PYRIMIDINE DERIVATIVES FOR PREVENTION AND TREATMENT OF BACTERIAL INFECTIONS

Abstract

Pyrimidine derivatives of formula (I):

##STR00001##

optionally with a detectable isotope, pharmaceutical composition and method of preparation thereof. Pyrimidine derivatives for use in treatment or prevention of bacterial infection in a host mammal in need of such treatment or prevention and use as inhibitors of biofilm formation on a surface of biomaterial or medical device, particularly of cardiovascular device such as prosthetic heart valve or pacemakers. Pyrimidine derivatives for use as radiotracer in diagnosing or prognosing bacterial infection in a host mammal.

Claims

1. A pyrimidine derivative represented by formula (I) ##STR00157## or isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts or prodrug thereof; wherein: X.sup.1 and X.sup.2 are independently N, CH, CR.sup.8 wherein R.sup.8 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; with the exception that if one of X.sup.1 or X.sup.2 is equal to N, then the remaining of X.sup.1 or X.sup.2 are selected from CH, CR.sup.8; Y is O or S; R.sup.1 and R.sup.2 are independently C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl, aryl, aryl-C.sub.1-6-alkyl wherein the alkyl or cycloalkyl moiety is optionally mono or polysubstituted with OH or an halogen and the aryl moiety is optionally mono or polysubstituted with an halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, OH, NO.sub.2, CN, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2 COOH, COOR.sup.8, CONH.sub.2, CONHR.sup.8, CON(R.sup.8).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, or SO.sub.2N(R.sup.8).sub.2; R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are independently H, an halogen, a C.sub.1-6 alkyl, C.sub.1-6 alkoxy, OH, NO.sub.2, CN, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2 COOH, COOR.sup.8, CONH.sub.2, CONHR.sup.8, CON(R.sup.8).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, or SO.sub.2N(R.sup.8).sub.2.

2. The pyrimidine derivative according to claim 1 comprising at least one detectable isotope.

3. The pyrimidine derivative according to claim 2 wherein the detectable isotope is selected from .sup.3H, .sup.18F, .sup.19F, .sup.11C, .sup.13C, .sup.14C, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.125I, .sup.131I, .sup.15O, and .sup.13N.

4. The pyrimidine derivative according to anyone of claim 1 wherein R.sup.3 and R.sup.7 are hydrogen and R.sup.4 and R.sup.5 are independently an halogen.

5. The pyrimidine derivative according to claim 1 wherein X.sup.1 is CH or CR.sup.8 and X.sup.2 is N.

6. The pyrimidine derivative according to claim 5 comprising a N-(2-phenylcyclopropyl)-9H-purin-6-amine represented by formula (V) ##STR00158##

7. The pyrimidine derivatives according to claim 5 selected from the group consisting of: N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c); 9-methyl-N-((1R,2S)-2-phenylcyclopropyl)-2-(propylthio)-9H-purin-6-amine (2c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(propylthio)-9H-purin-6-amine (3c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-propyl-2-(propylthio)-9H-purin-6-amine (4c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-isopropyl-2-(propylthio)-9H-purin-6-amine (5c); 9-cyclopropyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (6c); 9-butyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (7c); 9-(sec-butyl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (8c); 9-(tert-butyl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (9c); 9-cyclobutyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (10c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-pentyl-2-(propylthio)-9H-purin-6-amine (11c); 9-cyclopentyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (12c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-hexyl-2-(propylthio)-9H-purin-6-amine (13c); 9-cyclohexyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (14c); 9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c); 2-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)ethanol (16c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (17c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9-(2,2,2-trifluoroethyl)-9H-purin-6-amine (18c); (1S,2R,3S,4R)-4-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)cyclopentane-1,2,3-triol (19d); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(ethylthio)-9-methyl-9H-purin-6-amine (20c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(ethylthio)-9H-purin-6-amine (21c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(methylthio)-9H-purin-6-amine (22c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-propoxy-9H-purin-6-amine hydrochloride (23t.HCl); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (24c); 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (25c); and 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-9H-purin-6-amine (26c); or isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts or prodrug thereof.

8. (canceled)

9. The pyrimidine derivative according to claim 5 which is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c).

10. The pyrimidine derivative according to claim 1 wherein X.sup.1 is N and X.sup.2 is CH or CR.sup.8.

11. The pyrimidine derivative according to claim 10 selected from the group consisting of: N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (27k); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (28x.HCl); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(propylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (29x.HCl); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30k); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(ethylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (31x.HCl); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(propylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (32x.HCl); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-isopropyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (33k.HCl); and N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(methylthio)-1-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (34k.HCl); or isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts or prodrug thereof.

12. (canceled)

13. The pyrimidine derivative according to claim 1 wherein X.sup.1 and X.sup.2 are CH or CR.sup.8.

14. The pyrimidine derivative according to claim 13 which is: N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-7-ethyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (35p.HCl); or isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts or prodrug thereof.

15. The pyrimidine derivative according to claim 1 wherein R.sup.3 and R.sup.7 are H and R.sup.4, R.sup.5 is a fluorine.

16. (canceled)

17. A method of treating a bacterial infection in mammal in need of such treatment comprising administering to the mammal the pyrimidine derivative according to claim 1.

18. A pharmaceutical composition comprising a pyrimidine derivative according to claim 1 in combination with pharmaceutically acceptable diluent, adjuvant and/or carrier.

19. (canceled)

20. A method of reducing bacterial infection in a host mammal, wherein said method comprises applying said pyrimidine derivative according to claim 1 on the surface of a biomaterial implant prior to implantation of said implant in said host mammal.

21. (canceled)

22. A method for reducing bacterial growth in biofilm formation comprising applying on a surface of a medical device, an effective amount of pyrimidine derivatives according to anyone of claim 1.

23. The method according to claim 22 wherein the medical device is a cardiovascular device.

24. (canceled)

25. A method of preparation of pyrimidine derivatives of formula (I) according to claim 5, wherein X.sup.1 is CH or CR.sup.8, X.sup.2 is N; said method comprising the following steps: ##STR00159## 1) Preparation of a 2-substituted 4,6-dihalogenoropyrimidin-5-amine (Xh) as starting product; 2) reacting the 2-substituted 4,6-halogenopyrimidin-5-amine (Xh) with R.sup.2NH.sub.2 to obtain an intermediate (Xa) wherein R.sup.2 is as defined in formula (I); 3) reacting the intermediate (Xa) with trialkyl orthoformate under heating in presence of an acid to obtain intermediate 2,9-disubstituted 6-halogeno-9H-purine (Xb); 4) substituting the halogen atom of intermediate (Xb) by a (R.sup.3-R.sup.7)-substituted phenylcyclopropylamine under heating to obtain a pyrimidine derivative of formula (I) wherein Y is S (Xc); and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

26. The method according to claim 25 wherein the starting product (Xh) is obtained by: ##STR00160## 1) reacting thiobarbituric acid with R.sup.1-halide under heating to obtain a 2-substituted pyrimidine-4,6-diol (Xe); 2) reacting 2-substituted pyrimidine-4,6-diol (Xe) under cooling with nitric acid to obtain intermediate (Xf), followed by nucleophilic substitution in the presence of an organic base to provide a 2-substituted 4,6-dihalogeno-5-nitropyrimidine (Xg); 3) reducing the 2-substituted 4,6-dihalogeno-5-nitropyrimidine (Xg) to a corresponding 2-substituted 4,6-dihalogenopyrimidin-5-amine (Xh).

27. The method according to claim 25 further comprising a reaction of conversion of a thioether group of Xc wherein Y is S; into a corresponding ether function (YO) to obtain a pyrimidine derivative of formula (I) wherein Y is O (Xt); ##STR00161## and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

28. The method according to claim 26 further comprising a conversion reaction comprising: ##STR00162## 1) a first reaction of oxidation of the thioether function of (Xc) by a peracid to provide a methylsulfonyl group in an intermediate (Xq) and 2) a further reaction of nucleophilic substitution of the intermediate (Xq) with an alkyl thiol to provide pyrimidine derivatives of formula (I) wherein Y is S and R.sup.l is not methyl (Xw).

29. A method of preparation of pyrimidines derivatives of formula (I) wherein X.sup.1 is N and X.sup.2 is CH or CR.sup.8 according to claim 10; said method comprising the following steps: ##STR00163## 1) reacting thiobarbituric acid with a R.sup.1-halide under heating to obtain a 2-substituted pyrimidine-4,6-diol (Xe); 2) reacting the 2-substituted pyrimidine 4,6-diol (Xe) with phosphoryl halide in presence of DMF to obtain the corresponding 2-substituted 4,6-dihalogenopyrimidin-5-carbaldehyde (Xi); 3) reacting under cooling, the 2-substituted 4,6-dihalogenopyrimidin-5-carbaldehyde (Xi) with a non-substituted hydrazine to provide a non alkylated 1H-pyrazolo[3,4-d]pyrimidine (Xi), followed by an alkylation with a R.sup.2-halide to provide intermediate (Xj), and a nucleophilic substitution with a R.sup.3-R.sup.7-substituted phenylcyclopropylamine to provide (Xk); and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

30. The method according to claim 29 further comprising a reaction of conversion of a thioether group of Xk (YS) into a corresponding ether function (YO) to obtain pyrimidine derivatives of formula (I) wherein Y is O (Xu); ##STR00164## and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

31. The method of preparation according to claim 29 further comprising a reaction of conversion comprising: ##STR00165## a first reaction of oxidation of the thioether function of (Xk) by a peracid to provide a methylsulfonyl group in an intermediate (Xr) and a further reaction of nucleophilic substitution with an alkyl thiol to provide pyrimidines derivatives of formula (I) wherein Y is S and R.sup.1 is not methyl (Xx); and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

32. A method of preparation of pyrimidine derivatives of formula (I) wherein X.sup.1 and X.sup.2 are CH or CR.sup.8 according to claim 13; said method comprising the following steps: ##STR00166## 1) reacting under heating a 6-amino-4-hydroxypyrimidine-2-thiol with a R.sup.1-halide in alkaline medium to provide a 2-substituted 6-aminopyrimidine-4-ol (XI); 2) converting the 2-substituted 6-aminopyrimidine-4-ol (XI) with halogenoacetaldehyde under heating to provide a 2-substituted 7H-pyrrolo[2,3-d]pyrimidine-4-ol (Xm); 3) reacting (Xm) with phosphoryl halide under heating to provide 2-substituted 4-halogeno-7H-pyrrolo[2,3-d]pyrimidine (Xn) 4) substituting an halogen atom of (Xn) with a (R.sup.3-R.sup.7)-substituted phenylcyclopropyl amine to provide Xo, followed by an alkylation with a R.sup.2-halide in alkaline medium to provide (Xp); and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

33. The method according to claim 32 further comprising a reaction of conversion of a thioether group of (Xp) wherein Y is S into a corresponding ether function (YO) to obtain pyrimidine derivatives of formula (I) wherein Y is O (Xv); ##STR00167## and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

34. The method according to claim 32 further comprising a reaction of conversion comprising: ##STR00168## a first reaction of oxidation of the thioether function of (Xp) by a peracid to provide a methylsulfonyl group in an intermediate (Xs) and a further reaction of nucleophilic substitution with an alkyl thiol to provide pyrimidine derivatives of formula (I) wherein Y is S and R.sup.1 is not methyl (Xy); and optionally forming a pharmaceutically acceptable salt or prodrug thereof.

35. A method of diagnosing or prognosing a bacterial infection comprising using the pyrimidine derivative according to claim 1 comprising a marker for use in diagnosing or prognosing bacterial infection.

36. (canceled)

37. (canceled)

38. (canceled)

39. The method according to claim 17, wherein the bacterial infection is caused by Gram-positive bacteria.

40. The method according to claim 39 wherein the bacterial infection is caused by one or more of methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), glycopeptide intermediate S. aureus (GISA), Coagulase-negative staphylococci (CoNS), Vancomycin-resistant enterococci (VRE), beta-hemolytic Streptococcus agalactiae (Group B Streptococcus, GBS).

Description

BRIEF DESCRIPTION OF THE FIGURES

[0254] FIG. 1 illustrates the inhibition of Staphylococcus aureus (Xen29-ATCC 12600) biofilm formation (step 2) in medium containing the tested molecules 2329 (1c), 2348 (3c), 2412 (15c), 2452 (17c) at a concentration of 10 M compared to medium containing the vehicle alone as control (CTRL).

[0255] FIG. 2 illustrates the effect of a 24 h treatment with different concentrations of the molecule 2329 (1c) on a mature biofilm (step 3: 24-hour biofilm) of S. epidermidis. S. epidermidis film biomass, stained with crystal violet is proportional to absorbance of the dye at 570 nm.

[0256] FIG. 3 illustrates kinetics of Inhibition of Staphylococcus aureus (Xen29-ATCC 12600) biofilm formation (step 2) in medium containing the pyrazolo molecule 2666 (28x.HCl) and the purine molecule 2511 (24c) at a concentration of 20 M compared to medium containing the vehicle alone as control (Ctrl).

[0257] The invention is illustrated hereafter by the following non limiting examples.

[0258] 1. Preparation of New Pyrimidine Derivatives:

EXAMPLE 1

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c)

6-Chloro-N.SUP.4.-methyl-2-(propylthio)pyrimidine-4,5-diamine (1a)

[0259] ##STR00017##

[0260] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with a solution of methylamine 33% w/w in methanol (0.76 mL, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0261] Yield: 96%.

[0262] Melting point: 119-121 C.

[0263] .sup.1H NMR (DMSO-d.sub.6) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.64 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.87 (d, J=4.5 Hz, 3H, NHCH.sub.3), 2.96 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.71 (s, 2H, NH.sub.2), 7.01 (q, J=4.4 Hz, 1H, NHCH.sub.3).

[0264] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.6 (SCH.sub.2CH.sub.2CH.sub.3), 27.8 (NHCH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 120.0 (C-5), 137.1 (C-6), 153.2 (C-4), 155.4 (C-2).

6-Chloro-9-methyl-2-(propylthio)-9H-purine (1b)

[0265] ##STR00018##

[0266] A solution of (1a) (233.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0267] Yield: 77%.

[0268] Melting point: 75-78 C.

[0269] .sup.1H NMR (DMSO-d.sub.6) 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.74 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.18 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.79 (s, 3H, NCH.sub.3), 8.48 (s, 1H, 8-H).

[0270] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 22.0 (SCH.sub.2CH.sub.2CH.sub.3), 29.9 (NCH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 127.9 (C-5), 147.0 (C-8), 148.7 (C-6), 153.2 (C-4), 163.9 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c)

[0271] ##STR00019##

[0272] A solution of (1b) (122.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0273] Yield: 42%.

[0274] Melting point: 94-96 C.

[0275] .sup.1H NMR (CDCl.sub.3) 0.93 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 1.65 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 3.02 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.12 (bs, 1H, NHCH(CH.sub.2)CHPh), 3.76 (s, 3H, NCH.sub.3), 5.98 (bs, 1H, NH), 6.97 (m, 1H, 6-H), 7.07 (m, 2H, 2-H/5-H), 7.59 (s, 1H, 8-H).

[0276] .sup.13C NMR (CDCl.sub.3) 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 16.2 (NHCH(CH.sub.2)CHPh), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 29.7 (NCH.sub.3), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.4 (NHCH(CH.sub.2)CHPh), 115.5 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.4 (C-5), 122.6 (C-6), 137.9 (C-1), 139.5 (C-8), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.8 (C-4), 154.5 (C-6), 165.6 (C-2).

EXAMPLE 2

Synthesis of 9-methyl-N-((1R,2S)-2-phenylcyclopropyl)-2-(propylthio)-9H-purin-6-amine (2c)

9-Methyl-N-((1R,2S)-2-phenylcyclopropyl)-2-(propylthio)-9H-purin-6-amine (2c)

[0277] ##STR00020##

[0278] A solution of (1b) (122.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-phenylcyclopropanamine (56.0 mg, 1.1 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 4 h. After distillation of the solvents under vacuum, the residue was purified by silica gel column chromatography.

[0279] Yield: 27%.

[0280] Melting point: 171-172.5 C.

[0281] .sup.1H NMR (CDCl.sub.3) 0.88 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.33 (m, 2H, NHCH(CH.sub.2)CHPh), 1.60 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.13 (m, 1H, NHCH(CH.sub.2)CHPh), 2.92 (m, 1H, SCH.sub.2CH.sub.2CH.sub.3), 3.06 (m, 1H, SCH.sub.2CH.sub.2CH.sub.3), 3.22 (bs, 1H, NHCH(CH.sub.2)CHPh), 3.75 (s, 3H, NCH.sub.3), 5.97 (bs, 1H, NH), 7.19 (m, 3H, 2-H/4-H/6-H), 7.30 (m, 2H, 3-H/5-H), 7.58 (s, 1H, 8-H).

[0282] .sup.13C NMR (CDCl.sub.3) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 16.8 (NHCH(CH.sub.2)CHPh), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 25.7 (NHCH(CH.sub.2)CHPh), 29.7 (NCH.sub.3), 33.3 (SCH.sub.2CH.sub.2CH.sub.3), 33.5 (NHCH(CH.sub.2)CHPh), 117.4 (C-5), 126.0 (C-4), 126.2 (C-2/C-6), 128.3 (C-3/C-5), 139.5 (C-8), 140.9 (C-1), 150.8 (C-4), 154.6 (C-6), 165.6 (C-2).

EXAMPLE 3

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(propylthio)-9H-purin-6-amine (3c)

6-Chloro-N.SUP.4.-ethyl-2-(propylthio)pyrimidine-4,5-diamine (3a)

[0283] ##STR00021##

[0284] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in a solution of ethylamine 2.0 M in methanol (3.2 mL, 6.4 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0285] Yield: 77%.

[0286] Melting point: 96-98 C.

[0287] .sup.1H NMR (DMSO-d.sub.6) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.16 (t, J=7.2 Hz, 3H, NHCH.sub.2CH.sub.3), 1.63 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.94 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.37 (m, 2H, NHCH.sub.2CH.sub.3), 4.75 (s, 2H, NH.sub.2), 6.95 (t, J=4.8 Hz, 1H, NHCH.sub.2CH.sub.3).

[0288] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 14.3 (NHCH.sub.2CH.sub.3), 22.7 (SCH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 35.7 (NHCH.sub.2CH.sub.3), 119.8 (C-5), 137.3 (C-6), 152.5 (C-4), 155.3 (C-2).

6-Chloro-9-ethyl-2-(propylthio)-9H-purine (3b)

[0289] ##STR00022##

[0290] A solution of (3a) (247.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0291] Yield: 77%.

[0292] Melting point: 96-97.5 C.

[0293] .sup.1H NMR (DMSO-d.sub.6) 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.44 (t, J=7.3 Hz, 3H, NCH.sub.2CH.sub.3), 1.74 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.17 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.24 (q, J=7.3 Hz, 2H, NCH.sub.2CH.sub.3), 8.56 (s, 1H, 8-H).

[0294] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 14.6 (NCH.sub.2CH.sub.3), 22.0 (SCH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 39.9 (NCH.sub.2CH.sub.3), 128.1 (C-5), 146.0 (C-8), 148.8 (C-6), 152.7 (C-4), 163.8 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-ethyl-2-(propylthio)-9H-purin-6-amine (3c)

[0295] ##STR00023##

[0296] A solution of (3b) (129.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0297] Yield: 43%.

[0298] Melting point: 109.5-111.5 C.

[0299] .sup.1H NMR (CDCl.sub.3) 0.94 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 1.50 (t, J=7.3 Hz, 3H, NCH.sub.2CH.sub.3), 1.67 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.12 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.18 (q, J=7.3 Hz, 2H, NCH.sub.2CH.sub.3), 5.90 (bs, 1H, NH), 6.99 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.63 (s, 1H, 8-H).

[0300] .sup.13C NMR (CDCl.sub.3) 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 15.5 (NCH.sub.2CH.sub.3), 16.1 (NHCH(CH.sub.2)CHPh), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 38.7 (NCH.sub.2CH.sub.3), 115.6 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.6 (C-5), 122.7 (C-6), 137.9 (C-1), 138.5 (C-8), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.3 (C-4), 154.5 (C-6), 165.4 (C-2).

EXAMPLE 4

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-propyl-2-(propylthio)-9H-purin-6-amine (4c)

6-Chloro-N.SUP.4.-propyl-2-(propylthio)pyrimidine-4,5-diamine (4a)

[0301] ##STR00024##

[0302] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with n-propylamine (370.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 30 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0303] Yield: 91%.

[0304] Melting point: 100-102 C.

[0305] .sup.1H NMR (DMSO-d.sub.6) 0.91 (t, J=7.4 Hz, 3H, NHCH.sub.2CH.sub.2CH.sub.3), 0.95 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.56 (h, J=7.3 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.3), 1.64 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.93 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.32 (m, 2H, NHCH.sub.2CH.sub.2CH.sub.3), 4.76 (s, 2H, NH.sub.2), 6.96 (t, J=4.8 Hz, 1H, NHCH.sub.2CH.sub.2CH.sub.3).

[0306] .sup.13C NMR (DMSO-d.sub.6) 11.5 (NHCH.sub.2CH.sub.2CH.sub.3), 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 21.9 (NHCH.sub.2CH.sub.2CH.sub.3), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 42.7 (NHCH.sub.2CH.sub.2CH.sub.3), 119.8 (C-5), 137.3 (C-6), 152.6 (C-4), 155.2 (C-2).

6-Chloro-9-propyl-2-(propylthio)-9H-purine (4b)

[0307] ##STR00025##

[0308] A solution of (4a) (261.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0309] Yield: 94%.

[0310] Melting point: liquid.

[0311] .sup.1H NMR (DMSO-d.sub.6) 0.85 (t, J=7.4 Hz, 3H, NCH.sub.2CH.sub.2CH.sub.3), 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.74 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.86 (h, J=7.3 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.3), 3.17 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.18 (t, J=7.0 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.3), 8.55 (s, 1H, 8-H).

[0312] .sup.13C NMR (DMSO-d.sub.6) 10.9 (NCH.sub.2CH.sub.2CH.sub.3), 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 22.3 (NCH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 45.3 (NCH.sub.2CH.sub.2CH.sub.3), 128.0 (C-5), 146.4 (C-8), 148.9 (C-6), 152.9 (C-4), 163.8 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-propyl-2-(propylthio)-9H-purin-6-amine (4c)

[0313] ##STR00026##

[0314] A solution of (4b) (136.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0315] Yield: 45%.

[0316] Melting point: 97-99 C.

[0317] .sup.1H NMR (CDCl.sub.3) 0.94 (t, J=7.4 Hz, 6H, NCH.sub.2CH.sub.2CH.sub.3/SCH.sub.2CH.sub.2CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 1.67 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.90 (h, J=7.4 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.11 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.09 (t, J=7.1 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.3), 5.86 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.61 (s, 1H, 8-H).

[0318] .sup.13C NMR (CDCl.sub.3) 11.2 (NCH.sub.2CH.sub.2CH.sub.3), 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 15.7 (NHCH(CH.sub.2)CHPh), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 23.3 (NCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 45.3 (NCH.sub.2CH.sub.2CH.sub.3), 115.6 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.6 (C-5), 122.7 (C-6), 137.9 (C-1), 139.0 (C-8),147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.5 (C-4), 154.5 (C-6), 165.4 (C-2).

EXAMPLE 5

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-isopropyl-2-(propylthio)-9H-purin-6-amine (5c)

6-Chloro-N.SUP.4.-isopropyl-2-(propylthio)pyrimidine-4,5-diamine (5a)

[0319] ##STR00027##

[0320] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with isopropylamine (370.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 90 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0321] Yield: 95%.

[0322] Melting point: 81-83 C.

[0323] .sup.1H NMR (DMSO-d.sub.6) 0.95 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.19 (d, J=6.5 Hz, 6H, NHCH(CH.sub.3).sub.2), 1.63 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.93 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.16 (m, 1H, NHCH(CH.sub.3).sub.2), 4.81 (s, 2H, NH.sub.2), 6.69 (d, J=6.9 Hz, 1H, NHCH(CH.sub.3).sub.2).

[0324] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.2 (NHCH(CH.sub.3).sub.2), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 42.6 (NHCH(CH.sub.3).sub.2), 119.7 (C-5), 137.3 (C-6), 151.7 (C-4), 155.1 (C-2).

6-Chloro-9-isopropyl-2-(propylthio)-9H-purine (5b)

[0325] ##STR00028##

[0326] A solution of (5a) (261.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0327] Yield: 37%.

[0328] Melting point: 121-122.5 C.

[0329] .sup.1H NMR (DMSO-d.sub.6) 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.56 (d, J=6.8 Hz, 6H, NCH(CH.sub.3).sub.2), 1.74 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.16 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.80 (hept, J=6.8 Hz, 1H, NCH(CH.sub.3).sub.2), 8.62 (s, 1H, 8-H).

[0330] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 21.7 (NCH(CH.sub.3).sub.2), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 47.9 (NCH(CH.sub.3).sub.2), 128.4 (C-5), 144.7 (C-8), 148.9 (C-6), 152.3 (C-4), 163.5 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-isopropyl-2-(propylthio)-9H-purin-6-amine (5c)

[0331] ##STR00029##

[0332] A solution of (5b) (136.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0333] Yield: 47%.

[0334] Melting point: 98.5-100.5 C.

[0335] .sup.1H NMR (CDCl.sub.3) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.31 (m, 2H, NHCH(CH.sub.2)CHPh), 1.58 (dd, J=6.8 Hz/1.6 Hz, 6H, NCH(CH.sub.3).sub.2), 1.68 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.08 (m, 1H, NHCH(CH.sub.2)CHPh), 3.04 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.10 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.77 (hept, J=6.8 Hz, 1H, NCH(CH.sub.3).sub.2), 5.95 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.68 (s, 1H, 8-H).

[0336] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 16.0 (NHCH(CH.sub.2)CHPh), 22.6 (NCH(CH.sub.3).sub.2), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 47.0 (NCH(CH.sub.3).sub.2), 115.7 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.9 (C-5), 122.8 (C-6), 136.7 (C-8), 137.9 (C-1), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.0 (C-4), 154.6 (C-6), 165.1 (C-2).

EXAMPLE 6

Synthesis of 9-cyclopropyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (6c)

6-Chloro-N.SUP.4.-cyclopropyl-2-(propylthio)pyrimidine-4,5-diamine (6a)

[0337] ##STR00030##

[0338] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with cyclopropylamine (360.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 30 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0339] Yield: 92%.

[0340] Melting point: 96-98 C.

[0341] .sup.1H NMR (DMSO-d.sub.6) 0.49 (s, 2H, NHCH(CH.sub.2).sub.2), 0.73 (d, J=5.7 Hz, 2H, NHCH(CH.sub.2).sub.2), 0.95 (t, J=7.1 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.66 (h, J=7.0 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.80 (m, 1H, NHCH(CH.sub.2).sub.2), 2.97 (t, J=6.9 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.74 (s, 2H, NH.sub.2), 7.09 (s, 1H, NHCH(CH.sub.2).sub.2).

[0342] .sup.13C NMR (DMSO-d.sub.6) 6.2 (NHCH(CH.sub.2).sub.2), 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 24.1 (NHCH(CH.sub.2).sub.2), 32.2 (SCH.sub.2CH.sub.2CH.sub.3), 120.0 (C-5), 137.3 (C-6), 153.4 (C-4), 155.2 (C-2).

6-Chloro-9-cyclopropyl-2-(propylthio)-9H-purine (6b)

[0343] ##STR00031##

[0344] A solution of (6a) (259.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0345] Yield: 58%.

[0346] Melting point: 128.5-130 C.

[0347] .sup.1H NMR (DMSO-d.sub.6) 1.02 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.09 (m, 2H, NCH(CH.sub.2).sub.2), 1.16 (m, 2H, NCH(CH.sub.2).sub.2), 1.75 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.17 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.55 (m, 1H, NCH(CH.sub.2).sub.2), 8.52 (s, 1H, 8-H).

[0348] .sup.13C NMR (DMSO-d.sub.6) 5.4 (NCH(CH.sub.2).sub.2), 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 25.6 (NCH(CH.sub.2).sub.2), 32.7 (SCH.sub.2CH.sub.2CH.sub.3), 128.2 (C-5), 146.7 (C-8), 148.8 (C-6), 153.9 (C-4), 163.9 (C-2).

9-Cyclopropyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (6c)

[0349] ##STR00032##

[0350] A solution of (6b) (135.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0351] Yield: 40%.

[0352] Melting point: 137-139 C.

[0353] .sup.1H NMR (CDCl.sub.3) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.10 (m, 2H, NCH(CH.sub.2).sub.2), 1.13 (m, 2H, NCH(CH.sub.2).sub.2), 1.31 (m, 2H, NHCH(CH.sub.2)CHPh), 1.68 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.08 (m, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.10 (bs, 1H, NHCH(CH.sub.2)CHPh), 3.38 (tt, J=7.1 Hz/3.9 Hz, 1H, NCH(CH.sub.2).sub.2), 5.88 (bs, 1H, NH), 6.99 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.61 (s, 1H, 8-H).

[0354] .sup.13C NMR (CDCl.sub.3) 5.9 (NCH(CH.sub.2).sub.2), 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 16.1 (NHCH(CH.sub.2)CHPh), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 25.3 (NCH(CH.sub.2).sub.2), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 115.6 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.4 (C-5), 122.7 (C-6), 137.9 (C-1), 139.4 (C-8),147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 151.6 (C-4), 154.4 (C-6), 165.6 (C-2).

EXAMPLE 7

Synthesis of 9-butyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (7c)

N.SUP.4.-Butyl-6-chloro-2-(propylthio)pyrimidine-4,5-diamine (7a)

[0355] ##STR00033##

[0356] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with n-butylamine (460.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 30 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0357] Yield: 95%.

[0358] Melting point: liquid.

[0359] .sup.1H NMR (DMSO-d.sub.6) 0.91 (t, J=7.4 Hz, 3H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.35 (h, J=7.4 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.55 (p, J=7.5 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.64 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.95 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.37 (m, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.76 (s, 2H, NH.sub.2), 6.94 (t, J=5.2 Hz, 1H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3).

[0360] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 13.7 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 19.6 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 30.8 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 40.6 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 119.8 (C-5), 137.3 (C-6), 152.6 (C-4), 155.2 (C-2).

9-Butyl-6-chloro-2-(propylthio)-9H-purine (7b)

[0361] ##STR00034##

[0362] A solution of (7a) (275.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0363] Yield: 72%.

[0364] Melting point: liquid.

[0365] .sup.1H NMR (DMSO-d.sub.6) 0.90 (t, J=7.4 Hz, 3H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.26 (h, J=7.4 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.74 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.83 (p, J=7.2 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.16 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.22 (t, J=7.1 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 8.56 (s, 1H, 8-H).

[0366] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 13.3 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 19.2 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 30.9 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 43.3 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 127.9 (C-5), 146.3 (C-8), 148.9 (C-6), 152.8 (C-4), 163.8 (C-2).

9-Butyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (7c)

[0367] ##STR00035##

[0368] A solution of (7b) (143.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0369] Yield: 61%.

[0370] Melting point: 85-87 C.

[0371] .sup.1H NMR (CDCl.sub.3) 0.95 (m, 6H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3/SCH.sub.2CH.sub.2CH.sub.3), 1.33 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3/NHCH(CH.sub.2)CHPh), 1.68 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.86 (p, J=7.3 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.10 (m, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.13 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.14 (t, J=7.1 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 6.19 (bs, 1H, NH), 6.99 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.64 (s, 1H, 8-H).

[0372] .sup.13C NMR (CDCL.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3/NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 16.0 (NHCH(CH.sub.2)CHPh), 19.8 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 31.9 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.4 (NHCH(CH.sub.2)CHPh), 43.5 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 115.7 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.5 (C-5), 122.7 (C-6), 136.5 (C-8), 137.9 (C-1), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.4 (C-4), 154.3 (C-6), 165.8 (C-2).

EXAMPLE 8

Synthesis of 9-(sec-butyl)-N-(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (8c)

N.SUP.4.-(sec-Butyl)-6-chloro-2-(propylthio)pyrimidine-4,5-diamine (8a)

[0373] ##STR00036##

[0374] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with sec-butylamine (460.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 90 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0375] Yield: 81%.

[0376] Melting point: liquid.

[0377] .sup.1H NMR (DMSO-d.sub.6) 0.87 (t, J=7.4 Hz, 3H, NHCH(CH.sub.3)CH.sub.2CH.sub.3), 0.95 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.15 (d, J=6.6 Hz, 3H, NHCH(CH.sub.3)CH.sub.2CH.sub.3), 1.53 (m, 2H, NHCH(CH.sub.3)CH.sub.2CH.sub.3), 1.64 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.93 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.01 (hept, J=6.6 Hz, 1H, NHCH(CH.sub.3)CH.sub.2CH.sub.3), 4.81 (s, 2H, NH.sub.2), 6.64 (d, J=7.5 Hz, 1H, NHCH(CH.sub.3)CH.sub.2CH.sub.3).

[0378] .sup.13C NMR (DMSO-d.sub.6) 10.5 (NHCH(CH.sub.3)CH.sub.2CH.sub.3), 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 19.8 (NHCH(CH.sub.3)CH.sub.2CH.sub.3), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 28.6 (NHCH(CH.sub.3)CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 47.9 (NHCH(CH.sub.3)CH.sub.2CH.sub.3), 119.7 (C-5), 137.3 (C-6), 152.0 (C-4), 155.0 (C-2).

9-(sec-Butyl)-6-chloro-2-(propylthio)-9H-purine (8b)

[0379] ##STR00037##

[0380] A solution of (8a) (275.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 4 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0381] Yield: 39%.

[0382] Melting point: 64-66 C.

[0383] .sup.1H NMR (DMSO-d.sub.6) 0.74 (t, J=7.4 Hz, 3H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.57 (d, J=6.9 Hz, 3H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 1.74 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.95 (m, 2H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 3.15 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.57 (m, 1H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 8.63 (s, 1H, 8-H).

[0384] .sup.13C NMR (DMSO-d.sub.6) 10.5 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 19.8 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 28.3 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 53.6 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 128.2 (C-5), 145.1 (C-8), 149.0 (C-6), 152.5 (C-4), 163.6 (C-2).

9-(sec-Butyl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (8c)

[0385] ##STR00038##

[0386] A solution of (8b) (143.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 4 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0387] Yield: 66%.

[0388] Melting point: 68-71 C.

[0389] .sup.1H NMR (CDCl.sub.3) 0.85 (td, J=7.4 Hz/1.6 Hz, 3H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 0.96 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.33 (m, 2H, NHCH(CH.sub.2)CHPh), 1.57 (d, J=6.9 Hz, 3H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 1.69 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.95 (m, 2H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 2.10 (m, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.11 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.52 (m, 1H, NCH(CH.sub.3)CH.sub.2CH.sub.3), 6.12 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.10 (m, 2H, 2-H/5-H), 7.67 (s, 1H, 8-H).

[0390] .sup.13C NMR (CDCl.sub.3) 10.7 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 15.9 (NHCH(CH.sub.2)CHPh), 20.6 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 29.5 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 53.0 (NCH(CH.sub.3)CH.sub.2CH.sub.3), 115.8 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.3 (C-5), 122.8 (C-6), 137.0 (C-8), 137.9 (C-1), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.3 (C-4), 154.4 (C-6), 165.1 (C-2).

EXAMPLE 9

Synthesis of 9-(tert-butyl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (9c)

N.SUP.4.-(tert-Butyl)-6-chloro-2-(propylthio)pyrimidine-4,5-diamine (9a)

[0391] ##STR00039##

[0392] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with tert-butylamine (460.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 24 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0393] Yield: 88%.

[0394] Melting point: 88-89 C.

[0395] .sup.1H NMR (DMSO-d.sub.6) 0.95 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.43 (s, 9H, NHC(CH.sub.3).sub.3), 1.62 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.95 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.91 (bs, 2H, NH.sub.2), 6.19 (s, 1H, NHC(CH.sub.3).sub.3).

[0396] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 28.5 (NHC(CH.sub.3).sub.3), 31.9 (SCH.sub.2CH.sub.2CH.sub.3), 51.9 (NHC(CH.sub.3).sub.3), 120.3 (C-5), 137.6 (C-6), 152.1 (C-4), 154.5 (C-2).

9-(tert-Butyl)-6-chloro-2-(propylthio)-9H-purine (9b)

[0397] ##STR00040##

[0398] A solution of (9a) (275.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 10 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0399] Yield: 41%.

[0400] Melting point: 116-117 C.

[0401] .sup.1H NMR (DMSO-d.sub.6) 1.02 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.74 (m, 11H, SCH.sub.2CH.sub.2CH.sub.3/NC(CH.sub.3).sub.3), 3.14 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 8.54 (s, 1H, 8-H).

[0402] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 28.3 (NC(CH.sub.3).sub.3), 32.7 (SCH.sub.2CH.sub.2CH.sub.3), 58.0 (NC(CH.sub.3).sub.3), 129.0 (C-5), 144.2 (C-8), 149.3 (C-6), 152.6 (C-4), 162.9 (C-2).

9-(tert-Butyl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (9c)

[0403] ##STR00041##

[0404] A solution of (9b) (143.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 2 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0405] Yield: 56%.

[0406] Melting point: 125-128 C.

[0407] .sup.1H NMR (CDCl.sub.3) 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.29 (m, 2H, NHCH(CH.sub.2)CHPh), 1.77 (m, 11H, SCH.sub.2CH.sub.2CH.sub.3/NC(CH.sub.3).sub.3), 2.08 (m, 1H, NHCH(CH.sub.2)CHPh), 3.06 (m, 3H,

[0408] SCH.sub.2CH.sub.2CH.sub.3/NHCH(CH.sub.2)CHPh), 5.95 (bs, 1H, NH), 7.08 (m, 2H, 5-H/6-H), 7.17 (m, 1H, 2-H), 7.70 (s, 1H, 8-H).

[0409] .sup.13C NMR (CDCl.sub.3) 13.6 (SCH.sub.2CH.sub.2CH.sub.3), 15.6 (NHCH(CH.sub.2)CHPh), 23.1 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 29.0 (NC(CH.sub.3).sub.3), 33.0 (NHCH(CH.sub.2)CHPh), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 57.1 (NC(CH.sub.3).sub.3), 116.2 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 118.9 (C-5), 123.1 (C-6), 136.5 (C-8), 137.8 (C-1), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.7 (C-4), 154.9 (C-6), 164.3 (C-2).

EXAMPLE 10

Synthesis of 9-cyclobutyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (10c)

6-Chloro-N.SUP.4.-cyclobutyl-2-(propylthio)pyrimidine-4,5-diamine (10a)

[0410] ##STR00042##

[0411] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with cyclobutylamine (440.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0412] Yield: 96%.

[0413] Melting point: 73-75.5 C.

[0414] .sup.1H NMR (DMSO-d.sub.6) 0.96 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.63 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.72 (m, 2H, NHCH(CH.sub.2).sub.3), 1.95 (m, 2H, NHCH(CH.sub.2).sub.3), 2.29 (m, 2H, NHCH(CH.sub.2).sub.3), 2.94 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.38 (h, J=8.0 Hz, 1H, NHCH(CH.sub.2).sub.3), 4.80 (s, 2H, NH.sub.2), 7.11 (d, J=6.3 Hz, 1H, NHCH(CH.sub.2).sub.3).

[0415] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 14.9 (NHCH(CH.sub.2).sub.3), 22.7 (SCH.sub.2CH.sub.2CH.sub.3), 30.2 (NHCH(CH.sub.2).sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 46.3 (NHCH(CH.sub.2).sub.3), 119.7 (C-5), 137.4 (C-6), 151.5 (C-4), 155.1 (C-2).

6-Chloro-9-cyclobutyl-2-(propylthio)-9H-purine (10b)

[0416] ##STR00043##

[0417] A solution of (10a) (273.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0418] Yield: 62%.

[0419] Melting point: 89-91.5 C.

[0420] .sup.1H NMR (DMSO-d.sub.6) 1.02 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.75 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.90 (m, 2H, NCH(CH.sub.2).sub.3), 2.47 (m, 2H, NCH(CH.sub.2).sub.3), 2.73 (m, 2H, NCH(CH.sub.2).sub.3), 3.17 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 5.03 (p, J=8.6 Hz, 1H, NCH(CH.sub.2).sub.3), 8.66 (s, 1H, 8-H).

[0421] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 14.8 (NCH(CH.sub.2).sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 29.2 (NCH(CH.sub.2).sub.3), 32.7 (SCH.sub.2CH.sub.2CH.sub.3), 48.8 (NCH(CH.sub.2).sub.3), 128.3 (C-5), 145.1 (C-8), 148.9 (C-6), 152.5 (C-4), 163.7 (C-2).

9-Cyclobutyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (10c)

[0422] ##STR00044##

[0423] A solution of (10b) (142.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 2 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0424] Yield: 76%.

[0425] Melting point: 143-145 C.

[0426] .sup.1H NMR (CDCl.sub.3) 0.96 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 1.70 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.95 (m, 2H, NCH(CH.sub.2).sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 2.56 (m, 2H, NCH(CH.sub.2).sub.3), 2.64 (m, 2H, NCH(CH.sub.2).sub.3), 3.04 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.10 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.95 (p, J=8.6 Hz, 1H, NCH(CH.sub.2).sub.3), 6.06 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.74 (s, 1H, 8-H).

[0427] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 15.3 (NCH(CH.sub.2).sub.3), 16.0 (NHCH(CH.sub.2)CHPh), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 30.5 (NCH(CH.sub.2).sub.3), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 48.8 (NCH(CH.sub.2).sub.3), 115.8 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.5 (C-5), 122.8 (C-6), 137.3 (C-8), 137.8 (C-1), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.4 (C-4), 154.5 (C-6), 165.2 (C-2).

EXAMPLE 11

Synthesis of N-((1R,2S)-2-(3,4-difluorophenylcyclopropyl)-9-pentyl-2-(propylthio)-9H-purin-6-amine (11c)

6-Chloro-N.SUP.4.-pentyl-2-(propylthio)pyrimidine-4,5-diamine (11a)

[0428] ##STR00045##

[0429] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with n-pentylamine (550.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 30 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0430] Yield: 96%.

[0431] Melting point: 68-69 C.

[0432] .sup.1H NMR (DMSO-d.sub.6) 0.87 (t, J=7.0 Hz, 3H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.30 (m, 4H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.55 (p, J=7.3 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.63 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.94 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.34 (m, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.75 (s, 2H, NH.sub.2), 6.95 (t, J=5.2 Hz, 1H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

[0433] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 13.9 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.9 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 28.3 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 28.7 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 40.8 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 119.8 (C-5), 137.3 (C-6), 152.6 (C-4), 155.2 (C-2).

6-Chloro-9-pentyl-2-(propylthio)-9H-purine (11b)

[0434] ##STR00046##

[0435] A solution of (11a) (289.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0436] Yield: 87%.

[0437] Melting point: liquid.

[0438] .sup.1H NMR (DMSO-d.sub.6) 0.85 (t, J=7.3 Hz, 3H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.02 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.23 (m, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.31 (m, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.75 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.86 (p, J=7.2 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.17 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.22 (t, J=7.1 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 8.56 (s, 1H, 8-H).

[0439] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 13.7 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.5 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 28.1 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 28.5 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 43.6 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 127.9 (C-5), 146.3 (C-8), 148.9 (C-6), 152.8 (C-4), 163.8 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-pentyl-2-(propylthio)-9H-purin-6-amine (11c)

[0440] ##STR00047##

[0441] A solution of (11b) (150.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 3 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0442] Yield: 83%.

[0443] Melting point: 98-100.5 C.

[0444] .sup.1H NMR (CDCl.sub.3) 0.89 (t, J=7.2 Hz, 3H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.32 (m, 6H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3/NHCH(CH.sub.2)CHPh), 1.68 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.87 (p, J=7.3 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 3.04 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.10 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.12 (t, J=7.2 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5.97 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.60 (s, 1H, 8-H).

[0445] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 13.9 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 16.0 (NHCH(CH.sub.2)CHPh), 22.2 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 28.7 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.7 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 43.7 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 115.7 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.5 (C-5), 122.7 (C-6), 137.9 (C-11, 139.0 (C-8), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.5 (C-4), 154.6 (C-6), 165.4 (C-2).

EXAMPLE 12

Synthesis of 9-cyclopentyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (12c)

6-Chloro-N.SUP.4.-cyclopentyl-2-(propylthio)pyrimidine-4,5-diamine (12a)

[0446] ##STR00048##

[0447] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with cyclopentylamine (536.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 2 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0448] Yield: 95%.

[0449] Melting point: 86-88 C.

[0450] .sup.1H NMR (DMSO-d.sub.6) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.49 (m, 2H, NHCH(CH.sub.2).sub.4), 1.55 (m, 2H, NHCH(CH.sub.2).sub.4), 1.64 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.70 (m, 2H, NHCH(CH.sub.2).sub.4), 1.96 (m, 2H, NHCH(CH.sub.2).sub.4), 2.94 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.25 (h, J=6.7 Hz, 1H, NHCH(CH.sub.2).sub.4), 4.83 (s, 2H, NH.sub.2), 6.76 (d, J=6.3 Hz, 1H, NHCH(CH.sub.2).sub.4).

[0451] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 23.5 (NHCH(CH.sub.2).sub.4), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 32.2 (NHCH(CH.sub.2).sub.4), 52.7 (NHCH(CH.sub.2).sub.4), 119.9 (C-5), 137.2 (C-6), 152.0 (C-4), 155.0 (C-2).

6-Chloro-9-cyclopentyl-2-(propylthio)-9H-purine (12b)

[0452] ##STR00049##

[0453] A solution of (12a) (287.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0454] Yield: 37%.

[0455] Melting point: 81-83 C.

[0456] .sup.1H NMR (DMSO-d.sub.6) 1.01 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.74 (m, 4H, SCH.sub.2CH.sub.2CH.sub.3/NCH(CH.sub.2).sub.4), 1.90 (m, 2H, NCH(CH.sub.2).sub.4), 2.06 (m, 2H, NCH(CH.sub.2).sub.4), 2.19 (m, 2H, NCH(CH.sub.2).sub.4), 3.16 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.90 (p, J=7.6 Hz, 1H, NCH(CH.sub.2).sub.4), 8.59 (s, 1H, 8-H).

[0457] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 23.8 (NCH(CH.sub.2).sub.4), 31.5 (NCH(CH.sub.2).sub.4), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 56.4 (NCH(CH.sub.2).sub.4), 128.5 (C-5), 145.2 (C-8), 148.9 (C-6), 152.5 (C-4), 163.5 (C-2).

9-Cyclopentyl-N-(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (12c)

[0458] ##STR00050##

[0459] A solution of (12b) (149.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 3 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0460] Yield: 35%.

[0461] Melting point: 112-114 C.

[0462] .sup.1H NMR (CDCl.sub.3) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.31 (m, 2H, NHCH(CH.sub.2)CHPh), 1.68 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.79 (m, 2H, NCH(CH.sub.2).sub.4), 1.94 (m, 2H, NCH(CH.sub.2).sub.4), 1.99 (m, 2H, NCH(CH.sub.2).sub.4), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 2.26 (m, 2H, NCH(CH.sub.2).sub.4), 3.04 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.10 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.84 (p, J=7.4 Hz, 1H, NCH(CH.sub.2).sub.4), 5.92 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.65 (s, 1H, 8-H).

[0463] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 16.0 (NHCH(CH.sub.2)CHPh), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 24.1 (NCH(CH.sub.2).sub.4), 25.3 (NHCH(CH.sub.2)CHPh), 32.6 (NCH(CH.sub.2).sub.4), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 56.0 (NCH(CH.sub.2).sub.4), 115.7 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.9 (C-5), 122.8 (C-6), 137.4 (C-8), 137.9 (C-1), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.0 (C-4), 154.6 (C-6), 165.0 (C-2).

EXAMPLE 13

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl-9-hexyl-2-(propylthio)-9H-purin-6-amine (13c)

6-Chloro-N.SUP.4.-hexyl-2-(propylthio)pyrimidine-4,5-diamine (13a)

[0464] ##STR00051##

[0465] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with n-hexylamine (638.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0466] Yield: 85%.

[0467] Melting point: 54-57 C.

[0468] .sup.1H NMR (DMSO-d.sub.6) 0.87 (t, J=6.4 Hz, 3H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.95 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.29 (m, 6H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.54 (p, J=6.9 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.63 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.94 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.34 (m, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.76 (s, 2H, NH.sub.2), 6.95 (t, J=4.9 Hz, 1H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

[0469] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 13.9 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.1 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 26.1 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 28.6 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.0 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 40.9 (NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 119.8 (C-5), 137.3 (C-6), 152.6 (C-4), 155.2 (C-2).

6-Chloro-9-hexyl-2-(propylthio)-9H-purine (13b)

[0470] ##STR00052##

[0471] A solution of (13a) (303.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0472] Yield: 90%.

[0473] Melting point: liquid.

[0474] .sup.1H NMR (DMSO-d.sub.6) 0.83 (t, J=6.8 Hz, 3H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.25 (m, 6H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.74 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.84 (p, J=7.2 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.16 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.21 (t, J=7.1 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 8.56 (s, 1H, 8-H).

[0475] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 13.8 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.9 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.1 (SCH.sub.2CH.sub.2CH.sub.3), 25.5 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 28.8 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.5 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 43.6 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 127.9 (C-5), 146.3 (C-8), 148.9 (C-6), 152.8 (C-4), 163.8 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-hexyl-2-(propylthio)-9H-purin-6-amine (13c)

[0476] ##STR00053##

[0477] A solution of (13b) (157.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0478] Yield: 60%.

[0479] Melting point: 84-86 C.

[0480] .sup.1H NMR (CDCl.sub.3) 0.88 (m, 3H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.30 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3/NHCH(CH.sub.2)CHPh), 1.68 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.86 (m, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.10 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.12 (t, J=7.2 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5.96 (bs, 1H, NH), 6.99 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.60 (s, 1H, 8-H).

[0481] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 14.0 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 16.0 (NHCH(CH.sub.2)CHPh), 22.5 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 26.3 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.9 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.2 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 43.7 (NCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 115.7 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.5 (C-5), 122.7 (C-6), 137.9 (C-1), 139.0 (C-8), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.5 (C-4), 154.6 (C-6), 165.4 (C-2).

EXAMPLE 14

Synthesis of 9-cyclohexyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (14c)

6-Chloro-N.SUP.4.-cyclohexyl-2-(propylthio)pyrimidine-4,5-diamine (14a)

[0482] ##STR00054##

[0483] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with cyclohexylamine (625.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0484] Yield: 91%.

[0485] Melting point: 90-93 C.

[0486] .sup.1H NMR (DMSO-d.sub.6) 0.96 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.22 (m, 5H, NHCH(CH.sub.2).sub.5), 1.64 (m, 3H, SCH.sub.2CH.sub.2CH.sub.3/NHCH(CH.sub.2).sub.5), 1.75 (m, 2H, NHCH(CH.sub.2).sub.5), 1.93 (m, 2H, NHCH(CH.sub.2).sub.5), 2.92 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.84 (m, 1H, NHCH(CH.sub.2).sub.5), 4.82 (s, 2H, NH.sub.2), 6.68 (d, J=7.1 Hz, 1H, NHCH(CH.sub.2).sub.5).

[0487] .sup.13C NMR (DMSO-d.sub.6) 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 23.0 (SCH.sub.2CH.sub.2CH.sub.3), 24.8 (NHCH(CH.sub.2).sub.5), 25.3 (NHCH(CH.sub.2).sub.5), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 32.3 (NHCH(CH.sub.2).sub.5), 49.9 (NHCH(CH.sub.2).sub.5), 119.7 (C-5), 137.4 (C-6), 151.6 (C-4), 155.0 (C-2).

6-Chloro-9-cyclohexyl-2-(propylthio)-9H-purine (14b)

[0488] ##STR00055##

[0489] A solution of (14a) (301.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 2 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0490] Yield: 62%.

[0491] Melting point: 93-95 C.

[0492] .sup.1H NMR (DMSO-d.sub.6) 1.02 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.25 (m, 1H, NCH(CH.sub.2).sub.5), 1.44 (m, 2H, NCH(CH.sub.2).sub.5), 1.75 (m, 3H, SCH.sub.2CH.sub.2CH.sub.3/NCH(CH.sub.2).sub.5), 1.87 (m, 2H, NCH(CH.sub.2).sub.5), 1.99 (m, 4H, NCH(CH.sub.2).sub.5), 3.15 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.41 (m, 1H, NCH(CH.sub.2).sub.5), 8.61 (s, 1H, 8-H).

[0493] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.2 (SCH.sub.2CH.sub.2CH.sub.3), 24.8 (NCH(CH.sub.2).sub.5), 25.0 (NCH(CH.sub.2).sub.5), 31.7 (NCH(CH.sub.2).sub.5), 32.7 (SCH.sub.2CH.sub.2CH.sub.3), 55.0 (NCH(CH.sub.2).sub.5), 128.3 (C-5), 144.8 (C-8), 149.0 (C-6), 152.3 (C-4), 163.5 (C-2).

9-Cyclohexyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (14c)

[0494] ##STR00056##

[0495] A solution of (14b) (156.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0496] Yield: 84%.

[0497] Melting point: 85-88 C.

[0498] .sup.1H NMR (CDCl.sub.3) 0.94 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.30 (m, 3H, NHCH(CH.sub.2)CHPh/NCH(CH.sub.2).sub.5), 1.49 (m, 2H, NCH(CH.sub.2).sub.5), 1.68 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.79 (m, 3H, NCH(CH.sub.2).sub.5) 1.92 (m, 2H, NCH(CH.sub.2).sub.5), 2.08 (m, 1H, NHCH(CH.sub.2)CHPh), 2.14 (m, 2H, NCH(CH.sub.2).sub.5), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.11 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.36 (m, 1H, NCH(CH.sub.2).sub.5), 5.98 (bs, 1H, NH), 6.99 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.67 (s, 1H, 8-H).

[0499] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 16.1 (NHCH(CH.sub.2)CHPh), 23.0 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 25.3 (NCH(CH.sub.2).sub.5), 25.6 (NCH(CH.sub.2).sub.5), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 54.2 (NCH(CH.sub.2).sub.5), 115.6 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.7 (C-5), 122.7 (C-6), 137.0 (C-8), 138.0 (C-1), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.5 (C-4), 154.6 (C-6), 165.0 (C-2).

EXAMPLE 15

Synthesis of 9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c)

N.SUP.4.-Allyl-6-chloro-2-(propylthio)pyrimidine-4,5-diamine (15a)

[0500] ##STR00057##

[0501] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with allylamine (360.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 30 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0502] Yield: 92%.

[0503] Melting point: 55-57 C.

[0504] .sup.1H NMR (DMSO-d.sub.6) 0.94 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.62 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.93 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.02 (tt, J=5.4 Hz/1.5 Hz, 2H, NHCH.sub.2CHCH.sub.2), 4.80 (s, 2H, NH.sub.2), 5.11 (dq, J=10.3 Hz/1.4 Hz, 1H, NHCH.sub.2CHCH.sub.2), 5.18 (dq, J=17.2 Hz/1.5 Hz, 1H, NHCH.sub.2CHCH.sub.2), 5.92 (ddt, J=17.1 Hz/10.4 Hz/5.3 Hz, 1H, NHCH.sub.2CHCH.sub.2), 7.15 (t, J=5.4 Hz, 1H, NHCH.sub.2CHCH.sub.2).

[0505] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.7 (SCH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 43.1 (NHCH.sub.2CHCH.sub.2), 115.6 (NHCH.sub.2CHCH.sub.2), 120.0 (C-5), 135.0 (NHCH.sub.2CHCH.sub.2), 137.5 (C-6), 152.3 (C-4), 155.2 (C-2).

9-allyl-6-chloro-2-(propylthio)-9H-purine (15b)

[0506] ##STR00058##

[0507] A solution of (15a) (259.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 2 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0508] Yield: 89%.

[0509] Melting point: 47.5-49.5 C.

[0510] .sup.1H NMR (DMSO-d.sub.6) 1.00 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.73 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.15 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.87 (dt, J=5.5 Hz/1.3 Hz, 2H, NCH.sub.2CHCH.sub.2), 5.13 (dd, J=17.1 Hz/1.3 Hz, 1H, NCH.sub.2CHCH.sub.2), 5.24 (dd, J=10.3 Hz/1.3 Hz, 1H, NCH.sub.2CHCH.sub.2), 6.07 (m, 1H, NCH.sub.2CHCH.sub.2), 8.52 (s, 1H, 8-H).

[0511] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 22.0 (SCH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 45.7 (NCH.sub.2CHCH.sub.2), 118.2 (NCH.sub.2CHCH.sub.2), 127.9 (C-5), 132.4 (NCH.sub.2CHCH.sub.2), 146.2 (C-8), 149.0 (C-6), 152.7 (C-4), 164.1 (C-2).

9-Allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c)

[0512] ##STR00059##

[0513] A solution of (15b) (135.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0514] Yield: 89%.

[0515] Melting point: liquid.

[0516] .sup.1H NMR (CDCl.sub.3) 0.94 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 1.66 (h, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 3.04 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.12 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.74 (d, J=5.9 Hz, 2H, NCH.sub.2CHCH.sub.2), 5.23 (dd, J=17.1 Hz/1.0 Hz, 1H, NCH.sub.2CHCH.sub.2), 5.30 (dd, J=10.2 Hz/1.0 Hz, 1H, NCH.sub.2CHCH.sub.2), 6.01 (m, 2H, NCH.sub.2CHCH.sub.2/NH), 6.99 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.62 (s, 1H, 8-H).

[0517] .sup.13C NMR (CDCl.sub.3) 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 16.1 (NHCH(CH.sub.2)CHPh), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 45.6 (NCH.sub.2CHCH.sub.2), 115.6 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.3 (C-5), 119.0 (NCH.sub.2CHCH.sub.2), 122.7 (C-6), 132.0 (NCH.sub.2CHCH.sub.2), 137.9 (C-1), 138.7 (C-8),147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.3 (C-4), 154.6 (C-6), 165.7 (C-2).

EXAMPLE 16

Synthesis of 2-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)ethanol (16c)

2-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)ethanol (16a)

[0518] ##STR00060##

[0519] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with 2-aminoethanol (385.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 30 min. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0520] Yield: 79%.

[0521] Melting point: 99-102 C.

[0522] .sup.1H NMR (DMSO-d.sub.6) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.63 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.93 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.43 (d, J=5.7 Hz, 2H, NHCH.sub.2CH.sub.2OH), 3.55 (d, J=5.7 Hz, 2H, NHCH.sub.2CH.sub.2OH), 4.78 (t, J=5.5 Hz, 1H, NHCH.sub.2CH.sub.2OH), 4.80 (s, 2H, NH.sub.2), 7.03 (t, J=5.2 Hz, 1H, NHCH.sub.2CH.sub.2OH).

[0523] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.7 (SCH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 43.7 (NHCH.sub.2CH.sub.2OH), 59.2 (NHCH.sub.2CH.sub.2OH), 120.0 (C-5), 137.4 (C-6), 152.7 (C-4), 155.1 (C-2).

2-(6-Chloro-2-(propylthio)-9H-purin-9-yl)ethanol (16b)

[0524] ##STR00061##

[0525] A solution of (16a) (263.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 4 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0526] Yield: 57%.

[0527] Melting point: 81-83 C.

[0528] .sup.1H NMR (DMSO-d.sub.6) 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.73 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.17 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.78 (q, J=5.4 Hz, 2H, NCH.sub.2CH.sub.2OH), 4.26 (t, J=5.4 Hz, 2H, NCH.sub.2CH.sub.2OH), 4.99 (t, J=5.6 Hz, 1H, OH), 8.48 (s, 1H, 8-H).

[0529] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 22.0 (SCH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 46.5 (NCH.sub.2CH.sub.2OH), 58.7 (NCH.sub.2CH.sub.2OH), 128.0 (C-5), 146.8 (C-8), 148.7 (C-6), 153.0 (C-4), 163.7 (C-2).

2-(6-(((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)ethanol (16c)

[0530] ##STR00062##

[0531] A solution of (16b) (137.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0532] Yield: 42%.

[0533] Melting point: 81-83 C.

[0534] .sup.1H NMR (CDCl.sub.3) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 1.66 (bh, J=7.3 Hz, 3H, OH/SCH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 3.01 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.11 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.02 (m, 2H, NCH.sub.2CH.sub.2OH), 4.29 (m, 2H, NCH.sub.2CH.sub.2OH), 6.05 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.61 (s, 1H, 8-H).

[0535] .sup.13C NMR (CDCl.sub.3) 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 15.9 (NHCH(CH.sub.2)CHPh), 22.6 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 33.1 (SCH.sub.2CH.sub.2CH.sub.3), 33.2 (NHCH(CH.sub.2)CHPh), 48.2 (NCH.sub.2CH.sub.2OH), 61.6 (NCH.sub.2CH.sub.2OH), 115.7 (d, J=17 Hz, C-2), 117.0 (d, J=17 Hz, C-5), 117.7 (C-5), 122.7 (C-6), 137.7 (C-1), 139.7 (C-8), 147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 150.1 (C-4), 154.6 (C-6), 165.8 (C-2).

EXAMPLE 17

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine hydrochloride (17c.HCl)

6-Chloro-N.SUP.4.-(prop-2-yn-1-yl)-2-(propylthio)pyrimidine-4,5-diamine (17a)

[0536] ##STR00063##

[0537] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with propargylamine (347.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 3 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0538] Yield: 78%.

[0539] Melting point: 90-92 C.

[0540] .sup.1H NMR (DMSO-d.sub.6) 0.96 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.66 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.97 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.15 (t, J=2.4 Hz, 1H, NHCH.sub.2CCH), 4.16 (dd, J=4.8 Hz/2.3 Hz, 2H, NHCH.sub.2CCH), 4.83 (s, 2H, NH.sub.2), 7.41 (t, J=4.7 Hz, 1H, NHCH.sub.2CCH).

[0541] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.7 (SCH.sub.2CH.sub.2CH.sub.3), 30.1 (NHCH.sub.2CCH), 32.2 (SCH.sub.2CH.sub.2CH.sub.3), 73.1 (NHCH.sub.2CCH), 81.1 (NHCH.sub.2CCH), 120.3 (C-5), 137.9 (C-6), 151.8 (C-4), 155.1 (C-2).

6-Chloro-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purine (17b)

[0542] ##STR00064##

[0543] A solution of (17a) (258.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 2 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0544] Yield: 62%.

[0545] Melting point: 68-70 C.

[0546] .sup.1H NMR (DMSO-d.sub.6) 1.01 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.75 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.19 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.57 (t, J=2.5 Hz, 1H, NCH.sub.2CCH), 5.13 (d, J=2.5 Hz, 2H, NCH.sub.2CCH), 8.58 (s, 1H, 8-H).

[0547] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 22.0 (SCH.sub.2CH.sub.2CH.sub.3), 32.7 (SCH.sub.2CH.sub.2CH.sub.3), 33.1 (NCH.sub.2CCH), 76.6 (NCH.sub.2CCH), 77.2 (NCH.sub.2CCH), 127.9 (C-5), 145.5 (C-8), 149.1 (C-6), 152.3 (C-4), 164.4 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (17c)

[0548] ##STR00065##

[0549] A solution of (17b) (134.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 4 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0550] Yield: 86%.

[0551] Melting point: 72-74 C.

[0552] .sup.1H NMR (CDCl.sub.3) 0.94 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.33 (m, 2H, NHCH(CH.sub.2)CHPh), 1.65 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 2.50 (t, J=2.6 Hz, 1H, NCH.sub.2CCH), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.12 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.90 (d, J=2.6 Hz, 2H, NCH.sub.2CCH), 6.00 (bs, 1H, NH), 6.98 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.84 (s, 1H, 8-H).

[0553] .sup.13C NMR (CDCl.sub.3) 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 16.1 (NHCH(CH.sub.2)CHPh), 22.8 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 32.8 (NCH.sub.2CCH), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 74.9 (NCH.sub.2CCH), 76.1 (NCH.sub.2CCH), 115.6 (d, J=17 Hz, C-2), 116.9 (d, J=17 Hz, C-5), 117.3 (C-5), 122.6 (C-6), 137.8 (C-1), 138.1 (C-8),147.9-149.9 (dd, 246 Hz/13 Hz, C-4), 149.2-151.2 (dd, 247 Hz/13 Hz, C-3), 149.9 (C-4), 154.6 (C-6), 166.0 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine hydrochloride (17c.HCl)

[0554] ##STR00066##

[0555] To a solution of (17c) (200.0 mg, 0.5 mmol) in diethyl ether (5 mL) was added dropwise a saturated solution of HCl in diethyl ether. The resulting precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0556] Yield: 99%.

[0557] Melting point: 178-180 C.

EXAMPLE 18

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9-(2,2,2-trifluoroethyl)-9H-purin-6-amine (18c)

6-Chloro-2-(propylthio)-N.SUP.4.-(2,2,2-trifluoroethyl)pyrimidine-4,5-diamine (18a)

[0558] ##STR00067##

[0559] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with 2,2,2-trifluoroethanamine (625.0 mg, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 24 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0560] Yield: 76%.

[0561] Melting point: 107-109 C.

[0562] .sup.1H NMR (DMSO-d.sub.6) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.63 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.95 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.29 (m, 2H, NHCH.sub.2CF.sub.3), 4.95 (s, 2H, NH.sub.2), 7.53 (s, 1H, NHCH.sub.2CF.sub.3).

[0563] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 22.6 (SCH.sub.2CH.sub.2CH.sub.3), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 41.2 (q, J=33 Hz, NHCH.sub.2CF.sub.3), 120.5 (C-5), 122.7-126.0 (m, NHCH.sub.2CF.sub.3), 138.8 (C-6), 151.9 (C-4), 154.8 (C-2).

6-Chloro-2-(propylthio)-9-(2,2,2-trifluoroethyl)-9H-purine (18b)

[0564] ##STR00068##

[0565] A solution of (18a) (301.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 2 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0566] Yield: 48%.

[0567] Melting point: 140-143 C.

[0568] .sup.1H NMR (DMSO-d.sub.6) 1.00 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.73 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.19 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 5.27 (q, J=9.2 Hz, 2H, NCH.sub.2CF.sub.3), 8.60 (s, 1H, 8-H).

[0569] .sup.13C NMR (DMSO-d.sub.6) 13.1 (SCH.sub.2CH.sub.2CH.sub.3), 22.0 (SCH.sub.2CH.sub.2CH.sub.3), 32.6 (SCH.sub.2CH.sub.2CH.sub.3), 43.9 (q, J=35 Hz, NCH.sub.2CF.sub.3), 123.4 (q, J=280 Hz, NCH.sub.2CF.sub.3), 127.6 (C-5), 146.2 (C-8), 149.6 (C-6), 152.9 (C-4), 165.2 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-2-(propylthio)-9-(2,2,2-trifluoroethyl)-9H-purin-6-amine (18c)

[0570] ##STR00069##

[0571] A solution of (18b) (156.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0572] Yield: 89%.

[0573] Melting point: 102-104 C.

[0574] .sup.1H NMR (CDCl.sub.3) 0.95 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.34 (m, 2H, NHCH(CH.sub.2)CHPh), 1.67 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.11 (m, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.2CH.sub.3), 3.10 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.73 (qd, J=8.5 Hz/3.1 Hz, 2H, NCH.sub.2CF.sub.3), 6.06 (bs, 1H, NH), 6.99 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.70 (s, 1H, 8-H).

[0575] .sup.13C NMR (CDCl.sub.3) 13.4 (SCH.sub.2CH.sub.2CH.sub.3), 15.9 (NHCH(CH.sub.2)CHPh), 22.7 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 44.0 (q, J=36 Hz, NCH.sub.2CF.sub.3), 115.7 (d, J=17 Hz, C-2), 116.8 (C-5), 117.0 (d, J=17 Hz, C-5), 122.7 (C-6), 122.8 (q, J=279 Hz, CF.sub.3), 137.7 (C-1), 138.2 (C-8), 148.0-150.0 (dd, J=246 Hz/13 Hz, C-4), 149.2-151.2 (dd, J=247 Hz/13 Hz, C-3), 150.6 (C-4), 154.7 (C-6), 166.8 (C-2).

EXAMPLE 19

Synthesis of (1S,2R,3S,4R)-4-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)cyclopentane-1,2,3-triol (19d)

(3aR,4S,6R,6aS)-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (19a)

[0576] ##STR00070##

[0577] 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (0.5 g, 2.1 mmol) was dissolved in methanol (2 mL) and supplemented with (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1.1 g, 6.3 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 12 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0578] Yield: 90%.

[0579] Melting point: ND.

[0580] .sup.1H NMR (DMSO-d.sub.6) 0.96 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.21 (s, 3H, C(CH.sub.3).sub.2), 1.36 (s, 3H, C(CH.sub.3).sub.2), 1.64 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 1.71 (m, 1H, 5-H), 2.22 (m, 1H, 5-H), 2.98 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.06 (bs, 1H, 4-H), 4.26 (bs, 1H, 6-H), 4.41 (d, J=5.9 Hz, 1H, 3a-H), 4.51 (d, J=6.0 Hz, 1H, 6a-H), 4.70 (s, 2H, NH.sub.2), 5.27 (d, J=3.1 Hz, 1H, OH), 6.63 (d, J=7.1 Hz, 1H, NH).

[0581] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.9 (SCH.sub.2CH.sub.2CH.sub.3), 24.1 (C(CH.sub.3).sub.2), 26.5 (C(CH.sub.3).sub.2), 32.1 (SCH.sub.2CH.sub.2CH.sub.3), 35.9 (C-5), 57.2 (C-6), 75.3 (C-4), 84.5 (C-6a), 85.7 (3a), 109.7 (C(CH.sub.3).sub.2), 119.7 (C-5), 136.6 (C-6), 152.4 (C-4), 155.9 (C-2).

(3aR,4S,6R,6aS)-6-(6-Chloro-2-(propylthio)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (19b)

[0582] ##STR00071##

[0583] A solution of (19a) (375.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 10 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0584] Yield: 23%.

[0585] Melting point: ND.

[0586] .sup.1H NMR (DMSO-d.sub.6) 1.02 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.25 (s, 3H, C(CH.sub.3).sub.2), 1.45 (s, 3H, C(CH.sub.3).sub.2), 1.75 (h, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.25 (m, 1H, 5-H), 2.51 (m, 1H, 5-H), 3.16 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.18 (bs, 1H, 4-H), 4.56 (d, J=6.2 Hz, 1H, 3a-H), 4.86 (m, 1H, 6-H), 5.04 (dd, J=6.1 Hz/1.9 Hz, 1H, 6a-H), 5.47 (bs, 1H, OH), 8.59 (s, 1H, 8-H).

[0587] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 22.2 (SCH.sub.2CH.sub.2CH.sub.3), 24.3 (C(CH.sub.3).sub.2), 26.6 (C(CH.sub.3).sub.2), 32.7 (SCH.sub.2CH.sub.2CH.sub.3), 36.4 (C-5), 60.4 (C-6), 74.6 (C-4), 83.9 (C-6a), 86.1 (C-3a), 110.9 (C(CH.sub.3).sub.2), 128.1 (C-5), 146.0 (C-8), 148.9 (C-6), 152.7 (C-4), 163.9 (C-2).

(3aR,4S,6R,6aS)-6-(6-(((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (19c)

[0588] ##STR00072##

[0589] A solution of (19b) (193.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0590] Yield: 91%.

[0591] Melting point: ND.

[0592] .sup.1H NMR (CDCl.sub.3) 0.90 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.32 (s, 3H, C(CH.sub.3).sub.2), 1.34 (m, 2H, NHCH(CH.sub.2)CHPh), 1.51 (s, 3H, C(CH.sub.3).sub.2), 1.61 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 2.13 (m, 1H, 5-H), 2.96 (m, 3H, 5-H/SCH.sub.2CH.sub.2CH.sub.3), 3.13 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.42 (m, 1H, 4-H), 4.74 (m, 1H, 6-H), 4.79 (d, J=5.3 Hz, 1H, 3a-H), 4.98 (d, J=5.3 Hz, 1H, 6a-H), 5.99 (bs, 1H, OH), 6.03 (bs, 1H, NH), 6.93 (m, 1H, 6-H), 7.05 (m, 2H, 2-H/5-H), 7.67 (s, 1H, 8-H).

[0593] .sup.13C NMR (CDCl.sub.3) 13.3 (SCH.sub.2CH.sub.2CH.sub.3), 16.2 (NHCH(CH.sub.2)CHPh), 22.6 (SCH.sub.2CH.sub.2CH.sub.3), 24.5 (C(CH.sub.3).sub.2), 25.2 (NHCH(CH.sub.2)CHPh), 27.1 (C(CH.sub.3).sub.2), 33.2 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 38.8 (C-5), 64.0 (C-6), 76.0 (C-4), 86.2 (C-6a), 88.0 (C-3a), 111.4 (C(CH.sub.3).sub.2), 115.3 (d, J=17 Hz, C-2), 117.0 (d, J=17 Hz, C-5), 118.3 (C-5), 122.4 (C-6), 137.7 (C-1), 139.8 (C-8), 148.0-150.0 (dd, 246 Hz/13 Hz, C-4), 149.3-151.3 (dd, 247 Hz/13 Hz, C-3), 150.5 (C-4), 154.7 (C-6), 165.7 (C-2).

(1S,2R,3S,4R)-4-(6-(((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)cyclopentane-1,2,3-triol (19d)

[0594] ##STR00073##

[0595] A solution of (19c) (259.0 mg, 0.5 mmol) in methanol (2 mL) and 12N HCl (1 mL) was stirred at room temperature for 2 h. After distillation of the solvents under vacuum, the residue was purified by silica gel column chromatography.

[0596] Yield: 76%.

[0597] Melting point: 92-94 C.

[0598] .sup.1H NMR (CDCl.sub.3) 0.87 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.34 (m, 2H, NHCH(CH.sub.2)CHPh), 1.59 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.10 (m, 1H, NHCH(CH.sub.2)CHPh), 2.14 (m, 1H, 5-H), 2.71 (bs, 1H, 3-OH), 2.83 (m, 1H, SCH.sub.2CH.sub.2CH.sub.3), 2.98 (m, 2H, 5-H/SCH.sub.2CH.sub.2CH.sub.3), 3.12 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.14 (m, 1H, 3-H), 4.27 (m, 1H, 1-H), 4.47 (bs, 1H, 2-OH), 4.56 (m, 1H, 4-H), 4.76 (m, 1H, 2-H), 4.98 (bs, 1H, 1-OH), 6.16 (bs, 1H, NH), 6.93 (m, 1H, 6-H), 7.04 (m, 2H, 2-H/5-H), 7.59 (s, 1H, 8-H).

[0599] .sup.13C NMR (CDCl.sub.3) 13.2 (SCH.sub.2CH.sub.2CH.sub.3), 16.2 (NHCH(CH.sub.2)CHPh), 22.5 (SCH.sub.2CH.sub.2CH.sub.3), 25.2 (NHCH(CH.sub.2)CHPh), 33.1 (SCH.sub.2CH.sub.2CH.sub.3), 33.3 (NHCH(CH.sub.2)CHPh), 35.8 (C-5), 61.5 (C-4), 74.8 (C-1), 76.9 (C-2), 78.0 (C-3), 115.3 (d, J=17 Hz, C-2), 117.0 (d, J=17 Hz, C-5), 118.3 (C-5), 122.3 (C-6), 137.8 (C-1), 139.0 (C-8), 148.0-150.0 (dd, 246 Hz/13 Hz, C-4), 149.3-151.3 (dd, 247 Hz/13 Hz, C-3), 149.3 (C-4), 154.6 (C-6), 165.8 (C-2).

EXAMPLE 20

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl-2-(ethylthio)-9-methyl-9H-purin-6-amine (20c)

2-(Ethylthio)pyrimidine-4,6-diol (20e)

[0600] ##STR00074##

[0601] 2-Thiobarbituric acid (2.5 g, 17.4 mmol) was dissolved in KOH 10% (25 mL) and supplemented with ethyl iodide (1.63 mL, 20.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 80 C. for 1 h. After cooling on an ice bath to 5 C., the mixture was acidified by addition of hydrochloric acid 6N and the resulting precipitate was filtered off and washed with diethyl ether.

[0602] Yield: 69%.

[0603] Melting point: >300 C.

[0604] .sup.1H NMR (DMSO-d.sub.6) 1.28 (t, J=7.3 Hz, 3H, CH.sub.3), 3.08 (q, J=7.3 Hz, 2H, SCH.sub.2), 5.12 (s, 1H, CH), 11.68 (bs, 2H, OH). .sup.13C NMR (DMSO-d.sub.6) 14.6 (SCH.sub.3), 24.0 (CH.sub.2), 85.6 (CH), 158.1 (C-4/C-6), 162.8 (C-2)

2-(Ethylthio)-5-nitropyrimidine-4,6-diol (20f)

[0605] ##STR00075##

[0606] To 6 mL of acetic acid cooled at 5 C. on an ice bath were added fuming nitric acid (2.5 mL) and (20e) (1.8 g, 10.5 mmol). After 1 hour stirring at room temperature, the mixture was cooled at 5 C. on an ice bath, water (50 mL) was added and the resulting precipitate was filtered off.

[0607] Yield: 69%.

[0608] Melting point: 210-213 C. (decomposition).

[0609] .sup.1H NMR (DMSO-d.sub.6) 1.31 (t, J=7.3 Hz, 3H, CH.sub.3), 3.17 (q, J=7.3 Hz, 2H, SCH.sub.2).

[0610] .sup.13C NMR (DMSO-d.sub.6) 14.4 (CH.sub.3), 24.7 (SCH.sub.2), 117.4 (C-5), 158.9 (C-4/C-6), 164.0 (C-2).

4,6-Dichloro-2-(ethylthio)-5-nitropyrimidine (20g)

[0611] ##STR00076##

[0612] To a solution of (20f) (1.5 g, 6.9 mmol) in POCl.sub.3 (10 mL) cooled at 5 C. on an ice bath was added dropwise 2,6-lutidine (2.5 mL). After 2 hours stirring at 80 C., the mixture was poured on crushed ice and extracted with ethyl acetate (350 mL). The organic layers were washed with water and with an aqueous saturated solution of sodium hydrogenocarbonate and ethyl acetate was evaporated to dryness under vacuum. The resulting oily residue was used without further purification in the next step (20h).

[0613] Yield: 85%.

[0614] Melting point: oil.

[0615] .sup.1H NMR (DMSO-d.sub.6) 1.35 (t, J=7.3 Hz, 3H, CH.sub.3), 3.18 (q, J=7.3 Hz, 2H, SCH.sub.2).

[0616] .sup.13C NMR (DMSO-d.sub.6) 14.0 (CH.sub.3), 25.3 (SCH.sub.2), 149.1 (C-4/C-6), 154.5 (C-5), 165.4 (C-2).

4,6-Dichloro-2-(ethylthio)pyrimidin-5-amine (20h)

[0617] ##STR00077##

[0618] To a solution of (20g) (1.0 g, 3.9 mmol) in methanol (10 mL) and acetic acid (4 mL) was added iron powder (1.07 g, 19.5 mmol). After 1 hour stirring at room temperature, ethyl acetate (50 mL) was added and the suspension was filtered. The filtrate was washed with water and with an aqueous saturated solution of sodium hydrogenocarbonate and the organic layer was evaporated to dryness under vacuum. Water was added on the residue and the resulting precipitate was filtered off.

[0619] Yield: 86%.

[0620] Melting point: 48-50 C.

[0621] .sup.1H NMR (DMSO-d.sub.6) 1.28 (t, J=7.3 Hz, 3H, CH.sub.3), 3.02 (q, J=7.3 Hz, 2H, SCH.sub.2), 5.90 (s, 2H, NH.sub.2).

[0622] .sup.13C NMR (DMSO-d.sub.6) 14.3 (CH.sub.3), 24.9 (SCH.sub.2), 133.5 (C-5), 143.7 (C-4/C-6), 153.8 (C-2).

6-Chloro-2-(ethylthio)-N.SUP.4.-methylpyrimidine-4,5-diamine (20a)

[0623] ##STR00078##

[0624] 4,6-Dichloro-2-(ethylthio)pyrimidin-5-amine (20h) (0.5 g, 2.2 mmol) was dissolved in methanol (2 mL) and supplemented with a solution of methylamine 33% w/w in methanol (0.80 mL, 6.6 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0625] Yield: 87%.

[0626] Melting point: 112-114 C.

[0627] .sup.1H NMR (DMSO-d.sub.6) 1.27 (t, J=7.2 Hz, 3H, CH.sub.3), 2.87 (d, J=3.8 Hz, 3H, NHCH.sub.3), 2.97 (q, J=7.2 Hz, 2H, SCH.sub.2), 4.70 (s, 2H, NH.sub.2), 7.00 (s, 1H, NH).

[0628] .sup.13C NMR (DMSO-d.sub.6) 14.9 (CH.sub.3), 24.5 (SCH.sub.2), 27.8 (NHCH.sub.3), 120.1 (C-5), 137.2 (C-6), 153.3 (C-4), 155.4 (C-2).

6-Chloro-2-(ethylthio)-9-methyl-9H-purine (20b)

[0629] ##STR00079##

[0630] A solution of (20a) (219.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0631] Yield: 86%.

[0632] Melting point: 89-100 C.

[0633] .sup.1H NMR (DMSO-d.sub.6) 1.37 (t, J=7.3 Hz, 3H, CH.sub.3), 3.20 (q, J=7.3 Hz, 2H, SCH.sub.2), 3.79 (s, 3H, NCH.sub.3), 8.48 (s, 1H, CH).

[0634] .sup.13C NMR (DMSO-d.sub.6) 14.3 (CH.sub.3), 25.2 (SCH.sub.2), 30.0 (NCH.sub.3), 127.9 (C-5), 147.0 (C-8), 148.8 (C-6), 153.2 (C-4), 163.8 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-2-(ethylthio)-9-methyl-9H-purin-6-amine (20c)

[0635] ##STR00080##

[0636] A solution of (20b) (114.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0637] Yield: 89%.

[0638] Melting point: 116-118.5 C.

[0639] .sup.1H NMR (CDCl.sub.3) 1.25 (t, J=7.3 Hz, 3H, CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 2.09 (ddd, J=9.5 Hz/6.3 Hz/3.2 Hz, 1H, NHCH(CH.sub.2)CHPh), 3.02 (m, 2H, SCH.sub.2), 3.12 (bs, 1H, NHCH(CH.sub.2)CHPh), 3.76 (s, 3H, NCH.sub.3), 5.96 (bs, 1H, NH), 6.97 (m, 1H, 6-H), 7.07 (m, 2H, 2-H/5-H), 7.60 (s, 1H, 8-H).

[0640] .sup.13.sub.C NMR (CDCl.sub.3) 14.9 (CH.sub.3), 16.3 (NHCH(CH.sub.2)CHPh), 25.4 (NHCH(CH.sub.2)CHPh), 25.7 (SCH.sub.2), 29.8 (NCH.sub.3), 33.5 (NHCH(CH.sub.2)CHPh), 115.6 (d, J=17 Hz, C-2), 117.1 (d, J=17 Hz, C-5), 117.6 (C-5), 122.7 (C-6), 138.1 (C-1), 139.7 (C-8), 148.0-150.0 (dd, J=246 Hz/13 Hz, C-4), 149.3-151.3 (dd, J=247 Hz/13 Hz, C-3), 150.9 (C-4), 154.7 (C-6), 165.6 (C-2).

EXAMPLE 21

Synthesis of N-((1R,2S)-2-(3,4-difluorophenylcyclopropyl)-9-ethyl-2-(ethylthio)-9H-purin-6-amine (21c)

6-Chloro-N.SUP.4.-ethyl-2-(ethylthio)pyrimidine-4,5-diamine (21a)

[0641] ##STR00081##

[0642] 4,6-Dichloro-2-(ethylthio)pyrimidin-5-amine (20h) (0.5 g, 2.2 mmol) was dissolved in a solution of ethylamine 2.0 M in methanol (3.3 mL, 6.6 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0643] Yield: 91%.

[0644] Melting point: 93-95 C.

[0645] .sup.1H NMR (DMSO-d.sub.6) 1.16 (t, J=7.2 Hz, 3H, NHCH.sub.2CH.sub.3), 1.27 (t, J=7.2 Hz, 3H, SCH.sub.2CH.sub.3), 2.96 (q, J=7.2 Hz, 2H, SCH.sub.2CH.sub.3), 3.38 (p, J=6.1 Hz, 2H, NHCH.sub.2CH.sub.3), 4.74 (s, 2H, NH.sub.2), 6.93 (s, 1H, NH). .sup.13C NMR (DMSO-d.sub.6) 14.4 (NHCH.sub.2CH.sub.3), 15.0 (SCH.sub.2CH.sub.3), 24.5 (SCH.sub.2CH.sub.3), 35.8 (NHCH.sub.2CH.sub.3), 119.9 (C-5), 137.3 (C-6), 152.6 (C-4), 155.2 (C-2).

6-Chloro-9-ethyl-2-(ethylthio)-9H-purine (21b)

[0646] ##STR00082##

[0647] A solution of (21a) (233.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0648] Yield: 91%.

[0649] Melting point: 64-66 C.

[0650] .sup.1H NMR (DMSO-d.sub.6) 1.37 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.3), 1.45 (t, J=7.3 Hz, 3H, NCH.sub.2CH.sub.3), 3.19 (q, J=7.3 Hz, 2H, SCH.sub.2), 4.25 (q, J=7.3 Hz, 2H, NCH.sub.2), 8.56 (s, 1H, CH).

[0651] .sup.13C NMR (DMSO-d.sub.6) 14.3 (SCH.sub.2CH.sub.3), 14.7 (NCH.sub.2CH.sub.3), 25.2 (SCH.sub.2), 39.0 (NCH.sub.2), 128.1 (C-5), 146.1 (C-8), 148.9 (C-6), 152.7 (C-4), 163.7 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-ethyl-2-(ethylthio)-9H-purin-6-amine (21c)

[0652] ##STR00083##

[0653] A solution of (21b) (121.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0654] Yield: 96%.

[0655] Melting point: 107.5-109.5 C.

[0656] .sup.1H NMR (CDCl.sub.3) 1.26 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.3), 1.32 (m, 2H, NHCH(CH.sub.2)CHPh), 1.50 (t, J=7.3 Hz, 3H, NCH.sub.2CH.sub.3), 2.08 (ddd, J=9.5 Hz/6.4 Hz/3.3 Hz, 1H, NHCH(CH.sub.2)CHPh), 3.03 (m, 2H, SCH.sub.2CH.sub.3), 3.11 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.19 (q, J=7.3 Hz, 2H, NCH.sub.2CH.sub.3), 5.94 (bs, 1H, NH), 6.98 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.63 (s, 1H, 8-H).

[0657] .sup.13C NMR (CDCl.sub.3) 14.9 (SCH.sub.2CH.sub.3), 15.7 (NCH.sub.2CH.sub.3), 16.3 (NHCH(CH.sub.2)CHPh), 25.4 (NHCH(CH.sub.2)CHPh), 25.7 (SCH.sub.2CH.sub.3), 33.5 (NHCH(CH.sub.2)CHPh), 38.8 (NCH.sub.2CH.sub.3), 115.7 (d, J=17 Hz, C-2), 117.0 (d, J=17 Hz, C-5), 117.8 (C-5), 122.8 (C-6), 138.1 (C-1), 138.6 (C-8), 148.0-150.0 (dd, J=246 Hz/13 Hz, C-4), 149.3-151.3 (dd, J=247 Hz/13 Hz, C-3), 150.4 (C-4), 154.7 (C-6), 165.3 (C-2).

EXAMPLE 22

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(methylthio)-9H-purin-6-amine (22c)

2-(Methylthio)pyrimidine-4,6-diol (22e)

[0658] ##STR00084##

[0659] 2-Thiobarbituric acid (2.5 g, 17.4 mmol) was dissolved in KOH 10% (25 mL) and supplemented with methyl iodide (1.25 mL, 20.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 80 C. for 1 h. After cooling on an ice bath to 5 C., the mixture was acidified by addition of hydrochloric acid 6N and the resulting precipitate was filtered off and washed with diethyl ether.

[0660] Yield: 77%.

[0661] Melting point: >300 C.

[0662] .sup.1H NMR (DMSO-d.sub.6) 2.46 (s, 3H, SCH.sub.3), 5.13 (s, 1H, CH), 11.71 (bs, 2H, OH).

[0663] .sup.13C NMR (DMSO-d.sub.6) 12.7 (SCH.sub.3), 85.5 (CH), 158.9 (C-4/C-6), 163.5 (C-2).

2-(Methylthio)-5-nitropyrimidine-4,6-diol (22f)

[0664] ##STR00085##

[0665] To 6 mL of acetic acid cooled at 5 C. on an ice bath were added fuming nitric acid (2.5 mL) and (22e) (2.0 g, 12.6 mmol). After 1 hour stirring at room temperature, the mixture was cooled at 5 C. on an ice bath, water (50 mL) was added and the resulting precipitate was filtered off.

[0666] Yield: 67%.

[0667] Melting point: 220-221 C. (decomposition).

[0668] .sup.1H NMR (DMSO-d.sub.6) 2.56 (s, 3H, SCH.sub.3).

[0669] .sup.13C NMR (DMSO-d.sub.6) 13.2 (SCH.sub.3), 117.4 (C-5), 158.7 (C-4/C-6), 164.6 (C-2).

4,6-Dichloro-2-(methylthio)-5-nitropyrimidine (22g)

[0670] ##STR00086##

[0671] To a solution of (22f) (1.5 g, 7.4 mmol) in POCl.sub.3 (10 mL) cooled at 5 C. on an ice bath was added dropwise 2,6-lutidine (2.5 mL). After 2 hours stirring at 80 C., the mixture was poured on crushed ice and the resulting precipitate was filtered off.

[0672] Yield: 92%.

[0673] Melting point: 63-64 C.

[0674] .sup.1H NMR (DMSO-d.sub.6) 2.56 (s, 3H, SCH.sub.3).

[0675] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.3), 149.0 (C-4/C-6), 154.5 (C-5), 166.1 (C-2).

4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (22h)

[0676] ##STR00087##

[0677] To a solution of (22g) (1.0 g, 4.2 mmol) in methanol (10 mL) and acetic acid (4 mL) was added iron powder (1.07 g, 19.5 mmol). After 1 hour stirring at room temperature, ethyl acetate (50 mL) was added and the suspension was filtered. The filtrate was washed with water and with an aqueous saturated solution of sodium hydrogenocarbonate and the organic layer was evaporated to dryness under vacuum. Water was added on the residue and the resulting precipitate was filtered off.

[0678] Yield: 95%.

[0679] Melting point: 105-108 C.

[0680] .sup.1H NMR (DMSO-d.sub.6) 2.45 (s, 3H, SCH.sub.3), 5.90 (s, 2H, NH.sub.2).

[0681] .sup.13C NMR (DMSO-d.sub.6) 13.8 (SCH.sub.3), 133.4 (C-5), 143.7 (C-4/C-6), 154.4 (C-2).

6-Chloro-N.SUP.4.-methyl-2-(methylthio)pyrimidine-4,5-diamine (22a)

[0682] ##STR00088##

[0683] 4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (22h) (0.5 g, 2.4 mmol) was dissolved in methanol (2 mL) and supplemented with a solution of methylamine 33% w/w in methanol (0.87 mL, 7.2 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0684] Yield: 82%.

[0685] Melting point: 141-143 C.

[0686] .sup.1H NMR (DMSO-d.sub.6) 2.38 (s, 3H, SCH.sub.3), 2.88 (d, J=3.0 Hz, 3H, NHCH.sub.3), 4.70 (s, 2H, NH.sub.2), 7.01 (s, 1H, NH).

[0687] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.3), 27.8 (NHCH.sub.3), 120.1 (C-5), 137.2 (C-6), 153.3 (C-4), 155.9 (C-2).

6-Chloro-9-methyl-2-(methylthio)-9H-purine (22b)

[0688] ##STR00089##

[0689] A solution of (22a) (205.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0690] Yield: 92%.

[0691] Melting point: 140-142 C.

[0692] .sup.1H NMR (DMSO-d.sub.6) 2.61 (s, 3H, SCH.sub.3), 3.80 (s, 3H, NCH.sub.3), 8.49 (s, 1H, CH).

[0693] .sup.13C NMR (DMSO-d.sub.6) 14.1 (SCH.sub.3), 30.0 (NCH.sub.3), 127.9 (C-5), 147.0 (C-8), 148.8 (C-6), 153.2 (C-4), 164.4 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-methyl-2-(methylthio)-9H-purin-6-amine (22c)

[0694] ##STR00090##

[0695] A solution of (22b) (107.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0696] Yield: 80%.

[0697] Melting point: 156-159 C.

[0698] .sup.1H NMR (CDCl.sub.3) 1.33 (m, 2H, NHCH(CH.sub.2)CHPh), 2.09 (m, 1H, NHCH(CH.sub.2)CHPh), 2.45 (s, 3H, SCH.sub.3), 3.12 (bs, 1H, NHCH(CH.sub.2)CHPh), 3.77 (s, 3H, NCH.sub.3), 5.95 (bs, 1H, NH), 7.00 (m, 1H, 6-H), 7.09 (m, 2H, 2-H/5-H), 7.60 (s, 1H, 8-H).

[0699] .sup.13C NMR (CDCl.sub.3) 14.5 (SCH.sub.3), 16.1 (NHCH(CH.sub.2)CHPh), 25.4 (NHCH(CH.sub.2)CHPh), 29.8 (NCH.sub.3), 33.4 (NHCH(CH.sub.2)CHPh), 115.9 (d, J=17 Hz, C-2), 117.0 (d, J=17 Hz, C-5), 117.5 (C-5), 122.9 (C-6), 137.9 (C-1), 139.7 (C-8), 148.0-150.0 (dd, J=246 Hz/13 Hz, C-4), 149.3-151.3 (dd, J=247 Hz/13 Hz, C-3), 151.0 (C-4), 154.7 (C-6), 166.0 (C-2).

EXAMPLE 23

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-propoxy-9H-purin-6-amine hydrochloride (23t.HCl)

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-methyl-2-(methylsulfonyl)-9H-purin-6-amine (23q)

[0700] ##STR00091##

[0701] A solution of (22c) (125.0 mg, 0.36 mmol) in methylene chloride (10 mL) was cooled to 5 C. on an ice bath and supplemented with 3-chloroperbenzoic acid (140.0 mg, 0.80 mmol). After stirring at room temperature for 4 hours, the mixture was washed with a solution of NaOH 0.1 M (210 mL). The organic layer was dried, filtered and methylene chloride was evaporated to dryness under vacuum. The residue was suspended in ethyl acetate and filtered off.

[0702] Yield: 88%.

[0703] Melting point: 206-208.5 C.

[0704] .sup.1H NMR (CDCl.sub.3) 1.38 (m, 2H, NHCH(CH.sub.2)CHPh), 2.17 (td, J=8.0 Hz/3.3 Hz, 1H, NHCH(CH.sub.2)CHPh), 3.08 (bs, 1H, NHCH(CH.sub.2)CHPh), 3.19 (s, 3H, SO.sub.2CH.sub.3), 3.91 (s, 3H, NCH.sub.3), 6.49 (bs, 1H, NH), 7.11 (m, 3H, 2-H/5-H/6-H), 7.88 (s, 1H, 8-H).

[0705] .sup.13C NMR (CDCl.sub.3) 15.7 (NHCH(CH.sub.2)CHPh), 25.4 (NHCH(CH.sub.2)CHPh), 30.5 (NCH.sub.3), 33.1 (NHCH(CH.sub.2)CHPh), 39.4 (SO.sub.2CH.sub.3), 115.8 (d, J=16 Hz, C-2), 117.3 (d, J=17 Hz, C-5), 120.9 (C-5), 123.3 (C-6), 137.3 (C-1), 143.0 (C-8), 148.5-149.9 (dd, J=247 Hz/12 Hz, C-4), 149.7-151.1 (dd, J=248 Hz/13 Hz, C-3), 149.2 (C-4), 155.7 (C-6).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-methyl-2-propoxy-9H-purin-6-amine (23t)

[0706] ##STR00092##

[0707] Sodium was dissolved in propan-1-ol (3 mL) on an iced bath and (23q) (150.0 mg, 0.40 mmol) was added. After stirring at room temperature for 3 hours, the mixture was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography and the resulting oil was engaged in the next step (23t.HCl) without further purification.

[0708] Yield: 73%.

[0709] .sup.1H NMR (CDCl.sub.3) 0.94 (t, J=7.5 Hz, 3H, OCH.sub.2CH.sub.2CH.sub.3), 1.30 (dt, J=7.5 Hz/6.2 Hz, 1H, NHCH(CH.sub.2)CHPh), 1.39 (ddd, J=9.7 Hz/5.9 Hz/4.7 Hz, 1H, NHCH(CH.sub.2)CHPh), 1.75 (h, J=7.3 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.3), 2.10 (m, 1H, NHCH(CH.sub.2)CHPh), 3.16 (bs, 1H, NHCH(CH.sub.2)CHPh), 3.74 (s, 3H, NCH.sub.3), 4.18 (m, 2H, OCH.sub.2CH.sub.2CH.sub.3), 6.86 (bs, 1H, NH), 6.94 (m, 1H, 6-H), 7.07 (m, 2H, 2-H/5-H), 7.57 (s, 1H, 8-H).

[0710] .sup.13C NMR (CDCl.sub.3) 10.5 (OCH.sub.2CH.sub.2CH.sub.3), 16.2 (NHCH(CH.sub.2)CHPh), 22.4 (OCH.sub.2CH.sub.2CH.sub.3), 25.1 (NHCH(CH.sub.2)CHPh), 29.8 (NCH.sub.3), 33.6 (NHCH(CH.sub.2)CHPh), 69.3 (OCH.sub.2CH.sub.2CH.sub.3), 115.4 (C-5), 115.7 (C-2), 117.0 (C-5), 122.6 (C-6), 138.3 (C-1), 139.1 (C-8), 148.0-149.9 (C-4), 149.4-151.3 (C-3), 151.7 (C-4), 156.1 (C-6), 162.6 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-methyl-2-propoxy-9H-purin-6-amine hydrochloride (23t.HCl)

[0711] ##STR00093##

[0712] To a solution of (23t) (90.0 mg, 0.25 mmol) in diethyl ether (5 mL) was added dropwise a saturated solution of HCl in diethyl ether. The resulting precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0713] Yield: 95%.

[0714] Melting point: 199-202 C.

EXAMPLE 24

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (24c)

6-Chloro-N.SUP.4.-ethyl-2-(methylthio)pyrimidine-4,5-diamine (24a)

[0715] ##STR00094##

[0716] 4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (22h) (0.5 g, 2.4 mmol) was dissolved in a solution of ethylamine 2.0 M in methanol (3.6 mL, 7.2 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0717] Yield: 86%.

[0718] Melting point: 120-122 C.

[0719] .sup.1H NMR (DMSO-d.sub.6) 1.16 (t, J=7.2 Hz, 3H, CH.sub.3), 2.37 (s, 3H, SCH.sub.3), 3.38 (qd, J=7.2 Hz/5.3 Hz, 2H, NCH.sub.2), 4.76 (s, 2H, NH.sub.2), 6.94 (t, J=4.8 Hz, 1H, NH).

[0720] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.3), 14.3 (CH.sub.3), 35.7 (NCH.sub.2), 119.8 (C-5), 137.2 (C-6), 152.4 (C-4), 155.7 (C-2).

6-Chloro-9-ethyl-2-(methylthio)-9H-purine (24b)

[0721] ##STR00095##

[0722] A solution of (24a) (219.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0723] Yield: 77%.

[0724] Melting point: 99.5-101.5 C.

[0725] .sup.1H NMR (DMSO-d.sub.6) 1.45(t, J=7.3 Hz, 3H, CH.sub.3), 2.60 (s, 3H, SCH.sub.3), 4.25 (q, J=7.3 Hz, 2H, NCH.sub.2), 8.57 (s, 1H, CH).

[0726] .sup.13C NMR (DMSO-d.sub.6) 14.1 (SCH.sub.3), 14.7 (CH.sub.3), 39.0 (NCH.sub.2), 128.0 (C-5), 146.0 (C-8), 148.8 (C-6), 152.7 (C-4), 164.3 (C-2).

N-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (24c)

[0727] ##STR00096##

[0728] A solution of (24b) (114.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0729] Yield: 38%.

[0730] Melting point: 126-127.5 C.

[0731] .sup.1H NMR (CDCl.sub.3) 1.31 (td, J=8.0 Hz/6.9 Hz/4.0 Hz, 2H, NHCH(CH.sub.2)CHPh), 1.51 (t, J=7.3 Hz, 3H, CH.sub.3), 2.08 (td, J=8.1 Hz/6.7 Hz/3.2 Hz, 1H, NHCH(CH.sub.2)CHPh), 2.45 (s, 3H, SCH.sub.3), 3.11 (bs, 1H, NHCH(CH.sub.2)CHPh), 4.20 (q, J=7.3 Hz, 2H, NCH.sub.2), 5.97 (bs, 1H, NH), 7.01 (m, 1H, 6-H), 7.10 (m, 2H, 2-H/5-H), 7.64 (s, 1H, 8-H).

[0732] .sup.13C NMR (CDCl.sub.3) 14.6 (SCH.sub.3), 15.6 (CH.sub.3), 16.1 (NHCH(CH.sub.2)CHPh), 25.4 (NHCH(CH.sub.2)CHPh), 33.4 (NHCH(CH.sub.2)CHPh), 38.8 (NCH.sub.2), 115.9 (d, J=17 Hz, C-2), 117.0 (d, J=17 Hz, C-5), 117.7 (C-5), 123.0 (C-6), 138.0 (C-1), 138.6 (C-8), 148.0-150.0 (dd, J=246 Hz/13 Hz, C-4), 149.3-151.3 (dd, J=247 Hz/13 Hz, C-3), 150.4 (C-4), 154.7 (C-6), 165.8 (C-2).

EXAMPLE 25

Synthesis of 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (25c)

2-(Butylthio)pyrimidine-4,6-diol (25e)

[0733] ##STR00097##

[0734] 2-Thiobarbituric acid (2.5 g, 17.4 mmol) was dissolved in KOH 10% (25 mL) and supplemented with butyl iodide (2.27 mL, 20.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 80 C. for 1 h. After cooling on an ice bath to 5 C., the mixture was acidified by addition of hydrochloric acid 6N and the resulting precipitate was filtered off and washed with diethyl ether.

[0735] Yield: 72%.

[0736] Melting point: >300 C.

[0737] .sup.1H NMR (DMSO-d.sub.6) 0.90 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.38 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.60 (p, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.09 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5.12 (s, 1H, CH), 11.64 (bs, 2H, OH).

[0738] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.2 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.8 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 85.6 (CH), 158.1 (C-4/C-6), 162.9 (C-2).

2-(Butylthio)-5-nitropyrimidine-4,6-diol (25f)

[0739] ##STR00098##

[0740] To 6 mL of acetic acid cooled at 5 C. on an ice bath were added fuming nitric acid (2.5 mL) and (25e) (2.0 g, 10.0 mmol). After 1 hour stirring at room temperature, the mixture was cooled at 5 C. on an ice bath, water (50 mL) was added and the resulting precipitate was filtered off.

[0741] Yield: 68%.

[0742] Melting point: 178-179.5 C. (decomposition).

[0743] .sup.1H NMR (DMSO-d.sub.6) 0.90 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.63 (p, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.18 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3).

[0744] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.2 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.9 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 117.5 (C-5), 158.9 (C-4/C-6), 164.2 (C-2).

2-(Butylthio)-4,6-dichloro-5-nitropyrimidine (25g)

[0745] ##STR00099##

[0746] To a solution of (25f) (1.5 g, 6.1 mmol) in POCl.sub.3 (10 mL) cooled at 5 C. on an ice bath was added dropwise 2,6-lutidine (2.5 mL). After 2 hours stirring at 80 C., the mixture was poured on crushed ice and extracted with ethyl acetate (350 mL). The organic layers were washed with water and with an aqueous saturated solution of sodium hydrogenocarbonate and ethyl acetate was evaporated to dryness under vacuum. The resulting oily residue was used without further purification in the next step (25h).

[0747] Yield: 92%.

[0748] Melting point: oil.

[0749] .sup.1H NMR (DMSO-d.sub.6) 0.90 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.65 (p, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.17 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3).

[0750] .sup.13C NMR (DMSO-d.sub.6) 13.4 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.2 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.2 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 149.0 (C-4/C-6), 154.7 (C-5), 165.6 (C-2).

2-(Butylthio)-4,6-dichloropyrimidin-5-amine (25h)

[0751] ##STR00100##

[0752] To a solution of (25g) (1 g, 3.5 mmol) in methanol (10 mL) and acetic acid (4 mL) was added iron powder (0.78 g, 14.0 mmol). After 1 hour stirring at room temperature, ethyl acetate (50 mL) was added and the suspension was filtered. The filtrate was washed with water and with an aqueous saturated solution of sodium hydrogenocarbonate and the organic layer was evaporated to dryness under vacuum. The resulting oily residue was used without further purification in the next step (25a).

[0753] Yield: 97%.

[0754] Melting point: oil.

[0755] .sup.1H NMR (DMSO-d.sub.6) 0.90 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.61 (p, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.03 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5.88 (s, 2H, NH.sub.2).

[0756] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.2 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.7 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 133.5 (C-5), 143.7 (C-4/C-6), 154.0 (C-2).

2-(Butylhio)-6-chloro-2-N.SUP.4.-methylpyrimidine-4,5-diamine (25a)

[0757] ##STR00101##

[0758] 2-(Butylthio)-4,6-dichloropyrimidin-5-amine (25h) (0.5 g, 2.0 mmol) was dissolved in methanol (2 mL) and supplemented with a solution of methylamine 33% w/w in methanol (0.73 mL, 6.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0759] Yield: 87%.

[0760] Melting point: oil.

[0761] .sup.1H NMR (DMSO-d.sub.6) 0.89 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.38 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.61 (p, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.87 (d, J=4.5 Hz, 3H, NHCH.sub.3), 2.98 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.69 (s, 2H, NH.sub.2), 6.99 (q, J=4.4 Hz, 1H, NHCH.sub.3).

[0762] .sup.13C NMR (DMSO-d.sub.6) 13.6 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 27.8 (NHCH.sub.3), 29.8 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.4 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 120.0 (C-5), 137.2 (C-6), 153.3 (C-4), 155.5 (C-2).

2-(Butylthio)-6-chloro-9-methyl-9H-purine (25b)

[0763] ##STR00102##

[0764] A solution of (25a) (247.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0765] Yield: 76%.

[0766] Melting point: 56-58 C.

[0767] .sup.1H NMR (DMSO-d.sub.6) 0.93 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.44 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.70 (p, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.20 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.79 (s, 3H, NCH.sub.3), 8.48 (s, 1H, CH).

[0768] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.4 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.0 (NCH.sub.3), 30.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.8 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 127.9 (C-5), 147.0 (C-8), 148.8 (C-6), 153.2 (C-4), 163.9 (C-2).

2-(Butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (25c)

[0769] ##STR00103##

[0770] A solution of (25b) (128.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0771] Yield: 66%.

[0772] Melting point: 98-100 C.

[0773] .sup.1H NMR (CDCl.sub.3) 0.89 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.33 (m, 4H, NHCH(CH.sub.2)CHPh/SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.62 (p, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 (ddd, J=9.5 Hz/6.4 Hz/3.2 Hz, 1H, NHCH(CH.sub.2)CHPh), 3.02 (m, 1H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.11 (m, 2H, NHCH(CH.sub.2)CHPh/SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.76 (s, 3H, NCH.sub.3), 5.92 (bs, 1H, NH), 6.98 (m, 1H, 6-H), 7.07 (m, 2H, 2-H/5-H), 7.59 (s, 1H, 8-H).

[0774] .sup.13C NMR (CDCl.sub.3) 13.9 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 16.3 (NHCH(CH.sub.2)CHPh), 22.1 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 25.3 (NHCH(CH.sub.2)CHPh), 29.8 (NCH.sub.3), 31.1 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.8 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 33.5 (NHCH(CH.sub.2)CHPh), 115.7 (d, J=17 Hz, C-2), 117.1 (d, J=17 Hz, C-5), 117.6 (C-5), 122.8 (C-6), 138.0 (C-1), 139.7 (C-8), 148.0-150.0 (dd, J=246 Hz/13 Hz, C-4), 149.4-151.4 (dd, J=247 Hz/13 Hz, C-3), 150.8 (C-4), 154.7 (C-6), 165.6 (C-2).

EXAMPLE 26

Synthesis of 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-9H-purin-6-amine (26c)

2-(Butylthio)-6-chloro-N.SUP.4.-ethylpyrimidine-4,5-diamine (26a)

[0775] ##STR00104##

[0776] 4,6-Dichloro-2-(ethylthio)pyrimidin-5-amine (25h) (0.5 g, 2.0 mmol) was dissolved in a solution of ethylamine 2.0 M in methanol (3.0 mL, 6.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 100 C. for 1 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0777] Yield: 91%.

[0778] Melting point: 80-82 C.

[0779] .sup.1H NMR (DMSO-d.sub.6) 0.89 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.16 (t, J=7.1 Hz, 3H, NHCH.sub.2CH.sub.3), 1.38 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.60 (p, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.96 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.38 (p, J=7.0 Hz, 2H, NHCH.sub.2CH.sub.3), 4.74 (s, 2H, NH.sub.2), 6.95 (t, J=4.7 Hz, 1H, NHCH.sub.2CH.sub.3).

[0780] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 14.4 (NHCH.sub.2CH.sub.3), 21.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.8 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 35.7 (NHCH.sub.2CH.sub.3), 119.8 (C-5), 137.3 (C-6), 152.5 (C-4), 155.4 (C-2).

2-(Butylthio)-6-chloro-9-ethyl-9H-purine (26b)

[0781] ##STR00105##

[0782] A solution of (26a) (261.0 mg, 1 mmol) in acetic acid (2.5 mL) and triethyl orthoformate (2.5 mL, 15 mmol) was heated at a temperature of 130 C. under reflux for 1 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0783] Yield: 70%.

[0784] Melting point: 69-71 C.

[0785] .sup.1H NMR (DMSO-d.sub.6) 0.93 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.45 (m, 5H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3/NCH.sub.2CH.sub.3), 1.70 (p, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.19 (t, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.25 (q, J=7.3 Hz, 2H, NCH.sub.2CH.sub.3), 8.56 (s, 1H, CH).

[0786] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 14.7 (NCH.sub.2CH.sub.3), 21.4 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.8 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 39.0 (NCH.sub.2CH.sub.3), 128.1 (C-5), 146.0 (C-8), 148.9 (C-6), 152.7 (C-4), 163.8 (C-2).

2-(Butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-9H-purin-6-amine (26c)

[0787] ##STR00106##

[0788] A solution of (26b) (135.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0789] Yield: 56%.

[0790] Melting point: 92-94 C.

[0791] .sup.1H NMR (CDCl.sub.3) 0.89 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.31 (m, 2H, NHCH(CH.sub.2)CHPh), 1.36 (m, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.50 (t, J=7.3 Hz, 3H, NCH.sub.2CH.sub.3), 1.63 (p, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 (ddd, J=9.5 Hz/6.6 Hz/3.2 Hz, 1H, NHCH(CH.sub.2)CHPh), 3.02 (m, 1H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.10 (m, 2H, NHCH(CH.sub.2)CHPh/SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.18 (q, J=7.3 Hz, 2H, NCH.sub.2CH.sub.3), 5.93 (bs, 1H, NH), 6.99 (m, 1H, 6-H), 7.08 (m, 2H, 2-H/5-H), 7.63 (s, 1H, 8-H).

[0792] .sup.13C NMR (CDCl.sub.3) 13.9 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 15.6 (NCH.sub.2CH.sub.3), 16.2 (NHCH(CH.sub.2)CHPh), 22.1 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 25.4 (NHCH(CH.sub.2)CHPh), 31.1 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.8 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 33.5 (NHCH(CH.sub.2)CHPh), 38.8 (NCH.sub.2CH.sub.3), 115.8 (d, J=17 Hz, C-2), 117.1 (d, J=17 Hz, C-5), 117.8 (C-5), 122.9 (C-6), 138.1 (C-1), 138.6 (C-8), 148.2-150.1 (dd, J=246 Hz/12 Hz, C-4), 149.4-151.4 (dd, J=235 Hz/10 Hz, C-3), 150.3 (C-4), 154.7 (C-6), 165.6 (C-2).

EXAMPLE 27

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (27k)

4,6-Dichloro-2-(methylthio)pyrimidine-5-carbaldehyde (27i)

[0793] ##STR00107##

[0794] POCl.sub.3 (3.2 mL) was cooled at 5 C. on an ice bath and supplemented dropwise by dimethylformamide (20 mL, 215 mmol). 2-(Methylthio)pyrimidine-4,6-diol (22e) (5 g, 31.6 mmol) was then added portion-wise and the mixture was stirred at 100 C. for 20 h. The mixture was poured on crushed ice and extracted with CH.sub.2Cl.sub.2 (350 mL). The combined organic layers were dried and evaporated to dryness under vacuum.

[0795] Yield: 52%.

[0796] Melting point: 87-89 C.

[0797] .sup.1H NMR (DMSO-d.sub.6) 2.57 (s, 3H, SCH.sub.3), 10.07 (s, 1H, COH).

[0798] .sup.13C NMR (DMSO-d.sub.6) 13.3 (SCH.sub.3), 112.9 (C-5), 159.3 (C-4/C-6), 168.2 (C-2), 186.6 (COH).

4-chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (27i)

[0799] ##STR00108##

[0800] To a suspension of (27i) (2.5 g, 11.2 mmol) in THF (25 mL) cooled at 5 C. on an ice bath, were added dropwise hydrazine monohydrate (0.65 mL, 13 mmol) and triethylamine (1.8 mL, 13 mmol). After 1 hour stirring at 5 C., the mixture was evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography.

[0801] Yield: 95%.

[0802] Melting point: >300 C.

[0803] .sup.1H NMR (DMSO-d.sub.6) 2.59 (s, 3H, SCH.sub.3), 8.32 (s, 1H, CH), 14.25 (bs, 1H, NH).

[0804] .sup.13C NMR (DMSO-d.sub.6) 13.9 (SCH.sub.3), 109.6 (C-3a), 133.1 (C-3), 152.9-155.4 (C-4/C-7a), 168.7 (C-6).

4-chloro-1-methyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (27j)

[0805] ##STR00109##

[0806] To a solution of (27i) (1.0 g, 5.0 mmol) in acetonitrile (10 mL) cooled at 5 C. on an ice bath, were added NaH (144 mg, 6.0 mmol) and iodomethane (0.47 mL, 7.5 mmol). After 3 hours stirring at 50 C., acetonitrile was evaporated to dryness under vacuum and the residue was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

[0807] Yield: 82%.

[0808] Melting point: 85-87 C.

[0809] .sup.1H NMR (DMSO-d.sub.6) 2.63 (s, 3H, SCH.sub.3), 4.00 (s, 3H, NCH.sub.3), 8.34 (s, 1H, CH).

[0810] .sup.13C NMR (DMSO-d.sub.6) 13.9 (SCH.sub.3), 34.0 (NCH.sub.3), 110.0 (C-3a), 132.3 (C-3), 152.9 (C-4), 153.5 (C-7a), 168.8 (C-6).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (27k)

[0811] ##STR00110##

[0812] A solution of (27j) (107.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0813] Yield: 84%.

[0814] Melting point: 128.5-130 C.

[0815] .sup.1H NMR (CDCl.sub.3) 1.40 (m, 2H, NHCH(CH.sub.2)CHPh), 2.17 (s, 1H, NHCH(CH.sub.2)CHPh), 2.55 (s, 3H, SCH.sub.3), 3.10 (s, 1H, NHCH(CH.sub.2)CHPh), 3.95 (s, 3H, NCH.sub.3), 5.87 (bs, 1H, NH), 6.87 (m, 2H, 2-H/6-H), 7.12 (q, J=8.7 Hz, 1H, 5-H), 7.59 (s, 1H, 3-H).

[0816] .sup.13C NMR (CDCl.sub.3) 14.2 (SCH.sub.3), 18.3 (NHCH(CH.sub.2)CHPh), 25.6 (NHCH(CH.sub.2)CHPh), 33.8 (NCH.sub.3), 34.9 (NHCH(CH.sub.2)CHPh), 97.8 (C-3a), 114.6 (C-2), 117.4 (C-5), 121.7 (C-6), 132.0 (C-3), 136.8 (C-1), 149.7-150.8 (C-3/C-4), 154.8 (C-7a), 169.2 (C-6).

EXAMPLE 28

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (28x.HCl)

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-6-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (28r)

[0817] ##STR00111##

[0818] A solution of (27j) (125.0 mg, 0.36 mmol) in methylene chloride (10 mL) was cooled to 5 C. on an ice bath and supplemented with 3-chloroperbenzoic acid (140.0 mg, 0.80 mmol). After stirring at room temperature for 4 hours, the mixture was washed with a solution of NaOH 0.1 M (210 mL). The organic layer was dried, filtered and methylene chloride was evaporated to dryness under vacuum. The resulting oily residue was used without further purification in the next step (28x).

[0819] Yield: 58%.

[0820] Melting point: oil.

[0821] .sup.1H NMR (CDCl.sub.3) 1.50 (m, 2H, NHCH(CH.sub.2)CHPh), 2.23 (s, 1H, NHCH(CH.sub.2)CHPh), 3.18 (s, 1H, NHCH(CH.sub.2)CHPh), 3.34 (s, 3H, SO.sub.2CH.sub.3), 4.07 (s, 3H, NCH.sub.3), 6.48 (s, 1H, NH), 6.86 (m, 2H, 2-H/6-H), 7.15 (s, 1H, 5-H), 7.75 (s, 1H, 3-H).

[0822] .sup.13C NMR (CDCl.sub.3) 18.3 (NHCH(CH.sub.2)CHPh), 26.1 (NHCH(CH.sub.2)CHPh), 34.4 (NCH.sub.3), 35.1 (NHCH(CH.sub.2)CHPh), 39.1 (SO.sub.2CH.sub.3), 100.5 (C-3a), 114.5 (C-2), 117.9 (C-5), 121.8 (C-6), 133.0 (C-3), 136.0 (C-1), 150.1 (C-3/C-4), 153.4 (C-7a), 159.5 (C-4), 162.4 (C-6).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (28x.HCl)

[0823] ##STR00112##

[0824] A solution of (28r) (150.0 mg, 0.40 mmol) in THF (6 mL) was supplemented with ethanethiol (0.06 mL, 0.80 mmol) and K.sub.2CO.sub.3 (110.0 mg, 0.80 mmol). After stirring at room temperature for 24 hours, THF was evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0825] Yield: 67%.

[0826] Melting point: 164-168 C.

[0827] .sup.1H NMR (CDCl.sub.3) 1.46 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.3), 1.52 (d, J=6.0 Hz, 1H, NHCH(CH.sub.2)CHPh), 1.69 (m, 1H, NHCH(CH.sub.2)CHPh), 2.37 (s, 1H, NHCH(CH.sub.2)CHPh), 3.09 (s, 1H, NHCH(CH.sub.2)CHPh), 3.33 (q, J=7.2 Hz, 2H, SCH.sub.2CH.sub.3), 4.00 (s, 3H, NCH.sub.3), 6.84 (d, J=7.0 Hz, 1H, 6-H), 6.89 (t, J=8.5 Hz, 1H, 2-H), 7.15 (q, J=8.4 Hz, 1H, 5-H), 7.73 (s, 1H, 3-H), 10.48 (bs, 1H, NH).

[0828] .sup.13C NMR (CDCl.sub.3) 14.1 (SCH.sub.2CH.sub.3), 17.6 (NHCH(CH.sub.2)CHPh), 25.5 (NHCH(CH.sub.2)CHPh), 25.9 (SCH.sub.2CH.sub.3), 34.5 (NCH.sub.3), 35.3 (NHCH(CH.sub.2)CHPh), 96.3 (C-3a), 114.8 (C-2), 118.1 (C-5), 122.1 (C-6), 135.5 (C-3), 135.3 (C-1), 148.9-150.1 (C-4), 150.3-151.4 (C-3), 151.7 (C-4), 154.2 (C-7a), 160.8 (C-6).

EXAMPLE 29

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(propylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (29x. HCl)

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-6-(propylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (29x.HCl)

[0829] ##STR00113##

[0830] A solution of (28r) (150.0 mg, 0.40 mmol) in THF (6 mL) was supplemented with propanethiol (0.07 mL, 0.80 mmol) and K.sub.2CO.sub.3 (110.0 mg, 0.80 mmol). After stirring at room temperature for 24 hours, THF was evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0831] Yield: 66%.

[0832] Melting point: 110-115 C.

[0833] .sup.1H NMR (CDCl.sub.3) 1.08 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.51 (m, 1H, NHCH(CH.sub.2)CHPh), 1.68 (m, 1H, NHCH(CH.sub.2)CHPh), 1.82 (h, J=7.0 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.36 (s, 1H, NHCH(CH.sub.2)CHPh), 3.09 (m, 1H, NHCH(CH.sub.2)CHPh/SCH.sub.2CH.sub.2CH.sub.3), 3.29 (t, J=6.8 Hz, 1H, SCH.sub.2CH.sub.2CH.sub.3), 4.00 (s, 3H, NCH.sub.3), 6.84 (d, J=5.9 Hz, 1H, 6-H), 6.89 (t, J=8.5 Hz, 1H, 2-H), 7.15 (q, J=8.5 Hz, 1H, 5-H), 7.73 (s, 1H, 3-H), 10.37 (bs, 1H, NH).

[0834] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 17.6 (NHCH(CH.sub.2)CHPh), 22.3 (SCH.sub.2CH.sub.2CH.sub.3), 25.5 (NHCH(CH.sub.2)CHPh), 33.3 (SCH.sub.2CH.sub.2CH.sub.3), 34.4 (NCH.sub.3), 35.3 (NHCH(CH.sub.2)CHPh), 96.3 (C-3a), 114.8 (C-2), 118.1 (C-5), 122.1 (C-6), 135.1 (C-3), 135.6 (C-1), 148.9-150.1 (C-4), 150.4-151.4 (C-3), 151.8 (C-4), 154.3 (C-7a), 160.9 (C-6).

EXAMPLE 30

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (30k.HCl)

4-chloro-1-ethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (30j)

[0835] ##STR00114##

[0836] To a solution of (27i) (1.0 g, 5.0 mmol) in acetonitrile (10 mL) cooled at 5 C. on an ice bath, were added NaH (144 mg, 6.0 mmol) and iodoethane (0.60 mL, 7.5 mmol). After 3 hours stirring at 50 C., acetonitrile was evaporated to dryness under vacuum and the residue was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

[0837] Yield: 77%.

[0838] Melting point: 92-93.5 C.

[0839] .sup.1H NMR (DMSO-d.sub.6) 1.43 (t, J=7.2 Hz, 3H, NCH.sub.2CH.sub.3), 2.62 (s, 3H, SCH.sub.3), 4.42 (q, J=7.2 Hz, 2H, NCH.sub.2CH.sub.3), 8.34 (s, 1H, CH).

[0840] .sup.13C NMR (DMSO-d.sub.6) 13.9 (SCH.sub.3), 14.4 (NCH.sub.2CH.sub.3), 42.2 (NCH.sub.2CH.sub.3), 110.1 (C-3a), 132.3 (C-3), 153.0 (C-4/C-7a), 168.7 (C-6).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (30k.HCl)

[0841] ##STR00115##

[0842] A solution of (30j) (114.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0843] Yield: 54%.

[0844] Melting point: 176-180 C.

[0845] .sup.1H NMR (CDCl.sub.3) 1.51 (t, J=7.3 Hz, 4H, NHCH(CH.sub.2)CHPh/NCH.sub.2CH.sub.3), 1.69 (s, 1H, NHCH(CH.sub.2)CHPh), 2.37 (s, 1H, NHCH(CH.sub.2)CHPh), 2.71 (s, 3H, SCH.sub.3), 3.09 (s, 1H, NHCH(CH.sub.2)CHPh), 4.41 (m, 2H, NCH.sub.2CH.sub.3), 6.85 (d, J=6.8 Hz, 1H, 6-H), 6.89 (t, J=8.6 Hz, 1H, 2-H), 7.16 (q, J=8.4 Hz, 1H, 5-H), 7.75 (s, 1H, 3-H), 10.55 (s, 1H, NH).

[0846] .sup.13C NMR (CDCl.sub.3) 14.0 (SCH.sub.3), 14.7 (NCH.sub.2CH.sub.3), 17.7 (NHCH(CH.sub.2)CHPh), 25.4 (NHCH(CH.sub.2)CHPh), 35.3 (NHCH(CH.sub.2)CHPh), 43.0 (NCH.sub.2CH.sub.3), 96.3 (C-3a), 114.8 (C-2), 118.1 (C-5), 122.1 (C-6), 135.2 (C-3), 135.5 (C-1), 148.9-150.1 (C-4), 150.3-151.5 (C-3), 151.0 (C-7a), 154.2 (C-4), 160.8 (C-6).

EXAMPLE 31

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(ethylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (31x.HCl)

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (31r)

[0847] ##STR00116##

[0848] A solution of (30k) (125.0 mg, 0.35 mmol) in methylene chloride (10 mL) was cooled to 5 C. on an ice bath and supplemented with 3-chloroperbenzoic acid (140.0 mg, 0.80 mmol). After stirring at room temperature for 4 hours, the mixture was washed with a solution of NaOH 0.1 M (210 mL). The organic layer was dried and filtered, methylene chloride was evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography.

[0849] Yield: 87%.

[0850] Melting point: 95-100 C. (decomposition).

[0851] .sup.1H NMR (CDCl.sub.3) 1.51 (m, 5H, NHCH(CH.sub.2)CHPh/NCH.sub.2CH.sub.3), 2.24 (s, 1H, NHCH(CH.sub.2)CHPh), 3.20 (s, 1H, NHCH(CH.sub.2)CHPh), 3.33 (s, 3H, SO.sub.2CH.sub.3), 4.53 (m, 2H, NCH.sub.2CH.sub.3), 6.58 (bs, 1H, NH), 6.90 (m, 2H, 2-H/6-H), 7.15 (m, 1H, 5-H), 7.75 (s, 1H, 3-H).

[0852] .sup.13C NMR (CDCl.sub.3) 14.9 (NCH.sub.2CH.sub.3), 17.9 (NHCH(CH.sub.2)CHPh), 25.7 (NHCH(CH.sub.2)CHPh), 34.5 (NHCH(CH.sub.2)CHPh), 39.2 (SO.sub.2CH.sub.3), 42.8 (NCH.sub.2CH.sub.3), 99.5 (C-3a), 114.8 (C-2), 118.2 (C-5), 122.1 (C-6), 131.7 (C-3), 135.7 (C-1), 148.9-150.1 (C-4), 150.3-151.5 (C-3), 152.8 (C-7a), 159.3 (C-4), 162.3 (C-6).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(ethylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (31x.HCl)

[0853] ##STR00117##

[0854] A solution of (31r) (150.0 mg, 0.38 mmol) in THF (6 mL) was supplemented with ethanethiol (0.06 mL, 0.80 mmol) and K.sub.2CO.sub.3 (110.0 mg, 0.80 mmol). After stirring at room temperature for 24 hours, THF was evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0855] Yield: 64%.

[0856] Melting point: 168-172 C.

[0857] .sup.1H NMR (CDCl.sub.3) 1.45 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.3), 1.51 (t, J=7.2 Hz, 4H, NCH.sub.2CH.sub.3/NHCH(CH.sub.2)CHPh), 1.69 (s, 1H, NHCH(CH.sub.2)CHPh), 2.37 (s, 1H, NHCH(CH.sub.2)CHPh), 3.09 (s, 1H, NHCH(CH.sub.2)CHPh), 3.32 (q, J=7.1 Hz, 2H, SCH.sub.2CH.sub.3), 4.40 (hept, J=6.9 Hz, 2H, NCH.sub.2CH.sub.3), 6.85 (d, J=6.2 Hz, 1H, 6-H), 6.89 (t, J=8.8 Hz, 1H, 2-H), 7.15 (q, J=8.5 Hz, 1H, 5-H), 7.74 (s, 1H, 3-H), 10.49 (bs, 1H, NH).

[0858] .sup.13C NMR (CDCl.sub.3) 14.1 (SCH.sub.2CH.sub.3), 14.7 (NCH.sub.2CH.sub.3), 17.6 (NHCH(CH.sub.2)CHPh), 25.4 (NHCH(CH.sub.2)CHPh), 25.9 (SCH.sub.2CH.sub.3), 35.3 (NHCH(CH.sub.2)CHPh), 43.0 (NCH.sub.2CH.sub.3), 100.1 (C-3a), 114.8 (C-2), 118.1 (C-5), 122.1 (C-6), 135.2 (C-3), 135.6 (C-1), 148.9-150.1 (C-4), 150.3-151.4 (C-3), 151.1 (C-4), 154.2 (C-7a), 160.4 (C-6).

EXAMPLE 32

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(propylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (32x.HCl)

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(propylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (32x.HCl)

[0859] ##STR00118##

[0860] A solution of (31r) (150.0 mg, 0.38 mmol) in THF (6 mL) was supplemented with propanethiol (0.07 mL, 0.80 mmol) and K.sub.2CO.sub.3 (110.0 mg, 0.80 mmol). After stirring at room temperature for 24 hours, THF was evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0861] Yield: 62%.

[0862] Melting point: 150-154 C.

[0863] .sup.1H NMR (CDCl.sub.3) 1.08 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.3), 1.51 (t, J=7.3 Hz, 4H, NCH.sub.2CH.sub.3/NHCH(CH.sub.2)CHPh), 1.69 (s, 1H, NHCH(CH.sub.2)CHPh), 1.82 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 2.37 (s, 1H, NHCH(CH.sub.2)CHPh), 3.08 (s, 1H, NHCH(CH.sub.2)CHPh), 3.28 (t, J=7.1 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.3), 4.39 (hept, J=6.9 Hz, 2H, NCH.sub.2CH.sub.3), 6.85 (d, J=7.0 Hz, 1H, 6-H), 6.89 (t, J=8.8 Hz, 1H, 2-H), 7.15 (q, J=8.4 Hz, 1H, 5-H), 7.73 (s, 1H, 3-H), 10.50 (bs, 1H, NH).

[0864] .sup.13C NMR (CDCl.sub.3) 13.5 (SCH.sub.2CH.sub.2CH.sub.3), 14.7 (NCH.sub.2CH.sub.3), 17.6 (NHCH(CH.sub.2)CHPh), 22.3 (SCH.sub.2CH.sub.2CH.sub.3), 25.4 (NHCH(CH.sub.2)CHPh), 33.3 (SCH.sub.2CH.sub.2CH.sub.3), 35.3 (NHCH(CH.sub.2)CHPh), 43.0 (NCH.sub.2CH.sub.3), 96.3 (C-3a), 114.8 (C-2), 118.1 (C-5), 122.1 (C-6), 135.2 (C-3), 141.3 (C-1), 149.2-150.4 (C-4), 150.3-151.4 (C-3), 151.1 (C-4), 154.2 (C-7a), 160.6 (C-6).

EXAMPLE 33

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-isopropyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (33k.HCl)

4-chloro-1-isopropyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (33j)

[0865] ##STR00119##

[0866] To a solution of (27i) (1.0 g, 5.0 mmol) in acetonitrile (10 mL) cooled at 5 C. on an ice bath, were added NaH (144 mg, 6.0 mmol) and 2-iodopropane (0.75 mL, 7.5 mmol). After 3 hours stirring at 50 C., acetonitrile was evaporated to dryness under vacuum and the residue was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

[0867] Yield: 73%.

[0868] Melting point: 114-115.5 C.

[0869] .sup.1H NMR (DMSO-d.sub.6) 1.50 (d, J=6.5 Hz, 6H, CH(CH.sub.3).sub.2), 2.62 (s, 3H, SCH.sub.3), 5.07 (hept, J=6.6 Hz, 1H, CH(CH.sub.3).sub.2), 8.33 (s, 1H, CH).

[0870] .sup.13C NMR (DMSO-d.sub.6) 14.4 (SCH.sub.3), 22.1 (CH(CH.sub.3).sub.2), 49.9 (CH(CH.sub.3).sub.2), 110.7 (C-3a), 132.6 (C-3), 153.0-153.4 (C-4/C-7a), 169.0 (C-6).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-isopropyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (33k.HCl)

[0871] ##STR00120##

[0872] A solution of (33j) (121.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0873] Yield: 87%.

[0874] Melting point: 159-163 C.

[0875] .sup.1H NMR (CDCl.sub.3) 1.50 (q, J=6.7 Hz, 1H, NHCH(CH.sub.2)CHPh), 1.54 (d, J=6.7 Hz, 3H, NCH(CH.sub.3).sub.2), 1.55 (d, J=6.7 Hz, 3H, NCH(CH.sub.3).sub.2), 1.70 (ddd, J=10.4 Hz/6.6 Hz/4.5 Hz, 1H, NHCH(CH.sub.2)CHPh), 2.37 (ddd, J=9.7 Hz/6.4 Hz/3.1 Hz, 1H, NHCH(CH.sub.2)CHPh), 2.71 (s, 3H, SCH.sub.3), 3.09 (dq, J=7.3 Hz/3.2 Hz, 1H, NHCH(CH.sub.2)CHPh), 5.08 (hept, J=6.7 Hz, 1H, NCH(CH.sub.3).sub.2), 6.84 (d, J=8.4 Hz, 1H, 6-H), 6.89 (m, 1H, 2-H), 7.16 (dt, J=9.6 Hz/8.4 Hz, 1H, 5-H), 7.75 (s, 1H, 3-H), 10.57 (s, 1H, NH).

[0876] .sup.13C NMR (CDCl.sub.3) 14.0 (SCH.sub.3), 17.7 (NHCH(CH.sub.2)CHPh), 21.9 (CH(CH.sub.3).sub.2), 25.4 (NHCH(CH.sub.2)CHPh), 35.2 (NHCH(CH.sub.2)CHPh), 50.1 (CH(CH.sub.3).sub.2), 96.3 (C-3a), 114.7 (C-2), 118.1 (C-5), 122.0 (C-6), 135.0 (C-3), 135.6 (C-1), 148.9-150.1 (C-4), 150.3-151.5 (C-3), 150.4 (C-7a), 154.1 (C-4), 160.4 (C-6).

EXAMPLE 34

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(methylthio)-1-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (34k.HCl)

4-Chloro-1-propyl-6-(methylthio)-1-propyl-1H-pyrazolo[3,4-d]pyrimidine (34j)

[0877] ##STR00121##

[0878] To a solution of (27i) (1.0 g, 5.0 mmol) in acetonitrile (10 mL) cooled at 5 C. on an ice bath, were added NaH (144 mg, 6.0 mmol) and 1-iodopropane (0.73 mL, 7.5 mmol). After 3 hours stirring at 50 C., acetonitrile was evaporated to dryness under vacuum and the residue was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

[0879] Yield: 78%.

[0880] Melting point: 41-43 C.

[0881] .sup.1H NMR (DMSO-d.sub.6) 0.83 (t, J=6.0 Hz, 3H, NCH.sub.2CH.sub.2CH.sub.3), 1.88 (h, J=6.1 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.3), 2.62 (s, 3H, SCH.sub.3), 4.35 (t, J=6.2 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.3), 8.35 (s, 1H, CH).

[0882] .sup.13C NMR (DMSO-d.sub.6) 11.0 (NCH.sub.2CH.sub.2CH.sub.3), 13.9 (SCH.sub.3), 22.2 (NCH.sub.2CH.sub.2CH.sub.3), 48.6 (NCH.sub.2CH.sub.2CH.sub.3), 110.0 (C-3a), 132.4 (C-3), 153.0 (C-4), 153.5 (C-7a), 168.7 (C-6).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(methylthio)-1-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (34k.HCl)

[0883] ##STR00122##

[0884] A solution of (34j) (121.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (93.0 mg, 0.55 mmol) and triethylamine (0.13 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0885] Yield: 76%.

[0886] Melting point: 155-159 C.

[0887] .sup.1H NMR (CDCl.sub.3) 0.93 (t, J=7.4 Hz, 3H, NCH.sub.2CH.sub.2CH.sub.3), 1.51 (q, J=6.7 Hz, 1H, NHCH(CH.sub.2)CHPh), 1.69 (m, 1H, NHCH(CH.sub.2)CHPh), 1.94 (h, J=7.3 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.3), 2.38 (ddd, J=9.6 Hz/6.4 Hz/3.0 Hz, 1H, NHCH(CH.sub.2)CHPh), 2.71 (s, 3H, SCH.sub.3), 3.09 (dd, J=6.7 Hz/3.5 Hz, 1H, NHCH(CH.sub.2)CHPh), 4.32 (m, 2H, NCH.sub.2CH.sub.2CH.sub.3), 6.85 (d, J=8.3 Hz, 1H, 6-H), 6.89 (m, 1H, 2-H), 7.16 (m, 1H, 5-H), 7.75 (s, 1H, 3-H), 10.57 (s, 1H, NH).

[0888] .sup.13C NMR (CDCl.sub.3) 11.3 (NCH.sub.2CH.sub.2CH.sub.3), 14.0 (SCH.sub.3), 17.6 (NHCH(CH.sub.2)CHPh), 22.8 (NCH.sub.2CH.sub.2CH.sub.3), 25.4 (NHCH(CH.sub.2)CHPh), 35.3 (NHCH(CH.sub.2)CHPh), 49.5 (NCH.sub.2CH.sub.2CH.sub.3), 96.1 (C-3a), 114.8 (C-2), 118.1 (C-5), 122.0 (C-6), 135.2 (C-3), 135.5 (C-1), 148.9-150.1 (C-4), 150.3-151.5 (C-3), 151.5 (C-7a), 154.2 (C-4), 160.8 (C-6).

EXAMPLE 35

Synthesis of N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-7-ethyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (35p.HCl)

6-Amino-2-(methylthio)pyrimidin-4-ol (35l)

[0889] ##STR00123##

[0890] 6-Amino-2-mercaptopyrimidin-4-ol (2.5 g, 17.5 mmol) was dissolved in KOH 10% (25 mL) and supplemented with methyl iodide (1.25 mL, 20.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 80 C. for 1 h. After cooling on an ice bath to 5 C., the mixture was acidified by addition of hydrochloric acid 6N and the resulting precipitate was filtered off and dried.

[0891] Yield: 95%.

[0892] Melting point: 261-264 C.

[0893] .sup.1H NMR (DMSO-d.sub.6) 2.42 (s, 3H, SCH.sub.3), 4.90 (s, 1H, CH), 6.44 (s, 2H, NH.sub.2), 11.47 (s, 1H, OH).

[0894] .sup.13C NMR (DMSO-d.sub.6) 12.6 (SCH.sub.3), 81.2 (C-5), 163.6 (C-2), 164.3 (C-6).

2-(Methylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (35m)

[0895] ##STR00124##

[0896] To a suspension of 35l (1.57 g, 10.0 mmol) in water (40 mL) were added sodium acetate (2.0 g, 24.5 mmol) and a 50% chloracetaldehyde aqueous solution (2 mL, 14.2 mmol). After 1 hour at 80 C., the reaction mixture was cooled on an ice bath to 5 C. and the resulting precipitate was filtered off and purified by silica gel column chromatography.

[0897] Yield: 45%.

[0898] Melting point: >300 C.

[0899] .sup.1H NMR (DMSO-d.sub.6) 2.52 (s, 3H, SCH.sub.3), 6.36 (m, 1H, 5-H), 6.91 (m, 1H, 6-H), 11.75 (s, 1H, NH), 12.03 (s, 1H, OH).

[0900] .sup.13C NMR (DMSO-d.sub.6) 12.8 (SCH.sub.3), 102.0 (C-5), 104.2 (C-4a), 119.3 (C-6), 148.3 (C-7a), 154.2 (C-2), 158.8 (C-4).

4-Chloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (35n)

[0901] ##STR00125##

[0902] To a solution of (35m) (1.0 g, 5.5 mmol) in POCl.sub.3 (10 mL) cooled at 5 C. on an ice bath was added dropwise diethylaniline (1.0 mL, 6.2 mmol). After 2 hours stirring at 80 C., the mixture was poured on crushed ice and the resulting precipitate was filtered off and purified by silica gel column chromatography.

[0903] Yield: 33%.

[0904] Melting point: 206-208 C.

[0905] .sup.1H NMR (DMSO-d.sub.6) 2.56 (s, 3H, SCH.sub.3), 6.52 (s, 1H, 5-H), 7.52 (s, 1H, 6-H), 12.39 (s, 1H, NH).

[0906] .sup.13C NMR (DMSO-d.sub.6) 13.8 (SCH.sub.3), 99.0 (C-5), 113.2 (C-4a), 126.9 (C-6), 150.4-152.7 (C-4/C-7a), 162.7 (C-2).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (35o)

[0907] ##STR00126##

[0908] A solution of (35n) (200.0 mg, 1.0 mmol) in acetonitrile (5 mL) was supplemented with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (340.0 mg, 2.0 mmol) and triethylamine (0.30 mL) and then heated at 90 C. under reflux for 1 h. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[0909] Yield: 15%.

[0910] Melting point: 208-211 C.

[0911] .sup.1H NMR (DMSO-d.sub.6) 1.34 (m, 2H, NHCH(CH.sub.2)CHPh), 2.03 (s, 1H, NHCH(CH.sub.2)CHPh), 2.30 (s, 3H, SCH.sub.3), 3.03 (s, 1H, NHCH(CH.sub.2)CHPh), 6.40 (s, 1H, 5-H), 6.93 (s, 1H, 2-H), 7.08 (s, 1H, 6-H), 7.33 (m, 2H, 6-H/5-H), 7.84 (s, 1H, NHCH(CH.sub.2)CHPh), 11.40 (s, 1H, NH).

[0912] .sup.13C NMR (CDCl.sub.3) 13.3 (SCH.sub.3), 99.5 (C-5), 112.1 (C-4a), 117.0 (C-5), 119.9 (C-2), 122.9 (C-6), 139.6 (C-1), 147.0-148.3 (C-4), 148.6-150.0 (C-3), 162.3 (C-2).

N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-7-ethyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (35p.HCl)

[0913] ##STR00127##

[0914] To a solution of (35o) (166.0 mg, 0.5 mmol) in acetonitrile (10 mL) cooled at 5 C. on an ice bath, were added NaH (15 mg, 0.6 mmol) and iodoethane (0.060 mL, 0.75 mmol). After 1 hour stirring at 50 C., acetonitrile was evaporated to dryness under vacuum and the residue was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography. The resulting oil was dissolved in diethyl ether (10 mL) and supplemented dropwise with a saturated solution of HCl in diethyl ether. The precipitate of the title compound was collected by filtration, washed with diethyl ether and dried.

[0915] Yield: 74%.

[0916] Melting point: 189-194 C. .sup.1H NMR (CDCl.sub.3) 1.46 (t, J=7.3 Hz, 4H, NHCH(CH.sub.2)CHPh/NCH.sub.2CH.sub.3), 1.66 (m, 1H, NHCH(CH.sub.2)CHPh), 2.30 (m, 1H, NHCH(CH.sub.2)CHPh), 2.70 (s, 3H, SCH.sub.3), 3.09 (m, 1H, NHCH(CH.sub.2)CHPh), 4.22 (q, J=7.3 Hz, 2H, NCH.sub.2CH.sub.3), 6.35 (d, J=3.4 Hz, 1H, 5-H), 6.81 (d, J=8.3 Hz, 1H, 6-H), 6.87 (m, 1H, 2-H), 6.90 (d, J=3.6 Hz, 1H, 6-H), 7.13 (q, J=8.5 Hz, 1H, 5-H), 9.99 (s, 1H, NH).

[0917] .sup.13C NMR (CDCI.sub.3) 14.0 (SCH.sub.3), 15.5 (NCH.sub.2CH.sub.3), 17.9 (NHCH(CH.sub.2)CHPh), 25.7 (NHCH(CH.sub.2)CHPh), 35.2 (NHCH(CH.sub.2)CHPh), 40.3 (NCH.sub.2CH.sub.3), 98.1 (C-4a), 103.4 (C-5), 114.8 (C-2), 117.8 (C-5), 122.0 (C-6), 125.4 (C-6), 136.4 (C-1), 148.3 (7a), 149.1-151.1 (C-3/C-4), 153.4 (C-4), 155.9 (C-2).

[0918] 2. Examples of Pyrimidines Derivatives for Use in Prevention and Treatment of Bacterial Infection

EXAMPLE 1

Antibacterial Effects of Molecules 2329, 2348, 2412, 2452, and 2461 on S. epidermidis: Determination of Minimal Inhibitory Concentration (MIC)

[0919] Molecules 2329, 2348, 2412, 2452, and 2461 correspond respectively to the following formulations:

##STR00128##

[0920] 2329 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (also called 1c above)

[0921] 2348 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(propylthio)-9H-purin-6-amine (also called 3c above)

##STR00129##

[0922] 2412 is 9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (also called 15c)

[0923] 2461 is (1S,2R,3S,4R)-4-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylthio)-9H-purin-9-yl)cyclopentane-1,2,3-triol (also called 19d).

##STR00130##

[0924] 2452 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (also called 17c).

[0925] The Minimal Inhibitory Concentration (MIC) of molecules 2329, 2348, 2412, 2452 and 2461 was determined on Staphylococcus epidermidis (ATCC 35984, also known as RP62A) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommendations.

[0926] Briefly, a single colony grown on a Tryptic Soy Agar (TSA) plate was resuspended and cultured in Tryptic Soy Broth (TSB) overnight (O/N) in aerobic conditions (37 C. with 220 rpm shaking), next day a 1:50 inoculum in Mueller-Hinton broth (MHB) was incubated in aerobic conditions for 3 hr and an inoculum of 1:100 dilution, corresponding to 310.sup.5 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle). After O/N growth the OD of each culture was measured at 600 nm in a spectrophotometer (OD.sub.600). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (blank is the medium alone).

[0927] The MIC for molecules 2329, 2348 and 2461 against S. epidermidis (ATCC 35984) is equal to 20 M, while it is above 50 M for molecules 2412 and 2452.

EXAMPLE 2

Antibacterial Effects of Molecules 2329, 2348, 2412, 2452, and 2461 on S. aureus: Determination of Minimal Inhibitory Concentration (MIC)

[0928] Further experiments are conducted using different strains of S. aureus, as clinically relevant Gram-positive bacterial strains: S. aureus ATCC 25904, methicillin-resistant S. aureus (MRSA) ATCC BAA-1556, Glycopeptide intermediate-resistant (GISA) S. aureus Mu-50 (ATCC 700695) in order to determine the Minimal Inhibitory Concentration (MIC) which is the minimal concentration required to prevent bacterial growth. The bioluminescent strain S. aureus Xen29 (ATCC 12600) was also used. This strain is derived from the parental strain S. aureus ATCC 12600, a pleural fluid isolate, which is also designated as NCTC8532. S. aureus Xen29 possesses a stable copy of the modified Photorhabdus luminescens luxABCDE operon at a single integration site on the bacterial chromosome.

[0929] A single colony selected from the different strains of S. aureus is resuspended and cultured in brain heart infusion (BHI) broth overnight (O/N) in aerobic conditions (37 C. with 220 rpm shaking), next day a 1:100 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 3hr (=OD0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 310.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO. After O/N growth the OD of each culture was measured at 600 nm (OD.sub.600) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (blank is the medium alone). MIC for 2329, 2348, 2412, 2452, and 2461 against S. aureus ATCC 25904 and Xen29 (ATCC 12600) are equal to 20-25 M. Molecule 2329 is the most potent against methicillin-resistant S. aureus (MRSA) ATCC BAA-1556, with a MIC equal to 20 M, while molecules 2348 and 2461 had a MIC of 25 M, and the MIC for molecules 2412 and 2452 is comprised between 2-25 and 50 M. The MIC of molecule 2329 against Glycopeptide intermediate-resistant (GISA) S. aureus Mu-50 (ATCC 700695) is in between 25 and 30 M, while it is above 50 M for molecules 2348, 2412, and 2452.

EXAMPLE 3

Antibacterial Effects of Molecules 2329, 2348, 2412, 2452, And 2461 on E. faecalis: Determination of Minimal Inhibitory Concentration (MIC)

[0930] Further experiments were conducted using the clinically relevant Gram-positive bacterial strain of vancomycin-resistant (VRE) E. faecalis ATCC BAA-2365, in order to determine the Minimal Inhibitory Concentration (MIC) which is the minimal concentration required to prevent bacterial growth.

[0931] A single colony selected from E. faecalis VRE is resuspended and cultured in the brain heart infusion (BHI) broth overnight (O/N) in aerobic conditions (37 C. with 220 rpm shaking), next day a 1:100 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 3 hr (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 310.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO. After O/N growth the OD of each culture is measured at 600 nm (OD.sub.600) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (blank is the medium alone). MIC for molecules 2329 and 2461 against E. faecalis vancomycin-resistant (VRE) ATCC BAA-2365 was equal to 25 M, while it is above 50 M for molecules 2348, 2412 and 2452.

[0932] The results of all experiments are illustrated in Table 1.

TABLE-US-00001 TABLE 1 MIC: minimal inhibitory concentration of pyrimidine derivatives determined in Mueller-Hinton broth (MHB) against MRSA: methicillin-resistant S. aureus; GISA: Glycopeptide intermediate- resistant S. aureus; VRE: vancomycin-resistant E. faecalis; MIC is expressed in M. nd: not determined. Strains S. E. Mole- S. aureus epidermidis faecalis cules ATCC25904 Xen29 MRSA GISA RP62 VRE 2329 20-25 M 20-25 20 25-30 20 M 25 M (1c) M M M 2348 20-25 M 20-25 25 >50 20 M >50 M (3c) M M M 2412 20-25 M 20-25 25-50 >50 >50 M >50 M (15c) M M M 2452 20-25 M 20-25 25-50 >50 >50 M >50 M (17c) M M M 2461 20-25 M 20-25 25 nd 20 M 25 M (19d) M M

EXAMPLE 4

Use of Molecules 2329, 2348 as Inhibitors of S. aureus Biofilm Formation

[0933] Bioluminescent S. aureus (Xen29, Perkin Elmer-(ATCC 12600)) is grown overnight in TSB medium, before being diluted 100 fold in fresh TSB, and incubated aerobically at 37 C. until bacteria culture reached an OD.sub.600 of 0.6 (corresponding to approximately 1-310.sup.8 CFU/ml). Bacteria cultures are then diluted to 110.sup.4 CFU/ml in fresh TSB. 600 l aliquots of diluted bacteria suspensions are distributed in each well of a 48-well plate. Bacteria are allowed to adhere for 3 hours under static conditions at 37 C. After removing media, wells are rinsed 2 times with PBS to eliminate planktonic bacteria and re-filled with TSB supplemented with 0.5% glucose

[0934] Molecules 2329 or 2348 are then added at 10 M final concentration. Biofilm formation is imaged every 60 min, for 13 hours, using a IVIS camera system (Xenogen Corp.) Total photon emission from each well is then quantified using the Living Image software package (Xenogen Corp.).

[0935] In FIG. 1, biofilm formation is represented as the intensity of photon signal per surface unit. Molecules 2329 and 2348 fully prevented biofilm formation when used at a dose of 10 M.

EXAMPLE 5

Use of Molecules 2412 and 2452 to Delay S. aureus Biofilm Formation

[0936] Bioluminescent S. aureus (Xen29, Perkin Elmer-(ATCC 12600)) is grown overnight in TSB medium, before being diluted 100 fold in fresh TSB, and incubated aerobically at 37 C. until bacteria culture reached an OD.sub.600 of 0.6 (corresponding to approximately 1-310.sup.8 CFU/ml). Bacteria cultures are then diluted to 110.sup.4 CFU/ml in fresh TSB. 600 l aliquots of diluted bacteria suspensions were distributed in each well of a 48-well plate. Bacteria are allowed to adhere for 3 hours under static conditions at 37 C. After removing media, wells are rinsed 2 times with PBS to eliminate planktonic bacteria and re-filled with TSB supplemented with 0.5% glucose

[0937] Molecules 2412 or 2452 are then added at 10 M final concentration. Biofilm formation is imaged every 60 min, for 13 hours, using a IVIS camera system (Xenogen Corp.) Total photon emission from each well is then quantified using the Living Image software package (Xenogen Corp.).

[0938] In FIG. 1, biofilm formation is represented as the intensity of photon signal per surface unit. Molecules 2412 and 2452 are able to delay biofilm formation when used at a dose of 10 M as compared to vehicle control (DMSO 1%).

EXAMPLE 6

Effect of Molecule 2329 on S. epidermidis (ATCC 35984)24h-Mature Biofilm

[0939] In another experiment we let adhere 0.510.sup.8 CFU/ml S. epidermidis cells for 4 hr and let the biofilm form for additional 24 hr in presence of 0.25% glucose, at this point we treated the biofilm with different concentrations of molecule 2329 for 24 h in TSB with 0.25% glucose and determined the biofilm biomass using the crystal violet staining.

[0940] For biofilm analysis, we first washed the biofilm 3 times with NaCl 0.9% to eliminate all planktonic bacteria, before incubation with a staining Crystal Violet 1% solution in distilled H.sub.2O (dH.sub.2O).

[0941] Wells are washed 3 times with dH.sub.2O to eliminate unbound crystal violet. 400 l Acetic Acid 10% is then added and incubated at RT for 10 min. Absorbance is measured in triplicate at 570 nm, reflecting total biomass of the biofilm. FIG. 2 shows that 2329 80 M could reduce the S. epidermidis 24-hour mature biofilm.

EXAMPLE 7

Antibacterial Effects of Pyrazolopyrimidine Molecules 2539, 2544, 2666 2676, 2693, 2783, 2784 and 2782 and of Purine Molecules 2498, 2511, 2525, 2527, 2833 and 2840 on Staphylococcus epidermidis (S. epidermidis(ATCC 35984)) Also Called MRSE: Determination of Minimal Inhibitory Concentration (MIC)

[0942] Pyrazolopyrimidine molecules 2539, 2544, 2666, 2676, 2693, 2783, 2784 and 2782 correspond to the following formulations:

##STR00131##

[0943] 2539 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (also called 27k above);

[0944] 2544 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (also called 30k above).

##STR00132##

[0945] 2666 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (also called 28x.HCl above);

[0946] 2676 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-isopropyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (also called 33k.HCl above).

##STR00133##

[0947] 2693 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(methylthio)-1-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (also called 34k.HCl above).

##STR00134##

[0948] 2783 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (also called 31x.HCl above);

[0949] 2782 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(propylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (also called 29x.HCl above).

##STR00135##

[0950] 2784 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(propylthio)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (also called 32x.HCl above).

[0951] Purine molecules 2498, 2511, 2525, 2527, 2833 and 2840 correspond to the following formulations:

##STR00136##

[0952] 2498 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(methylthio)-9H-purin-6-amine (also called 22c above);

[0953] 2511 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (also called 24c above).

##STR00137##

[0954] 2525 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(ethylthio)-9-methyl-9H-purin-6-amine (also called 20c above);

[0955] 2527 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(ethylthio)-9H-purin-6-amine (also called 21c above).

##STR00138##

[0956] 2833 is 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (also called 25c above);

[0957] 2840 is 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-9H-purin-6-amine (also called 26c above).

[0958] The Minimal Inhibitory Concentration (MIC) of pyrazolopyrimidine molecules 2539, 2544, 2666,2676, 2693, 2783, 2784 and 2782 and of purine molecules 2498, 2511, 2525, 2527, 2833, and 2840 was determined on S. epidermidis (ATCC 35984, also known as RP62A or MRSE) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommendations.

[0959] Briefly, a single colony grown on an agar plate was resuspended and cultured in Triptic Soy Broth (TSB) medium overnight (O/N) in aerobic conditions (37 C. with 220rpm shaking), next day a 1:50 inoculum in Mueller-Hinton broth (MHB) was incubated in aerobic conditions for 3hr (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 310.sup.5 CFU/ml, was incubated in presence or absence of different concentrations of each of the molecules in 1% DMSO (vehicle). After O/N growth the OD of each culture was measured at 600 nm (600) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (where OD is the difference between the OD with the molecule and the OD of the blank, the medium alone).

[0960] The pyrazolopyrimidine molecules 2539, 2544, 2666 and 2676 and purine molecules 2498, 2511, 2525, 2527 and 2833 were able to inhibit MRSE growth in MHB medium. MIC values are reported in Table 2. The pyrazolopyrimidine molecules 2693, 2782, 2783 and 2784, and the purine molecules 2511 and 2840 were inactive against S. epidermidis up to 100 M.

EXAMPLE 8

Antibacterial Effects of Pyrazolopyrimidine Molecules 2539, 2544, 2666 2676, 2693, 2783, 2784 and 2782 and of Purine Molecules 2498, 2511, 2525, 2527, 2833 and 2840 on Staphylococcus aureus (S. aureus): Determination of Minimal Inhibitory Concentration (MIC)

[0961] Further experiments are conducted using different strains of S. aureus, as clinically relevant Gram-positive bacterial strains: methicillin-resistant S. aureus (MRSA) ATCC BAA-1556 and S. aureus Xen29 (Perkin Elmer ATCC 12600).

[0962] To determine the MIC of the above mentioned molecules in MRSA or in Xen29, a single colony of MRSA or Xen29 is resuspended and cultured in brain heart infusion (BHI) broth overnight (O/N) in aerobic conditions (37 C. with 220 rpm shaking), next day a 1:100 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 3hr (OD =0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 310.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO. After O/N growth the OD of each culture was measured at 600 nm (OD.sub.600) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (blank is the medium alone).

[0963] The pyrazolopyrimidine molecules 2539, 2544, 2666, 2676, 2693, 2783, 2782, 2784 and the purine molecules 2498, 2511, 2525, 2527, 2833 and 2840 were active against MRSA (ATCC BAA-1556), while molecules 2539, 2544, 2666, 2498, 2511, 2525, and 2527 were able to inhibit Xen29 (ATCC 12600) growth. MIC values of these molecules against these S. aureus strains are reported in Table 2.

TABLE-US-00002 TABLE 2 MIC values of pyrimidine derivatives, expressed in M as determined in MHB medium against MRSE, MRSA and Xen29 Gram-positive strains. (nd: not determined). All molecules were tested up to a concentration of 100 M. Molecule X.sup.1 X.sup.2 Y R.sup.1 R.sup.2 MRSE MRSA Xen29 2539 N C S CH.sub.3 CH.sub.3 50 25 30 2544 N C S CH.sub.3 CH.sub.2CH.sub.3 80 50 50 2693 N C S CH.sub.3 CH.sub.2CH.sub.2CH.sub.3 >100 20 >100 2676 N C S CH.sub.3 CH(CH.sub.3).sub.2 50 20 >100 2666 N C S CH.sub.2CH.sub.3 CH.sub.3 50 20 20 2783 N C S CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 >100 25 nd 2782 N C S CH.sub.2CH.sub.2CH.sub.3 CH.sub.3 >100 25 nd 2784 N C S CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 >100 50 nd 2498 C N S CH.sub.3 CH.sub.3 60 30 30 2511 C N S CH.sub.3 CH.sub.2CH.sub.3 >100 30 30 2525 C N S CH.sub.2CH.sub.3 CH.sub.3 40 25 30 2527 C N S CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 25 25 30 2833 C N S CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CH.sub.3 30 50 nd 2840 C N S CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 >100 50 nd

EXAMPLE 9

Use of the Pyrazolopyrimidine Molecule 2666 and the Purine Molecule 2511 as Inhibitors of Staphylococcus aureus (Xen29-ATCC 12600) Biofilm Formation

[0964] Bioluminescent S. aureus was grown O/N in TSB medium, before being diluted 100 fold in fresh TSB, and incubated aerobically at 37 C. until bacteria culture reached an OD600 of 0.6 (corresponding to approximately 1-310.sup.8 CFU/ml). Bacteria cultures were then diluted to 110.sup.4 CFU/ml in fresh TSB and aliquots of 600 l were distributed in each well of a 48-well plate. Bacteria were allowed to adhere for 3 hours under static conditions at 37 C. After removing media, wells were rinsed 2 times with PBS to eliminate planktonic bacteria and re-filled with TSB supplemented with 0.5% glucose. Molecules 2666 and 2511 were then added at 20 M final concentration. Biofilm formation is imaged every 60 min, for 13 hours, using a IVIS camera system (Xenogen Corp.) Total photon emission from each well (photon/second:p/s) is then quantified using the Living Image software package (Xenogen Corp.).

[0965] FIG. 3 shows the kinetics of inhibition of Staphylococcus aureus (Xen29-ATCC 12600) biofilm formation (step 2) by the pyrazolopyrimidine molecule 2666 and the purine molecule 2511 at 20 M compared to the biofilm formation in the presence of the vehicle control (Ctrl).

[0966] The biofilm formation is proportional to the intensity of photon signal per second (radiance) irradiated from each well. Molecules 2666 and 2511 inhibited biofilm growth when used at 20 M.

EXAMPLE 10

Use of the Pyrazolopyrimidine Molecule 2666 as Bactericidal Agent Against MRSA and the Purine Molecules 2329 and 2833 as Bactericidal Agents Respectively Against MRSA and MRSE

[0967] We have determined the Minimal Bactericidal Concentration (MBC) of the pyrazolopyrimidine molecule 2666 for the MRSA strain and the MBC of the purine molecules 2329 and 2833 for MRSA and the MRSE strain respectively.

[0968] To determine the MBC, bacteria were grown as per MIC determination in presence of the pyrazolopyrimidine molecule 2666 for MRSA or in presence of the purine molecule 2833 for MRSE or 2329 for MRSA. At 24 hours bacteria were plated on TSB agar plates by the broth microdilution method, and colonies formed on the plates were counted next day.

[0969] The MBC represents the lowest concentration at which 99.9% bacteria of the initial inoculum are killed over 24 hours.

[0970] The MBC of molecule 2666 and 2329 for MRSA was 40 M, while the MBC of 2833 for MRSE was 50 M, which corresponds to only around 2 times their MIC.

[0971] 3. Comparison of Pyrimidine Derivatives According to the Present Invention with Purines Disclosed in WO2009/034386.

[0972] We have synthesized 2 molecules (25, 81) from WO2009/034386 examples. In this patent application, the ability of these 2 molecules to inhibit the Murl enzyme from E. faecalis, E. faecium and S. aureus is described. The 2 molecules were able to inhibit the enzymatic activity of Murl isozymes from E. faecalis and E. faecium with half maximal inhibitory concentrations (IC.sub.50) equal to 2 and 5 M, respectively (Table 9 of WO2009/034386). In contrast, IC.sub.50>400 M is reported against S. aureus Murl isozyme for the 2 molecules, indicating a failure to inhibit the Murl enzyme from this bacterial strain. WO2009/034386 does not report any other testing demonstrating the antibacterial efficacy of these purine molecules.

[0973] We found no antibacterial activity of these molecules against the two S. aureus strains tested, methicillin resistant strains (MRSA, ATCC BAA-1556) and Xen29 (Perkin Elmer-ATCC 12600) nor against S. epidermidis (MRSE ATCC 35984).

[0974] The molecules were synthesized according to a similar chemical pathway as described in the present invention, with the exception that the nucleophilic substitution of the chlorine atom on Xb is carried out by another amine.

##STR00139##

[0975] When R.sup.1CH.sub.3, the corresponding alkoxy-substituted compounds Xz wherein YO was provided starting from Xz according to scheme 6 below:

##STR00140##

EXAMPLE 1

2-(butylthio)-9-(3-chloro-2,6-difluorobenzyl)-9H-purin-6-amine (36z)

[0976] ##STR00141##

[0977] 36z (molecule 25 in WO2009/034386) was synthesized according to a similar chemical pathway as described in the present invention, with the exception that the nucleophilic substitution of the chlorine atom on Xb is carried out with another amine R.sup.9NH.sub.2, ammonia in the present example.

2-(Butylthio)-6-chloro-N.SUP.4.-(3-chloro-2,6-difluorobenzyl)pyrimidine-4,5-diamine (36a)

[0978] ##STR00142##

[0979] 2-(Butylthio)-4,6-dichloropyrimidin-5-amine (25h) (0.5 g, 2.0 mmol) was dissolved in methanol (10 mL) and supplemented with 3-chloro-2,6-difluorobenzylamine (0.78 mL, 6.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 130 C. for 2 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[0980] Yield: 77%.

[0981] Melting point: 148-150 C.

[0982] .sup.1H NMR (DMSO-d.sub.6) 0.88 (t, J=7.3 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.37 (h, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.58 (p, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.97 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.65 (d, J=4.5 Hz, 2H, NHCH.sub.2), 4.83 (s, 2H, NH.sub.2), 7.20 (t, J=8.9 Hz, 1H, 5-H), 7.34 (s, 1H, NH), 7.62 (q, J=8.6 Hz, 1H, 4-H).

[0983] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.4 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.7 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.2 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 33.4 (NCH.sub.2), 112.6 (C-5), 115.4 (C-3), 116.0 (C-1), 120.2 (C-5), 130.0 (C-4), 137.7 (C-6), 151.8 (C-4), 155.1 (C-2), 155.2-157.2 (C-6), 158.7-160.6 (C-2).

2-(Butylthio)-6-chloro-9-(3-chloro-2,6-difluorobenzyl)-9H-purine (36b)

[0984] ##STR00143##

[0985] A solution of (36a) (393.0 mg, 1 mmol) in acetic acid (3.0 mL) and triethyl orthoformate (3.0 mL, 18 mmol) was heated at a temperature of 130 C. under reflux for 4 h. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[0986] Yield: 59%.

[0987] Melting point: 109-111 C.

[0988] .sup.1H NMR (DMSO-d.sub.6) 0.90 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.40 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.62 (p, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.11 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5.57 (s, 2H, NCH.sub.2), 7.22 (td, J=9.1 Hz/1.5 Hz, 1H, 5-H), 7.69 (td, J=8.8 Hz/5.8 Hz, 1H, 4-H), 8.66 (s, 1H, 8-H).

[0989] .sup.13C NMR (DMSO-d.sub.6) 13.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.2 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.6 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 36.1 (NCH.sub.2), 112.9 (C-5), 113.1 (C-1), 115.7 (C-3), 127.7 (C-5), 131.3 (C-4), 149.1 (C-4), 152.5 (C-6), 155.3-156.7 (C-6), 158.8-160.2 (C-2), 164.4 (C-2).

2-(Butylthio)-9-(3-chloro-2,6-difluorobenzyl)-9H-purin-6-amine (36z)

[0990] ##STR00144##

[0991] Ammonia was bubbled for 5 minutes in a solution of (36b) (200.0 mg, 0.5 mmol) in acetonitrile (2.5 mL) placed in a sealed vessel. The mixture was heated at 110 C. for 3 hours. After distillation of acetonitrile and ammonia under vacuum, the residue was purified by silica gel column chromatography.

[0992] Yield: 29%.

[0993] Melting point: 133.5-135.5 C.

[0994] The conformity and the purity of 36z was attested by NMR spectroscopy and elemental analysis and is reported hereafter:

[0995] .sup.1H NMR (DMSO-d.sub.6) 0.88 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.38 (h, J=7.4 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.57 (p, J=7.3 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3.00 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5.42 (s, 2H, NCH.sub.2), 7.20 (t, J=8.8 Hz, 1H, 5-H), 7.28 (s, 2H, NH.sub.2), 7.66 (m, 1H, 4-H), 8.11 (s, 1H, 8-H).

[0996] .sup.13C NMR (DMSO-d.sub.6) 13.6 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.5 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.1 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 35.4 (NCH.sub.2), 112.8 (C-5), 113.9 (C-1), 115.6 (C-3), 116.2 (C-5), 130.9 (C-4), 149.9 (C-4), 155.2-156.7 (C-6), 155.4 (C-6), 158.8-160.2 (C-2), 163.8 (C-2).

[0997] Anal. (C.sub.16H.sub.16ClF.sub.2N.sub.5S) theoretical: C, 50.06; H, 4.20; N, 18.25; S, 8.35. Found: C, 49.84; H, 4.25; N, 18.09; S, 7.93.

[0998] Molecule 36z has been tested for its potential antibacterial activity by determining its minimal inhibitory concentration (MIC) according to protocols recommended by EUCAST to assess the efficacy of antibiotics against bacterial strains. In brief MIC in MRSA (ATCC BAA-1556) or in Xen29 (Perkin Elmer-ATCC 12600) for 36z (molecule 25 in WO2009/034386) was determined by culturing a single colony of MRSA or Xen29 in brain heart infusion (BHI) broth overnight (O/N) in aerobic conditions (37 C. with 220 rpm shaking), while MIC for MRSE (ATCC 35984) was determined by culturing MRSE in TSB O/N. Next day a 1:100 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 3 hr (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 310.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO. After O/N growth the OD of each culture was measured at 600 nm (OD.sub.600) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (blank is the medium alone). No antibacterial activity was found against MRSA (ATCC BAA-1556), Xen29 (Perkin Elmer-ATCC 12600 or MRSE (ATCC 35984) strains when the molecule was used at concentrations up to 200 M.

EXAMPLE 2

2-butoxy-9-(3-chloro-2,6-difluorobenzyp-N-(pyridin-3-ylmethyl)-9H-purin-6-amine (37z)

[0999] ##STR00145##

[1000] 37 z (molecule 81 in WO2009/034386) was synthesized according to a similar chemical pathway as described in the present invention, with the exception that the nucleophilic substitution of the chlorine atom on Xb is carried out with another amine R.sup.9-NH.sub.2 (3-(aminomethyl)pyridine in the present example).

6-Chloro-N.SUP.4.-(3-chloro-2,6-difluorobenzyl)-2-(methylthio)pyrimidine-4,5-diamine (37a)

[1001] ##STR00146##

[1002] 4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (22h) (0.5 g, 2.4 mmol) was dissolved in methanol (10 mL) and supplemented with 3-chloro-2,6-difluorobenzylamine (0.78 mL, 6.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 130 C. for 2 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[1003] Yield: 96%.

[1004] Melting point: 207-212 C.

[1005] .sup.1H NMR (DMSO-d.sub.6) 2.36 (s, 3H, SCH.sub.3), 4.65 (d, J=5.0 Hz, 2H, NHCH.sub.2), 4.85 (s, 2H, NH.sub.2), 7.19 (td, J=9.0 Hz/1.1 Hz, 1H, 5-H), 7.38 (t, J=5.1 Hz, 1H, NH), 7.62 (td, J=8.7 Hz/5.7 Hz, 1H, 4-H). .sup.13C NMR (DMSO-d.sub.6) 13.4 (SCH.sub.3), 33.4 (NHCH.sub.2), 112.6 (C-5), 115.4 (C-3), 116.1 (C-1), 120.2 (C-5), 129.9 (C-4), 137.7 (C-6), 151.8 (C-4), 155.5 (C-2), 155.5-156.9 (C-6), 159.0-160.4 (C-2).

6-Chloro-9-(3-chloro-2,6-difluorobenzyl)-2-(methylthio)-9H-purine (37b)

[1006] ##STR00147##

[1007] A solution of (37a) (351.0 mg, 1 mmol) in acetic acid (3.0 mL) and triethyl orthoformate (3.0 mL, 18 mmol) was heated at a temperature of 130 C. under reflux for 4 hours. After distillation of the acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[1008] Yield: 68%.

[1009] Melting point: 167-169.5 C.

[1010] .sup.1H NMR (DMSO-d.sub.6) 2.51 (s, 3H, SCH.sub.3), 5.57 (s, 2H, NCH.sub.2), 7.23 (td, J=9.0 Hz/1.1 Hz, 1H, 5-H), 7.69 (td, J=8.8 Hz/5.8 Hz, 1H, 4-H), 8.67 (s, 1H, 8-H).

[1011] .sup.13C NMR (DMSO-d.sub.6) 13.8 (SCH.sub.3), 36.1 (NCH.sub.2), 112.9 (C-5), 113.0 (C-1), 115.6 (C-3), 127.6 (C-5), 131.3 (C-4), 149.1 (C-4), 152.5 (C-6), 155.4-156.8 (C-6), 158.8-160.2 (C-2), 164.8 (C-2).

9-(3-Chloro-2,6-difluorobenzyl)-2-(methylthio)-N-(pyridin-3-ylmethyl)-9H-purin-6-amine (37z)

[1012] ##STR00148##

[1013] A solution of (37b) (180.0 mg, 0.5 mmol) in acetonitrile (3 mL) was supplemented with 3-(aminomethyl)pyridine (0.10 mL, 1.0 mmol) and triethylamine (0.10 mL) and then heated at 90 C. under reflux for 5 hours. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[1014] Yield: 92%.

[1015] Melting point: 149-151 C.

[1016] .sup.1H NMR (CDCl.sub.3) 2.54 (s, 3H, SCH.sub.3), 4.84 (bs, 2H, NHCH.sub.2), 5.39 (s, 2H, NCH.sub.2), 6.17 (bs, 1H, NHCH.sub.2), 6.91 (t, J=8.8 Hz, 1H, 5-H), 7.23 (dd, J=7.7 Hz/4.8 Hz, 1H, 5-H), 7.39 (td, J=8.6 Hz/5.8 Hz, 1H, 4-H), 7.70 (m, 2H, 8-H/6-H), 8.51 (dd, J=4.7 Hz/1.3 Hz, 1H, 4-H), 8.62 (d, J=1.6 Hz, 1H, 2-H).

[1017] .sup.13C NMR (CDCl.sub.3) 14.5 (SCH.sub.3), 35.3 (NCH.sub.2), 42.1 (NHCH.sub.2), 112.4 (C-5), 113.3 (C-1), 117.3 (C-3/C-5), 123.6 (C-5), 131.3 (C-4), 134.4 (C-1), 135.7 (C-6/C-6), 138.8 (C-8), 149.0 (C-4), 149.5 (C-2), 153.9 (C-4), 156.2-157.7 (C-6), 159.1-160.6 (C-2), 166.4 (C-2).

9-(3-Chloro-2,6-difluorobenzyl)-2-(methylsulfonyl)-N-(pyridin-3-ylmethyl)-9H-purin-6-amine (37z)

[1018] ##STR00149##

[1019] A solution of (37z) (250.0 mg, 0.58 mmol) in methylene chloride (10 mL) was cooled to 5 C. on an ice bath and supplemented with 3-chloroperbenzoic acid (225.0 mg, 1.30 mmol). After stirring at room temperature for 2 hours, the mixture was washed with a solution of NaOH 0.1 M (210 mL). The organic layer was dried, filtered and methylene chloride was evaporated to dryness under vacuum. The residue was engaged in the next step (37z) without further purification.

[1020] Yield: 72%.

2-Butoxy-9-(3-chloro-2,6-difluorobenzyl)-N-(pyridin-3-ylmethyl)-9H-purin-6-amine (37z)

[1021] ##STR00150##

[1022] Sodium metal (46.0 mg, 2 mmol) was dissolved in butan-1-ol (3 mL) on an iced bath and (37z) (150.0 mg, 0.32 mmol) was added. After stirring at room temperature for 3 hours, the mixture was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

[1023] Yield: 78%.

[1024] Melting point: 143-145 C.

[1025] The conformity and the purity of compound 37z was attested by NMR spectroscopy and elemental analysis and is reported hereafter:

[1026] .sup.1H NMR (CDCl.sub.3) 0.97 (t, J=7.4 Hz, 3H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.49 (h, J=7.4 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.78 (p, J=7.3 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.34 (t, J=6.8 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.85 (bs, 2H, NHCH.sub.2), 5.36 (s, 2H, NCH.sub.2), 5.75 (bs, 1H, NHCH.sub.2), 6.92 (td, J=8.9 Hz/1.5 Hz, 1H, 5-H), 7.24 (dd, J=7.8 Hz/4.8 Hz, 1H, 5-H), 7.39 (td, J=8.6 Hz/5.7 Hz, 1H, 4-H), 7.63 (s, 1H, 8-H), 7.69 (d, J=7.9 Hz, 1H, 6-H), 8.52 (dd, J=4.8 Hz/1.4 Hz, 1H, 4-H), 8.62 (d, J=1.8 Hz, 1H, 2-H).

[1027] .sup.13C NMR (CDCl.sub.3) 14.1 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 19.4 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.2 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 35.1 (NCH.sub.2), 42.1 (NHCH.sub.2), 67.5 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 112.4 (C-5), 113.4 (C-1), 117.3 (C-3/C-5), 123.6 (C-5), 131.3 (C-4), 134.3 (C-1), 135.6 (C-6/C-6), 138.4 (C-8), 149.1 (C-4), 149.5 (C-2), 151.5 (C-4), 155.5 (C-6), 156.2-157.7 (C-6), 159.2-160.6 (C-2), 162.5 (C-2).

[1028] Anal. (C.sub.22H.sub.21CIF.sub.2N.sub.6O) theoretical: C, 57.58; H, 4.61; N, 18.31. Found: C, 57.19; H, 4.68; N, 18.07.

[1029] Molecule 37z has been tested for its potential antibacterial activity by determining an eventual minimal inhibitory concentration according to protocols recommended by EUCAST to assess the efficacy of antibiotics against bacterial strains. In brief MIC in MRSA (ATCC BAA-1556) or in Xen29 (Perkin Elmer-ATCC 12600) for 37z (molecule 81 in WO2009/034386) was determined by culturing a single colony of MRSA or Xen29 in brain heart infusion (BHI) broth overnight (O/N) in aerobic conditions (37 C. with 220 rpm shaking), while MIC for MRSE (ATCC 35984) was determined by culturing MRSE in TSB O/N. Next day a 1:100 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 3 hr (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 310.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO. After O/N growth the OD of each culture was measured at 600 nm (OD.sub.600) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (blank is the medium alone). NO antibacterial activity was found against MRSA (ATCC BAA-1556), Xen29 (Perkin Elmer-ATCC 12600) or MRSE (ATCC 35984) strains when the molecule was used at concentrations up to 200 M.

EXAMPLE 3

2-butoxy-N-cyclopropyl-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine (38z)

[1030] ##STR00151##

[1031] We have synthesized 38z (molecule 129 in WO2009/034386) that is bearing a cyclopropyl ring attached to the nitrogen atom linked at position-6 of the heterocycle ring. The chemical structure of this compound is the most tightly related to that of the compounds described in the present application.

6-Chloro-N.SUP.4.-(2,6-difluoro-3-methylbenzyl)-2-(methylthio)pyrimidine-4,5-diamine (38a)

[1032] ##STR00152##

[1033] 4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (22h) (0.5 g, 2.4 mmol) was dissolved in methanol (10 mL) and supplemented with 2,6-difluoro-3-methylbenzylamine (0.80 mL, 6.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 130 C. for 2 h. After concentration of the reaction mixture to dryness under vacuum, the residue was purified by silica gel column chromatography.

[1034] Yield: 95%.

[1035] Melting point: 190-192 C.

[1036] .sup.1H NMR (DMSO-d.sub.6) 2.21 (s, 3H, CH.sub.3), 2.38 (s, 3H, SCH.sub.3), 4.61 (d, J=4.8 Hz, 2H, NHCH.sub.2), 4.85 (s, 2H, NH.sub.2), 7.01 (t, J=8.8 Hz, 1H, 5-H), 7.27 (m, 2H, NHCH.sub.2/4-H).

[1037] .sup.13C NMR (DMSO-d.sub.6) 13.4 (SCH.sub.3), 13.8 (CH.sub.3), 33.1 (NHCH.sub.2), 110.8 (C-5), 113.4 (C-1), 120.1 (C-5), 120.2 (C-3), 130.8 (C-4), 137.5 (C-6), 151.8 (C-4), 155.5 (C-2), 158.5-159.9 (C-2/C-6).

6-Chloro-9-(2,6-difluoro-3-methylbenzyl)-2-(methylthio)-9H-purine (38b)

[1038] ##STR00153##

[1039] A solution of (38a) (331.0 mg, 1 mmol) in acetic acid (3.0 mL) and triethyl orthoformate (3.0 mL, 18 mmol) was heated at a temperature of 130 C. under reflux for 3 hours. After distillation of acetic acid and triethyl orthoformate under vacuum, the residue was purified by silica gel column chromatography.

[1040] Yield: 66%.

[1041] Melting point: 124-126 C.

[1042] .sup.1H NMR (DMSO-d.sub.6) 2.19 (s, 3H, CH.sub.3), 2.52 (s, 3H, SCH.sub.3), 5.52 (s, 2H, NCH.sub.2), 7.05 (t, J=8.9 Hz, 1H, 5-H), 7.34 (q, J=8.4 Hz, 1H, 4-H), 8.63 (s, 1H, 8-H).

[1043] .sup.13C NMR (DMSO-d.sub.6) 13.6 (CH.sub.3), 13.8 (SCH.sub.3), 35.9 (NCH.sub.2), 110.6 (C-1), 111.1 (m, C-5), 120.6 (C-3), 127.6 (C-5), 132.2 (C-4), 149.0 (C-4), 152.5 (C-6), 158.3-159.7 (C-2/C-6), 164.7 (C-2).

N-Cyclopropyl-9-(2,6-difluoro-3-methylbenzyl)-2-(methylthio)-9H-purin-6-amine (38z)

[1044] ##STR00154##

[1045] A solution of (38b) (170.0 mg, 0.5 mmol) in acetonitrile (3 mL) was supplemented with cyclopropylamine (0.07 mL, 1.0 mmol) and triethylamine (0.10 mL) and then heated at 90 C. under reflux for 5 hours. After distillation of acetonitrile and triethylamine under vacuum, the residue was purified by silica gel column chromatography.

[1046] Yield: 86%.

[1047] Melting point: 150-152 C.

[1048] .sup.1H NMR (CDCl.sub.3) 0.60 (m, 2H, CH(CH.sub.2).sub.2), 0.86 (m, 2H, CH(CH.sub.2).sub.2), 2.23 (s, 3H, CH.sub.3), 2.60 (s, 3H, SCH.sub.3), 3.06 (bs, 1H, CH(CH.sub.2).sub.2), 5.36 (s, 2H, NCH.sub.2), 5.77 (bs, 1H, NH), 6.83 (t, J=8.3 Hz, 1H, 5-H), 7.14 (q, J=8.3 Hz, 1H, 4-H), 7.66 (s, 1H, 8-H).

[1049] .sup.13C NMR (CDCl.sub.3) 7.6 (CH(CH.sub.2).sub.2), 14.3 (CH.sub.3), 14.6 (SCH.sub.3), 24.4 (CH(CH.sub.2).sub.2), 35.1 (NCH.sub.2), 111.1 (C-5), 111.2 (C-1), 117.1 (C-5), 121.1 (C-3), 132.0 (C-4), 138.8 (C-8), 155.2 (C-4), 159.0-160.4 (C-2/C-6), 166.0 (C-2).

N-Cyclopropyl-9-(2,6-difluoro-3-methylbenzyl)-2-(methylsulfonyl)-9H-purin-6-amine (38z)

[1050] ##STR00155##

[1051] A solution of (38z) (195.0 mg, 0.54 mmol) in methylene chloride (10 mL) was cooled to 5 C. on an ice bath and supplemented with 3-chloroperbenzoic acid (208.0 mg, 1.20 mmol). After stirring at room temperature for 2 hours, the mixture was washed with a solution of NaOH 0.1 M (210 mL). The organic layer was dried, filtered and methylene chloride was evaporated to dryness under vacuum. The residue was engaged in the next step (38z) without further purification.

[1052] Yield: 69%.

2-Butoxy-N-cyclopropyl-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine (38z)

[1053] ##STR00156##

[1054] Sodium metal (46.0 mg, 2 mmol) was dissolved in butan-1-ol (3 mL) on an iced bath and (37z) (150.0 mg, 0.38 mmol) was added. After stirring at room temperature for 3 hours, the mixture was partitioned between water (50 mL) and dichloromethane (250 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

[1055] Yield: 75%.

[1056] Melting point: 123-125 C.

[1057] The conformity and the purity of compound 38z was attested by NMR spectroscopy and elemental analysis and is reported hereafter:

[1058] .sup.1H NMR (CDCl.sub.3) 0.60 (m, 2H, CH(CH.sub.2).sub.2), 0.86 (m, 2H, CH(CH.sub.2).sub.2), 0.98 (t, J=7.4 Hz, 3H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.50 (h, J=7.4 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.81 (p, J=7.0 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.23 (s, 3H, CH.sub.3), 3.06 (bs, 1H, CH(CH.sub.2).sub.2), 4.38 (t, J=6.9 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5.32 (s, 2H, NCH.sub.2), 5.75 (bs, 1H, NH), 6.83 (td, J=8.7 Hz/1.1 Hz, 1H, 5-H), 7.14 (q, J=8.3 Hz, 1H, 4-H), 7.59 (s, 1H, 8-H).

[1059] .sup.13C NMR (CDCl.sub.3) 7.6 (CH(CH.sub.2).sub.2), 14.1 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 14.3 (CH.sub.3), 19.4 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 24.2 (CH(CH.sub.2).sub.2), 31.2 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 34.8 (NCH.sub.2), 67.2 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 111.0 (C-5), 111.3 (C-1), 115.8 (C-5), 121.2 (C-3), 132.0 (C-4), 138.4 (C-8), 156.8 (C-4), 158.7-160.6 (C-2/C-6), 160.7 (C-2).

[1060] Anal. (C.sub.20H.sub.23F.sub.2N.sub.5O) theoretical: C, 62.00; H, 5.98; N, 18.08. Found: C, 61.97; H, 6.07; N, 18.03.

[1061] The molecule 38z (molecule 129 in WO2009/034386) was tested for its potential antibacterial activity by determining an eventual minimal inhibitory concentration according to protocols recommended by EUCAST to assess the efficacy of antibiotics against bacterial strains. In brief MIC in MRSA (ATCC BAA-1556) or in Xen29 (Perkin Elmer-ATCC 12600) for 38z (molecule 129 in WO2009/034386) was determined by culturing a single colony of MRSA or Xen29 in brain heart infusion (BHI) broth overnight (O/N) in aerobic conditions (37 C. with 220 rpm shaking), while MIC for MRSE (ATCC 35984) was determined by culturing MRSE in TSB O/N. Next day a 1:100 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 3 hr (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 310.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO. After O/N growth the OD of each culture was measured at 600 nm (OD.sub.600) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. OD at 600 nm equal to zero (blank is the medium alone). NO antibacterial activity was found against MRSA, Xen29 and MRSE strains when the molecule was used at concentrations up to 200 M.