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PYRIMIDINE DERIVATIVES FOR PREVENTION AND TREATMENT OF GRAM-NEGATIVE BACTERIAL INFECTION, CONTAMINATION AND FOULING

20210290625 · 2021-09-23

    Inventors

    Cpc classification

    International classification

    Abstract

    New pyrimidine derivatives together with a membrane penetrating agent, optionally with a detectable isotope and pharmaceutical composition for use in treatment or prevention of Gram-negative bacterial infection in a host mammal in need of such treatment or prevention and use as inhibitors of Gram-negative biofilm formation on a surface of biomaterial or medical device, particularly of cardiovascular device such as prosthetic heart valve or pacemakers. New pyrimidine derivatives together with a membrane penetrating agent; for use as radiotracer in diagnosing or prognosing Gram-negative bacterial infection in a host mammal.

    Claims

    1. Method of treating or preventing a Gram-negative bacterial infection in a host mammal in need of such treatment or prevention, comprising administering to the host mammal a pyrimidine derivative represented by formula (I) ##STR00164## or isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts or prodrug thereof; together with a membrane penetrating agent; wherein: X.sup.1 and X.sup.2 are independently N, CH, or 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, or 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.1-6alkoxy, —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; and 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.1-6alkoxy, —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. A method according to claim 1, wherein R.sup.3 and R.sup.7 are hydrogen and R.sup.4 and R.sup.5 are independently a halogen.

    3. A method according to claim 1, wherein X.sup.1 is CH or CR.sup.8 and X.sup.2 is N.

    4. A method according to claim 3, wherein The pyrimidine derivative is 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.

    5. The method according to claim 3, wherein the pyrimidine derivative is selected from the group consisting of: N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(propylthio)-9H-purin-6-amine (3c); 9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (17c); (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)-9-methyl-2-(methylthio)-9H-purin-6-amine (22c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (24c); 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); and 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (25c); or isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts or prodrug thereof.

    6. The method according to claim 3, wherein the pyrimidine derivative is selected from the group consisting of: N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c); 9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (17c); and (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).

    7. The method according to claim 1, wherein X.sup.1 is N and X.sup.2 is CH or CR.sup.8.

    8. The method according to claim 1, wherein the pyrimidine derivative is 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.

    9. The method according to claim 7, wherein the pyrimidine derivative is 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)-1-ethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30k); N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (28x.HCl); and N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-isopropyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (33k.HCl); or isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts or prodrug thereof.

    10. The method according to claim 1, wherein X.sup.1 and X.sup.2 are CH or CR.sup.8.

    11. The method according to claim 10, wherein the pyrimidine derivative 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.

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

    13. A method for killing or preventing Gram-negative bacterial growth in biofilm formation comprising applying on a surface of a medical device, an effective amount of pyrimidine derivatives represented by formula (I) together with a membrane penetrating agent: ##STR00165## wherein: X.sup.1 and X.sup.2 are independently N, CH, or 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, or 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.1-6alkoxy, —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.1-6alkyl, C.sub.1-6alkoxy, —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, wherein said method is not a method of treatment of the human or animal body.

    14. The method according to claim 13, wherein the medical device is a cardiovascular device.

    15. A method of diagnosing or prognosing a Gram-negative bacterial infection comprising using the pyrimidine derivative represented by formula (I) together with a membrane penetrating agent: ##STR00166## wherein: X.sup.1 and X.sup.2 are independently N, CH, or 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 or 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.1-6alkoxy, —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.1-6alkyl, C.sub.1-6alkoxy, —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; and wherein the pyrimidine derivative comprises a detectable marker.

    16. The method according to claim 1, wherein the membrane penetrating agent is polymyxin B nonapeptide.

    17. The method according to claim 13, wherein the membrane penetrating agent is polymyxin B nonapeptide.

    18. The method according to claim 15, wherein the membrane penetrating agent is polymyxin B nonapeptide.

    Description

    BRIEF DESCRIPTION OF THE FIGURE

    [0320] FIG. 1 illustrates a cell wall structure comparison between Gram-negative bacteria (1) and Gram-positive bacteria (2) envelope with a similar inner cytoplasmic membrane (B) made of porins (D) and a peptidoglycan cell wall (A) made of peptide chains generally crosslinked for both class of bacteria. The Gram-negactive bacterium (1) differs from the Gram-positive bacterium (2) by an additional outer membrane (C) made of lipids (E), lipopolysaccharides (LPS) and porins (D).

    [0321] FIG. 2 illustrates the effect of molecules 2329 (purine) and 2666 (pyrazolopyimidine) at different concentrations combined with 35 μg/ml PMBN (represented by P) on E. coli biofilm formation.

    [0322] FIG. 3 illustrates the kinetic of inhibition of E. coli of a pyrazolo molecule (2666) and a purine (2329) in combination with 50 μg/ml PMBN (represented by P50) compared to Ampicillin.

    [0323] FIG. 4 illustrates a comparison of the pyrimidine derivatives according to the invention with purines (127=39z″; 128=40z″; 129=38z″ and 84=41z″) disclosed in WO 2009/034386.

    [0324] The invention is illustrated hereafter by the following non limiting examples.

    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)

    [0325] ##STR00029##

    [0326] 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).

    [0327] 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.

    [0328] Yield: 96%.

    [0329] Melting point: 119-121° C.

    [0330] .sup.1H NMR (DMSO-d.sub.6) δ0.95 (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).

    [0331] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0332] ##STR00030##

    [0333] 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.

    [0334] Yield: 77%.

    [0335] Melting point: 75-78° C.

    [0336] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0337] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0338] ##STR00031##

    [0339] 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.

    [0340] Yield: 42%.

    [0341] Melting point: 94-96° C.

    [0342] .sup.1H NMR (CDCl.sub.3) δ 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)CH Ph), 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).

    [0343] .sup.13C NMR (CDCl.sub.3) S 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)

    [0344] ##STR00032##

    [0345] 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.

    [0346] Yield: 27%.

    [0347] Melting point: 171-172.5° C.

    [0348] .sup.1H NMR (CDCl.sub.3) δ0.88 (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).

    [0349] .sup.13C NMR (CDCl.sub.3) S 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)

    [0350] ##STR00033##

    [0351] 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.

    [0352] Yield: 77%.

    [0353] Melting point: 96-98° C.

    [0354] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0355] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0356] ##STR00034##

    [0357] 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.

    [0358] Yield: 77%.

    [0359] Melting point: 96-97.5° C.

    [0360] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0361] .sup.13C NMR (DMSO-d.sub.6) δ13.2 (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)

    [0362] ##STR00035##

    [0363] 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.

    [0364] Yield: 43%.

    [0365] Melting point: 109.5-111.5° C.

    [0366] .sup.1H NMR (CDCl.sub.3) δ0.94 (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).

    [0367] .sup.13C NMR (CDCl.sub.3) S 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)

    [0368] ##STR00036##

    [0369] 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.

    [0370] Yield: 91%.

    [0371] Melting point: 100-102° C.

    [0372] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0373] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0374] ##STR00037##

    [0375] 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.

    [0376] Yield: 94%.

    [0377] Melting point: liquid.

    [0378] .sup.1H NMR (DMSO-d.sub.6) δ0.85 (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).

    [0379] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0380] ##STR00038##

    [0381] 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.

    [0382] Yield: 45%.

    [0383] Melting point: 97-99° C.

    [0384] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0385] .sup.13C NMR (CDCl.sub.3) S 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)

    [0386] ##STR00039##

    [0387] 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.

    [0388] Yield: 95%.

    [0389] Melting point: 81-83° C.

    [0390] .sup.1H NMR (DMSO-d.sub.6) δ0.95 (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).

    [0391] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0392] ##STR00040##

    [0393] 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.

    [0394] Yield: 37%.

    [0395] Melting point: 121-122.5° C.

    [0396] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0397] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0398] ##STR00041##

    [0399] 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.

    [0400] Yield: 47%.

    [0401] Melting point: 98.5-100.5° C.

    [0402] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0403] .sup.13C NMR (CDCl.sub.3) S 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)

    [0404] ##STR00042##

    [0405] 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.

    [0406] Yield: 92%.

    [0407] Melting point: 96-98° C.

    [0408] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0409] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0410] ##STR00043##

    [0411] 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.

    [0412] Yield: 58%.

    [0413] Melting point: 128.5-130° C.

    [0414] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0415] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0416] ##STR00044##

    [0417] 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.

    [0418] Yield: 40%.

    [0419] Melting point: 137-139° C.

    [0420] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0421] .sup.13C NMR (CDCl.sub.3) S 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)

    [0422] ##STR00045##

    [0423] 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.

    [0424] Yield: 95%.

    [0425] Melting point: liquid.

    [0426] .sup.1H NMR (DMSO-d.sub.6) δ0.91 (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).

    [0427] .sup.13C NMR (DMSO-d.sub.6) δ13.3 (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)

    [0428] ##STR00046##

    [0429] 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.

    [0430] Yield: 72%.

    [0431] Melting point: liquid.

    [0432] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0433] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0434] ##STR00047##

    [0435] 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.

    [0436] Yield: 61%.

    [0437] Melting point: 85-87° C.

    [0438] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0439] .sup.13C NMR (CDCl.sub.3) S 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)

    [0440] ##STR00048##

    [0441] 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.

    [0442] Yield: 81%.

    [0443] Melting point: liquid.

    [0444] .sup.1H NMR (DMSO-d.sub.6) δ0.87 (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).

    [0445] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0446] ##STR00049##

    [0447] 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.

    [0448] Yield: 39%.

    [0449] Melting point: 64-66° C.

    [0450] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0451] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0452] ##STR00050##

    [0453] 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.

    [0454] Yield: 66%.

    [0455] Melting point: 68-71° C.

    [0456] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0457] .sup.13C NMR (CDCl.sub.3) S 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)

    [0458] ##STR00051##

    [0459] 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.

    [0460] Yield: 88%.

    [0461] Melting point: 88-89° C.

    [0462] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0463] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0464] ##STR00052##

    [0465] 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.

    [0466] Yield: 41%.

    [0467] Melting point: 116-117° C.

    [0468] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0469] .sup.13C NMR (DMSO-d.sub.6) δ 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), δ8.0 (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)

    [0470] ##STR00053##

    [0471] 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.

    [0472] Yield: 56%.

    [0473] Melting point: 125-128° C.

    [0474] .sup.1H NMR (CDCl.sub.3) δ 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, 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).

    [0475] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0476] ##STR00054##

    [0477] 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.

    [0478] Yield: 96%.

    [0479] Melting point: 73-75.5° C.

    [0480] .sup.1H NMR (DMSO-d.sub.6) δ0.96 (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).

    [0481] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0482] ##STR00055##

    [0483] 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.

    [0484] Yield: 62%.

    [0485] Melting point: 89-91.5° C.

    [0486] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0487] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0488] ##STR00056##

    [0489] 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.

    [0490] Yield: 76%.

    [0491] Melting point: 143-145° C.

    [0492] .sup.1H NMR (CDCl.sub.3) δ0.96 (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).

    [0493] .sup.13C NMR (CDCl.sub.3) S 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-difluorophenyl)cyclopropyl)-9-pentyl-2-(propylthio)-9H-purin-6-amine (11c)

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

    [0494] ##STR00057##

    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.

    [0495] Yield: 96%.

    [0496] Melting point: 68-69° C.

    [0497] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0498] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0499] ##STR00058##

    [0500] 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.

    [0501] Yield: 87%.

    [0502] Melting point: liquid.

    [0503] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0504] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0505] ##STR00059##

    [0506] 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.

    [0507] Yield: 83%.

    [0508] Melting point: 98-100.5° C.

    [0509] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0510] .sup.13C NMR (CDCl.sub.3) S 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-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 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)

    [0511] ##STR00060##

    [0512] 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.

    [0513] Yield: 95%.

    [0514] Melting point: 86-88° C.

    [0515] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0516] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0517] ##STR00061##

    [0518] 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.

    [0519] Yield: 37%.

    [0520] Melting point: 81-83° C.

    [0521] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0522] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0523] ##STR00062##

    [0524] 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.

    [0525] Yield: 35%.

    [0526] Melting point: 112-114° C.

    [0527] .sup.1H NMR (CDCl.sub.3) δ0.95 (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).

    [0528] .sup.13C NMR (CDCl.sub.3) S 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)

    [0529] ##STR00063##

    [0530] 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.

    [0531] Yield: 85%.

    [0532] Melting point: 54-57° C.

    [0533] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0534] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0535] ##STR00064##

    [0536] 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.

    [0537] Yield: 90%.

    [0538] Melting point: liquid.

    [0539] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0540] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0541] ##STR00065##

    [0542] 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.

    [0543] Yield: 60%.

    [0544] Melting point: 84-86° C.

    [0545] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0546] .sup.13C NMR (CDCl.sub.3) S 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)

    [0547] ##STR00066##

    [0548] 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.

    [0549] Yield: 91%.

    [0550] Melting point: 90-93° C.

    [0551] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0552] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0553] ##STR00067##

    [0554] 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.

    [0555] Yield: 62%.

    [0556] Melting point: 93-95° C.

    [0557] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0558] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0559] ##STR00068##

    [0560] 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.

    [0561] Yield: 84%.

    [0562] Melting point: 85-88° C.

    [0563] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0564] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0565] ##STR00069##

    [0566] 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.

    [0567] Yield: 92%.

    [0568] Melting point: 55-57° C.

    [0569] .sup.1H NMR (DMSO-d.sub.6) δ0.94 (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).

    [0570] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0571] ##STR00070##

    [0572] 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.

    [0573] Yield: 89%.

    [0574] Melting point: 47.5-49.5° C.

    [0575] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0576] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0577] ##STR00071##

    [0578] 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.

    [0579] Yield: 89%.

    [0580] Melting point: liquid.

    [0581] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0582] .sup.13C NMR (CDCl.sub.3) S 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)

    [0583] ##STR00072##

    [0584] 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.

    [0585] Yield: 79%.

    [0586] Melting point: 99-102° C.

    [0587] .sup.1H NMR (DMSO-d.sub.6) δ0.95 (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).

    [0588] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0589] ##STR00073##

    [0590] 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.

    [0591] Yield: 57%.

    [0592] Melting point: 81-83° C.

    [0593] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0594] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0595] ##STR00074##

    [0596] 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.

    [0597] Yield: 42%.

    [0598] Melting point: 81-83° C.

    [0599] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0600] .sup.13C NMR (CDCl.sub.3) S 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)

    [0601] ##STR00075##

    [0602] 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.

    [0603] Yield: 78%.

    [0604] Melting point: 90-92° C.

    [0605] .sup.1H NMR (DMSO-d.sub.6) δ0.96 (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).

    [0606] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0607] ##STR00076##

    [0608] 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.

    [0609] Yield: 62%.

    [0610] Melting point: 68-70° C.

    [0611] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0612] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0613] ##STR00077##

    [0614] 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.

    [0615] Yield: 86%.

    [0616] Melting point: 72-74° C.

    [0617] .sup.1H NMR (CDCl.sub.3) δ0.94 (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).

    [0618] .sup.13C NMR (CDCl.sub.3) S 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)

    [0619] ##STR00078##

    [0620] 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.

    [0621] Yield: 99%.

    [0622] 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)

    [0623] ##STR00079##

    [0624] 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.

    [0625] Yield: 76%.

    [0626] Melting point: 107-109° C.

    [0627] .sup.1H NMR (DMSO-d.sub.6) δ0.95 (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).

    [0628] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0629] ##STR00080##

    [0630] 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.

    [0631] Yield: 48%.

    [0632] Melting point: 140-143° C.

    [0633] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0634] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0635] ##STR00081##

    [0636] 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.

    [0637] Yield: 89%.

    [0638] Melting point: 102-104° C.

    [0639] .sup.1H NMR (CDCl.sub.3) δ0.95 (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).

    [0640] .sup.13C NMR (CDCl.sub.3) S 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)

    [0641] ##STR00082##

    [0642] 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.

    [0643] Yield: 90%.

    [0644] Melting point: ND.

    [0645] .sup.1H NMR (DMSO-d.sub.6) δ0.96 (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).

    [0646] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0647] ##STR00083##

    [0648] 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.

    [0649] Yield: 23%.

    [0650] Melting point: ND.

    [0651] .sup.1H NMR (DMSO-d.sub.6) δ1.02 (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).

    [0652] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0653] ##STR00084##

    [0654] 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.

    [0655] Yield: 91%.

    [0656] Melting point: ND.

    [0657] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0658] .sup.13C NMR (CDCl.sub.3) S 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)

    [0659] ##STR00085##

    [0660] 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.

    [0661] Yield: 76%.

    [0662] Melting point: 92-94° C.

    [0663] .sup.1H NMR (CDCl.sub.3) δ0.87 (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).

    [0664] .sup.13C NMR (CDCl.sub.3) S 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)

    [0665] ##STR00086##

    [0666] 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.

    [0667] Yield: 69%.

    [0668] Melting point: >300° C.

    [0669] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0670] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0671] ##STR00087##

    [0672] 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.

    [0673] Yield: 69%.

    [0674] Melting point: 210-213° C. (decomposition).

    [0675] .sup.1H NMR (DMSO-d.sub.6) δ 1.31 (t, J=7.3 Hz, 3H, CH.sub.3), 3.17 (q, J=7.3 Hz, 2H, SCH.sub.2).

    [0676] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0677] ##STR00088##

    [0678] 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 (3×50 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).

    [0679] Yield: 85%.

    [0680] Melting point: oil.

    [0681] .sup.1H NMR (DMSO-d.sub.6) δ 1.35 (t, J=7.3 Hz, 3H, CH.sub.3), 3.18 (q, J=7.3 Hz, 2H, SCH.sub.2).

    [0682] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0683] ##STR00089##

    [0684] 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.

    [0685] Yield: 86%.

    [0686] Melting point: 48-50° C.

    [0687] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0688] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0689] ##STR00090##

    [0690] 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.

    [0691] Yield: 87%.

    [0692] Melting point: 112-114° C.

    [0693] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0694] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0695] ##STR00091##

    [0696] 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.

    [0697] Yield: 86%.

    [0698] Melting point: 89-100° C.

    [0699] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0700] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0701] ##STR00092##

    [0702] 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.

    [0703] Yield: 89%.

    [0704] Melting point: 116-118.5° C.

    [0705] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0706] .sup.13C NMR (CDCl.sub.3) δ 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-difluorophenyl)cyclopropyl)-9-ethyl-2-(ethylthio)-9H-purin-6-amine (21c)

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

    [0707] ##STR00093##

    [0708] 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.

    [0709] Yield: 91%.

    [0710] Melting point: 93-95° C.

    [0711] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0712] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0713] ##STR00094##

    [0714] 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.

    [0715] Yield: 91%.

    [0716] Melting point: 64-66° C.

    [0717] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0718] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0719] ##STR00095##

    [0720] 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.

    [0721] Yield: 96%.

    [0722] Melting point: 107.5-109.5° C.

    [0723] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0724] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0725] ##STR00096##

    [0726] 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.

    [0727] Yield: 77%.

    [0728] Melting point: >300° C.

    [0729] .sup.1H NMR (DMSO-d.sub.6) δ 2.46 (s, 3H, SCH.sub.3), 5.13 (s, 1H, CH), 11.71 (bs, 2H, OH).

    [0730] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0731] ##STR00097##

    [0732] 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.

    [0733] Yield: 67%.

    [0734] Melting point: 220-221° C. (decomposition).

    [0735] .sup.1H NMR (DMSO-d.sub.6) δ 2.56 (s, 3H, SCH.sub.3).

    [0736] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0737] ##STR00098##

    [0738] 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.

    [0739] Yield: 92%.

    [0740] Melting point: 63-64° C.

    [0741] .sup.1H NMR (DMSO-d.sub.6) δ 2.56 (s, 3H, SCH.sub.3).

    [0742] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0743] ##STR00099##

    [0744] 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.

    [0745] Yield: 95%.

    [0746] Melting point: 105-108° C.

    [0747] .sup.1H NMR (DMSO-d.sub.6) δ 2.45 (s, 3H, SCH.sub.3), 5.90 (s, 2H, NH.sub.2).

    [0748] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0749] ##STR00100##

    [0750] 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.

    [0751] Yield: 82%.

    [0752] Melting point: 141-143° C.

    [0753] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0754] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0755] ##STR00101##

    [0756] 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.

    [0757] Yield: 92%.

    [0758] Melting point: 140-142° C.

    [0759] .sup.1H NMR (DMSO-d.sub.6) δ 2.61 (s, 3H, SCH.sub.3), 3.80 (s, 3H, NCH.sub.3), 8.49 (s, 1H, CH).

    [0760] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0761] ##STR00102##

    [0762] 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.

    [0763] Yield: 80%.

    [0764] Melting point: 156-159° C.

    [0765] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0766] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0767] ##STR00103##

    [0768] 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 (2×10 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.

    [0769] Yield: 88%.

    [0770] Melting point: 206-208.5° C.

    [0771] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0772] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0773] ##STR00104##

    [0774] 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 (2×50 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.

    [0775] Yield: 73%.

    [0776] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0777] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0778] ##STR00105##

    [0779] 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.

    [0780] Yield: 95%.

    [0781] 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)

    [0782] ##STR00106##

    [0783] 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.

    [0784] Yield: 86%.

    [0785] Melting point: 120-122° C.

    [0786] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0787] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0788] ##STR00107##

    [0789] 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.

    [0790] Yield: 77%.

    [0791] Melting point: 99.5-101.5° C.

    [0792] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0793] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0794] ##STR00108##

    [0795] 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.

    [0796] Yield: 38%.

    [0797] Melting point: 126-127.5° C.

    [0798] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0799] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0800] ##STR00109##

    [0801] 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.

    [0802] Yield: 72%.

    [0803] Melting point: >300° C.

    [0804] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0805] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0806] ##STR00110##

    [0807] 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.

    [0808] Yield: 68%.

    [0809] Melting point: 178-179.5° C. (decomposition).

    [0810] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0811] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0812] ##STR00111##

    [0813] 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 (3×50 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).

    [0814] Yield: 92%.

    [0815] Melting point: oil.

    [0816] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0817] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0818] ##STR00112##

    [0819] 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).

    [0820] Yield: 97%.

    [0821] Melting point: oil.

    [0822] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0823] .sup.13C NMR (DMSO-d.sub.6) δ 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-(Butylhtio)-6-chloro-2-N.SUP.4.-methylpyrimidine-4,5-diamine (25a)

    [0824] ##STR00113##

    [0825] 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.

    [0826] Yield: 87%.

    [0827] Melting point: oil.

    [0828] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0829] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0830] ##STR00114##

    [0831] 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.

    [0832] Yield: 76%.

    [0833] Melting point: 56-58° C.

    [0834] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0835] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0836] ##STR00115##

    [0837] 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.

    [0838] Yield: 66%.

    [0839] Melting point: 98-100° C.

    [0840] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0841] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0842] ##STR00116##

    [0843] 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.

    [0844] Yield: 91%.

    [0845] Melting point: 80-82° C.

    [0846] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0847] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0848] ##STR00117##

    [0849] 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.

    [0850] Yield: 70%.

    [0851] Melting point: 69-71° C.

    [0852] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0853] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0854] ##STR00118##

    [0855] 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.

    [0856] Yield: 56%.

    [0857] Melting point: 92-94° C.

    [0858] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0859] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0860] ##STR00119##

    [0861] 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 (3×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum.

    [0862] Yield: 52%.

    [0863] Melting point: 87-89° C.

    [0864] .sup.1H NMR (DMSO-d.sub.6) δ 2.57 (s, 3H, SCH.sub.3), 10.07 (s, 1H, COH).

    [0865] .sup.13C NMR (DMSO-d.sub.6) δ 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′)

    [0866] ##STR00120##

    [0867] 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.

    [0868] Yield: 95%.

    [0869] Melting point: >300° C.

    [0870] .sup.1H NMR (DMSO-d.sub.6) δ 2.59 (s, 3H, SCH.sub.3), 8.32 (s, 1H, CH), 14.25 (bs, 1H, NH).

    [0871] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0872] ##STR00121##

    [0873] To a solution of (27′) (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 (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [0874] Yield: 82%.

    [0875] Melting point: 85-87° C.

    [0876] .sup.1H NMR (DMSO-d.sub.6) δ 2.63 (s, 3H, SCH.sub.3), 4.00 (s, 3H, NCH.sub.3), 8.34 (s, 1H, CH).

    [0877] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0878] ##STR00122##

    [0879] 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.

    [0880] Yield: 84%.

    [0881] Melting point: 128.5-130° C.

    [0882] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0883] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0884] ##STR00123##

    [0885] 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 (2×10 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).

    [0886] Yield: 58%.

    [0887] Melting point: oil.

    [0888] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0889] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0890] ##STR00124##

    [0891] 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.

    [0892] Yield: 67%.

    [0893] Melting point: 164-168° C.

    [0894] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0895] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0896] ##STR00125##

    [0897] 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.

    [0898] Yield: 66%.

    [0899] Melting point: 110-115° C.

    [0900] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0901] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0902] ##STR00126##

    [0903] 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 (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [0904] Yield: 77%.

    [0905] Melting point: 92-93.5° C.

    [0906] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0907] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0908] ##STR00127##

    [0909] 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.

    [0910] Yield: 54%.

    [0911] Melting point: 176-180° C.

    [0912] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0913] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0914] ##STR00128##

    [0915] 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 (2×10 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.

    [0916] Yield: 87%.

    [0917] Melting point: 95-100° C. (decomposition).

    [0918] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0919] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0920] ##STR00129##

    [0921] 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.

    [0922] Yield: 64%.

    [0923] Melting point: 168-172° C.

    [0924] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0925] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0926] ##STR00130##

    [0927] 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.

    [0928] Yield: 62%.

    [0929] Melting point: 150-154° C.

    [0930] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0931] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0932] ##STR00131##

    [0933] 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 (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [0934] Yield: 73%.

    [0935] Melting point: 114-115.5° C.

    [0936] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0937] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0938] ##STR00132##

    [0939] 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.

    [0940] Yield: 87%.

    [0941] Melting point: 159-163° C.

    [0942] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0943] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0944] ##STR00133##

    [0945] 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 (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [0946] Yield: 78%.

    [0947] Melting point: 41-43° C.

    [0948] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0949] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0950] ##STR00134##

    [0951] 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.

    [0952] Yield: 76%.

    [0953] Melting point: 155-159° C.

    [0954] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0955] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0956] ##STR00135##

    [0957] 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.

    [0958] Yield: 95%.

    [0959] Melting point: 261-264° C.

    [0960] .sup.1H NMR (DMSO-d.sub.6) δ 2.42 (s, 3H, SCH.sub.3), 4.90 (s, 1H, CH), 6.44 (s, 2H, NH.sub.2), 11.47 (s, 1H, OH).

    [0961] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0962] ##STR00136##

    [0963] 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% chloroacetaldehyde 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.

    [0964] Yield: 45%.

    [0965] Melting point: >300° C.

    [0966] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0967] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [0968] ##STR00137##

    [0969] 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.

    [0970] Yield: 33%.

    [0971] Melting point: 206-208° C.

    [0972] .sup.1H NMR (DMSO-d.sub.6) δ 2.56 (s, 3H, SCH.sub.3), 6.52 (s, 1H, 5-H), 7.52 (s, 1H, 6-H), 12.39 (s, 1H, NH).

    [0973] .sup.13C NMR (DMSO-d.sub.6) δ 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′)

    [0974] ##STR00138##

    [0975] 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.

    [0976] Yield: 15%.

    [0977] Melting point: 208-211° C.

    [0978] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [0979] .sup.13C NMR (CDCl.sub.3) δ 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)

    [0980] ##STR00139##

    [0981] 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 (2×50 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.

    [0982] Yield: 74%.

    [0983] Melting point: 189-194° C.

    [0984] .sup.1H NMR (CDCl.sub.3) δ 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).

    [0985] .sup.13C NMR (CDCl.sub.3) δ 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).

    2. Examples of Pyrimidines Derivatives for Use in Prevention and Treatment of Gram-Negative Bacterial Infection

    [0986] The following biological examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention.

    Example 1: Antibacterial Effects of Molecules 2329, 2412, 2452, and 2461 Together with Polymyxin B Nonapeptide on Escherichia coli (ATCC8739): Determination of Minimal Inhibitory Concentration (MIC)

    [0987] Molecules 2329, 2412, 2452, and 2461 correspond respectively to the following formulae:

    ##STR00140##

    [0988] 2329 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (also called 1c above)

    ##STR00141##

    [0989] 2412 is 9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (also called 15c)

    [0990] 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).

    ##STR00142##

    [0991] 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).

    [0992] Polymyxin B nonapeptide (PMBN) is represented by the following formula (VII) and is produced by Sigma-Aldrich (product P2076).

    ##STR00143## [0993] wherein R is Ph.

    [0994] The Minimal Inhibitory Concentration (MIC) of molecules 2329, 2412, 2452 and 2461 together with polymyxin B nonapeptide (PMBN) was determined on Escherichia coli (ATCC 8739) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommendations.

    [0995] Briefly, a single colony grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in the LB medium 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 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle) with or without Polymyxin B nonapeptide (PMBN) at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone.

    [0996] As shown in Table 1, the MIC for molecules 2329, 2452 and 2461 together with PMBN against Escherichia coli (ATCC 8739) is equal to 10 μM, while it is 50 μM for molecules 2412. The molecules 2329, 2452, 2461 and 2412 taken alone in concentrations up to 100 μM or 40 μg/ml PMBN alone was unable to inhibit E. coli growth.

    Example 2: Antibacterial Effects of Pyrazolopyrimidine Molecule 2666 Together with Polymyxin B Nonapeptide on Escherichia coli (ATCC 8739): Determination of Minimal Inhibitory Concentration (MIC)

    [0997] Pyrazolopyrimidine molecule 2666 corresponds to

    ##STR00144##

    [0998] 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);

    [0999] Further experiments were conducted in order to determine the Minimal Inhibitory Concentration (MIC) which is the minimal-concentration required to prevent bacterial growth-A single colony grown on an Lurian-Bertani (LB) agar plate is resuspended and cultured in LB medium overnight (O/N) in aerobic conditions (37° C. with 220 rpm shaking), next day a 1:50 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO (vehicle) with or without PMBN at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone.

    [1000] As shown in Table 1, the MIC for 2666 together with PMBN against Escherichia coli (ATCC 8739) is equal to 10 μM. The molecule 2666 alone in concentrations up to 100 μM or 40 μg/ml PMBN alone did not inhibit E. coli growth.

    Example 3: Antibacterial Effects of Molecules 2329, 2412, 2452, and 2461 Together with Polymyxin B Nonapeptide on Pseudomonas aeruginosa: Determination of Minimal Inhibitory Concentration (MIC)

    [1001] Further experiments were conducted using the clinically relevant Gram-negative bacterial strain of Pseudomonas aeruginosa (ATCC27853).

    [1002] A single colony grown on an tryptic soy agar plate is resuspended and cultured in tryptic soy broth medium 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 3h (OD=0.5-0.6) and an inoculum of 1:1000 dilution, corresponding to 1-3×10.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO (vehicle) with or without PMBN at 0.5 μg/ml. After 28-30h 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. ΔOD at 600 nm equal to zero (blank is the medium alone) wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone.

    [1003] As shown in Table 1, the MIC for molecules 2329, 2412, 2452 and 2461 together with PMBN against Pseudomonas aeruginosa (ATCC27853) is equal to 50 μM.

    [1004] Molecules 2329, 2412, 2452, and 2461 alone in concentrations up to 100 μM or 0.5 μg/ml PMBN alone did not inhibit Pseudomonas aeruginosa growth.

    Example 4: Antibacterial Effects of Pyrazolopyrimidine Molecule 2666 Together with Polymyxin B Nonapeptide on Pseudomonas aeruginosa (ATCC27853): Determination of Minimal Inhibitory Concentration (MIC)

    [1005] Further experiments were conducted using the clinically relevant Gram-negative bacterial strain of Pseudomonas aeruginosa (ATCC27853).

    [1006] A single colony grown on an tryptic soy agar plate is resuspended and cultured in tryptic soy broth medium 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 3h (OD=0.5-0.6) and an inoculum of 1:1000 dilution, corresponding to 1-3×10.sup.5 CFU/ml, is incubated in presence or absence of different concentrations of the tested molecules in 1% DMSO (vehicle) with or without PMBN at 0.5 μg/ml. After 28-30h 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. ΔOD at 600 nm equal to zero (blank is the medium alone) wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone.

    [1007] As shown in Table 1, the MIC for molecules 2666 together with PMBN against Pseudomonas aeruginosa is equal to 50 μM. Molecule 2666 alone in concentration up to 100 μM or 0.5 μg/ml PMBN alone, did not inhibit P. aeruginosa growth.

    Example 5: Antibacterial Effects of Purine Molecules 2511, 2525 and 2833 Together with Polymyxin B Nonapeptide on Escherichia coli (ATCC8739): Determination of Minimal Inhibitory Concentration (MIC)

    [1008] Molecules 2511, 2525 and 2833 correspond respectively to the following formulae:

    ##STR00145##

    [1009] 2511 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (also called 24c above).

    [1010] 2525 is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(ethylthio)-9-methyl-9H-purin-6-amine (also called 20c above);

    [1011] 2833 is 2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (also called 25c above);

    [1012] Further experiments were conducted in order to determine the Minimal Inhibitory Concentration (MIC) of molecules 2511, 2525 and 2833 together with polymyxin B nonapeptide (PMBN) provided by MedChemExpress #HY-106783. MIC was determined on Escherichia coli (ATCC 8739) according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommendations.

    [1013] Briefly, a single colony grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in LB medium 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 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the above-mentioned molecules in 1% DMSO (vehicle) with or without Polymyxin B nonapeptide (PMBN) at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone.

    [1014] As shown in Table 1, the MIC for molecules 2511 and 2525 together with PMBN against Escherichia coli (ATCC 8739) is equal to 50 μM, while it is 90 μM for molecule 2833. The molecules 2511, 2525 and 2833 taken alone in concentrations up to 100 μM or 40 μg/ml PMBN alone was unable to inhibit E. coli growth.

    Example 6: Antibacterial Effects of Pyrazolopyrimidine Molecule 2539 Together with Polymyxin B Nonapeptide (Provided by MedChemExpress #HY-106783) on Escherichia coli (ATCC 8739): Determination of Minimal Inhibitory Concentration (MIC)

    [1015] Pyrazolopyrimidine molecule 2539 corresponds to

    ##STR00146##

    [1016] 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);

    [1017] Further experiments were conducted in order to determine the Minimal Inhibitory Concentration (MIC) which is the minimal concentration required to prevent bacterial growth.

    [1018] A single colony grown on a Luria-Bertani (LB) agar plate is resuspended and cultured in LB medium overnight (O/N) in aerobic conditions (37° C. with 220 rpm shaking), next day a 1:50 inoculum in Mueller-Hinton broth (MHB) is incubated in aerobic conditions for 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, is incubated in presence or absence of different concentrations of the above-mentioned pyrazolopyrimidine molecule in 1% DMSO (vehicle) with or without PMBN at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone.

    [1019] As shown in Table 1, the MIC for 2539 together with PMBN against Escherichia coli (ATCC 8739) is equal to 25 μM. The molecule 2539 alone in concentrations up to 100 μM or 40 μg/ml PMBN alone did not inhibit E. coli growth.

    TABLE-US-00001 TABLE 1 Minimal Inhibitory Concentrations of purines and pyrazolopyrimidine molecules together with PMBN against E. coli and P. aeruginosa. PMBN (polymyxin B nonapeptide) was used at 40 μg/ml for E. coli and 0.5 μg/ml for P. aeruginosa. Minimal inhibitory concentration (in μM) without With Strains Group molecules PMBN PMBN E. coli Purin 2329 >100 10 (ATCC 8739) 2412 >100 50 2452 >100 10 2461 >100 10 2511 >100 50 2525 >100 50 2833 >100 90 Pyrazolo 2539 >100 25 2666 >100 10 Pseudomonas Purin 2329 >100 50 aeruginosa 2412 >100 50 (ATCC 27853) 2452 >100 50 2461 >100 50 Pyrazolo 2666 >100 50

    3. Examples of Pyrimidine Derivatives for Use in Inhibition of Biofilm Formation of Gram-Negative Bacteria with and without Polymixyn B Nonapeptide

    [1020] 1.5×10.sup.4 CFU of E. coli (ATCC 8739) in early logarithmic phase were added in a well of a 48-well polystyrene plate containing Luria Bertani (LB) medium supplemented with 5% mannose (purchased from Sigma-aldrich #M6020-25G) and incubated for 48h at 37° C. The incubation was carried in static conditions in presence or absence of different concentrations of the molecules 2329 or 2666 in combination or not with the penetrating agent polymyxin B nonapeptide (PMBN) (35 μg/ml) (provided by Sigma-aldrich #P2076-5MG). After incubation, planktonic bacteria, which are bacteria floating in the liquid medium, were removed and adherent bacteria were washed 2 times in PBS. Crystal Violet (Sigma-aldrich #C0775-25G) (1% solution in dH.sub.2O) was then added to the wells for 15 min at RT to stain the biofilm. Wells were washed 3 times with PBS (phosphate buffered saline provided by Lonza #17-516F) to eliminate unbound crystal violet and 2501 Acetic Acid 20% was added and incubated at RT for 10 min. The absorbance of the solution was measured at 570 nm with an Infinite 200 PRO (Tecan) reflecting the total biomass of the biofilm, which corresponds to the sum of live and dead bacteria. The Biofilm Mass, expressed in percentage, is calculated by the following formula: Abs(sample)/Abs(DMSO 1%)*100, wherein the Abs(sample) or Abs(DMSO) represents the difference between the absorbance of the sample or DMSO and the blank (blank is the medium alone without bacteria).

    [1021] As shown in FIG. 2, the purine 2329 molecule (5 μM) combined with 35 μg/ml PMBN fully inhibited E. coli biofilm formation in a synergistic manner. The molecule 2329 alone had no effect, while PMBN (35 μg/ml) alone only reduced by half biofilm growth. Similarly, the pyrazolopyrimidine 2666 molecule (10 μM) combined with 35 μg/ml PMBN fully inhibited E. coli biofilm formation in a synergistic manner. The molecule 2666 alone had no effect on biofilm growth.

    TABLE-US-00002 TABLE 2 Reduction E. coli biofilm mass expressed in percentage, in presence of different concentration of pyrimidine derivatives (2329 and 2666) with and without polymixyn B nonapeptide (called P in the table) DMSO PMBN 2329 P + 2329 P + 2329 2666 P + 2666 P + 2666 1% 35 μg/ml 20 μM 5 μM 10 μM 20 μM 5 μM 10 μM 90.97 53.90 97.41 −1.25 2.96 100.43 0.40 1.07 90.05 50.87 107.12 −1.59 3.11 100.95 0.49 0.92 109.44 47.94 110.45 12.79 0.12 85.72 53.62 0.95 109.53 48.98 124.24 11.45 −1.01 87.82 51.67 −0.122

    4. Comparison of Pyrimidine Derivatives According to the Present Invention with Purines Disclosed in WO2009/034386

    [1022] We have synthesized 4 molecules (84, 127, 128 and 129) from WO2009/034386. In this patent application, the ability of 2 molecules (25 and 81) to inhibit the MurI enzyme from E. faecalis, E. faecium and S. aureus is described. The 2 molecules were able to inhibit the enzymatic activity of MurI isozymes from E. faecalis and E. faecium with half maximal inhibitory concentrations (IC.sub.50) equal to 2 and 5 μM, respectively (Table 9 of WO2009/034386). In contrast, IC.sub.50>400 μM is reported against S. aureus MurI isozyme for the 2 molecules, indicating a failure to inhibit the MurI enzyme from this bacterial strain. WO2009/034386 does not report any other testing demonstrating the antibacterial efficacy of these purine molecules.

    [1023] We found no antibacterial activity of molecules 84, 127, 128 and 129 against E. coli (ATCC8739)

    [1024] The molecules 84, 127, 128 and 129 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.

    ##STR00147##

    [1025] When R.sup.1=CH.sub.3, the corresponding alkoxy-substituted compounds Xz″ wherein Y═O was provided starting from Xz according to scheme 6 below:

    ##STR00148##

    Example 1

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

    [1026] ##STR00149##

    [1027] 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)

    [1028] ##STR00150##

    [1029] 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.

    [1030] Yield: 95%.

    [1031] Melting point: 190-192° C.

    [1032] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [1033] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [1034] ##STR00151##

    [1035] 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.

    [1036] Yield: 66%.

    [1037] Melting point: 124-126° C.

    [1038] .sup.1H NMR (DMSO-d.sub.6) δ 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).

    [1039] .sup.13C NMR (DMSO-d.sub.6) δ 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)

    [1040] ##STR00152##

    [1041] 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.

    [1042] Yield: 86%.

    [1043] Melting point: 150-152° C.

    [1044] .sup.1H NMR (CDCl.sub.3) δ 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).

    [1045] .sup.13C NMR (CDCl.sub.3) δ 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′)

    [1046] ##STR00153##

    [1047] 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 (2×10 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.

    [1048] Yield: 69%.

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

    [1049] ##STR00154##

    [1050] 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 (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [1051] Yield: 75%.

    [1052] Melting point: 123-125° C.

    [1053] The conformity and the purity of compound 38z″ was attested by NMR spectroscopy and elemental analysis and is reported hereafter:

    [1054] .sup.1H NMR (CDCl.sub.3) δ 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).

    [1055] .sup.13C NMR (CDCl.sub.3) δ 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).

    [1056] 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.

    [1057] 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. MIC for 38z″ (molecule 129 in WO2009/034386) together with polymyxin B nonapeptide (PMBN) provided by Sigma-aldrich #P2076-5MG was determined on Escherichia coli (ATCC 8739). Briefly, a single colony grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in the LB medium 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 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle) with or without Polymyxin B nonapeptide (PMBN) at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone. NO antibacterial activity was found against the Escherichia coli (ATCC 8739) strain when the molecule 38z″ was used at concentrations up to 100 μM together with 40 μg/ml PMBN.

    Example 2: N-benzyl-2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine (39z″)

    [1058] ##STR00155##

    [1059] We have synthesized compound 127 (39z″) reported in WO2009/034386.

    N-Benzyl-9-(2,6-difluoro-3-methylbenzyl)-2-(methylthio)-9H-purin-6-amine (39z)

    [1060] ##STR00156##

    [1061] A solution of (38b) (170.0 mg, 0.5 mmol) in acetonitrile (3 mL) was supplemented with benzylamine (0.09 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.

    [1062] Yield: 78%.

    [1063] Melting point: 164-165.5° C.

    [1064] .sup.1H NMR (DMSO-d.sub.6) δ 2.18 (s, 3H, CH.sub.3), 2.38 (s, 3H, SCH.sub.3), 4.61 (s, 2H, NHCH.sub.2), 5.37 (s, 2H, NCH.sub.2), 6.17 (bs, 1H, NHCH.sub.2), 7.02 (t, J=8.8 Hz, 1H, 5″-H), 7.20 (t, J=7.5 Hz, 1H, 4′-H), 7.27-7.33 (m, 5H, 2′-H/3′-H/5′-H/6′-H/4″-H), 8.06 (s, 1H, 8-H), 8.42 (s, 1H, NH).

    [1065] .sup.13C NMR (DMSO-d.sub.6) δ 13.5 (SCH.sub.3), 13.7 (CH.sub.3), 35.0 (NCH.sub.2), 42.9 (NHCH.sub.2), 111.0 (d, J=21 Hz, C-5″), 111.4 (t, J=19 Hz, C-1″), 116.4 (C-5), 120.5 (C-3″), 126.6 (C-4′), 127.3 (C-2′/C-6′), 128.2 (C-3′/C-5′), 131.8 (C-4″), 139.8 (C-8), 139.9 (C-1′), 149.5 (C-4), 153.6 (C-6), 158.2-159.6 (dd, J=248 Hz/7 Hz, C-2′), 158.3-159.7 (dd, J=247 Hz/7 Hz, C-6′), 164.0 (C-2).

    N-Benzyl-9-(2,6-difluoro-3-methylbenzyl)-2-(methylsulfonyl)-9H-purin-6-amine (39z′)

    [1066] ##STR00157##

    [1067] A solution of (39z) (180.0 mg, 0.41 mmol) in methylene chloride (10 mL) was cooled to 5° C. on an ice bath and supplemented with 3-chloroperbenzoic acid (155.0 mg, 0.90 mmol). After stirring at room temperature for 2 hours, the mixture was washed with a solution of NaOH 0.1 M (2×10 mL). The organic layer was dried, filtered and the solvent was evaporated to dryness under vacuum. The residue was recrystallized in a mixture of ethyl acetate and hexane.

    [1068] Yield: 65%.

    [1069] Melting point: 143-144° C.

    [1070] .sup.1H NMR (DMSO-d.sub.6) δ 2.18 (s, 3H, CH.sub.3), 3.24 (s, 3H, SO.sub.2CH.sub.3), 4.69 (d, J=6.1 Hz, 2H, NHCH.sub.2), 5.48 (s, 2H, NCH.sub.2), 6.17 (bs, 1H, NHCH.sub.2), 7.04 (t, J=8.9 Hz, 1H, 5″-H), 7.22 (t, J=7.3 Hz, 1H, 4′-H), 7.28-7.38 (m, 5H, 2′-H/3′-H/5′-H/6′-H/4″-H), 8.39 (s, 1H, 8-H), 9.10 (t, J=6.1 Hz, 1H, NH).

    [1071] .sup.13C NMR (DMSO-d.sub.6) δ 13.7 (CH.sub.3), 35.5 (NCH.sub.2), 38.9 (SO.sub.2CH.sub.3), 43.4 (NHCH.sub.2), 111.0 (C-1″), 111.1 (d, J=21 Hz, C-5″), 119.7 (C-5), 120.7 (d, J=17 Hz, C-3″), 126.9 (C-4′), 127.6 (C-2′/C-6′), 128.3 (C-3′/C-5′), 132.1 (C-4″), 139.2 (C-1′), 143.2 (C-8), 147.8 (C-4), 154.3 (C-6), 158.2-159.6 (C-2′/C-6′), 159.4 (C-2).

    N-Benzyl-2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine (39z″)

    [1072] ##STR00158##

    [1073] Sodium metal was dissolved in 1-butanol (3 mL) on an ice bath and (39z′) (150.0 mg, 0.34 mmol) was added. After stirring at room temperature for 3 hours, the mixture was partitioned between water (50 mL) and dichloromethane (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [1074] Yield: 72%.

    [1075] Melting point: 124-127.5° C.

    [1076] The conformity and the purity of compound 127 was attested by NMR spectroscopy and elemental analysis (see below):

    [1077] .sup.1H NMR (DMSO-d.sub.6) δ 0.89 (t, J=7.4 Hz, 3H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.34 (h, J=7.0 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.60 (p, J=6.9 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.18 (s, 3H, CH.sub.3), 4.14 (t, J=6.7 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.60 (d, J=4.5 Hz, 2H, NHCH.sub.2), 5.32 (s, 2H, NCH.sub.2), 7.01 (t, J=8.9 Hz, 1H, 5″-H), 7.19 (t, J=7.1 Hz, 1H, 4′-H), 7.26-7.33 (m, 5H, 2′-H/3′-H/5′-H/6′-H/4″-H), 7.96 (s, 1H, 8-H), 8.33 (t, J=5.0 Hz, 1H, NH).

    [1078] .sup.13C NMR (DMSO-d.sub.6) δ 13.7 (CH.sub.3/OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 18.7 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 30.5 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 34.8 (NCH.sub.2), 42.9 (NHCH.sub.2), 67.8 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 111.0 (d, J=21 Hz, C-5″), 111.5 (t, J=19 Hz, C-1″), 115.1 (C-5), 120.5 (d, J=18 Hz, C-3″), 126.6 (C-4′), 127.1 (C-2′/C-6′), 128.2 (C-3′/C-5′), 131.8 (C-4″), 139.3 (C-1′), 140.1 (C-8), 150.3 (C-4), 155.1 (C-6), 158.3-159.7 (C-2′/C-6′), 161.4 (C-2).

    [1079] Anal. (C.sub.24H.sub.25F.sub.2N.sub.5O) theoretical: C, 65.89; H, 5.76; N, 16.01. Found: C, 65.98; H, 6.03; N, 16.24.

    [1080] The molecule 39z″ (molecule 127 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. MIC for 39z″ (molecule 127 in WO2009/034386) together with polymyxin B nonapeptide (PMBN) provided by Sigma-aldrich #P2076-5MG was determined on Escherichia coli (ATCC 8739). Briefly, a single colony grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in the LB medium 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 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle) with or without Polymyxin B nonapeptide (PMBN) at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone. NO antibacterial activity was found against the Escherichia coli (ATCC 8739) strain when the molecule 39z″ was used at concentrations up to 100 μM together with 40 μg/ml PMBN.

    Example 3: N-benzyl-9-(2,6-difluoro-3-methylbenzyl)-2(pentyloxy)-9H-purin-6-amine (40z″)

    [1081] ##STR00159##

    [1082] We have synthesized compound 128 (40z″) reported in WO2009/034386.

    [1083] Sodium metal was dissolved in 1-pentanol (3 mL) on an ice bath and (39z′) (150.0 mg, 0.34 mmol) was added. After stirring at room temperature for 3 hours, the mixture was partitioned between water (50 mL) and dichloromethane (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [1084] Yield: 68%.

    [1085] Melting point: 112-114° C.

    [1086] The conformity and the purity of compound 128 was attested by NMR spectroscopy and elemental analysis (see below):

    [1087] .sup.1H NMR (DMSO-d.sub.6) δ 0.87 (t, J=6.6 Hz, 3H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.30 (m, 4H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3/OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.62 (m, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.18 (s, 3H, CH.sub.3), 4.14 (t, J=6.7 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.60 (d, J=4.4 Hz, 2H, NHCH.sub.2), 5.32 (s, 2H, NCH.sub.2), 7.01 (t, J=8.8 Hz, 1H, 5″-H), 7.19 (t, J=7.1 Hz, 1H, 4′-H), 7.26-7.33 (m, 5H, 2′-H/3′-H/5′-H/6′-H/4″-H), 7.96 (s, 1H, 8-H), 8.33 (t, J=5.0 Hz, 1H, NH).

    [1088] .sup.13C NMR (DMSO-d.sub.6) δ 13.7 (CH.sub.3), 13.9 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 21.9 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 27.7 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 28.2 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 34.8 (NCH.sub.2), 42.9 (NHCH.sub.2), 66.1 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 111.0 (dd, J=21 Hz/3 Hz, C-5″), 111.5 (t, J=19 Hz, C-1″), 115.1 (C-5), 120.5 (dd, J=18 Hz/3 Hz, C-3″), 126.6 (C-4′), 127.1 (C-2′/C-6′), 128.1 (C-3′/C-5′), 131.8 (C-4″), 139.3 (C-1′), 140.1 (C-8), 150.4 (C-4), 155.1 (C-6), 158.3-159.7 (C-2′/C-6′), 161.3 (C-2).

    [1089] Anal. (C.sub.25H.sub.27F.sub.2N.sub.5O) theoretical: C, 66.50; H, 6.03; N, 15.51. Found: C, 66.60; H, 6.36; N, 15.88.

    [1090] The molecule 40z″ (molecule 128 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. 40z″ (molecule 127 in WO2009/034386) together with polymyxin B nonapeptide (PMBN) provided by Sigma-aldrich #P2076-5MG was determined on Escherichia coli (ATCC 8739). Briefly, a single colony grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in the LB medium 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 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle) with or without Polymyxin B nonapeptide (PMBN) at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone. NO antibacterial activity was found against the Escherichia coli (ATCC 8739) strain when the molecule 40z″ was used at concentrations up to 100 μM together with 40 μg/ml PMBN.

    Example 4: 2-(butylthio)-N,9-bis(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine (41z″)

    [1091] ##STR00160##

    [1092] We have synthesized compound 84 (41z″) reported in WO2009/034386.

    N,9-bis(2,6-difluoro-3-methylbenzyl)-2-(methylthio)-9H-purin-6-amine (41z)

    [1093] ##STR00161##

    [1094] A solution of (38b) (170.0 mg, 0.5 mmol) in acetonitrile (3 mL) was supplemented with 2,6-difluoro-3-methylbenzylamine (0.135 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.

    [1095] Yield: 75%.

    [1096] Melting point: 151-153° C.

    [1097] .sup.1H NMR (DMSO-d.sub.6) δ 2.17 (s, 3H, CH.sub.3), 2.18 (s, 3H, CH.sub.3), 2.40 (s, 3H, SCH.sub.3), 4.65 (bs, 2H, NHCH.sub.2), 5.37 (s, 2H, NCH.sub.2), 6.93 (t, J=8.8 Hz, 1H, 5′-H), 7.01 (t, J=8.8 Hz, 1H, 5″-H), 7.21 (m, 1H, 4′-H), 7.31 (m, 1H, 4″-H), 8.04 (s, 1H, 8-H), 8.22 (bs, 1H, NH).

    [1098] .sup.13C NMR (DMSO-d.sub.6) δ 13.3 (SCH.sub.3), 13.7 (CH.sub.3), 13.8 (CH.sub.3), 32.2 (NHCH.sub.2), 35.1 (NCH.sub.2), 110.6 (d, J=21 Hz, C-5′), 111.0 (dd, J=21 Hz/3 Hz, C-5″), 111.4 (t, J=19 Hz, C-1″), 113.9 (t, J=17 Hz, C-1′), 116.4 (C-5), 120.0 (dd, J=18 Hz/4 Hz, C-3′), 120.5 (dd, J=17 Hz/3 Hz, C-3″), 130.4 (C-4′), 131.8 (C-4″), 139.8 (C-8), 149.5 (C-4), 153.2 (C-6), 158.3-159.7 (C-6′/C-6″), 158.6-160.0 (C-2′/C-2″), 164.0 (C-2).

    N,9-bis(2,6-difluoro-3-methylbenzyl)-2-(methylsulfonyl)-9H-purin-6-amine (41z′)

    [1099] ##STR00162##

    [1100] A solution of (39z) (180.0 mg, 0.39 mmol) in methylene chloride (10 mL) was cooled to 5° C. on an ice bath and supplemented with 3-chloroperbenzoic acid (155.0 mg, 0.90 mmol). After stirring at room temperature for 2 hours, the mixture was washed with a solution of NaOH 0.1 M (2×10 mL). The organic layer was dried, filtered and the solvent was evaporated to dryness under vacuum. The residue was recrystallized in a mixture of ethyl acetate and hexane.

    [1101] Yield: 72%.

    [1102] Melting point: 183-185° C.

    [1103] .sup.1H NMR (DMSO-d.sub.6) δ 2.17 (s, 3H, CH.sub.3), 2.18 (s, 3H, CH.sub.3), 3.28 (s, 3H, SO.sub.2CH.sub.3), 4.74 (d, J=4.9 Hz, 2H, NHCH.sub.2), 5.48 (s, 2H, NCH.sub.2), 6.95 (t, J=8.8 Hz, 1H, 5′-H), 7.04 (t, J=8.8 Hz, 1H, 5″-H), 7.23 (m, 1H, 4′-H), 7.33 (m, 1H, 4″-H), 8.37 (s, 1H, 8-H), 8.97 (t, J=4.3 Hz, 1H, NH).

    [1104] .sup.13C NMR (DMSO-d.sub.6) δ 13.7 (CH.sub.3), 13.8 (CH.sub.3), 32.5 (NHCH.sub.2), 35.5 (NCH.sub.2), 38.8 (SO.sub.2CH.sub.3), 110.7 (dd, J=22 Hz/3 Hz, C-5′), 110.9 (t, J=19 Hz, C-1″), 111.1 (dd, J=21 Hz/4 Hz, C-5″), 113.3 (t, J=20 Hz, C-1′), 119.7 (C-5), 120.1 (dd, J=19 Hz/5 Hz, C-3′), 120.7 (dd, J=17 Hz/3 Hz, C-3″), 130.6 (t, J=8 Hz, C-4′), 132.2 (t, J=8 Hz, C-4″), 143.2 (C-8), 147.9 (C-4), 154.0 (C-6), 158.2-159.6 (dd, J=249 Hz/7 Hz, C-6′/C-6″), 158.5-159.9 (dd, J=247 Hz/9 Hz, C-2′/C-2″), 159.3 (C-2).

    2-(Butylthio)-N,9-bis(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine (41z″)

    [1105] ##STR00163##

    [1106] A solution of (41z′) (150.0 mg, 0.30 mmol) in acetonitrile (3 mL) was supplemented with K.sub.2CO.sub.3 (100 mg, 0.72 mmol) and butanethiol (0.08 mL, 0.75 mmol). After stirring at 100° C. for 4 hours in a sealed vessel, the mixture was evaporated and partitioned between water (50 mL) and dichloromethane (2×50 mL). The combined organic layers were dried and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography.

    [1107] Yield: 65%.

    [1108] Melting point: 127.5-129.5° C.

    [1109] The conformity and the purity of compound 84 was attested by NMR spectroscopy and elemental analysis (see below):

    [1110] .sup.1H NMR (DMSO-d.sub.6) δ 0.89 (t, J=7.4 Hz, 3H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (h, J=7.4 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.59 (p, J=7.4 Hz, 2H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.17 (s, 3H, CH.sub.3), 2.18 (s, 3H, CH.sub.3), 3.03 (t, J=7.2 Hz, 2H, SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 4.65 (s, 2H, NHCH.sub.2), 5.37 (s, 2H, NCH.sub.2), 6.93 (t, J=8.8 Hz, 1H, 5′-H), 7.01 (t, J=8.8 Hz, 1H, 5″-H), 7.21 (m, 1H, 4′-H), 7.31 (m, 1H, 4″-H), 8.03 (s, 1H, 8-H), 8.19 (bs, J=4.3 Hz, 1H, NH).

    [1111] .sup.13C NMR (DMSO-d.sub.6) δ 13.6 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 13.7 (CH.sub.3), 13.8 (CH.sub.3), 21.4 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 29.7 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 31.3 (SCH.sub.2CH.sub.2CH.sub.2CH.sub.3), 32.2 (NHCH.sub.2), 35.0 (NCH.sub.2), 110.6 (dd, J=23 Hz/3 Hz, C-5′), 111.0 (dd, J=21 Hz/3 Hz, C-5″), 111.5 (t, J=19 Hz, C-1″), 113.8 (C-1′), 120.0 (C-5/C-3′), 120.5 (dd, J=18 Hz/3 Hz, C-3″), 130.4 (C-4′), 131.8 (C-4″), 139.8 (C-8), 149.5 (C-4), 153.3 (C-6), 158.2-159.6 (C-6′/C-6″), 158.6-160.0 (C-2′/C-2″), 163.6 (C-2).

    [1112] Anal. (C.sub.25H.sub.25F.sub.4N.sub.5S) theoretical: C, 59.63; H, 5.00; N, 13.91; S, 6.37. Found: C, 59.46; H, 5.12; N, 13.92; S, 6.11.

    [1113] The molecule 41z″ (molecule 84 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. 41z″ (molecule 84 in WO2009/034386) together with polymyxin B nonapeptide (PMBN) provided by Sigma-aldrich #P2076-5MG, was determined on Escherichia coli (ATCC 8739). Briefly, a single colony grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in the LB medium 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 1h30 (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle) with or without Polymyxin B nonapeptide (PMBN) at 40 μg/ml. 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. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone. NO antibacterial activity was found against the Escherichia coli (ATCC 8739) strain when the molecule 41z″ was used at concentrations up to 100 μM together with 40 μg/ml PMBN.

    Example 5. Time-Kill Experiments: Comparison of Pyrimidine Derivatives According to the Present Invention with Ampicillin as Bactericidal Antibiotic Against E. coli

    [1114] To evaluate the bactericidal effect of the molecules 2329 and 2666 on Gram-negative bacteria, we exposed an inoculum of 1×10.sup.8 CFU/ml E. coli (ATCC 8739) to 5 times the MIC of one or the other molecule in combination with 50 μg/ml PMBN in Luria-Bertani (LB) medium. E. coli were grown for 240 min at 37° C. with 220 rpm shaking.

    [1115] An aliquot of the culture was taken before the addition of the tested molecules and after 30, 90, 150 and 240 min of incubation.

    [1116] The diluted culture aliquot was spread on a LB agar plate to evaluate the number of CFU at each time point. These numbers are represented as Log (c.f.u. E. coli per ml) in FIG. 3 which illustrates the antibacterial effect of the tested molecules.

    [1117] The antibacterial effect of the molecules was also compared to 100 μg/ml Ampicillin (AMP) provided by Sigma-aldrich #A0166-5G. The antibacterial effect of the pyrimidine derivatives 2329 and 2666 combined with Polymyxin B nonapeptide (called P in FIG. 3) on Escherichia coli (ATCC8739) is surprisingly similar to Ampicillin.

    Example 6: Optimization of PMBN Concentration to be Used in Combination with Pyrimidine Derivatives Against Escherichia coli

    [1118] Each of the following molecules synthetised as described in the specification (2329, 2666, 2461, 2511, 2525, 2539) was tested in combination with 5, 10, 20, 30, 35, 40, 50 g/ml PMBN provided by Sigma-Aldrich #P2076-5MG and according to the following protocol. 1% DMSO is used as vehicle.

    [1119] A single colony of Escherichia coli (ATCC 8739) grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in the LB medium 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 1.5 hours (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle) with 40 μg/ml PMBN. After O/N growth the OD of each culture was measured at 600 nm (OD.sub.600 nm) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone.

    [1120] The best minimum range of PMBN concentration to get an effect against Escherichia coli is 35 to 40 μg/ml. The latter 40 g/ml will be further used in example 7.

    Example 7: Comparison of Pyrimidine Derivatives According to the Present Invention with Purines Disclosed in WO2009/034386

    [1121] Each of the following molecules (38z″, 39z″, 40z″, 41z″) synthetized as described in examples 1 to 4 was tested again for its potential antibacterial activity against Escherichia coli (ATCC 8739) in presence of polymyxin B nonapeptide (PMBN), provided by Sigma-aldrich #P2076-5MG, by determining an eventual minimal inhibitory concentration (MIC) according to protocols recommended by EUCAST to assess the efficacy of antibiotics against bacterial strains. In these experiments, the antibacterial activity of these molecules combined with PMBN was compared to the antibacterial activity of our molecules 2329, 2666, 2461, 2511, 2525, 2539 combined with PMBN according to the following protocol.

    [1122] A single colony of Escherichia coli (ATCC 8739) grown on a Luria-Bertani Agar (LB) plate was resuspended and cultured in the LB medium 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 1.5 hours (OD=0.08-0.1) and an inoculum of 1:300 dilution, corresponding to 3×10.sup.6 CFU/ml, was incubated in presence or absence of different concentrations of the molecules in 1% DMSO (vehicle) with PMBN at 40 μg/ml in DMSO. After O/N growth the OD of each culture was measured at 600 nm (OD.sub.600 nm) in a spectrophotometer (Victor 3-Perkin Elmer). The MIC represents the concentration at which there is no visible growth of bacteria, i.e. ΔOD at 600 nm equal to zero wherein ΔOD is the difference between the resulting optical density (OD) with the molecule together with PMBN, and the optical density (OD) of the blank (blank is the medium) alone. In sharp contrast with our molecules 2329, 2666, 2461, 2511, 2525, 2539 (FIG. 4), no antibacterial activity was found against Escherichia coli (ATCC 8739) when any of the molecules 38z″, 39z″, 40z″ or 41z″ were used at concentrations up to 100 μM in presence of PMBN at 40 μg/ml.

    [1123] The results are displayed in FIG. 4, which represents the OD.sub.600 nm values obtained after O/N growth of Escherichia coli (ATCC 8739) in presence of 1% DMSO vehicle (Ctrl) or the indicated concentrations of tested molecules combined with 40 g/ml PMBN. The OD.sub.600 nm value obtained in presence of molecules 38z″, 39z″, 40z″ or 41z″ did not differ from vehicle control (DMSO), indicating that none of the four molecules reported in WO2009/034386 shows antibacterial activity against Escherichia coli (ATCC 8739) when used at 100 μM together with 40 μg/ml PMBN. In contrast, the OD.sub.600 nm values obtained in presence of molecules 2329 (10 μM), 2666 (20 μM), 2461 (20 μM), 2511 (50 μM), 2525 (50 μM) or 2539 (50 μM) with 40 μg/ml PMBN were much lower than that of vehicle control (Ctrl), and reached levels corresponding to MHB growth medium without bacteria (Medium), indicating that molecules 2329, 2666, 2461, 2511, 2525 or 2539 with 40 μg/ml PMBN killed all bacteria.

    [1124] We therefore demonstrate that molecules 2329, 2666, 2461, 2511, 2525 or 2539 with 40 g/ml PMBN have bactericidal activity against Escherichia coli (ATCC 8739), while molecules 38z″, 39z″, 40z″ and 41z″ with 10 to 50 g/ml PMBN, particularly 40 μg/ml have no antibacterial activity.

    [1125] We conclude that a phenyl unit on a cyclopropyl group in the pyrimidine derivative according to the invention, which is lacking in the purine 38z″, 39z″, 40z″ and 41z″ disclosed in WO2009/034386 play an essential role in antibacterial activity.