOH·H2O (80 mg, 1.84 mmol, 3 eq.) were reacted according to GP3.

Yield: 220 mg (92%). Grayish solid. Mp.: 266°C (dec.). IR (KBr): 3446br, w; 3061w; 2447br, w; 1696m; 1632w; 1603m; 1469s; 1440m; 1373w; 1326w; 1273s; 1213s; 1182m; 1054s; 1015m; 949w; 921w; 906w; 832m; 789w, 777w; 765m; 701m; 640w. 1H-NMR (300 MHz, (CD3)2SO): 7.46-7.48 (m, 6 H, Harom, Ketal); 7.52-7.58 (m, 4 H, Harom, Ketal); 7.67 (d, J = 4.4,2 H, Harom, pyridyl); 7.73 (m, 2 H, Harom, Cat.); 8.59 (d, J = 4.4, 2 H, Harom, pyridyl). 13C-NMR (75 MHz, CDCl3): 110.7; 113.9; 117.9; 120.8; 121.6; 125.8; 128.6; 129.6; 131.1; 138.7; 145.6; 147.8; 148.5; 150.0; 164.6. HR-MS (MALDI): calcd. for C25H18NO4 ([M+H]+): 396.1236, found 396.1234.

c) 2,2-Diphenyl-6-pyridin-4-yl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo [3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

The reaction of 2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylic acid (160 mg, 0.405 mmol,1 1 eq.), EDC·HCl (117 mg, 0.608 mmol, 1.5 eq.), N-hydroxy-succinimide (61 mg, 0.527 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethyl-perhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine (100 mg, 0.3 mmol, 0.74 eq.) and Et3N (0.1 mL, 0.68 mmol) was carried out in CH2Cl2 / DMF 1:1 according to GP7.

Yield: 95 mg (45%). Yellowish foam. IR (neat, dropcast from CH2Cl2): 3321br, w; 2963m; 1696m; 1645m; 1597m; 1530w; 1468s; 1435w; 1374w; 1261s; 1213s; 1053s; 867w; 799m; 699m; 642w. 1H-NMR (300 MHz, CDCl3): 1.37 (s, 3 H, CH3-exo); 1.61 (s, 3 H, CH3-endo); 4.08 (m, 2 H, H-C(7'), H-C(7")); 4.70 (m, 1 H, H-C(4')); 4.96 (dd; J= 6.3, 3.9, 1H, H-C(3')); 5.45 (dd, J= 6.3, 2.3, 1 H, H-C(2')); 5.86 (m, 2 H, H-C(5'), H-C(6')); 5.98 (bs, 2 H, NH2); 6.08 (d, J= 2.3, 1H, H-C(1')); 7.16 (t, J= 5.7, 1H, NHCO); 7.31 (d, J= 1.7, 1 H, Harom, Cat.); 7.36-7.42 (m, 6 H, Harom,Ketal); 7.47-7.55 (m, 6 H, Harom,Ketal, Harom, pyridyl); 7.86 (s, 1H, H-C(8)); 7.92 (d, J= 1.7, 2 H, Harom, Cat.); 8.18 (s, 1H, H-C(2)); 8.61 (d, J= 6.3, Harom, pyridyl). 13C-NMR (75 MHz, CDCl3): 25.6; 27.4; 41.1; 84.3; 84.7; 87.4; 90.5; 110.4; 114.9; 116.0; 119.7; 120.4; 121.6; 122.0; 126.2; 126.7; 128.8; 130.2; 130.8; 132.8; 138.8; 140.1; 145.9; 147.6; 148.6; 149.6; 150.2; 153.0; 155.6; 163.1. HR-MS (MALDI): calcd. for C40H35N7O6Na ([M+Na]+): 732.2547, found 732.2549.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-S-pyridin-4-yl-2,3-dihydroaty benzamide

GP8, starting from the protected precursor (35 mg, 0.049 mmol) afforded the desired product as a yellowish solid.

Yield: 15 mg (63%). Mp.: 133-137°C (dec.). tR, analyt.: 10.6 min. IR (KBr): 3384 br, s; 1684s; 1633m; 1474w; 1431m; 1321m; 1202s; 1134m; 832w; 723w. 1H-NMR (500 MHz, (CD3)2SO): 4.02 (m, 2 H, H-C(7'), H-C(7")); 4.11 (t, J = 4.8, 1H, H-C(4')); 4.37 (m; 1 H, H-C(3')); 4.67 (t, J = 5.1, 1H, H-C(2')); 5.82-5.94 (m, 2 H, H-C(5'), H-C(6')); 5.91 (d, J = 5.1, H-C(1')); 7.52 (d, J = 1.8, 1H, Harom, Cat.); 7.85 (bs, 1 H, OH); 8.01 (d, J = 1.8, 1H, Harom, Cat.); 8.08 (d, J = 5.2, 1H, Harom, pyridyl); 8.17 (s, 1H, H-C(8)); 8.42 (s, 1 H, H-C(2)); 8.79 (d, J = 5.2, 1H, Harom, pyridyl); 9.23 (t, J = 5.5,1 H, H-NHCO); 9.69 (bs, 1H, OH); 13.35 (bs, 1H, OH). 13C-NMR (125 MHz, (CD3)2SO): 40.1; 72.9; 73.9; 84.1; 87.7; 115.2; 117.0; 117.2; 119.1; 121.8; 124.8; 129.1; 129.6; 140.7; 144.9; 147.3; 149.0; 150.3; 152.6; 154.2;169.2. HR-MS (MALDI): calcd. for C24H23N7O6Na ([M+Na]+): 528.1608, found 528.1607.

Example 13 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl]-5-(4-methyl-benzyl)-2,3-dihydroxybenzamide a) Methyl 2,2-diphenyl-6-(4-methyl-benzyl)-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (200 mg, 1.486 mmol, 1 eq.), Pd(PPh3)4 (57 mg, 0.049 mmol, 0.1 eq.), bis(pinacolato)diboron (160 mg, 0.632 mmol, 1.3 eq.) and KOAc (72 mg, 0.73 mmol, 1.5 eq.), then Pd(PPh3)4 (57 mg, 0.049 mmol, 0.1 eq.), 1-bromomethyl-4-methyl-benzene (117 mg, 0.63 mmol, 1.3 eq.) and K2CO3 (336 mg, 2.43 mmol, 5 eq.) were reacted according to GP6 to yield the title product as a colorless, very slowly solidifying oil.

Yield: 197 mg (80%). IR (neat): 3030w; 2950w; 1722s; 1636w; 1603w; 1477s; 1449s; 1381w; 1251s; 1202s; 1047s; 1019m; 948w; 918w; 829w; 782m; 763m; 699m; 642m. 1H-NMR (300 MHz, CDCl3): 2.32 (s, 3 H, CH3); 3.85 (s, 2H, CH2); 3.93 (s, 3H, OCH3); 6.83 (d, J = 1.8, 1 H, Harom, Cat.); 7.06 (d, J = 8.6, 2 H, Harom, p-Tol.); 7.10 (d, J = 8.6, 1 H, Harom, p-Tol.); 7.29 (d, J = 1.8, 1 H, Harom, Cat.); 7.35-7.38 (m, 6 H, Harom, Ketal); 7.57-7.60 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 21.0; 41.1; 52.0; 112.2; 113.1; 117.9; 122.3; 126.3; 128.2; 128.7; 129.1; 129.2; 134.9; 135.8; 137.5; 139.8; 146.6; 148.5; 165.2. HR-MS (MALDI): calcd. for C29H24O4Na ([M+Na]+): 459.1572, found 459.1573.

b) 2,2-diphenyl-6-(4-methyl-benzyl)-1,3 benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-(4-methyl-benzyl)-1,3-benzodioxole-4-carboxylate (300 mg, 0.69 mmol, 1 eq.) and LiOH·H2O (87 mg, 2.06 mmol, 3 eq.) were reacted according to GP3.

Yield: 287 mg (99%). Colorless solid. Mp.: 211-213°C. IR (KBr): 3434br, w; 2904w; 2571w; 1685m; 1638w; 1604w; 1479m; 1464m; 1304m; 1252m; 1209s; 1050m; 1027m; 947w; 921w; 828w; 784m; 750w; 797m; 641w. 1H-NMR (300 MHz, CDCl3): 2.32 (s, 3 H, CH3); 3.86 (s, 2H, CH2); 6.88 (d, J= 1.2,1 H, Harom, Cat.); 7.07 (d, J= 8.4, 2 H, Harom, p-Tol.); 7.11 (d, J= 8.4,1 H, Harom, p-Tol.); 7.34-7.40 (m, 7 H, Harom, Cat., Harom, Ketal); 7.58-7.62 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 21.0; 41.1; 111.3; 113.9; 118.4; 122.7; 126.4; 128.3; 128.7; 129.3; 135.2; 135.9; 137.4; 139.6; 147.3; 148.6; 169.7. HR-MS (MALDI): calcd. for C28H22O4Na ([M+Na]+): 445.1416, found 445.1415.

c) 2,2-Diphenyl-6-(4-methyl-benzyl)-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R, 6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-(4-methyl-benzyl)-1,3-benzodioxole-4-carboxylic acid (165 mg, 0.39 mmol, 1 eq.), EDC-HCl (115 mg, 0.59 mmol, 1.5 eq.), N-hydroxy-succinimide (57 mg, 0.49 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethyperhydrofuro[3,4-d][1,3] di-oxol-4-yl}-9H-purin-6-amine (100 mg, 0.3 mmol, 0.77 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 172 mg (78%). Colorless foam. Mp.: 107-110°C. IR (KBr): 3426m; 3176w; 2986w; 1636s; 1597s; 1529m; 1474s; 1440m; 1374w; 1328w; 1254s; 1207s; 1156w; 1082m; 1049m; 1020m; 868w; 776w; 699m; 642w. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 2.29 (s, 3 H, CH3, p-Tol.); 3.87 (s, 2H, CH2, benzyl.); 4.05 (m, 2 H, H-C(7'), H-C(7")); 4.71 (m, 1 H, H-C(4')); 4.91 (dd; j = 6.4, 3.6, 1H, H-C(3')); 5.38 (dd, J = 6.4, 2.4, 1H, H-C(2')); 5.83 (m, 2 H, H-C(5'), H-C(6')); 6.09 (d, J= 2.4, 1H, H-C(1')); 6.40 (bs, 2 H, NH2); 6.83 (d, J = 1.8, 1H, Harom, Cat.); 7.07 (s, 4 H, Harom, p-tolyl); 7.14 (t, J = 5.7, 1 H, NHCO); 7.33-7.38 (m, 6 H, Harom, Ketal); 7.45-7.49 (m, 5 H, Harom, Ketal, Harom, Cat.); 7.91 (s, 1H, H-C(8)); 8.16 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 21.1; 25.4; 27.2; 40.7; 41.3; 84.2; 84.4; 87.1; 90.4; 112.5; 114.7; 114.8; 118.2; 119.9; 122.1; 126.3; 127.7; 128.3; 128.6; 129.1; 129.5; 131.0; 135.7; 136.0; 137.5; 138.9; 140.5; 143.0; 147.3; 148.9; 149.8; 153.8;163.4. HR-MS (MALDI): calcd. for C43H40N6O6Na ([M+Na]+): 759.2907, found 759.2909. Anal. calcd. for C43H40N6O6: C 70.09, H 5.47, N 11.41, found C 69.89, H 5.60, N 11.33.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-methyl-benzyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (90 mg, 0.122 mmol) afforded the desired product as a colorless solid.

Yield: 63 mg (97%). tR, analyt.: 15.8 min. IR (KBr): 3384 br, s; 1700s; 1640m; 1596m; 1534w; 1513w; 1484w; 1437m; 1324m; 1290w; 1205s; 1133m; 1048w; 972w; 836w, 799w; 725w. 1H-NMR (500 MHz, CD3OD): 2.25 (s, 3 H, ArCH3); 3.79 (s, 2H, CH2, benzyl.); 4.03 (m, 2 H, H-C(7'), H-C(7")); 4.22 (t, J= 5.0, 1H, H-C(4')); 4.51 (m, 1H, H-C(3')); 4.73 (t, J = 4.9, 1H, H-C(2')); 5.93 (m, 2 H, H-C(5'), H-C(6')); 6.05 (d, J = 4.9, H-C(1')); 6.76 (d, J = 2.1, 1 H, Harom, Cat.); 7.04 (s, 4 H, Harom, p-Tol); 7.14 (d, J = 2.1, 1 H, Harom, Cat.); 8.17 (s, 1 H, H-C(8)); 8.39 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CD30D): 21.1; 41.6; 41.9; 75.3; 75.7; 86.2; 90.7; 116.5; 118.8; 120.6; 120.8; 129.7; 130.1; 130.2; 131.2; 133.6; 136.7; 139.7; 143.5; 147.3; 147.6; 148.5; 150.2; 153.4; 171.3. HR-MS (MALDI): calcd. for C27H28N6O6Na ([M+Na]+): 555.1968, found 555.1957.

Example 14 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-dimethylcarbamoyl-2,3-dihydroxy-benzamide a) 6-Dimethylcarbamoyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.486 mmol), LiH (10 mg, 0.97 mmol, 2 eq.) and dimethylcarbamoylchloride (0.18 mL, 1.94 mmol, 4 eq.) as the electrophile were reacted according to GP4, Method B. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH 67:30:3) to give the title compound as a colorless solid.

Yield: 40 mg (21%). Mp.: 207-208°C. IR (KBr): 3417w; 2935w; 1718s; 1635m; 1607s; 1448s; 1415m; 1247s; 1207s; 1075w; 1041s; 1023s; 949m; 881m; 788m; 765m; 701s; 643m. 1H-NMR (300 MHz, CDCl3): 3.06 (bs, 6H, CH3); 7.20 (d, J = 1.5, 1H, Harom, Cat.); 7.37-7.41 (m, 6 H, Harom, Cat.); 7.56 (d, J = 1.5, 1 H, Harom, Cat.); 7.58-7.62 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 35.8; 40.0; 111.2; 112.4; 119.3; 122.7; 126.4; 128.4; 129.4; 129.5; 139.1; 148.8; 149.8; 168.5; 170.1. HR-MS (MALDI): calcd. for C23H20NO4 ([M+H]+): 390.1341, found 390.1340.

b) 6-Dimethylcarbamoyl-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo [3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-Dimethylcarbamol-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (120 mg, 0.31 mmol, 1 eq.), EDC-HCl (90 mg, 0.46 mmol, 1.5 eq.), N-hydroxy-succinimide (46 mg, 0.4 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3] di-oxol-4-yl}-9H-purin-6-amine (93 mg, 0.28 mmol, 0.9 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 160 mg (81%). Colorless foam. IR (KBr): 3425m; 3193w; 2932w; 1639s; 1528m; 1471m; 1449m; 1396w; 1329w; 1263m; 1208s; 1157w; 1082m; 1048m; 1018m; 867w; 781w; 700m; 643w. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.61 (s, 3 H, CH3-endo); 3.02 (bs, 3 H, N(CH3)2); 3.07 (bs, 3H, N(CH3)2); 4.05 (m, 2 H, H-C(7'), H-C(7")); 4.74 (dd, j = 7.2, 3.3, 1 H, H-C(4')); 4.91 (dd; j = 6.5, 3.3, 1 H, H-C(3')); 5.43 (dd, J = 6.5, 2.0, 1 H, H-C(2')); 5.79 (m, 2 H, H-C(5'), H-C(6')); 6.08 (d, J= 2.0,1 H, H-C(1')); 6.18 (bs, 2 H, NH2); 7.08 (t, J= 5.7, 1 H, NHCO); 7.16 (d, J= 1.8, 1 H, Harom, Cat.); 7.35-7.42 (m, 6 H, Harom,Ketal); 7.46-7.51 (m, 4 H, Harom, Ketal); 7.69 (d, J= 1.8, 1 H, Harom, Cat.); 7.82 (s, 1 H, H-C(8)); 8.17 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3):25.3; 27.0; 35.5; 39.8; 40.6; 84.4; 84.6; 87.5; 90.7; 111.2; 114.5; 114.6; 119.3; 120.1; 122.2; 126.4; 128.0; 128.5; 129.8; 130.3; 130.8; 138.5; 139.9; 145.6; 147.5; 149.1; 151.6; 154.8; 162.7; 170.3. HR-MS (MALDI): calcd. for C38H38N7O7 ([M+H]+): 704.2833, found 704.2834.

c) N1-{(E)-3-((3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-dimethylcarbamoyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (90 mg, 0.128 mmol) afforded the desired product as a colorless solid.

Yield: 54 mg (86%). tR, analyt.: 7.3 min. IR (KBr): 3385 br, s; 1700s; 1605s; 1548w; 1509w; 1478w; 1416w; 1326w; 1296m; 1253w; 1202s; 1137m; 1048w; 972w; 838w; 801w; 725w. 1H-NMR (500 MHz, CD3OD): 2.96 (bs, 6 H, N(CH3)2); 3.95 (m, 2 H, H-C(7'), H-C(7")); 4.14 (t, J= 4.9, 1H, H-C(4')); 4.42 (t, J = 4.9,1 H, H-C(3')); 4.66 (t, J = 4.8, 1H, H-C(2')); 5.83 (m, 2 H, H-C(5'), H-C(6')); 5.96 (d, J = 4.8, H-C(1')); 6.92 (d, J = 2.0, 1H, Harom, Cat); 7.29 (d, J = 2.0, 1 H, Harom,Cat.); 8.15 (s, 1H, H-C(8)); 8.31 (s, 1H, H-C(2)). 13C-NMR (125 MHz, CD3OD): 34.4; 38.8; 40.1; 73.7; 74.2; 84.8; 89.3; 115.1; 116.7; 116.8; 119.3; 126.0; 128.7; 129.4; 142.4; 145.4; 146.1; 148.6; 150.3; 151.5; 169.0; 171.8. HR-MS (MALDI): calcd. for C22H26N707 ([M+H]+): 500.1894, found 500.1894.

Example 15 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-((E)-2-dimethylcarbamoyl-vinyl)-2,3-dihydroxy-benzamide a) Methyl 6-((E)-2-dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

A solution of methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (130 mg, 0.32 mmol), N,N-dimethylacrylamide (47 mg, 0.47 mmol, 1.5 eq.), P(OPh)3 (980 mg, 3.16 mmol, 10 eq.), Bu4NBr (20 mg, 0.06 mmol, 0.2 eq.), Na2CO3 (40 mg, 0.38 mmol, 1.2 eq.) and Pd(OAc)2 (10 mg, 0.03 mmol, 0.1 eq.) in 10 mL dimethylacetamide was stirred at 140°C for 72 h. After cooling to r.t. the mixture was partitioned between EtOAc and H2O. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 5:1 → 3:2) to yield the desired compound as a colorless, slowly solidifying viscous oil.

Yield: 60 mg (44%). IR (KBr): 3059w; 2927w, 1721s; 1652s; 1607m; 1481m; 1447s; 1396m; 1300m; 1256s; 1203s; 1046m; 1017m; 970w; 779w; 699m; 641w. 1H-NMR (300 MHz, CDCl3): 3.11 (bs, 6 H, N(CH3)2); 3.96 (s, 3H, OCH3); 6.75 (d, J = 15.6, 1H, C(O)CH); 7.20 (d, J= 1.8, 1H, Harom, Cat.); 7.36-7.41 (m, 6H, Harom, Ketal); 7.55-7.61 (m, 6 H, Harom, Ketal, Harom,Cat.,Ar-CH). 13C-NMR (75 MHz, CDCl3): 36.2; 37.7; 52.5; 110.5; 113.0; 116.8; 119.1; 124.1; 126.6; 128.6; 129.6; 129.7; 139.6; 141.5; 149.2; 149.5; 164.9; 166.7. HR-MS (MALDI): calcd. for C26H23NO5Na ([M+Na]+): 452.1474, found 452.1473.

b) 6-((E)-2-Dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-((E)-2-dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (170 mg, 0.4 mmol, 1 eq.) and LiOH·H2O (50 mg, 1.19 mmol, 3 eq.) were reacted according to GP3.

Yield: 126 mg (77%). Mp.: 230-231°C. IR (KBr): 3431w; 3058w; 1710s; 1653m; 1596m; 1467m; 1445m; 1404w, 1249s; 1212m; 1176m; 1050m; 1027w; 975w; 843w; 784w; 697w; 641w. 1H-NMR (300 MHz, CDCl3): 3.07 (s, 3 H, N(CH3)2); 3.16 (s, 3H, N(CH3)2); 6.75 (d, J = 15.3, 1H, C(O)CH); 7.24 (d, f = 1.5, 1H, Harom, Cat.); 7.35-7.40 (m, 6H, Harom,Ketal); 7.59-7.62 (m, 5 H, Harom, Ketal., Ar-CH); 7.67 (d, J=1.5, 1H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 36.1; 37.5; 110.6; 112.3; 116.4; 119.2; 124.6; 126.3; 128.4; 129.4; 129.5; 139.2; 141.5; 149.1; 149.8; 166.8; 167.8. HR-MS (MALDI): calcd. for C25H22NO5 ([M+H]+): 416.1498, found 416.1498.

c) 6-((E)-2-Dimethylcarbamoyl-vinyl)-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-((E)-2-Dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (90 mg, 0.22 mmol, eq.), EDC-HCl (63 mg, 0.33 mmol, 1.5 eq.), N-hydroxy-succinimide (33 mg, 0.28 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl)-2,2-dimethylperhydro-furo[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (72 mg, 0.22 mmol, 1 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 63 mg (40%). Colorless foam. IR (KBr): 3424m; 2931w; 1653s; 1598s; 1528m; 1474m; 1437m; 1374w; 1259m; 1207m; 1154w; 1081m; 1049m; 1019m; 973w; 867w; 776w; 699w; 642w. 1H-NMR (300 MHz, CDCl3): 1.37 (s, 3 H, CH3-exo); 1.61 (s, 3 H,CH3-endo); 3.05 (s, 3 H, N(CH3)2); 3.14 (s, 3 H, N(CH3)2); 4.05 (m, 2 H, H-C(7'), H-C(7")); 4.69 (m, 1 H, H-C(4')); 4.96 (dd; J= 6.6, 3.9, 1 H, H-C(3')); 5.46 (dd, J= 6.6, 2.1, 1 H, H-C(2')); 5.70 (bs, 2 H, NH2); 5.84 (m, 2 H, H-C(5'), H-C(6')); 6.08 (d, J = 2.1, 1H, H-C(1')); 6.82 (d, J = 15.5,1 H, C(O)CH); 7.07 (t, J = 6.0, 1H, NHCO); 7.17 (d, J = 1.7, 1H, Harom, Cat.); 7.35-7.42 (m, 6H, Harom, Ketal); 7.47-7.52 (m, 4H, Harom, Ketal); 7.60 (d, J= 15.5, 1H, Ar-CH); 7.80 (d, J = 1.7, 1H, Harom, Cat.); 7.84 (s, 1 H, H-C(8)); 8.19 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.4; 27.1; 35.9; 37.4; 40.7; 84.1; 84.5; 87.2; 90.3; 110.6; 114.6; 115.4; 117.0; 119.2; 120.2; 122.8;126.4; 128.5; 129.8; 130.3; 130.5; 138.5; 138.6; 139.8; 141.2; 145.6; 147.9; 149.4; 153.0; 155.3; 162.9; 166.5. HR-MS (MALDI): calcd. for C40H40N7O7([M+H)+): 730.2989, found 730.2993.

d) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-((E)-2-dimethylcarbamoyl-vinyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (35 mg, 0.048 mmol) afforded the desired product as a colorless solid.

Yield: 12 mg (48%). tR, analyt.: 9.7 min. IR (KBr): 3373 br, s; 1696s; 1642s; 1591s; 1499w, 1419w; 1307w; 1264w; 1201m; 1138w; 1052w; 977w, 840w, 800w; 723w; 642w. 1H-NMR (500 MHz,): 3.05 (s, 3 H, N(CH3)2); 3.22 (s, 3 H, N(CH3)2); 4.07 (m, 2 H, H-C(7'), H-C(7")); 4.24 (t, J = 5.0, 1H, H-C(4')); 4.53 (in, 1 H, H-C(3')); 4.74 (t, J = 4.8, 1H, H-C(2')); 5.95 (m, 2 H, H-C(5'), H-C(6')); 6.06 (d, J= 4.8, H-C(1')); 6.96 (d, J= 15.4, 1H, C(O)CH); 7.25 (d, j = 1.8, 1H, Harom, Cat.); 7.46 (d,J= 15.4, 1 H, Ar-CH); 7.53 (d, J= 1.8, 1 H, Harom, cat.); 8.26 (s, 1H, H-C(8)); 8.40 (s, 1H, H-C(2)). 13C-NMR (125 MHz,): 36.3; 37.9; 41.7; 75.3; 75.8; 86.2; 90.7; 116.5; 116.6; 117.9; 199.9; 120.8; 127.5; 130.4; 131.0; 143.5; 143.6; 147.5; 148.0; 150.2; 152.4; 153.3; 169.3; 171.0. HR-MS (MALDI): calcd. for C24H27N7O7Na ([M+Na]+): 548.1864, found 548.1859.

Example 16 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-trifluoromethyl-2,3-dihydroxy-benzamide a) 2-Methoxymethoxy-5-trifluoromethyl-phenol

To a solution of 1-methoxymethoxy-4-trifluoromethyl-benzene (4.6 g, 22.31 mmol) in 60 mL dry THF cooled to -78°C, BuLi (21 mL of a 1.6 m sol. in hexane, 1.5 eq.) was added drop-wise via a syringe and the mixture was stirred at low temperature for 2 h, then the cooling bath was removed and the mixture was allowed to gradually warm to 0°C during 30 min. After cooling again to -78°C, B(OCH3)3 (3.95 g, 38 mmol, 1.7 eq.) was added to the reaction and the stirring was continued for another 1.5 h at -78°C, then the solution was allowed to warm to -10°C during 20 min. Re-cooling to -78°C was followed by addition of H2O2 (5.82 mL of a 30% solution in H2O, 2 eq.) and NaOHaq (5.8 mL of a 5 m aqueous solution,1.3 eq.). This solution was stirred 16 h at r.t., then saturated NH4Cl-solution was added and the mixture was extracted twice with 30 mL EtOAc. The pooled organic fractions were washed with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane / EtOAc 4:1) to yield the desired product as a yellowish oil.

Yield: 3.5 g (70%). IR (neat): 3426br, m; 2962m; 1709w; 1622m; 1516s; 1464m; 1330s; 1290s; 1162s; 1123s; 1085s; 982s; 914s; 879m; 816m; 762w; 658w; 618w. 1H-NMR (300 MHz, CDCl3): 3.52 (s, 3 H, OCH3); 5.26 (s, 2H, OCH2O); 5.97 (s,1H, OH); 7.10-7.20 (m, 3 H, Harom). 13C-NMR (75 MHz, CDCl3): 56.6; 95.5; 112.4 (d, J= 3.6); 114.7; 117.5 (d, J = 3.6); 120.3 (q, J= 260); 125.0 (q, J = 32.8); 146.1; 146.7. 19F-NMR (282 MHz, CDCl3): - 62.4 (s). HR-MS (EI+): calcd. for C9H9F3O3 ([M)+): 222.0504, found 222.0501.

b) 3-Bromo-5-trifluoromethyl-benzene-1,2-diol

To a solution of 4-trifluoromethyl-benzene-1,2-diol (870 mg, 4.8 mmol) in 20 mL CCl4, Br2 (770 mg, 4.8 mmol, 1 eq.) was added and the mixture was stirred at 60°C for 10 h. The sol-vent was then removed in vacuo and the crude product was purified by flash chromatography (silica gel, hexane / EtOAc 4:1→ 3:2) to yield the desired product as a yellowish oil.

Yield: 910 mg (74%). 1H-NMR (300 MHz, CDCl3): 5.68 (bs, 1H, OH); 5.81 (bs, 1H, OH); 7.14 (dd, J = 2.3, 0.6, 1H, Harom); 7.32 (dd, J = 2.3, 0.6, 1H, Harom).

c) 1,2- Bis-benzyloxy-3-bromo-5-trifluoromethyl-benzene

To a solution of 3-bromo-5-trifluoromethyl-benzene-1,2-diol (510 mg, 1.98 mmol) in 10 mL acetone, K2CO3 (2.74 g, 19.84 mmol, 10 eq.) and benzyl bromide (1.02 g, 5.95 mmol, 3 eq.) were added and the solution was refluxed for 4 h. After cooling to r.t., H2O and EtOAc were added to the mixture and the phases were separated. The organic fraction was washed with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane / EtOAc 10:1) to yield the title compound as a colorless solid.

Yield: 750 mg (87%). Mp.: 79-80°C. IR (KBr): 3032w; 2935w; 2884w; 1576w; 1499w; 1485w; 1455w; 1424m; 1382w; 1335s; 1290m; 1230m; 1164s; 1120s; 1011m; 957m; 919w; 859w; 751m; 698m. 1H-NMR (300 MHz, CDCl3): 5.09 (s, 2 H, OCH2Ar); 5.15 (s, 2 H, OCH2Ar); 5.97 (s, 1H, OH); 7.18 (d, J = 1.5, 1 H, Harom, Cat.); 7.32-7.47 (m, 11 H, Harom, Cat., Harom, Benzyl.). 13C-NMR (75 MHz, CDCl3): 71.5; 75.0; 110.3 (d, J = 3.9); 118.4; 122.5 (d, J = 3.9); 123.1 (q, J = 271); 127.0 (q, J = 33.6); 127.6; 128.2; 128.3; 128.4; 128.5; 128.6; 135.5; 136.3; 148.4; 152.8. 19F-NMR (282 MHz, CDCl3): -62.6 (s). HR-MS (MALDI): calcd. for C21H16BrF3O2Na ([M+Na]+): 459.0183, found 459.0169.

d) Methyl 2,3-bis-benzyloxy-5-trifluoromethyl-benzoate

To a solution of 1,2-bis-benzyloxy-3-bromo-5-trifluoromethyl-benzene (750 mg, 1.76 mmol) in 10 mL dry THF cooled to -90°C, BuLi (3.3 mL of a 1.6 m solution in hexane, 5.28 mmol, 3 eq.) was slowly added via a syringe and the yellow solution was stirred at low temperature for 15 min. Methyl chloroformate (1.66 g, 17.6 mmol, 10 eq.) was then added to the solution and the reaction mixture was allowed to warm to r.t. where the stirring was continued for 1 h. The mixture was then poured into a separatory funnel containing H2O and EtOAc and the phases were separated. The organic phase was washed with brine, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane / EtOAc 10:1) to yield the desired compound as a colorless solid.

Yield: 383 mg (52%). Mp.: 78-79°C. IR (KBr): 3033w; 2950w; 1733s; 1610w; 1486w; 1430m; 1363s; 1299m; 1250s; 1199m; 1151m; 1121s; 1045s; 956w; 935w; 909w; 867w; 750w; 698m. 1H-NMR (300 MHz, CDCl3): 3.87 (s, 3H, OCH3); 5.14 (s, 2 H, OCH2Ar); 5.17 (s, 2 H, OCH2Ar); 7.30-7.45 (m, 11 H, Harom, Cat., Harom, Benzyl.); 7.65 (dd, J = 1.8, 1.2, 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 52.5; 71.6; 75.8; 113.9 (d, J = 3.3); 118.0; 119.9 (d, J = 3.3); 123.4 (q, J = 270); 126.0 (q, J = 33.6); 127.0; 127.6; 128.1; 128.3; 128.4; 128.5; 128.6; 135.5; 136.6; 150.7; 153.0; 165.4. 19F-NMR (282 MHz, CDCl3): -62.7 (s). HR-MS (MALDI): calcd. for C23H19F3O2Na ([M+Na]+): 439.1133, found 439.1132. Anal. calcd. for C23H19O4F3: C 66.34, H 4.60 found C 66.16, H 4.78.

e) Methyl 2,3-dihydroxy-5-triluoromethyl-benzoate

To a solution of methyl 2,3-bis-benzyloxy-5-trifluoromethyl-benzoate (280 mg, 0.67 mmol) in 10 mL MeOH, Pd/C (10%, 30 mg) was added and the mixture was stirred 16 h under a H2 atmosphere. The reaction mixture was then filtered through Celite and evaporated in vacuo to yield the title compound as a greyish solid.

Yield: 148 mg (99%). IR (KBr): 3462m; 3132w; 2961w; 1676m; 1494m; 1447m; 1338s; 1245s; 1199m; 1120s; 1014w, 936w; 887w; 793m; 679m. 1H-NMR (300 MHz, CD3OD) 3.97 (s, 3H, OCH3); 7.17 (s, 1H, Harom, Cat); 7.58 (s, 1H, Harom, Cat.). 13C-NMR (75 MHz, CD3OD): 53.2; 113.6; 116.9; 118.0; 121.8 (q, J= 32.8); 125.3 (q, J= 268); 148.6; 154.6; 170.9. 19F-NMR (282 MHz, CD3OD): -62.0 (s). HR-MS (MALDI): calcd. for C8H3F3O3 ([M-CH3OH]+): 204.0034, found 204.0024.

f) Methyl 2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylate

4,4'-Dimethoxybenzophenone (213 mg, 0.88 mmol, 1.5 eq.), oxalyl chloride (900 mg, 7.1 mmol, 8 eq.) and methyl 2,3-dihydroxy-5-trifluoromethyl-benzoate (130 mg, 0.59 mmol, 1 eq.) were reacted according to GP2.2. The crude product was purified using flash chromato-graphy (silica gel, hexane / Et2O 10:1) to yield the title compound as a yellowish, very viscous oil.

Yield: 170 mg (63%). IR (neat): 3003w; 2956w; 2839w; 1727s; 1642w; 1612s; 1585w; 1514s; 1486m; 1445s; 1324s; 1268s; 1234s; 1175s; 1123m; 1042s; 1005m; 935w; 832m; 783w; 674w. 1H-NMR (300 MHz, CDCl3): 3.81 (s, 6H, ArOCH3); 3.95 (s, 3H, C(O)OCH3); 6.90 (dd, J= 6.7, 2.3, 4 H, Harom, Ketal); 7.18 (d, J = 1.5, 1 H, Harom,Cat); 7.47 (dd, J = 6.7, 2.3, 4 H, Harom, Ketal); 7.74 (d, J= 1.5, 1H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 52.4; 55.4; 108.6 (d, j = 3.1); 112.3; 113.7; 120.2; 120.8 (d, J = 4.3); 123.5 (q, J= 270); 123.6 (q, J= 33.4); 128.0; 131.0; 148.9; 150.7; 160.4; 163.8. 19F-NMR (282 MHz, CDCl3): -61.8 (s). HR-MS (MALDI): calcd. for C24H20F3O6 ([M+H]+): 461.1212, found 461.1202. Anal. calcd. for C24H19O6F3: C 62.61, H 4.16 found C 62.52, H 4.26.

g) 2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylate (60 mg, 0.13 mmol, eq.) and LiOH·H2O (28 mg, 0.65 mmol, 5 eq.) were reacted according to GP3.

Yield: 53 mg (91%). Mp.:. IR (KBr): 3441br, w; 2936w; 2837w; 1687w; 1611s; 1513s; 1442m; 1364m; 1312s; 1253s; 1175s; 1121m; 1031s; 1005m; 952w; 931w; 831m; 676w. 1H-NMR (300 MHz, CDCl3): 3.79 (s, 6H, ArOCH3); 6.94 (dd, J = 6.9,2.1,4 H, Harom, Ketal); 7.30 (d, J = 1.5, 1H, Harom, Cat); 7.46 (dd, J = 6.9, 2.1, 4 H, Harom, Ketal); 7.70 (d, J = 1.5, 1 H, Harom, Cat.). 19F-NMR (282 MHz, CDCl3): -63.7 (s). HR-MS (MALDI): calcd. for C24H20F3O6 ([M+H]+): 447.1055, found 447.1059.

h) 2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylic acid (90 mg, 0.2 mmol, 1 eq.), EDC·HCl (58 mg, 0.3 mmol, 1.5 eq.), N-hydroxy-succinimide (31 mg, 0.26 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro [3,4-d][1,3]di-oxo1-4-yl}-9H-purin-6-amine (70 mg, 0.2 mmol, 1 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 119 mg (77%). Colorless foam. Mp.: 114-118°C. IR (KBr): 3426m; 3178w; 2935w; 2837w; 1640s; 1607s; 1514m; 1443w; 1375w, 1317s; 1254s; 1210m; 1175s; 1121m; 1025m; 1004w; 867w; 732m. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 3.81 (s, 6 H, OCH3); 4.04 (m, 2 H, H-C(7'), H-C(7")); 4.68 (m, 1 H, H-C(4')); 4.95 (dd; J= 6.6, 3.6, 1 H, H-C(3')); 5.45 (dd, J= 6.6, 2.1, 1 H, H-C(2')); 5.81 (m, 4 H, H-C(5'), H-C(6'), NH2); 6.08 (d, J = 2.1, 1 H, H-C(1')); 6.88-6.92 (m, 4 H, Harom, Ketal); 7.09 (t, J = 5.7, 1 H, NHCO); 7.19 (d, J = 2.1, 1 H, Harom, Cat.); 7.36-7.42 (m, 4 H, Harom, Ketal); 7.85 (s, 1 H, H-C(8)); 7.91 (d, J = 2.1, 1 H, Harom, Cat.); 8.22 (s,1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 25.4; 27.2; 40.9; 55.4; 84.1; 84.5; 87.1; 90.2; 108.3; 113.7; 114.6; 115.1; 120.1; 120.6; 120.7; 123.54 (q, J= 270); 124.6 (q, J= 33.5); 128.1; 128.5; 130.1; 130.3; 139.8; 147.2; 147.9; 149.2; 152.3; 155.1; 160.7; 162.0.19F-NMR (282 MHz, CDCl3): -61.7 (s). HR-MS (MALDI): calcd. for C38H36F3N6O8 ([M+H]+): 761.2547, found 759.2535.

i) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-trifluoromethyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (75 mg, 0.1 mmol) afforded the desired product as a colorless solid.

Yield: 48 mg (99%). tR,analyt.: 14.7 min. IR (KBr): 3409 br, s; 1670s; 1649m; 1607m; 1545w; 1398w; 1327m; 1194m; 1124m; 1049w; 801w; 725w. 1H-NMR (500 MHz,): 4.06 (m, 2 H, H-C(7'), H-C(7")); 4.24 (t, J = 5.1, 1H, H-C(4')); 4.52 (m, 1 H, H-C(3')); 4.71 (t, J= 4.8, 1 H, H-C(2')); 5.95 (m, 2 H, H-C(5'), H-C(6')); 6.06 (d, J = 4.8, H-C(1')); 7.15 (d, J = 1.2,1 H, Harom,Cat.); 7.64 (d, J = 1.2,1 H, Harom,Cat.); 8.29 (s, 1 H, H-C(8)); 8.39 (s, 1 H, H-C(2)). 13C-NMR (125 MHz,): 41.8; 75.3; 75.6; 86.1; 90.6; 115.5 (q, J = 2.5); 116.4 (q, J = 5.0); 116.9; 120.8; 121.9 (q, J= 32.5); 125.7 (q, J= 269); 130.5; 130.9; 143.4; 147.8; 148.3; 150.3; 153.3; 153.6; 170.1. 19F-NMR (282 MHz, CDCl3): -61.6 (s). HR-MS (MALDI): calcd. for C20H20F3N6O6 ([M+H]+): 497.1396, found 497.1401.

Example 17 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-isopropyl-2,3-dihydroxy-benzamide a) 4-Isopropenyl-2-methoxy-1-methoxymethoxy-benzene

A suspension of methyltriphenylphosphonium bromide (1.1 g, 3.09 mmol, 1.3 eq.) in 5 mL dry THF cooled to -80°C was slowly treated with BuLi (1.94 mL of a 1.6 m solution in hexane, 1.3 eq.). To this yellow suspension a solution of 1-(3-methoxy-4-methoxymethoxy-phenyl)-ethanone (500 mg, 2.38 mmol, 1 eq.) in 5 mL dry THF was added and the reaction mixture was allowed to warm to r.t. where stirring was continued for 12 h. The suspension was filtered and the solvent was evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane /EtOAc 6:1) to yield the desired product as a color-less oil.

Yield: 424 mg (86%). IR (neat): 3085w; 2952m; 2827w; 1627w; 1602w; 1580m; 1513s; 1463m; 1413m; 1300m; 1248s; 1224m; 1157s; 1139s; 1077s; 997s; 922m; 885m; 855m; 817w; 765w. 1H-NMR (300 MHz, CDCl3): 2.14 (s, 3 H, CH3); 3.52 (s, 3 H, Ar-OCH3); 3.91 (s, 3 H, OCH3); 5.03 (qu, J = 1.5,1H, CH2); 5.23 (s, 2 H, OCH2O); 5.29 (qu, J = 1.5, 1 H, CH2); 6.98-7.03 (m, 2 H, Harom); 7.11 (d, J = 8.4; 1 H, Harom). 13C-NMR (75 MHz, CDCl3): 21.9; 55.8; 56.2; 95.4; 109.2; 111.4; 115.9; 118.1; 135.9; 142.9; 146.0; 149.3. HR-MS (EI+): calcd. for C12H16O3 ([M]+): 208.1099, found 208.1097.

b) 4-Isopropyl-2-methoxy-1-methoxymethoxy-benzene

To a solution of 4-isopropenyl-2-methoxy-1-methoxymethoxy-benzene (3.5 g, 16.81 mmol) in 20 mL MeOH, Pd/C (10%, 350 mg) was added and the mixture was stirred 16 h under a H2 atmosphere. The reaction mixture was then filtered through Celite and evaporated in vacuo and briefly dried under vacuum to yield the title compound as a colorless oil.

Yield: 3.31 g (94%). IR (neat): 2959s; 2827w; 1592w; 1516s; 1464s; 1419m; 1297w; 1266s; 1228s; 1198m; 1156s; 1079s; 1037w; 1004s; 923m; 852w; 815w; 763w; 653w. 1H-NMR (300 MHz, CDCl3): 1.24 (d, J= 7.0, 6 H, CH3); 2.86 (sep, J = 7.0,1 H, CH); 3.52 (s, 3 H, Ar-OCH3); 3.88 (s, 3 H, OCH3); 5.20 (s, 2 H, OCH2O); 6.73-6.78 (m, 2 H, Harom); 7.07 (d, J= 8.1; 1 H, Harom). 13C-NMR (75 MHz, CDCl3): 24.1; 33.8; 55.8; 56.1; 95.6; 110.3; 116.5; 118.2; 143.5; 144.4; 149.5. HR-MS (EI+): calcd. for C12H18O3 ([M]+): 210.1256, found 210.1246.

c) Methyl 5-Isopropyl-3-methoxy-2-methoxymethoxy-benzoate

To a solution of 4-isopropyl-2-methoxy-1-methoxymethoxy-benzene (2.0 g, 9.51 mmol) in 35 mL dry THF cooled to 0°C, BuLi (9 mL of a 1.6 m solution in hexane, 1.5 eq.) was added dropwise via a syringe and the reaction mixture was stirred 2.5 h at 0°C. This solution was then slowly added to a solution of methyl chloroformate (9g, 95.1 mmol, 10 eq.) in 10 mL dry THF at 0°C. The mixture was stirred 12 h at r.t. Saturated KHCO3 solution and EtOAc were then added to the solution and the phases were separated. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane EtOAc 9:1 → 6:1) to yield the title compound as a yellowish oil.

Yield: 1.3 g (51%).IR (neat): 2960m; 2841w; 1769m; 1729s; 1586w; 1487m; 1464m; 1439m; 1339m; 1263s; 1207s; 1157m; 1063s; 961s; 860w; 797w; 656w. 1H-NMR (300 MHz, CDCl3): 1.24 (d, J = 6.9, 6 H, CH3); 2.88 (sep, J = 6.9, 1 H, CH); 3.57 (s, 3 H, Ar-OCH3); 3.86 (s, 3 H, OCH3); 3.90 (s, 3 H, C(O)OCH3); 5.10 (s, 2 H, OCH2O); 6.91 (d, J = 2.1, 1 H, Harom); 7.18 (d, J = 2.1; 1 H, Harom). 13C-NMR (75 MHz, CDCl3): 24.0; 34.0; 52.2; 56.2; 75.4; 99.4; 114.4; 119.8; 126.0; 143.3; 144.9; 152.8; 166.8. HR-MS (EI+): calcd. for C14H20O5 ([M]+): 268.1311, found 268.1300.

d) 2,3-Dihydroxy-5-isopropyl-benzoic acid

To a solution of methyl 5-Isopropyl-3-methoxy-2-methoxymethoxy-benzoate in 5 mL dry CH2Cl2 cooled to -80°C, BBr3 (3.4 mL of a 1 m solution in CH2Cl2) was added dropwise via a syringe. The mixture was then stirred 30 min. at -70°C, then the cooling bath was removed and the stirring continued at r.t. for 1 h. The reaction was the quenched by addition of H2O and the resulting mixture was extracted twice with 30 mL CH2Cl2. The combined organic fractions were dried over MgSO4 and evaporated in vacuo to yield a brown solid. This material was redissolved in 1 mL AcOH to which 2.5 mL HBr (33% in AcOH) was added. The mixture was stirred at 120°C for 5 h, then H2O was slowly added and the mixture was extracted with EtOAc. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo to yield the desired product as a brown solid.

Yield: 45 mg (41%). Mp.: 151-152°C. IR (KBr): 3311m; 2958s; 1675s; 1613w; 1483s; 1384w; 1276s; 1161s; 986w; 872w; 796w; 778w; 728w; 703w. 1H-NMR (300 MHz, CDCl3): 1.22 (d, J = 7.1, 6 H, CH3); 2.84 (sep, J = 7.1, 1H, CH); 5.64 (bs, 1 H, OH); 7.09 (d, J = 2.4, 1 H, Harom); 7.30 (d, J = 2.4; 1 H, Harom); 10.29 (s, 1 H, OH). 13C-NMR (75 MHz, CDCl3): 23.9; 33.5; 110.8; 118.7; 119.7; 140.5; 144.8; 147.4; 174.8. HR-MS (EI+): calcd. for C10H10O3 ([M-H2O]+): 278.0630, found 278.0623.

e) Methyl 2,3-dihydroxy-5-isopropyl-benzoate

2,3-Dihydroxy-5-isopropyl-benzoic acid (140 mg, 0.71 mmol, 1 eq.) and SOCl2 (430 mg, 3.6 mmol, 5 eq.) were reacted according to GP1.

Yield: 125 mg (83%). Grayish solid. Mp.: 66-67°C. IR (KBr): 3425s; 2955m; 1688s; 1485s; 1438s; 1338s; 1276s; 1231m; 1159m; 1112w; 1018m; 964w; 893w, 785m; 693w; 641w. 1H-NMR (300 MHz, CDCl3): 1.21 (d, J = 6.9, 6 H, CH3); 2.82 (sep, J = 6.9,1 H, CH); 3.95 (s, 3 H, OCH3); 5.61 (s, 1 H, OH); 7.02 (d, J = 2.0, 1 H, Harom); 7.21 (d, J = 2.0, 1 H, Harom); 10.69 (s, 1H, OH). 13C-NMR (75 MHz, CDCl3): 23.9; 33.5; 52.3; 111.8; 117.7; 118.4; 140.1; 144.7; 146.9; 170.8. HR-MS (EI+): calcd. for C11H14O4 ([M]+): 210.0892, found 210.0892.

f) Methyl 6-isopropyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 2,3-dihydroxy-5-isopropyl-benzoate (85 mg, 0.4 mmol, 1 eq.) and dichlorodiphenyl-methane (125 mg, 0.53 mmol, 1.3 eq.) were reacted according to GP2, Method B.

Yield: 112 mg (74%). Colorless solid. Mp.: 108-110°C. IR (KBr): 2959w, 1714s; 1478s; 1447s; 1385w; 1285m; 1045m; 1017m; 915w; 868w; 807m; 782m; 701s; 641m. 1H-NMR (300 MHz, CDCl3): 1.21 (d, J = 6.8,6 H, CH3); 2.85 (sep, J = 6.8, 1H, CH); 3.94 (s, 3 H, OCH3); 6.92 (d, J= 1.9, 1H, Harom,Cat.); 7.26 (d, J = 1.9, 1H, Harom); 7.35-7.41 (m, 6 H, Harom, Ketal); 7.60-7.65 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 24.0; 33.9; 52.0; 111.0; 112.1; 117.7; 119.9; 126.4; 128.2; 129.2; 140.0; 142.5; 146.3; 148.3; 165.4. HR-MS (MALDI): calcd. for C24H22O4Na ([M+Na]+): 397.1416, found 397.1414.

g) 6-Isopropyl-2,2-diphenyl-1,3-benzodiozole-4-carboxylic acid

Methyl 6-isopropyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (100 mg, 0.267 mmol, 1 eq.) and LiOH·H2O (45 mg, 1.07 mmol, 4 eq.) were reacted according to GP3.

Yield: 91 mg (95%). Colorless solid. IR (KBr): 2958m; 2630w; 1683s; 1478s; 1450s; 1254s; 1207s; 1044m; 1023m; 947w; 864w; 760w; 697m; 641w. 1H-NMR (300 MHz, CDCl3): 1.21 (d, J = 6.9, 6 H, CH3); 2.86 (sep, J = 6.9, 1 H, CH); 6.97 (d, J = 1.8, 1 H, Harom, Cat.); 7.31 (d, J = 1.8, 1 H, Harom); 7.35-7.42 (m, 6 H, Harom, Ketal); 7.61-7.64 (m, 4 H, Harom, Ketal). 13C-NMR (75 MHz, CDCl3): 24.0; 33.8; 111.2; 111.9; 118.2; 120.3; 126.4; 128.3; 129.3; 139.8; 142.7; 146.9; 148.4; 169.6. HR-MS (MALDI): calcd. for C23H20O4Na ([M+Na]+): 383.1259, found 383.1250.

h) 2,2-Diphenyl-6-isopropyl-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d] [1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-lsopropyl-2,2-diphenyl-l,3-benzodioxole-4-carboxylic acid (80 mg, 0.22 mmol, 1 eq.), EDC·HCl (64 mg, 0.33 mmol, 1.5 eq.), N hydroxy-succinimide (34 mg, 0.29 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (81 mg, 0.24 mmol, 1.1 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 89 mg (57%). Colorless foam. IR (KBr): 3424m; 3179w; 2960w; 1645s; 1598s; 1530m; 1475s; 1449m; 1330w; 1255s; 1208s; 1156w; 1081m; 1047m; 1018m; 949w; 867w; 779w; 699w; 642w. 1H-NMR (300 MHz, CDCl3): 1.21 (d, J = 6.9, 6 H, CH3); 1.37 (s, 3 H, CH3-exo); 1.62 (s, 3 H, CH3-endo); 2.88 (sep, J= 6.9, 1H, CH); 4.05 (m, 2 H, H-C(7'), H-C(7")); 4.68 (m, H, H-C(4')); 4.93 (dd; J= 6.6, 3.9, 1H, H-C(3')); 5.44 (dd, J= 6.6, 2.4, 1 H, H-C(2')); 5.79 (bs, 2 H, NH2); 5.86 (m, 2 H, H-C(5'), H-C(6')); 6.08 (d, J= 2.4, 1H, H-C(1')); 6.92 (d, J = 1.5,1 H, Harom, Cat.); 7.14 (t, J= 5.4, 1H, NHCO); 7.35-7.39 (m, 6 H, Harom, Ketal); 7.43 (d, J = 1.5, 1H, Harom,Cat.); 7.48-7.53 (m, 4 H, Harom, Ketal); 7.86 (s, 1 H, H-C(8)); 8.23 (s, 1 H, H-C(2)). 13C-NMR (75 MHz, CDCl3): 24.1; 25.5; 27.2; 34.1; 40.7; 84.0; 84.4; 87.0; 90.1; 110.3;114.7; 118.0;119.7; 120.1; 126.3; 128.0; 128.3; 128.4; 129.5; 130.8; 139.1; 139.8; 142.7; 143.4; 147.1; 149.3; 152.5; 155.0; 163.5. HR-MS (MALDI): calcd. for C38H39N6O6 ([M+H]+): 675.2931, found 675.2947.

i) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl]-5-isopropyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (50 mg, 0.074 mmol) afforded the desired product as a grayish solid.

Yield: 29 mg (85%). tR,analyt.: 12.2 min. IR (KBr): 3378br, s; 2962m; 1700s; 1641m; 1594m; 1542m; 1484w; 1430w; 1323w; 1201s; 1137m; 1049w; 970w; 836w, 800w; 724w; 642w. 1H-NMR (500 MHz, CD3OD): 1.21 (d, J= 6.8, 6 H, CH3); 2.79 (sep, J = 6.8,1 H, CH); 4.03 (m, 2 H, H-C(7'), H-C(7")); 4.23 (t, J= 4.9, 1 H, H-C(4')); 4.51 (m, 1 H, H-C(3')); 4.73 (t, J = 4.8, 1 H, H-C(2')); 5.94 (m, 2 H, H-C(5'), H-C(6')); 6.03 (d, J= 4.8, H-C(1')); 6.85 (d, J= 2.0, 1 H, Harom, Cat.); 7.12 (d, J = 2.0, 1 H, Harom, Cat.); 8.22 (s, 1 H, H-C(8)); 8.37 (s, 1 H, H-C(2)). 13 C-NMR (125 MHz, CD3OD): 24.5; 35.0; 41.6; 75.2; 75.6; 86.1; 90.6; 116.2; 116.3; 118.2; 120.8; 130.2; 131.2; 140.7; 143.2; 147.1; 148.2;148.7; 150.3; 154.1; 171.5. HR-MS (MALDI): calcd. for C22H27N6O6 ([M+H]+): 471.1992, found 471.1981.

Example 18 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(toluene-4-sulfonyl)-2,3-dihydroxybenzamide a) Methyl 2,3-dimethoxy-5-(toluene-4-sulfonyl)-benzoate

To a solution of methyl 5-iodo-2,3-dimethoxy-benzoate (2.25 g, 7.0 mmol) in 20 mL DMF, sodium p-toluenesulfinate hydrate (2.21 g,11.26 mmol, 1.6 eq.) and CuI (2.22 g, 11.6 mmol, 1.66 eq.) were added and light green solution was stirred at 110°C for 14 h. H2O and EtOAc were then added to the mixture and the phases were separated. The organic layer was washed with saturated NaCl solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified using flash chromatography (silica gel, hexane / EtOAc 8:2 → 3:2) to yield the desired product as a colorless solid.

Yield. 1.41 g (58%). Mp.: 114°C. IR (KBr): 3081w; 2945w; 1731s; 1594w; 1482m; 1426w; 1317s; 1273s; 1146s; 1104m; 994w; 872w; 811w; 713w; 665m; 585m; 535w. 1H-NMR (300 MHz, CDCl3): 2.40 (s, 3 H, ArCH3); 3.90 (s, 3 H, ArOCH3); 3.92 (s, 3 H, ArOCH3); 3.92 (s, 3 H, C(O)OCH3); 7.31 (d, J= 8.1, 2 H, Harom, p-Tol.); 7.54 (d, J = 2.1, 1 H, Harom, Cat.); 7.82 (d, J = 8.1, 2 H, Harom, p-Tol.); 7.87 (d, J= 2.1; 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 21.7; 52.6; 56.5; 61.7; 113.4; 122.0; 126.4; 127.5; 129.9; 136.8; 138.2; 144.2; 152.7; 153.8; 164.9. HR-MS (MALDI): calcd. for C17H18O6SNa ([M+Na]+): 373.0722, found 373.0714. Anal. calcd. for C17H18O6S: C 58.27, H 5.18, found C 58.38, H 5.36.

b) 2,3-Dihydroxy 5-(toluene-4-sulfonyl)-benzoic acid

Methyl 2,3-dimethoxy-5-(toluene-4-sulfonyl)-benzoate (1.3 g, 4.036 mmol) was dissolved in 5 mL AcOH to which HBr (15 mL of a 33% solution in AcOH) and Bu4NBr (1.1 g, 3.4 mmol, 0.85 eq.) were added. The reaction mixture was stirred at 140°C for 20 h, then H2O was slowly added and the mixture was extracted with EtOAc. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane / EtOAc / AcOH 3:2:0.2 → 1:3:0.2) to yield the desired product as an orange solid.

Yield: 560 mg (45 %). Mp.: 223-225°C (dec.). IR (KBr): 3165br, m; 1692m; 1597w; 1467m; 1403w; 1282s; 1214w; 1141s; 1094m; 967w; 893w; 799w; 743w; 709m; 665m. 1H-NMR (300 MHz, DMSO-d6): 2.35 (s, 3 H, ArCH3); 4.42 (bs, 1 H, OH); 7.28 (d, J= 2.1, 1 H, Harom, Cat.); 7.39 (d, J = 8.1, 2 H, Harom, p-Tol.); 7.75 (m, 3 H, Harom, Cat., Harom, p-Tol.); 9.86 (bs, 1 H, OH). 13C-NMR (75 MHz, DMSO-d6): 21.0; 114.7; 115.6; 120.0; 126.8; 128.7; 130.0; 138.9; 143.6; 147.1; 156.4; 170.5. HR-MS (MALDI): calcd. for C14H12O6SNa ([M+Na]+): 331.0252, found 331.0246.

c) Methyl 2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzoate

2,3-Dihydroxy-5-(toluene-4-sulfonyl)-benzoic acid (410 mg, 1.33 mmol, 1 eq.) and SOCl2 (790 mg, 6.65 mmol, 5 eq.) were reacted according to GP1.

Yield: 321 mg (75%). Orange solid. Mp.: 168-170°C (dec.). IR (KBr): 3362br, m; 2956w; 1695s; 1596m; 1494m; 1447m; 1284s; 1243s; 1146s; 1094s; 1018m; 937w; 883m; 810m; 736w; 700w; 666s. 1H-NMR (300 MHz, CDCl3): 2.39 (s, 3H, ArCH3); 4.00 (s, 3 H, OCH3); 5.91 (bs, 1 H, OH); 7.29 (d, J= 7.8, 2 H, Harom, p-Tol.); 7.55 (d, J= 1.2, 1H, Harom, Cat.); 7.83 (d, J = 7.8, 2 H, Harom, p-Tol.); 8.05 (d, J = 1.2, 1 H, Harom, Cat.); 11.43 (bs, 1 H, OH). 13C-NMR (75 MHz, CDCl3): 21.7; 53.1; 112.2; 117.8; 120.9; 127.4; 129.8; 132.8; 138.5; 144.1; 145.6; 152.5; 169.6. HR-MS (MALDI): calcd. for C15H14O6SNa ([M+Na]+): 345.0409, found 345.0402.

d) Methyl 2,2-bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylate

4,4'-Dimethoxybenzophenone (225 mg, 0.93 mmol, 1.5 eq.), oxalyl chloride (944 mg, 7.44 mmol, 8 eq.) and methyl 2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzoate (200 mg, 0.62 mmol, 1 eq.) were reacted according to GP2.2. The crude product was purified using flash chromatography (silica gel, hexane / EtOAc 20:1 → 9:1) to yield the title compound as a colorless solid.

Yield: 260 mg (77%). Mp.: 79-82°C. IR (KBr): 2951w; 2832w; 1727m; 1610m; 1512m; 1464s; 1320m; 1285m; 1248s; 1210m; 1175s; 1150s; 1090m; 1042m; 1004w; 885w; 832w; 739w; 663w; 616w. 1H-NMR (300 MHz, CDCl3): 2.39 (s, 3 H, ArCH3); 3.80 (s, 6 H, ArOCH3); 3.93 (s, 3 H, C(O)OCH3); 6.88 (dt, J= 8.7, 2.5, 4 H, Harom, Ketal); 7.29 (d, J = 8.1, 2 H, Harom, p.Tol.); 7.43 (m, 5 H, Harom, Cat., Harom, Ketal); 7.81 (d, J = 8.7, 2 H, Harom, p-Tol.); 8.09 (d, J = 1.8,1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 21.7; 52.5; 55.4; 110.1; 112.5; 113.6; 120.9; 124.0; 127.5; 127.9; 129.9; 130.7; 134.9; 138.4; 144.1; 149.2; 151.9; 160.4; 163.4. HR-MS (MALDI): calcd. for C30H27O8S ([M+H]+): 547.1427, found 547.1428. Anal. calcd. for C30H26O8S: C 65.65, H 4.87, found C 65.92, H 4.79.

e) 2,2-Bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylate (205 mg, 0.375 mmol, 1 eq.) and LiOH·H2O (79 mg, 1.88 mmol, 5 eq.) were reacted following GP3.

Yield: 197 mg (99%). Colorless solid. IR (KBr): 3423br, w; 2961w; 2837w; 1649w; 1611m; 1514m; 1443m; 1313s; 1254s; 1175s; 1119m; 1030s; 931w; 903w; 832m; 675w. 1H-NMR (300 MHz, CD3OD): 2.32 (s, 3 H, ArCH3); 3.73 (s, 6 H, ArOCH3); 6.85 (d, J = 8.7, 4 H, Harom, Ketal); 7.27 (d, J= 8.1, 2 H, Harom, p-Tol.); 7.38 (d, J= 8.7, 4 H, Harom, Ketal); 7.43 (d, J= 1.8, 1H, Harom, Cat.); 7.74 (d, J = 8.1, 2 H, Harom, p-Tol.); 8.03 (d, J = 1.8, 1H, Harom, Cat.). 13C-NMR (75 MHz, CD3OD): 21.5; 55.8; 110.1; 114.0; 114.5; 125.4; 128.1; 128.4; 129.1; 130.8; 131.0; 132.0; 133.2; 135.9; 139.1; 145.7; 150.5; 162.0. HR-MS (MALDI): calcd. for C29H25O8S ([M+H]+): 533.1270, found 533.1274.

f) 2,2-Bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-benzo[1,3]dioxole-4-carboxylic acid {3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylic acid (160 mg, 0.3 mmol, 1 eq.), EDC·HCl (86 mg, 0.45 mmol, 1.5 eq.), N-hydroxy-succinimide (46 mg, 0.39 mmol, 1.3 eq.), 9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydro-furo[3,4-d] [1,3]di-oxol-4-yl}-9H-purin-6-amine (100 mg, 0.31 mmol, 1 eq.) and Et3N (0.1 mL, 0.68 mmol) were reacted according to GP7.

Yield: 146 mg (62%). Colorless foam. Mp.: 124-128°C. IR (KBr): 3424m; 2930w, 1640s; 1638s; 1607s; 1514s; 1458s; 1374w, 1315m; 1249s; 1209m; 1175s; 1184s; 1090s; 1004m; 833m; 664m; 616w. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, CH3-exo); 1.61 (s, 3H, CH3-endo); 2.38 (s, 3 H, ArCH3); 3.80 (s, 6 H, OCH3); 4.01 (m, 2 H, H-C(7'), H-C(7")); 4.69 (m, 1H, H-C(4')); 4.94 (dd; J = 6.5, 3.6, 1H, H-C(3')); 5.45 (dd, J = 6.5, 2.1, 1 H, H-C(2')); 5.77 (m, 2 H, H-C(5'), H-C(6')); 5.83 (bs, 2 H, NH2); 6.09 (d, J= 2.1,1 H, H-C(1')); 6.88 (dt, J = 8.7, 1.8, 4 H, Harom, Ketal); 6.99 (t, J = 5.7,1 H, NHCO); 7.27 (d, J= 7.8,2 H, Harom, p-Tol.); 7.31-7.38 (m, 4 H, Harom, Ketal); 7.48 (d, J = 1.8, 1 H, Harom, Cat.); 7.83 (d, J = 7.8, 2 H, Harom, p-Tol.); 7.84 (s, 1H, H-C(8)); 8.21 (s, 1H, H-C(2)); 8.22 (d, J = 1.8, 1 H, Harom, Cat.). 13C-NMR (75 MHz, CDCl3): 21.7; 25.4; 27.2; 40.9; 55.4; 84.2; 84.5; 87.2; 90.3; 109.8; 113.7; 114.5; 115.4; 120.1; 121.2; 124.0; 127.7; 128.1; 128.5; 129.8; 130.2; 136.1; 138.2; 139.8; 144.1; 148.1; 148.3; 149.2; 152.4; 155.0; 160.7; 161.6. HR-MS (MALDI): calcd. for C44H43N6O10S ([M+H]+): 847.2761, found 847.2747. Anal. calcd. for C44H42N6O10S: C 62.40, H 5.00, N 9.92 found C 62.16, H 5.21, N 9.81.

g) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl] prop-2-enyl}-5-(toluene-4-sulfonyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (90 mg, 0.106 mmol) afforded the desired product as a colorless solid.

Yield: 61 mg (98%). tR, analyt.: 13.9 min. IR (KBr): 3375br, s; 1695s; 1639m; 1597m; 1548w; 1467w; 1430w; 1286m; 1201s; 1144s; 1098w; 1051w; 973w; 799w; 723w; 666m. 1H-NMR (500 MHz, CD3OD): 2.37 (s, 3 H, CH3); 4.05 (m, 2 H, H-C(7'), H-C(7")); 4.23 (t, J= 4.9, 1 H, H-C(4')); 4.51 (t,J= 4.9, 1H, H-C(3')); 4.72 (t, J= 4.8, 1 H, H-C(2')); 5.94 (m, 2 H, H-C(5'), H-C(6')); 6.05 (d, J= 4.8, H-C(1')); 7.33 (d, J= 8.2, Harom, p-Tol.); 7.35 (d, J = 2.2, 1H, Harom, Cat.); 7.78 (d, J= 8.2, Harom, p-Tol.); 7.95 (d, J= 2.2, 1H, Harom, Cat.); 8.25 (s, 1H, H-C(8)); 8.38 (s, 1 H, H-C(2)). 13C-NMR (125 MHz, CD3OD) 21.51; 41.8; 75.3; 75.6; 86.1; 90.7; 117.0; 117.2;119.5; 120.8; 128.5; 130.5; 130.8; 131.1; 133.0; 140.5; 143.5; 145.7; 147.7; 148.6; 150.2; 153.5; 154.7; 169.8. HR-MS (MALDI): calcd. for C26H27N6O6S ([M+H]+): 583.1611, found 583.1600.

Example 19 Preparation of N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy tetrahydrofuran-2-yl]prop-2-enyl}-5-(4-methyl-benzoyl)-2,3-dihydroxy-benzamide a) (3-[1,3]Dioxan-2-yl-4,5-dimethoxy-phenyl)-p-tolyl-methanol

To a solution of 2-(5-Bromo-2,3-dimethoxy-phenyl)-[1,3]dioxane (2 g, 6.6 mmol) in 13 mL dry THF cooled to -78°C, t-BuLi (1.5M solution in pentane, 2.5 eq.) was added dropwise via a syringe and the resulting dark red suspension was stirred 30 min. at -78°C. p-Tolualdehyde (1.2 g, 10 mmol, 1.5 eq.) was added dropwise to the mixture and the resulting clear solution was stirred 30 min at -78°C, then 30 min at 0°C. H2O (25 mL) was slowly added and the resulting solution was extracted with EtOAc (3 x 25 mL). The pooled organic fractions were dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 3:2) to yield the desired compound as a colorless solid.

(Takamitsu Hosoya, Eiji Takashiro, Takashi Matsumoto, Keisuke Suzuki, J. Am. Chem. Soc. 1994, 116, 1004-1015).

Yield: 2.13 g (94%). Mp.: 83-84°C. IR (KBr): 3464br, s; 2964m; 2851m; 1596w; 1490s; 1380s; 1317s; 1241s; 1140s; 1079s; 999s; 896m; 824w; 772m. 1H-NMR (300 MHz, CDCl3): 1.43 (bd, J= 13.8, 1 H, CH2); 2.23 (m, 1 H, CH2); 2.32 (s, 3 H, Ar-CH3); 3.80 (s, 3 H, OCH3); 3.83 (s, 3 H, OCH3); 4.01 (tt, J=12.0, 2.7, 2 H, OCH2); 4.24 (m, 2 H, OCH2); 5.76 (bs, 1 H, O-CH(Ar)-O); 5.83 (s, 1 H, Ar-CH(OH)-Ar); 6.91 (d, J = 1.8, 2 H, Harom); 7.12 (d, J= 8.1; 1 H, Harom, p-Tol.); 7.25 (m, 3 H, Harom, Harom, p-Tol.). 13C-NMR (75 MHz, CDCl3): 21.2; 25.9; 55.9; 61.4; 67.5; 75.9; 97.2; 110.8; 116.6; 126.4; 129.0; 132.1; 136.9; 140.1; 140.5; 145.8; 152.4. HR-MS (MALDI): calcd. for C20H24O5Na ([M+Na]+): 367.1521, found 367.1513. Anal. calcd. for C20H24O5: C 69.75, H 7.02, found C 69.81, H 7.15.

b) 2,3-Dimethoxy-5-(4-methyl-benzoyl)-benzoic acid

To a solution of (3-[1,3]Dioxan-2-yl-4,5-dimethoxy-phenyl)-p-tolyl-methanol (2.13 g, 6.18 mmol) in 75 mL THF, 56 mL 8N H2SO4 was added and the resulting solution was stirred 2 h at 50°C. After addition of 50 mL saturated NaCl-solution the mixture was extracted with EtOAc (3 x 50 mL). The pooled organic fractions were washed with saturated NaHCO3-solution (50 mL), then saturated NaCl-solution (50 mL) before being dried over MgSO4 and evaporated under reduced pressure to yield the desired product as a colorless oil. This crude product (2 g) was added to a mixture of 45 mL t-BuOH, 24 mL of a 1.25M K2HPO4-solution and 37 mL of a 1M KMnO4-solution and stirred 45 min. at 60°C. The mixture was partitioned between 100 mL saturated NaCl-solution and 100 mL CHCl3 and the aqueous phase was extracted with CHCl3 (3 x 100 mL). The pooled organic fractions were extracted with 2N NaOH-solution (3 x 100 mL), then the combined aqueous fractions were acidified with conc. HCl and extracted with CHCl3 (4 x 100 mL). The organic fractions were pooled, dried over MgSO4 and evaporated in vacuo to yield the title compound as a colorless solid.

Yield: 1.54 g (83%). Mp.: 135-136°C. IR (KBr): 2945br, s; 2620m; 1684s; 1598s; 1487s; 1442s; 1405s; 1339s; 1277s; 1129s; 1069s; 995s; 909m; 847m; 753s. 1H-NMR (300 MHz, CDCl3): 2.45 (s, 3 H, Ar-CH3); 4.01 (s,3 H, OCH3); 4.19 (s, 3 H, OCH3); 7.30 (d, J = 8.1, 2 H, Harom, p-Tol); 7.69 (d, J = 8.1; 1H, Harom, p-Tol.); 7.72 (d, J = 2.1; 1H, Harom); 8.06 (d, J = 2.1; 1 H, Harom). 13C-NMR (75 MHz, CDCl3): 21.8; 56.4; 62.4; 117.4;121.7; 126.3; 129.1; 130.0; 133.9; 134.0; 143.6; 151.5; 152.5; 165.6; 194.3. HR-MS (MALDI): calcd. for C17H17O5 ([M+H]+): 301.1076, found 301.1072.

c) 2,3-Dihydroxy-5-(4-methyl-benzoyl)-benzoic acid

2,3-Dimethoxy-5-(4-methyl-benzoyl)-benzoic acid (300 mg, 1 mmol) was treated with a mixture of 6 mL 48% HBr and 3 mL AcOH and the mixture was stirred 14 h at 140°C. After cooling to r.t., the product was precipitated by addition of H2O (60 mL). The precipitate was collected by filtration, washed with 60 mL H2O and dried under reduced pressure.

Yield: 264 mg (97%). Mp.: 95-97°C (dec.). IR (KBr): 3417br, s; 2566m; 1680s; 1609s, 1566m; 1432s; 1295s; 1253s; 1179s; 1123m; 862m; 801m; 753s. 1H-NMR (300 MHz, CD3OD): 2.44 (s, 3 H, Ar-CH3); 7.33 (d, J = 8.1, 2 H, Harom, p-Tol.); 7.47 (d, J = 2.2; 1 H, Harom); 7.62 (d, J = 8.1; 1 H, Harom, p-Tol.); 7.79 (d, J = 2.2; 1 H, Harom). 13C-NMR (75 MHz, CD3OD): 21.6; 113.4; 121.5; 125.5; 129.4; 129.9; 130.7; 136.1; 144.3; 147.2; 155.8; 173.1; 196.5. HR-MS (MALDI): calcd. for C15H11O5 ([M+H]-): 271.0607, found 271.0610.

d) 2,3-Dihydroxy-5-(4-methyl-benzoyl)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester

To a solution of 2,3-dihydroxy-5-(4-methyl-benzoyl)-benzoic acid (214 mg, 0.79 mmol) in 10 mL dry THF cooled to 0°C, N-hydroxysuccinimide (136 mg, 1.18 mmol, 1.5 eq.) and N-cyclohexylcarbodiimide, N'-methyl polystyrene HL (Novabiochem) (1.9 eq./g, 832 mg, 2 eq.) were added and the solution was stirred 14 h while the cooling bath slowly warmed up to r.t. The solution was filtered and the filtrate was evaporated under reduced pressure. The crude product was recrystallised from H2O to yield the desired product as a brownish solid.

Yield: 233 mg (80%). Mp.: 93-95°C (dec.). IR (KBr): 3341br, s; 2949m; 1738s; 1653m; 1606m; 1482w; 1368m; 1323m; 1203s; 1068s; 914w; 755w; 645w. 1H-NNM (300 MHz, CD3OD): 2.42 (s, 3 H, Ar-CH3); 2.87 (s, 4 H, CH2-CH2); 7.33 (d, J = 8.0, 2 H, Harom, p-Tol.); 7.57 (d, J = 1.7; 1H, Harom); 7.65 (d, J = 8.0; 1H, Harom, p-Tol.); 7.87 (d, J = 1.7; 1 H, Harom). 13C-NMR (75 MHz, CD3OD): 21.4; 26.4; 110.3; 121.9; 125.2; 129.8; 130.0; 130.6; 135.7; 144.3; 147.6; 154.6; 163.6; 171.2; 195.6. HR-MS (MALDI): calcd. for C19H16NO7 ([M+H]+): 370.0927, found 370.0918.

e) N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-methyl-benzoyl)-2,3-dihydroxy-benzamide

To a solution of 2,3-dihydroxy-5-(4-methyl-benzoyl)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (100 mg, 0.27 mmol) in DMF (4 mL), (2R,3S,4R,5R)-2-((E)-3-Amino-propenyl)-5-(6-amino-purin-9-yl)-tetrahydro-furan-3,4-diol (79 mg, 0.27 mmol, 1 eq.) and Et3N (113 µL, 0.81 mmol, 3 eq.) were added and the solution was stirred 18 h at r.t. The crude product was purified using HPLC (RP C18, linear gradient of CH3CN in H2O with 0.1% TFA, 5 → 100% in 20 min, flow of 1 mL / min (analytical), UV-detection at 254 nm) to yield the title compound as a colorless solid.

Yield: 54 mg (37%). tR, analyt.: 13.6 min. IR (KBr): 3378 br, s; 1642s; 1604s; 1427m; 1296s; 1120m; 1043w; 753w. 1H-NMR (500 MHz, CD3OD): 2.32 (s, 3 H, CH3), 3.94 (m, 2 H, H-C(7'), H-C(7")); 4.13 (t, J= 5.0, 1 H, H-C(4')); 4.41 (m, 1H, H-C(3')); 4.63 (t, J= 4.8, 1 H, H-C(2')); 5.83 (m, 2 H, H-C(5'), H-C(6')); 5.95 (d, J= 4.8, 1H, H-C(1')); 7.22 (d, J = 8.2, 1H, Harom, Cat., p-Tol.); 7.28 (d, J = 2, 1H, Harom, Cat.); 7.54 (d, J = 8.2, 1H, Harom, Cat, p-Tol.); 7.70 (d, J= 2,1 H, Harom, Cat.); 8.18 (s, 1H, H-C(8)); 8.28 (s, 1H, H-C(2)). 13C-NMR (125 MHz, (CD3OD): 21.6; 41.6; 75.2; 75.6; 86.1; 90.6; 116.4; 120.3; 120.7; 122.7; 129.7; 130.1; 130.3; 130.9; 131.1; 136.4; 143.3; 144.5; 147.5; 148.0; 150.2; 153.6; 154.4; 170.4; 197.1. HR-MS (MALDI): calcd. for C27H27N6O7 ([M+H]+): 547.1941, found 547.1934. Tablet Formulation (Wet Granulation) Item Ingredients mg/tablet 25 mg 100 mg 1. Compound of formula I 25 100 2. Lactose Anhydrous DTG 105 30 3. Sta-Rx 1500 6 6 4. Microcrystalline Cellulose 30 30 5. Magnesium Stearate 1 1 Total 167 167

Manufacturing Procedure

  1. 1. Mix items 1, 2, 3 and 4 and granulate with purified water.
  2. 2. Dry the granules at 50°C.
  3. 3. Pass the granules through suitable milling equipment
  4. 4. Add item 5 and mix for three minutes; compress on a suitable press.
Capsule Formulation Item Ingredients mg/capsule 25 mg 100 mg 1. Compound of formula I 25 100 2. Hydrous Lactose 123 148 3. Corn Starch 35 40 4. Talc 15 10 5. Magnesium Stearate 2 2 Total 200 300

Manufacturing Procedure

  1. 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
  2. 2. Add items 4 and 5 and mix for 3 minutes.
  3. 3. Fill into a suitable capsule.


Anspruch[de]
Verbindungen der Formel worin R1 H, CN, Halogen, -COR2, -S(O)xR2, C1-12-Alkyl, C2-12-Alkenyl, C3-8-Cycloalkyl, eine Heterocyclylgruppe, eine Arylgruppe, eine Heteroarylgruppe, C3-8-Cycloalkyl-(C1-3)-alkyl, eine Heterocyclyl-(C1-3)-alkylgruppe, eine Aryl-(C1-3)-alkyl- oder eine Heteroaryl-(C1-3)-alkylgruppe ist; wobei die Alkyl-, Alkenyl-, Alkoxy-, Cycloalkyl-, Heterocyclylgruppe, Aryl- und Heteroarylgruppen alle gegebenenfalls substituiert sein können; R2 -N(R3,R3'), C1-6-Alkyl, C3-8-Cycloalkyl, Heterocyclyl, Aryl, Heteroaryl, C3-8-Cycloalkyl-(C1-3)-alkyl, eine Heterocyclyl-(C1-3)-alkylgruppe, eine Aryl-(C1-3)-alkyl- oder eine Heteroaryl-(C1-3)-alkylgruppe ist, wobei das C1-6-Alkyl, C3-8-Cycloalkyl, Heterocyclyl, Aryl, Heteroaryl alle gegebenenfalls substituiert sein können; R3 und R3' unabhängig Wasserstoff oder (C1-3)-Alkyl sind x 0, 1 oder 2 ist; und die Ester davon, die unter physiologischen Bedingungen hydrolysierbar sind, und die pharmazeutisch akzeptablen Salze davon. Verbindungen nach Anspruch 1, worin R1 Wasserstoff, Cyano, Halogen, -COR2, -S(O)2R2, C1-6-Alkyl, C1-6-Alkyl, substituiert mit Halogen, C2-6-Alkenyl, substituiert mit COR2, Phenyl oder Phenyl, substituiert mit C1-6-Alkyl oder Halogen, Benzyl oder Benzyl, substituiert mit C1-6-Alkyl, oder Heteroaryl, wie Pyridinyl, Thiazolyl oder Benzthiazolyl, ist und worin R2 C1-6-Alkyl, C1-6-Alkyl, substituiert mit Halogen, oder -N(R3,R3') ist und R3 und R3' C1-3-Alkyl sind, worin ferner R2 Phenyl oder Phenyl, substituiert mit C1-6-Alkyl oder Halogen, Cyclohexyl oder Heteroaryl, wie Pyridinyl, Thiazolyl oder Benzthiazolyl, ist. Verbindungen nach Anspruch 1 oder 2, worin R1 Wasserstoff, Cyano oder Halogen ist. Verbindungen nach den Ansprüchen 1 oder 2, worin R1 C1-6-Alkyl, C1-6-Alkyl, substituiert mit Halogen, C2-6-Alkenyl, substituiert mit COR2, ist und worin R2 -N(R3,R3') ist, und R3 und R3' C1-3-Alkyl sind. Verbindungen nach Anspruch 4

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-isopropyl-benzamid,

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-(2-dimethylcarbamoyl-vinyl)-2,3-dihydroxy-benzamid,

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluormethyl-benzamid.
Verbindungen nach den Ansprüchen 1 oder 2, worin R1 -COR2 ist und R2 C1-6-Alkyl, C1-6-Alkyl, substituiert mit Halogen, -N(R3,R3') ist und R3 und R3' C1-3 -Alkyl sind. Verbindungen nach Anspruch 5

N- {3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoracetyl-benzamid,

N3-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-4,5-dihydroxy-N1,N1-dimethyl-isophthalamid.
Verbindungen nach den Ansprüchen 1 oder 2, worin R1 -COR2 ist und worin R2 Phenyl, Phenyl, substituiert mit C1-6-Alkyl oder Halogen, C3-8-Cyclohexyl oder Heteroaryl, wie Pyridinyl, Thiazolyl oder Benzthiazolyl, ist. Verbindungen nach Anspruch 8

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzoyl)-benzamid,

N- {3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyclohexancarbonyl-2,3-dihydroxy-benzamid,

N- {3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(pyridin-4-carbonyl)-benzamid.
Verbindungen nach den Ansprüchen 1 oder 2, worin R1 -S(O)2R2 ist und worin R2 C1-6-Alkyl, C1-6-Alkyl, substituiert mit Halogen, -N(R3,R3') ist und R3 und R3' C1-3-Alkyl sind, worin ferner R2 Phenyl, Phenyl, substituiert mit C1-6-Alkyl oder Halogen, Cyclohexyl oder Heteroaryl, wie Pyridinyl, Thiazolyl oder Benzthiazolyl, ist. Verbindung nach Anspruch 10

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(toluol-4-sulfonyl)-benzamid.
Verbindungen nach Anspruch 1 oder 2, worin R1 Phenyl oder Phenyl, substituiert mit C1-6-Alkyl oder Halogen, Pyridinyl, Thiazolyl, Benzthiazolyl, Benzyl oder Benzyl, substituiert mit C1-6-Alkyl, ist. Verbindungen nach Anspruch 12

4'-Fluor-4,5-dihydroxy-biphenyl-3-carbonsäure{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]-allyl}-amid,

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-thiazol-2-yl-benzamid,

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-pyridin-4-yl-benzamid,

4,5-Dihydroxy-4'-methyl-biphenyl-3-carbonsäure{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]-allyl}-amid,

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamid,

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzyl)-benzamid.
Medikament, enthaltend eine oder mehrere der Verbindungen nach einem der Ansprüche 1 bis 13 und pharmazeutisch akzeptable Trägerstoffe. Medikament nach Anspruch 14 zur Behandlung von Krankheiten, die die COMT-Inhibierung betreffen. Medikament nach Anspruch 15, worin die Krankheit Depression oder die Parkinson-Krankheit ist. Medikament nach Anspruch 14 zur Verbesserung der Wahrnehmung. Verwendung der Verbindungen nach einem der Ansprüche 1 bis 13 zur Herstellung eines Medikaments zur Vorbeugung und Behandlung von Krankheiten, die die COMT-Inhibierung betreffen, wie Depression, die Parkinson-Krankheit, oder zur Verbesserung der Wahrnehmung.
Anspruch[en]
Compounds of formula wherein R1 is H, CN, halogen, -COR2, -S(O)xR2, C1-12-alkyl, C2-12-alkenyl, C3-8-Cycloalkyl, a heterocyclyl group, an aryl group, a heteroaryl group, C3-8-cycloalkyl-(C1-3)-alkyl, a heteroryclyl-(C1-3)-alkyl group, an aryl-(C1-3)-alkyl or a heteroaryl-(C1-3)-alkyl group; the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclyl group, aryl and heteroaryl groups may all be optionally substituted; R2 is -N(R3, R3'), C1-6-alkyl, C3-8-cycloalkyl, heteroryclyl, aryl, heteroaryl, C3-8-cycloalkyl-(C1-3)-alkyl, a heterocyclyl-(C1-3)-alkyl group, an aryl-(C1-3)-alkyl or a heteroaryl-(C1-3)-alkyl group, the C1-6-alkyl, C3-8-cycloalkyl, heterocyclyl, aryl, heteroaryl may all be optionally substituted; R3 and R3' are independently hydrogen or (C1-3)-alkyl x is 0,1 or 2; and the ester thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof Compounds according to claim 1, wherein R1 is a hydrogen, cyano, halogen, -COR2, -S(O)2R2, C1-6-alkyl, C1-6-alkyl substituted with halogen, C2-6-alkenyl substituted with COR2, phenyl or phenyl substituted with C1-6-alkyl or halogen, benzyl or benzyl substituted with C1-6-alkyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl and wherein R2 is C1-6-alkyl, C1-6-alkyl substituted with halogen or -N(R3,R3') and R3 and R3' are C1-3-alkyl, furthermore wherein R2 is phenyl or phenyl substituted with C1-6-alkyl or halogen, cyclohexyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl. The compounds according to claim 1 or 2 wherein R1 is hydrogen cyano or halogen. The compounds according to claims 1 or 2, wherein R1 is C1-6-alkyl) C1-6-alkyl substituted with halogen, C2-6-alkenyl substituted with COR2, and wherein R2 is -NR3,R3' and R3 and R3' are C1-3-alkyl. The compounds according to claim 4

N-{3- [5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-isopropyl-benzamide

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-(2-dimethylcarbamoyl-vinyl)-2,3-dihydroxy-benzamide

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoromethyl-benzamide
The compounds according to claims 1 or 2 wherein R1 is -COR2 and R2 is C1-6-alkyl, C1-6-alkyl substituted with halogen, -N(R3,R3') and R3 and R3' are C1-3 -alkyl. The compounds according to claim 5

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoroacetyl-benzamide

N3-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2_yl]_allyl}_4,5_ dihydroxy-N1,N1-dimethyl-isophthalamide
The compounds according to claims 1 or 2 wherein R1 is -COR2) and wherein R2 is phenyl, phenyl substituted with C1-6-alkyl or halogen, C3-8-cyclohexyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl. The compounds according to claim 8

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5=(4-methyl-benzoyl)-benzamide

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cycloheacanecarbonyl-2,3-dihydroxy-benzamide

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy 5-(pyridine-4-carbonyl)-benzamide
The compounds according to claims 1 or 2 wherein R1 is -s(O)2R2, and wherein R2 is C1-6-alkyl, C1-6-alkyl substituted with halogen, -N(R3,R3') and R3 and R3' are C1-3-alkyl, furthermore wherein R2 is phenyl, phenyl substituted with C1-6-alkyl or halogen, cyclohexyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl. The compound according to claim 10, N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl] -allyl}-2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzamide The compounds according to claim 1 or 2 wherein R1 is phenyl or phenyl substituted with C1-6-alkyl or halogen, pyridinyl, thiazolyl, benzthiazolyl, benzyl or benzyl substituted with C1-6-alkyl. The compounds according to claim 12

4'-Fluoro-4,5-dihydroxy-biphenyl-3-carboxylic acid {3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl] -allyl}-amide

N-{3-(5-[6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-thiazol-2-yl-benzamide

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-pyridin-4-yl-benzamide

4,5-Dihydroxy-4'-methyl-biphenyl-3-carboxylic acid {3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamide

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzyl)-benzamide
A medicament containing one or morre compounds as claimed in anyone of claims 1 to 13 and pharmaceutically acceptable excipients. A medicament according to claim 14 for the treatment of diseases related to the COMT inhibition. A medicament according to claim 15 wherein the disease is depression or Parkinson's disease. A medicament according to claim 14 to improve cognition. The use of compounds according to anyone of claims 1 to 13 for the manufacture of a medicament for the prevention and treatment of diseases related to the COMT inhibition such as depression, Parkinson's disease, or to improve cognition.
Anspruch[fr]
Composés de formule dans laquelle R1 est H, CN, un halogène, -COR2, -S(O)xR2, un groupe alkyle en C1-12, alcényle en C2-12, cycloalkyle en C3-8 , hétérocyclyle, aryle, hétéroaryle, (cycloalkyle en C3-8) (alkyle en C1-3), hétérocyclyl (alkyle en C1-3), aryl (alkyle en C1-3) ou hétéroaryl (alkyle en C1-3) ; le groupe alkyle, alcényle, alcoxy, cycloalkyle, hétérocyclyle, les groupes aryle et hétéroaryle pouvant tous être éventuellement substitués ; R2 est -N (R3, R3'), un groupe alkyle en C1-6, cycloalkyle en C3-8, hétérocyclyle, aryle, hétéroaryle, (cycloalkyle en C3-8)(alkyle en C1-3), hétérocyclyl (alkyle en C1-3), aryl (alkyle en C1-3) ou hétéroaryl (alkyle en C1-3), les groupes alkyle en C1-6, cycloalkyle en C3-8, hétérocyclyle, aryle, hétéroaryle pouvant tous être éventuellement substitués ; R3 et R3' sont indépendamment un hydrogène ou un groupe alkyle en C1-3 x vaut 0, 1 ou 2 ; et les esters de ceux-ci qui sont hydrolysables dans des conditions physiologiques et leurs sels pharmaceutiquement acceptables. Composés selon la revendication 1, dans lesquels R1 est un hydrogène, un groupe cyano, un halogène, -COR2, -S (O) 2R2, un groupe alkyle en C1-6, alkyle en C1-6 substitué par un halogène, alcényle en C2-6 substitué par COR2, phényle ou phényle substitué par un groupe alkyle en C1-6 ou par un halogène, benzyle ou benzyle substitué par un groupe alkyle en C1-6, ou hétéroaryle tel que pyridinyle, thiazolyle ou benzothiazolyle et dans lesquels R2 est un groupe alkyle en C1-6, alkyle en C1-6 substitué par un halogène ou - N (R3, R3') et R3 et R3' sont des groupes alkyle en C1-3, de plus dans lesquels R2 est un groupe phényle ou phényle substitué par un groupe alkyle en C1-6 ou par un halogène, cyclohexyle, ou hétéroaryle tel que pyridinyle, thiazolyle ou benzothiazolyle. Composés selon la revendication 1 ou 2 dans lesquels R1 est un hydrogène, un groupe cyano ou un halogène. Composés selon les revendications 1 ou 2, dans lesquels R1 est un groupe alkyle en C1-6, alkyle en C1-6 substitué par un halogène, alcéyle en C2-6 substitué par COR 2 et dans lesquels R2 est -NR3, R3' et R3 et R3' sont des groupes alkyle en C1-3. Composés selon la revendication 4

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-isopropylbenzamide,

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-5-(2-diméthylarbamoyl-vinyl)-2,3-dihydroxybenzamide,

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-2,3-dihydroxy-5-trifluorométhylbenzamide.
Composés selon les revendications 1 ou 2 dans lesquels R1 est -COR2 et R2 est un groupe alkyle en C1-6, alkyle en C1-6 substitué par un halogène, -N (R3, R3') et R3 et R3' sont des groupes alkyle en C1-3. Composés selon la revendication 5

N-{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxytétrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoroacétyl-benzamide,

N3-{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxytétrahydro-furan-2-yl]-allyl}-4,5-dihydroxy-N1,N1-diméthyl-isophtalamide.
Composés selon les revendications 1 ou 2 dans lesquels R1 est -COR2, et dans lesquels R2 est un groupe phényle, phényle substitué par un groupe alkyle en C1-6 ou par un halogène, cyclohexyle en C3-8, ou hétéroaryle tel que pyridinyle, thiazolyle ou benzothiazolyle. Composés selon la revendication 8

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-2,3-dihydroxy-5-(4-méthylbenzoyl)-benzamide,

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-5-cyclohexanecarbonyl-2,3-dihydroxybenzamide,

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-2,3-dihydroxy-5-(pyridine-4-carbonyl)-benzamide.
Composés selon les revendications 1 ou 2 dans lesquels R1 est -S (O) 2R2, et dans lesquels R2 est un groupe alkyle en C1-6, alkyle en C1-6 substitué par un halogène, -N (R3, R3') et R3 et R3' sont des groupes alkyle en C1-3, de plus dans lesquels R2 est un groupe phényle, phényle substitué par un groupe alkyle en C1-6 ou par un halogène, cyclohexyle, ou hétéroaryle tel que pyridinyle, thiazolyle ou benzothiazolyle. Composé selon la revendication 10, N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxy-tétrahydrofuran-2-yl]-allyl}-2,3-dihydroxy-5-(toluène-4-sulfonyl)-benzamide. Composés selon les revendications 1 ou 2 dans lesquels R1 est un groupe phényle ou phényle substitué par un groupe alkyle en C1-6 ou un halogène, pyridinyle, thiazolyle, benzothiazolyle, benzyle ou benzyle substitué par un groupe alkyle en C1-6. Composés selon la revendication 12

{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-amide de l'acide 4'-fluoro-4,5-dihydroxybiphényl- 3-carboxylique,

N-(3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-2,3-dihydroxy-5-thiazol-2-ylbenzamide,

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-2,3-dihydroxy-5-pyridin-4-ylbenzamide,

{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-amide de l'acide 4,5-dihydroxy-4'-méthylbiphényl-3-carboxylique,

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxybenzamide,

N-{3-[5-(6-aminopurin-9-yl)-3,4-dihydroxytétrahydrofuran-2-yl] -allyl)-2,3-dihydroxy-5- (4-méthylbenzyl)-benzamide.
Médicament contenant un ou plusieurs composés selon l'une quelconque des revendications 1 à 13 et des excipients pharmaceutiquement acceptables. Médicament selon la revendication 14 pour le traitement de maladies liées à l'inhibition de COMT. Médicament selon la revendication 15 où la maladie est la dépression ou la maladie de Parkinson. Médicament selon la revendication 14 pour améliorer la cognition. Utilisation de composés selon l'une quelconque des revendications 1 à 13 pour la fabrication d'un médicament pour la prévention ou le traitement de maladies liées à l'inhibition de COMT telles que la dépression, la maladie de Parkinson, ou pour améliorer la cognition.






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