HETEROAROMATIC ANALOGUES OF 3-BENZYLMENADIONE DERIVATIVES AND PROCESSES FOR THEIR PREPARATION

Abstract

A compound having the formula (I):

##STR00001##

wherein: R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl; and R.sup.2 is an optionally substituted heteroaryl group, as well as processes for the preparation of the compound, and intermediate compounds.

Claims

1-15. (canceled)

16. A compound having the formula (I): ##STR00162## wherein: R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl; and R.sup.2 is a heteroaryl group, said heteroaryl group being different from the following heteroaryl groups: ##STR00163## provided that the compound of formula (I) is different from the following compound: ##STR00164##

17. The compound according to claim 16, wherein the heteroaryl group is substituted with at least one substituent selected from the group consisting of: halogen, halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CN, (C.sub.1-C.sub.6)alkyl, NO.sub.2, NR.sub.aR.sub.b, R.sub.a and R.sub.b, identical or different, being independently H or a (C.sub.1-C.sub.6)alkyl, such as NH.sub.2, (C.sub.2-C.sub.6)alkynyl, such as C?C, OR, R.sub.c being a cycloheteroalkyl, preferably an oxetanyl group, SF.sub.3, SF.sub.5, C(?O)(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, and (C1-C6)alkoxy.

18. The compound according to claim 16, wherein R.sup.2 is a heteroaryl group comprising a 5- to 10-membered aromatic monocyclic or bicyclic group containing from 1 to 4 heteroatoms selected from O, S or N.

19. The compound according to claim 16, wherein R.sup.1 is H or F and/or R.sup.2 is selected from the group consisting of: pyridinyl other than ##STR00165## pyrimidinyl other than ##STR00166## quinolinyl, thiophenyl, and furanyl groups.

20. The compound according to claim 19, wherein R.sup.2 is selected from the group consisting of: pyridinyl other than ##STR00167## pyrimidinyl other than ##STR00168## quinolinyl, thiophenyl, and furanyl groups, said groups being substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, C?C, and CN.

21. The compound according to claim 16, being selected from the following compounds: ##STR00169## ##STR00170##

22. A process for the preparation of a compound having the formula (1): ##STR00171## wherein: R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl; and R.sup.2 is a heteroaryl group, said heteroaryl group being different from the following heteroaryl groups: ##STR00172## said process comprising the preparation of a compound having the following formula (IV): wherein: ##STR00173## R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl; and X is Cl or Br, by the chloromethylation or bromomethylation of a compound having the following formula (V): ##STR00174## wherein R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl.

23. The process according to claim 22, wherein the heteroaryl group is substituted with at least one substituent selected from the group consisting of: halogen, halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CN, (C.sub.1-C.sub.6)alkyl, NR.sub.aR.sub.b, R.sub.a and R.sub.b, identical or different, being independently H or a (C.sub.1-C.sub.6)alkyl, such as NH.sub.2, (C.sub.2-C.sub.6)alkynyl, such as C?C, OR, R being a cycloheteroalkyl, preferably an oxetanyl group, NO.sub.2, SF.sub.3, SF.sub.5, C(?O)(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)alkoxy.

24. The process according to claim 22, wherein the chloromethylation or bromomethylation step is carried out with a mixture of hydrochloric acid or hydrobromic acid with paraformaldehyde in the presence of a solvent selected from the group consisting of: water, acetic acid, and dioxane.

25. The process according to claim 22, further comprising the pallado-catalyzed Suzuki coupling of the compound of formula (IV) with a boronic acid compound having the formula (III) or (III): ##STR00175## wherein R.sup.2 is selected from the group consisting of: pyridinyl other than ##STR00176## pyrimidinyl other than ##STR00177## quinolinyl, thiophenyl, and furanyl groups in order to obtain a compound having the following formula (II): ##STR00178## wherein R.sup.1 is H or F and/or R.sup.2 is selected from the group consisting of: pyridinyl other than ##STR00179## pyrimidinyl other than ##STR00180## quinolinyl, thiophenyl, and furanyl groups.

26. The process according to claim 25, wherein the pallado-catalyzed coupling is carried out with a palladium catalyst selected from the group consisting of: Pd(PPh.sub.3).sub.4, PdCl.sub.2, PdCl.sub.2(dppf), Pd(OAc).sub.2 and PPh.sub.3, and with a base selected from the group consisting of: Na.sub.2CO.sub.3, K.sub.2CO.sub.3, KOtBu, Cs.sub.2CO.sub.3, NaOH, and NEt.sub.3, or with K.sub.3PO.sub.4 in toluene.

27. The process according to claim 25, further comprising an oxidative demethylation step of the compound of formula (II) in the presence of an oxidant, in order to obtain the compound of formula (1).

28. The process according to claim 27, wherein the oxidant is selected from the group consisting of: ceric ammonium nitrate, silver oxide (AgO/Ag.sub.2O), OsO.sub.4/NalO.sub.4, oxone, BBr.sub.3 with O.sub.2 or open air, and boron trichloride/tetra-n-butylammonium iodide (BCl.sub.3/TBAI) with O.sub.2 or open air.

29. The process according to claim 22, wherein the compound of formula (V) is prepared by reacting a compound having the following formula (VI): ##STR00181## wherein R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl, with a reducing agent, in particular being SnCl.sub.2 and HCl, or sodium dithionite, followed by a methylation step, in order to obtain the compound of formula (V).

30. The process according to claim 22, wherein R.sup.2 is selected from the group consisting of: pyridinyl other than ##STR00182## pyrimidinyl other than ##STR00183## quinolinyl, thiophenyl, and furanyl groups.

31. The process according to claim 30, wherein R.sup.2 is selected from the group consisting of: pyridinyl other than ##STR00184## pyrimidinyl other than ##STR00185## quinolinyl, thiophenyl, and furanyl groups, said groups being substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, C?C, and CN.

32. A compound having the following formula (II): ##STR00186## wherein: R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl; and R.sup.2 is a heteroaryl group, said heteroaryl group being different from the following heteroaryl groups: ##STR00187## provided that the compound of formula (II) is different from the following compound: ##STR00188##

33. The compound according to claim 32, wherein the heteroaryl group is substituted with at least one substituent selected from the group consisting of: halogen, halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CN, (C.sub.1-C.sub.6)alkyl, NR.sub.aR.sub.b, R.sub.a and R.sub.b, identical or different, being independently H or a (C.sub.1-C.sub.6)alkyl, such as NH.sub.2, (C.sub.2-C.sub.6)alkynyl, such as C?C, OR, R.sub.c being a cycloheteroalkyl, preferably an oxetanyl group, NO.sub.2, SF.sub.3, SF.sub.5, C(?O)(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)alkoxy.

34. A compound having the following formula (IV): ##STR00189## wherein R.sup.1 is selected from the group consisting of: H, F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl, provided that the compound of formula (IV) is different from the following compounds: ##STR00190##

35. A compound having the following formula (V): ##STR00191## wherein R.sup.1 is selected from the group consisting of: F, (C.sub.1-C.sub.6)alkoxy, and halo(C.sub.1-C.sub.6)alkyl.

Description

EXAMPLES

[0146] Heteroarylboronic acids and reactants were purchased from commercial sources, such as Fluorochem, Sigma-Aldrich and Alfa Aesar. 1,4-dimethoxy-2-methylnaphthalene and 6-fluoro-1,4-dimethoxy-2-methylnaphthalene were synthetized according to a previously published method (T. Mller, L. Johann, B. Jannack, M. Bruckner, D. A. Lanfranchi, H. Bauer, C. Sanchez, V. Yardleyll, C. Deregnaucourt, J. Schrevel, M. Lanzer, R. H. Schirmer, E. Davioud-Charvet, J. Am. Chem. Soc. 2011, 133, 30, 11557-11571). The 6-fluoro-1,4-dimethoxy-2-methylnaphthalene was synthesized from the 6-fluoro-menadione, prepared according to Cesar Rodo E., Feng L., Jida, M., Ehrhardt K., Bielitza M., Boilevin J., Lanzer M., Williams D. L., Lanfranchi, D. A., Davioud-Charvet, E. A platform of regioselective methodologies to access to polysubstituted 2-methyl-1,4-naphthoquinones derivatives: scope and limitations. Eur. J. Org. Chem. 2016, 11, 1982-1993. doi: 10.1002/ejoc.201600144.

[0147] The compounds of formula (1) according to the invention are prepared according to the following general scheme:

##STR00031##

Preparation of Compounds of Formula (II) (by Suzuki Reaction Between 2-Methyl-3-Chloromethyl-1,4,-Dimethoxynaphtalene and Boronic Acids of Formula (III))

[0148] The compounds of formula (II) wherein R.sup.1?H are prepared according to the following reaction scheme:

##STR00032##

Synthesis of 2-(Chloromethyl)-1,4-dimethoxy-3-methylnaphthalene

[0149] ##STR00033##

1,4-dimethoxy-2-methylnaphthalene (1 equiv., 4 g, 19.8 mmol), paraformaldehyde (5 equiv., 3.13 g, 2.89 mL, 98.9 mmol) and 37% C, aqueous HCl (50 mL) were heated at 80? C. during 2 h. The OMe mixture was cooled down, diluted with water and extracted three times with EtOAc. The reunited organic layers were washed with brine, dried over MgSO.sub.4 and the solvent was removed under reduced pressure. The crude oil was purified by silica gel chromatography using 8:2 Cyclohexane:Toluene as eluant system to afford 4.086 g (81% yield) of 2-(chloromethyl)-1,4-dimethoxy-3-methylnaphthalene as a colorless oil which crystallized on standing. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.17-8.00 (m, 2H), 7.64-7.41 (m, 2H), 4.92 (s, 2H), 4.04 (s, 3H), 3.89 (s, 3H), 2.54 (s, 3H).

General procedure for the Suzuki coupling between 2-(chloromethyl)-1,4-dimethoxy-3-methylnaphthalene and heteroarylboronic acid

[0150] In a sealable tube, 2-(chloromethyl)-1,4-dimethoxy-3-methylnaphthalene (1 equiv), the corresponding heteroarylboronic acid (1.2 equiv) and sodium carbonate (2.1 equiv) were dissolved in a 2:1 mixture of dimethoxyethane:water (0.15M). The mixture was bubbled 30 min with argon, and then tetrakis(triphenylphosphine)palladium (2-5 mol %) was added at once. The tube was sealed and the mixture was heated 1 h at 100? C. under stirring. The mixture was then, allowed to cool down to room temperature, diluted with water and extracted three times with ethyl acetate. Reunited organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure to afford a crude, which was purified on silica gel chromatography using the adequate eluant system to afford the corresponding coupling product.

TABLE-US-00001 Boronic acid of formula (III) Compound of formula (II) Yield [00034] [00035] 97% [00036] [00037] 71% [00038] [00039] 87% [00040] [00041] 97% [00042] [00043] 85% [00044] [00045] 87% [00046] [00047] 97% [00048] [00049] 71% [00050] [00051] 69% [00052] [00053] 75% [00054] [00055] 100%

Preparation of 3-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) quinoline (21)

[0151] ##STR00056##

5 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (7:3), yellowish solid, 97% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.92 (d, J=2.3 Hz, 1H), 8.17-8.10 (m, 2H), 8.07 (dd, J=8.4, 1.0 Hz, 1H), 7.69-7.59 (m, 3H), 7.58-7.50 (m, 2H), 7.46 (ddd, J=8.1, 6.7, 1.2 Hz, 1H), 4.44 (s, 2H), 3.87 (s, 6H), 2.29 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 151.95, 150.90, 150.77, 146.96, 133.87, 133.49, 129.24, 128.85, 128.36, 128.30, 127.90, 127.58, 127.38, 126.73, 126.19, 125.81, 122.69, 122.46, 62.58, 61.61, 30.50, 12.89. HRMS (ESI) calcd. for C.sub.23H.sub.22NO.sub.2: 344.1645. Found: 344.1659 (MH.sup.+).

Preparation of 3-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) pyridine (21)

[0152] ##STR00057##

5 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (1:1), yellowish solid, 71% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.50N (dd, J=2.3, 1.0 Hz, 1H), 8.41 (dd, J=4.8, 1.6 Hz, 1H), 8.12-8.04 (m, 2H), 7.63-7.42 (m, 2H), 7.39-7.32 (m, 1H), 7.13 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 4.25 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.26 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 150.75, 150.70, 149.92, 147.50, 136.08, 135.67, 128.28, 128.00, 127.30, 126.64, 126.12, 125.77, 123.55, 122.60, 122.43, 62.45, 61.58, 30.28, 12.83. HRMS (ESI) calcd. for C.sub.19H.sub.20NO.sub.2: 294.1489. Found: 294.1490 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) pyrimidine (22)

[0153] ##STR00058##

5 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (1:1), N beige solid, 87% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 9.04 (s, IN 1H), 8.54 (s, 2H), 8.13-7.98 (m, 2H), 7.61-7.41 (m, 2H), 4.22 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.29 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 156.91, 156.77, 150.91, 150.80, 133.90, 128.49, 127.29, 126.68, 126.40, 125.99, 122.62, 122.52, 62.46, 61.66, 28.10, 12.92. HRMS (ESI) calcd. for C.sub.18H.sub.19N.sub.2O.sub.2: 295.1441. Found: 295.1450 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(trifluoromethyl)pyridine (23)

[0154] ##STR00059##

5 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (9:1), translucid oil, 97% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.64 (d, J=1.4 Hz, 1H), 8.16-8.04 (m, 2H), 7.61-7.46 (m, 4H), 4.31 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.26 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 150.81, 150.77, 150.08, 145.99 (q, J=34.6 Hz), 139.66, 136.79, 128.42, 127.24, 127.05, 126.29, 126.17, 125.88, 122.55, 121.78 (q, J=273.7 Hz), 120.31 (q, J=2.7 Hz), 62.33, 61.50, 30.13, 12.77. .sup.19F NMR (471 MHz, CDCl.sub.3) ??67.68. HRMS (ESI) calcd. for C.sub.20H.sub.19F.sub.3NO.sub.2: 362.1362. Found: 362.1368 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-fluoropyridine (24)

[0155] ##STR00060##

2 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (9:1), white solid, 89% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.94-7.70 (m, 3H), 7.40-7.19 (m, 3H), 6.54 (ddd, J=8.4, 3.1, 0.6 Hz, 1H), 3.98 (s, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.03 (s, 3H). .sup.19F NMR (377 MHz, CDCl.sub.3) ??72.09 (d, J=8.0 Hz). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 162.42 (d, J=237.2 Hz), 150.78, 150.65, 146.98 (d, J=14.4 Hz), 141.02 (d, J=7.6 Hz), 133.65 (d, J=4.5 Hz), 128.33, 127.92, 127.29, 126.39, 126.21, 125.84, 122.59, 122.46, 109.33 (d, J=37.4 Hz), 62.43, 61.58, 29.38 (d, J=1.5 Hz), 12.78. HRMS (ESI) calcd. for C.sub.19H.sub.19FNO.sub.2: 312.1394. Found: 312.1403 (MH.sup.+).

Preparation of 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyridine (25)

[0156] ##STR00061##

5 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (9:1), white solid, 87% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.19 (dd, J=2.6, 0.8 Hz, 1H), 8.07-7.91 (m, 2H), 7.51-7.38 (m, 2H), 7.26 (dd, J=8.2, 2.5 Hz, 1H), 7.08 (dd, J=8.2, 0.7 Hz, 1H), 4.13 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 2.18 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 150.80, 150.72, 149.55, 149.22, 138.71, 135.12, 128.38, 127.56, 127.28, 126.34, 126.27, 125.88, 124.18, 122.60, 122.48, 62.46, 61.60, 29.57, 12.82. HRMS (ESI) calcd. for C.sub.19H.sub.19ClNO.sub.2: 328.1099. Found: 328.1102 (MH.sup.+).

Preparation of 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (26)

[0157] ##STR00062##

2 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (8:2), white solid, 97% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.43 (s, 2H), 8.13-8.00 (m, 2H), 7.61-7.43 (m, 2H), 4.18 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 159.40, 150.96, 150.73, 132.58, 128.54, 127.23, 126.50, 126.22, 126.05, 125.67, 122.59, 122.52, 62.42, 61.63, 27.32, 12.90. HRMS (ESI) calcd. for C.sub.18H.sub.18ClN.sub.2O.sub.2: 329.1051. Found: 329.1054 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(trifluoromethyl)pyrimidine (27)

[0158] ##STR00063##

2 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (8:2), white solid, 71% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.70 (s, 2H), 8.23-7.97 (m, 2H), 7.68-7.33 (m, 2H), 4.28 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H). .sup.19F NMR (377 MHz, CDCl.sub.3) ??70.15. HRMS (ESI) calcd. for C.sub.17H.sub.12F.sub.3N.sub.2O.sub.2: 333.0845. Found: 333.0868 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-methoxypyridine (28)

[0159] ##STR00064##

2 mol % Pd(PPh.sub.3).sub.4, Eluant Cyclohexane:Ethyl acetate (95:5), translucid oil, 69% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.14-8.04 (m, 2H), 8.02-7.94 (m, 1H), 7.58-7.44 (m, 2H), 7.32 (dd, J=8.5, 2.6 Hz, 1H), 6.61 (dd, J=8.6, 0.7 Hz, 1H), 4.16 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.85 (s, 3H), 2.28 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 162.80, 150.63, 150.59, 146.04, 138.87, 128.68, 128.57, 128.16, 127.33, 126.73, 125.98, 125.67, 122.57, 122.39, 110.72, 62.43, 61.55, 53.41, 29.37, 12.75. HRMS (ESI) calcd. for C.sub.20H.sub.22NO.sub.3: 324.1594. Found: 324.1617 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(methoxy)pyrimidine (29)

[0160] ##STR00065##

2 mol % Pd(PPh.sub.3).sub.4, Eluant Cyclohexane:Ethyl acetate (60:40), translucid oil, 71% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.31 (s, 2H), 8.18-7.95 (m, 2H), 7.60-7.44 (m, 2H), 4.13 (s, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.30 (s, 3H). HRMS (ESI) calcd. for C.sub.19H.sub.20N.sub.2NaO.sub.3: 347.1366. Found: 347.1357 (MNa.sup.+).

Preparation of 2-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)furan (30)

[0161] ##STR00066##

2 mol % Pd(PPh.sub.3).sub.4, Eluant Cyclohexane:Ethyl acetate (99:1 up to 98:2), translucid oil, 99% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.19-8.03 (m, 2H), 7.62-7.46 (m, 2H), 7.34 (dd, J=1.8, 0.9 Hz, 1H), 6.27 (dd, J=3.2, 1.9 Hz, 1H), 5.85 (dq, J=3.2, 1.1 Hz, 1H), 4.27 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.41 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 154.30, 150.68, 150.37, 141.15, 128.18, 127.29, 127.06, 126.87, 125.98, 125.54, 122.62, 122.31, 110.37, 105.90, 62.63, 61.46, 26.34, 12.45. HRMS (ESI) calcd. for C.sub.18H.sub.19O.sub.3: 283.1329. Found: 283.1334 (MH.sup.+).

Post-Modifications of Suzuki Coupling Products

[0162] ##STR00067##

Preparation of 5-((1,4-dimeth oxy-3-methylnaphthalen-2-yl)methyl) pyrimidine-2-carbonitrile (32)

[0163] ##STR00068##

[0164] To a solution of sodium cyanide (2 equiv., 44.7 mg, 0.912 mmol) and DABCO (0.2 equiv., 10.8 mg, 0.0912 mmol), in a mixture of DMSO (1.5 mL) and water (0.2 mL), 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (1 eq., 150 mg, 0.456 mmol) in DMSO (1.5 mL) was added dropwise and the reaction mixture was stirred at 50? C. 20 h. After TLC analysis showed complete conversion, the mixture was allowed to cool down to room temperature and was extracted twice with diethyl ether. The reunited organic layers were washed with brine, dried over MgSO.sub.4 and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography was performed using 75:25 Cyclohexane:Ethyl Acetate as eluant system to afford 122 mg (84% yield) of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine-2-carbonitrile as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.64 (s, 2H), 8.16-7.97 (m, 2H), 7.63-7.43 (m, 2H), 4.27 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 2.29 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 157.79, 151.07, 150.80, 143.08, 137.17, 128.69, 127.21, 126.68, 126.19, 125.51, 125.46, 122.60, 122.58, 115.87, 62.40, 61.68, 28.33, 12.98. HRMS (ESI) calcd. for C.sub.17H.sub.12N.sub.3O.sub.2: 290.0924. Found: 290.0918 (MH.sup.+).

Preparation of 2-bromo-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (33)

[0165] ##STR00069##

To a solution of 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (1 equiv., 150 mg, 0.456 mmol) in propionitrile (1.5 mL) was added trimethylbromosilane (2 equiv., 139 mg, 0.12 mL, 0.912 mmol). A white precipitate appeared. The mixture was heated at reflux 5 h and allowed to cool down to room temperature. The mixture was treated with an aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted three times with ethyl acetate, the reunited organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography was performed using 95:5 Toluene:Ethyl Acetate as eluant system to afford 160 mg (94% yield) of 2-bromo-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine as a translucid solid. m.p: 99-100? C. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.37 (s, 2H), 8.11-7.98 (m, 2H), 7.65-7.47 (m, 2H), 4.16 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 159.33, 150.97, 150.80, 150.74, 133.07, 128.55, 127.23, 126.52, 126.13, 126.07, 125.67, 122.61, 122.54, 62.44, 61.66, 27.39, 12.92. HRMS (ESI) calcd. for C.sub.16H.sub.12BrN.sub.2O.sub.2: 343.0077. Found: 343.0099 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) pyrimidin-2-amine (57)

[0166] ##STR00070##

2 mol % Pd(PPh.sub.3), Eluant Cyclohexane:Ethyl acetate (8/2), white solid, 80% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.04-8.00 (m, 2H), 7.99 (s, 2H), 7.57-7.51 (m, 2H), 6.45 (s, 2H), 3.97 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.26 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 162.7, 157.8 (2C), 150.34, 150.30, 129.1, 127.8, 127.1, 126.7, 126.5, 126.3, 122.7, 122.5, 121.5, 62.6, 61.6, 26.8, 12.9. HRMS (ESI+) calcd. for C.sub.18H.sub.20N.sub.3O.sub.2: 310.1550. Found: 310.1539 (MH.sup.+). M. p.=198-200? C.

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl) methyl)-2-(trifluoromethyl)pyridine (58)

[0167] ##STR00071##

2 mol % Pd(PPh.sub.3), Eluant cyclohexane/ethyl acetate (8/2) then pentane/diethyl ether (gradient from 9/1 to 0/1), colourless oil, 55% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.62 (s, 1H), 8.09 (dd, J=9.2, 5.6 Hz, 1H), 7.66 (dd, J=10.3, 2.5 Hz, 1H), 7.53 (d, J=1.4 Hz, 2H), 7.28 (ddd, J=9.2, 8.3, 2.6 Hz, 1H), 4.30 (s, 2H), 3.84 (s, 6H), 2.24 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 162.4, 159.9, 151.0 (d, .sup.5J.sub.C-F=1.3 Hz), 150.3 (d, .sup.4J.sub.C-F=5.4 Hz), 150.1, 146.2 (q, .sup.2J.sub.C-F=34.7 Hz), 140.0-138.9 (m), 136.8, 128.6, 128.3 (d, .sup.3J.sub.C-F=8.6 Hz), 125.5 (d, .sup.3J.sub.C-F=7.2 Hz), 125.4 (d, .sup.3J.sub.C-F=9.0 Hz), 121.8 (q, .sup.1J.sub.C-F=273.7 Hz), 120.4 (q, .sup.4J.sub.C-F=2.7 Hz), 116.6 (d, .sup.2J.sub.C-F=25.4 Hz), 106.4 (d, .sup.2J.sub.C-F=22.4 Hz), 62.3, 61.7, 30.3, 12.7. .sup.19F NMR (377 MHz, CDCl.sub.3): ??67.71, ?114.25 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS (ESI+) calcd. for C.sub.20H.sub.18F.sub.4NO.sub.2: 380.126818. Found: 380.125589 (MH.sup.+).

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl) methyl)benzo[d]thiazole (59)

[0168] ##STR00072##

2 mol % Pd(PPh.sub.3), Eluant cyclohexane/ethyl acetate (7/3) then pentane/diethyl ether (7/3), colourless oil, 83% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.97 (s, 1H), 8.10 (dd, J=9.2, 5.6 Hz, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.70 (dd, J=10.4, 2.5 Hz, 1H), 7.34-7.25 (m, 2H), 4.43 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 161.0 (d, .sup.1J.sub.C-F=245.2 Hz), 150.8 (d, .sup.5J.sub.C-F=1.1 Hz), 150.2 (d, .sup.4J.sub.C-F=5.3 Hz), 139.0, 130.3, 128.4, 128.3, 126.4 (2C), 126.2 (d, .sup.4J.sub.C-F=2.4 Hz), 125.23, 125.17 (d, .sup.3J.sub.C-F=8.9 Hz), 122.7, 121.7 (2C), 116.1 (d, .sup.2J.sub.C-F=25.4 Hz), 106.3 (d, .sup.2J.sub.C-F=22.3 Hz), 62.3, 61.6, 32.8, 12.7. .sup.19F NMR (377 MHz, CDCl.sub.3): ?-114.78 (ddd, J=10.2, 8.5, 5.7 Hz). HRMS (ESI+) calcd. for C.sub.21H.sub.19FNO.sub.2S: 368.111504. Found: 368.110660 (MH.sup.+).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) benzo[d]thiazole (60)

[0169] ##STR00073##

2 mol % Pd(PPh.sub.3), Eluant cyclohexane/ethyl acetate (7/3) then pentane/diethyl ether (7/3), white solid, 81% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.94 (s, 1H), 8.22-8.04 (m, 2H), 7.89 (s, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.60-7.48 (m, 2H), 7.31 (d, J=8.2 Hz, 1H), 4.46 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.31 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 154.3, 153.8, 150.7, 150.5, 139.2, 131.3, 128.8, 128.1, 127.3, 126.9, 126.3, 125.9, 125.5, 122.7, 122.5, 122.3, 121.6, 62.4, 61.5, 32.7, 12.8. HRMS (ESI+) calcd. for C.sub.21H.sub.20NO.sub.2S: 350.120926. Found: 350.120240 (MH.sup.+). M.p.=139-141? C.

Preparation of 6-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) benzo[d]thiazole (61)

[0170] ##STR00074##

2 mol % Pd(PPh.sub.3), Eluant cyclohexane/ethyl acetate (8/2), colourless oil, 91% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.90 (s, 1H), 8.14-8.10 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.55-7.51 (m, 2H), 7.41-7.37 (m, 1H), 4.43 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.28 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 153.5, 151.8, 150.8, 150.7, 138.6, 134.3, 128.9, 128.3, 127.4, 127.2, 127.0, 126.1, 125.7, 123.4, 122.7, 122.4, 120.8, 62.5, 61.6, 32.8, 12.9. HRMS (ESI+) calcd. for C.sub.21H.sub.20NO.sub.2S: 350.120926. Found: 350.121033 (MH.sup.+).

Preparation of 6-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl) methyl)benzo[d]thiazole (62)

[0171] ##STR00075##

2 mol % Pd(PPh.sub.3), Eluant cyclohexane/ethyl acetate (8/2), colourless oil, 62% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.94 (s, 1H), 8.11 (dd, J=9.2, 5.6 Hz, 1H), 8.04 (br d, J=4.4 Hz, 1H), 7.71 (dd, J=10.4, 2.5 Hz, 1 H), 7.61 (s, 1H), 7.38 (br d, J=2.8 Hz, 1H), 7.28 (td, J=8.8, 2.5 Hz, 1H), 4.41 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.26 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 161.0 (d, .sup.1J.sub.C-F=245.4 Hz), 153.8, 152.2, 150.8 (d, .sup.4J.sub.C-F=1.2 Hz), 150.2 (d, .sup.3J.sub.C-F=5.3 Hz), 138.2, 134.7, 130.4, 128.3 (d, .sup.3J.sub.C-F=8.6 Hz), 127.1, 126.2 (d, .sup.4J.sub.C-F=2.5 Hz), 125.3, 125.2, 123.4, 120.7, 116.2 (d, .sup.2J.sub.C-F=25.4 Hz), 106.4 (d, .sup.2J.sub.C-F=22.3 Hz), 62.3, 61.7, 32.9, 12.7. .sup.19F NMR (CDC.sub.3, 377 MHz): ?-114.66 (ddd, J=10.2, 8.4, 5.7 Hz). HRMS (ESI+) calcd. for C.sub.21H.sub.9NO.sub.2S: 368.111504. Found: 368.111827 (MH.sup.+).

Preparation of 5-[(1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl]pyridin-2-amine (63)

[0172] ##STR00076##

7 mol % Pd(PPh.sub.3), Eluant ethyl acetate, orange solid, 72% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.08 (tdd, J=5.3, 4.0, 3.2 Hz, 2H), 7.91 (s, 1H), 7.74-7.61 (m, 2H), 7.15 (dd, J=8.5, 2.3 Hz, 1H), 6.38 (d, J=8.4 Hz, 1H), 4.36 (s, 2H), 4.10 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.28 (s, 3H). .sup.13C {.sup.1H} NMR (101 MHz, CDCl.sub.3) ? 171.2, 156.7, 150.4, 147.1, 137.9, 128.6, 128.5, 125.8, 125.5, 122.4, 122.2, 108.8, 62.3, 61.4, 29.3, 12.6.

Post-Modifications of Suzuki Coupling Products:

[0173] ##STR00077##

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(oxetan-3-yloxy)pyridine (64)

[0174] ##STR00078##

To a solution of oxetan-3-ol (110 ?L, 1.73 mmol, 5.0 equiv.) in anhydrous DMSO (800 ?L), NaH (42 mg, 1.73 mmol, 5.0 equiv.) was added portion-wise under argon atmosphere. The mixture was stirred until homogenous and was added dropwise to a solution of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-fluoropyridine (108 mg, 0.35 mmol, 1.0 equiv.) in anhydrous DMSO (500 ?L), in a sealed tube, and stirred for 18 h at room temperature under argon atmosphere. The reaction mixture was quenched with a 1 M aqueous solution of hydrochloric acid and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The organic phase was washed with water, brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Cyclohexane/ethyl acetate, 8/2, v/v, UV) to afford 64 as a colourless oil (64 mg, 50%). .sup.1H NMR (CDC.sub.3, 400 MHz): ? 8.12-8.04 (m, 2H), 7.88 (d, J=1.8 Hz, 1H), 7.53-7.46 (m, 2H), 7.37 (dd, J=8.5, 2.4 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 5.55 (p, J=5.8 Hz, 1H), 4.95 (t, J=7.0 Hz, 2H), 4.71 (dd, J=7.6, 5.6 Hz, 2H), 4.15 (s, 2H), 3.86 (d, J=1.4 Hz, 6H), 2.28 (s, 3H). .sup.13C {.sup.1H}NMR (CDCl.sub.3, 126 MHz): ? 160.9, 150.6, 150.5, 146.1, 139.2, 129.3, 128.4, 128.2, 127.3, 126.6, 126.0, 125.7, 122.5, 122.4, 110.7, 78.4 (2C), 69.0, 62.4, 61.5, 29.4, 12.7. HRMS (ESI+) calcd. for C.sub.22H.sub.24NO.sub.4: 366.169985. Found: 366.169403 (MH.sup.+).

5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(oxetan-3-yloxy)pyrimidine (65)

[0175] ##STR00079##

In a flame-dried tube was added 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (100 mg, 0.304 mmol, 1 equiv.), oxetan-3-ol (39 ?L, 0.608 mmol, 2 equiv.), anhydrous THF (1.5 mL) and potassium tert-butoxide (68.3 mg, 0.608 mmol, 2 equiv.). The tube was sealed and the mixture stirred at room temperature during 3 hours. The mixture was diluted with water addition and extracted three times with ethyl acetate. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 1/1, v/v, UV) to afford 65 (82 mg, 74%) as a colorless oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.29 (s, 2H), 8.11-8.03 (m, 2H), 7.55-7.47 (m, 2H), 5.53 (q, J=6.2 Hz, 1H), 4.96-4.89 (m, 2H), 4.76 (dd, J=8.0, 5.5 Hz, 2H), 4.12 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 162.9, 159.2 (2C), 150.9, 150.6, 128.4, 127.7, 127.3, 127.2, 126.3, 125.98, 125.95, 122.6, 122.5, 78.0 (2C), 70.1, 62.4, 61.6, 27.1, 12.9. HRMS (ESI+) calcd. for C.sub.21H.sub.23N.sub.2O.sub.4: 367.165324. Found: 367.165015 (MH.sup.+).

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(oxetan-3-yloxy)pyrimidine (66)

[0176] ##STR00080##

In a flame-dried tube was added 36 (92 mg, 0.27 mmol, 1 equiv.), oxetan-3-ol (34 ?L, 0.53 mmol, 2 equiv.), anhydrous THF (1.3 mL) and potassium tert-butoxide (60 mg, 0.53 mmol, 2 equiv.). The tube was sealed and the mixture stirred at room temperature overnight. The mixture was diluted with water addition and extracted three times with ethyl acetate. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 1/1, v/v, UV) to afford MR00331 (85 mg, 83%) as a colorless oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.28 (s, 2H), 8.07 (dd, J=9.2, 5.5 Hz, 1H), 7.64 (dd, J=10.3, 2.5 Hz, 1H), 7.27 (ddd, J=9.2, 8.3, 2.6 Hz, 1H), 5.53 (p, J=6.0 Hz, 1H), 4.92 (t, J=7.1 Hz, 2H), 4.76 (dd, J=7.8, 5.6 Hz, 2H), 4.10 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 162.9, 161.1 (d, .sup.1J.sub.C-F=245.9 Hz), 159.1 (2C), 151.0 (d, .sup.5J.sub.C-F=1.3 Hz), 150.1 (d, .sup.4J.sub.C-F=5.4 Hz), 128.7, 128.3 (d, .sup.3J.sub.C-F=8.7 Hz), 127.4, 125.44 (d, .sup.5J.sub.C-F=1.1 Hz), 125.36 (d, .sup.3J.sub.C-F=8.9 Hz), 125.2 (d, .sup.4J.sub.C-F=2.5 Hz), 116.6 (d, .sup.2J.sub.C-F=25.4 Hz), 106.4 (d, .sup.2J.sub.C-F=22.4 Hz), 77.9 (2C), 70.1, 62.3, 61.8, 27.2, 12.7. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-114.23 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS (ESI+) calcd. for C.sub.21H.sub.22FN.sub.2O.sub.4: 385.155812. Found: 385.156295 (MH.sup.+).

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(oxetan-3-yloxy)pyridine (67)

[0177] ##STR00081##

In a flame-dried tube was added 34 (83 mg, 0.25 mmol, 1 equiv.), oxetan-3-ol (32 ?L, 0.50 mmol, 2 equiv.), anhydrous THF (1.3 mL) and potassium tert-butoxide (56 mg, 0.50 mmol, 2 equiv.). The tube was sealed and the mixture stirred at 55? C. overnight. The mixture was diluted with water addition and extracted three times with ethyl acetate. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) to afford MR00340 (74 mg, 77%) as a colorless oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.07 (dd, J=9.2, 5.6 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.66 (dd, J=10.4, 2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.4 Hz, 1H), 7.29-7.22 (m, 1H), 6.67 (d, J=8.5 Hz, 1H), 5.55 (p, J=5.8 Hz, 1H), 4.95 (t, J=7.0 Hz, 2H), 4.74-4.67 (m, 2H), 4.13 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.26 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 161.0 (d, .sup.1J.sub.C-F=245.4 Hz), 160.9, 150.8 (d, .sup.5J.sub.C-F=1.2 Hz), 150.0 (d, .sup.4J.sub.C-F=5.4 Hz), 146.0, 139.2, 130.0, 129.0, 128.30, 128.27 (d, .sup.3J.sub.C-F=8.6 Hz), 125.8 (d, .sup.4J.sub.C-F=2.5 Hz), 125.21 (d, .sup.3J.sub.C-F=8.8 Hz), 125.20, 116.2 (d, .sup.2J.sub.C-F=25.4 Hz), 110.8, 106.3 (d, .sup.2J.sub.C-F=22.3 Hz), 78.4 (2C), 69.0, 62.2, 61.6, 29.4, 12.6. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-114.64 (ddd, J=10.2, 8.4, 5.7 Hz). HRMS (ESI+) calcd. for C.sub.22H.sub.23FNO.sub.4: 384.160563. Found: 384.161191 (MH.sup.+).

##STR00082##

Preparation of 5-[(1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl]-2-[2-(trimethylsilyl)ethynyl]pyrimidine (68)

[0178] ##STR00083##

In a flame dried sealable tube, under argon, to a solution of 33 (100 mg, 0.27 mmol, 1 equiv.) in triethylamine (8.5 mL) was added dichlorobis(triphenylphosphine)palladium(II) (11.9 mg, 0.017 mmol, 0.05 equiv.) followed by iodocopper (6.5 mg, 0.034 mmol, 0.1 equiv.). The mixture reaction was degassed with argon before the addition of ethynyl(trimethyl)silane (0.14 mL, 1.018 mmol, 3 equiv.). The tube was sealed and stirred at 70? C. for 24 hours. At room temperature, the mixture reaction was quenched with a solution of brine and water (1/1, v/v). The resulting aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/toluene, 8/2, v/v, UV) to afford 68 (104 mg, 99% yield) as a brown oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.49 (s, 2H), 8.13-8.03 (m, 2H), 7.58-7.47 (m, 2H), 4.21 (s, 2H), 3.85 (s, 3H), 3.85 (s, 3H), 2.26 (s, 3H), 0.27 (s, 9H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 157.0 (2C), 150.9, 150.8, 150.4, 132.8, 128.5, 127.2, 126.4, 126.3, 125.9, 125.8, 122.6, 122.5, 102.4, 93.8, 62.4, 61.6, 28.0, 12.9, 1.1 (3C). HRMS (ESI+) calcd. for C.sub.23H.sub.27SiN.sub.2O.sub.2: 391.183631. Found: 391.181585 (MH.sup.+).

Preparation of 5-[(1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl]-2-ethynylpyrimidine (68)

[0179] ##STR00084##

To a solution of 68 (324 mg, 0.83 mmol, 1 equiv.) in THF (4.2 mL) was added dropwise a solution of tetra-n-butylammonium fluoride (602 mg, 1.91 mmol, 2.3 equiv.) in THF (4.2 mL). The reaction mixture was stirred at room temperature for 1.5 h. The mixture was quenched with a saturated aqueous solution of NH.sub.4Cl. The aqueous layers were extracted three times with diethyl ether. The organic extracts were dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 95/5, v/v, UV) to afford BDU0090 (163 mg, 62% yield) as a brown oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.50 (s, 2H), 8.18-7.96 (m, 2H), 7.61-7.44 (m, 2H), 4.21 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.07 (s, 1H), 2.27 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 157.1, 150.9, 150.8, 150.0, 133.3, 128.5, 127.2, 126.4, 126.2, 126.0, 125.8, 122.6, 122.5, 81.9, 75.4, 62.4, 61.6, 28.1, 12.9. HRMS (ESI+) calcd. for C.sub.20H.sub.19N.sub.2O.sub.2: 319.144104. Found: 319.143171 (MH.sup.+).

Preparation of Compounds of Formula (1) (by Oxidative Deprotection from the Compounds of Formula (11))

[0180] The compounds of formula (1) wherein R.sup.1?H or F are prepared according to the following reaction scheme:

##STR00085##

General Procedure for the Oxidative Deprotection:

[0181] Suzuki coupling derivative (1 equiv) was dissolved in stirring acetonitrile. Then, at room temperature, CAN (2.1 equiv) dissolved in water was added drop by drop (ratio ACN/H.sub.2O 3:1, 0.05M). The mixture was stirred at room temperature during 1 h. Then after TLC analysis showed complete conversion, the aqueous layer was extracted three times with dichloromethane. Combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification by silica gel chromatography was performed using the adequate eluent.

TABLE-US-00002 Compound of formula (I) Yield [00086] 72% [00087] 86% [00088] 88% [00089] 87% [00090] 97% [00091] 100% [00092] 93% [00093] 95% [00094] 87% [00095] 96% [00096] 87% [00097] 74% [00098] 79%

Preparation of 2-methyl-3-(pyridin-3-ylmethyl)naphthalene-1,4-dione (1)

[0182] ##STR00099##

Eluant Cyclohexane:Ethyl acetate (1:1), yellow solid, 74% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.54-8.51 (m, 1H), 8.43 (dd, J=4.8, 1.6 Hz, 1H), 8.16-7.97 (m, 2H), 7.70 (dd, J=5.8, 3.3 Hz, 2H), 7.54 (ddd, J=7.9, 2.4, 1.6 Hz, 1H), 7.18 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 4.01 (s, 2H), 2.25 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 185.16, 184.56, 150.05, 148.02, 144.83, 144.37, 136.22, 133.93, 133.78, 133.76, 132.16, 131.98, 126.61, 126.51, 123.69, 30.00, 13.44. HRMS (ESI) calcd. for C.sub.17H.sub.14NO.sub.2: 264.1019. Found: 264.1018 (MH.sup.+).

Preparation of 2-methyl-3-(quinolin-3-ylmethyl)naphthalene-1,4-dione (1)

[0183] ##STR00100##

Eluant Cyclohexane:Ethyl acetate (1:1), yellow solid, 86% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.87 (d, J=2.2 Hz, 1H), 8.14-8.06 (m, 2H), 8.05 (dd, J=8.5, 1.0 Hz, 1 H), 7.92 (dd, J=2.3, 1.0 Hz, 1H), 7.75-7.68 (m, 3H), 7.64 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.49 (ddd, J=8.1, 6.8, 1.2 Hz, 1H), 4.20 (s, 2H), 2.31 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 185.20, 184.58, 151.69, 147.08, 144.91, 144.38, 134.76, 133.80, 133.78, 132.19, 132.02, 131.12, 129.29, 129.20, 128.14, 127.57, 126.94, 126.65, 126.54, 30.19, 13.58. HRMS (ESI) calcd. for C.sub.21H.sub.16NO.sub.2: 314.1176. Found: 314.1177 (MH.sup.+).

Preparation of 2-methyl-3-(pyrimidin-5-ylmethyl)naphthalene-1,4-dione (2)

[0184] ##STR00101##

Eluant Cyclohexane:Ethyl acetate (1:1), yellow solid, 88% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 9.04 (s, 1H), 8.64 (s, 2H), 8.10-7.98 (m, 2H), 7.76-7.61 (m, 2H), 3.98 (s, 2H), 2.27 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 184.80, 184.28, 157.22, 157.01, 145.07, 143.18, 133.96, 133.89, 132.05, 132.01, 131.79, 126.62, 27.82, 13.53. HRMS (ESI) calcd. for C.sub.16H.sub.13N.sub.2O.sub.2: 265.0972. Found: 265.0982 (MH.sup.+).

Preparation of 2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl) naphthalene-1,4-dione 3)

[0185] ##STR00102##

Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 87% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.66 (d, J=2.2 Hz, 1H), 8.20-7.97 (m, 2H), 7.89-7.68 (m, 3H), 7.58 (dd, J=8.1, 0.8 Hz, 1H), 4.09 (s, 2H), 2.28 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 184.92, 184.43, 150.31, 146.62 (q, J=34.8 Hz), 145.23, 143.50, 137.47, 137.40, 133.99, 133.92, 132.11, 131.86, 126.66, 126.64, 121.62 (q, J=279.6 Hz), 120.54 (q, J=2.7 Hz), 30.00, 13.56. .sup.19F NMR (471 MHz, CDCl.sub.3) ??67.81. HRMS (ESI) calcd. for C.sub.18H.sub.13F.sub.3NO.sub.2: 332.0893. Found: 332.0915 (MH.sup.+).

Preparation of 2-((6-fluoropyridin-3-yl)methyl)-3-methylnaphthalene-1,4-dione (4)

[0186] ##STR00103##

Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 97% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.13 (d, J=2.6 Hz, 1H), 8.08 (ddd, J=7.4, 5.8, 3.3 Hz, 2H), 7.72 (dd, J=5.8, 3.3 Hz, 2H), 7.67 (td, J=8.1, 2.6 Hz, 1H), 6.84 (dd, J=8.4, 3.0 Hz, 1H), 4.00 (s, 2H), 2.27 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 185.12, 184.59, 162.61 (d, J=238.4 Hz), 147.46 (d, J=14.7 Hz), 144.83, 144.17, 141.52 (d, J=7.8 Hz), 133.91, 133.86, 132.15, 131.95, 131.52 (d, J=4.7 Hz), 126.64, 126.60, 109.63 (d, J=37.5 Hz), 29.15, 13.45. .sup.19F NMR (377 MHz, CDCl.sub.3) ??70.88 (d, J=7.7 Hz). HRMS (ESI) calcd. for C.sub.17H.sub.13FNO.sub.2: 282.0925. Found: 282.0920 (MH.sup.+).

Preparation of 2-((6-chloropyridin-3-yl)methyl)-3-methylnaphthalene-1,4-dione (5)

[0187] ##STR00104##

Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 99% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.30 (d, J=2.5 Hz, 1H), 8.11-7.96 (m, 2H), 7.75-7.63 (m, 2H), 7.51 (dd, J=8.2, 2.6 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 3.97 (s, 2H), 2.25 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) ? 184.98, 184.45, 149.79, 149.75, 144.92, 143.86, 139.11, 133.88, 133.82, 132.87, 132.08, 131.86, 126.59, 126.55, 124.33, 29.30, 13.45. HRMS (ESI) calcd. for C.sub.17H.sub.13ClNO.sub.2: 298.0629. Found: 298.0648 (MH.sup.+).

Preparation of 2-((2-chloropyrimidin-5-yl)methyl)-3-methylnaphthalene-1,4-dione (6)

[0188] ##STR00105##

Eluant Cyclohexane:Ethyl acetate (7:3), yellow solid, 93% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.54 (s, 2H), 8.20-7.92 (m, 2H), 7.85-7.57 (m, 2H), 3.96 (s, 2H), 2.29 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 184.58, 184.14, 159.74, 159.58, 145.09, 142.64, 133.97, 133.89, 131.93, 131.63, 130.56, 126.58, 126.55, 27.06, 13.49. HRMS (ESI) calcd. for C.sub.16H.sub.12ClN.sub.2O.sub.2: 299.0582. Found: 299.0596 (MH.sup.+).

Preparation of 2-methyl-3-((2-(trifluoromethyl)pyrimidin-5-yl)methyl) naphthalene-1,4-dione (7)

[0189] ##STR00106##

Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 3 95% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.82 (s, 2H), 8.25-8.01 (m, 2H), 7.84-7.65 (m, 2H), 4.08 (s, 2H), 2.32 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 184.63, 184.23, 158.01, 155.31 (q, J=37.1 Hz), 145.49, 142.43, 134.44, 134.19, 134.08, 132.06, 131.72, 126.77, 126.73, 119.66 (q, J=275.1 Hz), 27.91, 13.68. .sup.19F NMR (377 MHz, CDCl.sub.3) ??70.23. HRMS (ESI) calcd. for C.sub.17H.sub.12F.sub.3N.sub.2O.sub.2: 333.0845. Found: 333.0868 (MH.sup.+).

Preparation of 2-((6-methoxypyridin-3-yl)methyl)-3-methylnaphthalene-1,4-dione (8)

[0190] ##STR00107##

Eluant Cyclohexane:Ethyl acetate (90:10), yellow solid, 87% yield. m.p: 120-121? C. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.11-7.95 (m, 3H), 7.67 (dd, J=5.8, 3.3 Hz, 2H), 7.50 (dd, J=8.6, 2.5 Hz, 21), 6.67 (d, J=8.6 Hz, 1H), 3.91 (s, 2H), 3.88 (s, 3H), 2.24 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 185.19, 184.61, 162.78, 145.90, 144.66, 144.43, 139.91, 133.70, 133.67, 132.11, 131.97, 126.66, 126.52, 126.43, 111.02, 53.79, 29.03, 13.31. HRMS (ESI) calcd. for C.sub.18H.sub.15NO.sub.3: 294.112470. Found: 294.112517 (MH.sup.+).

Preparation of 2-((2-methoxypyrimidin-5-yl)methyl)-3-methylnaphthalene-1,4-dione (9)

[0191] ##STR00108##

Eluant Cyclohexane:Ethyl acetate (70:30), yellow solid, 74% yield. m.p: 161-162? C. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.40 (s, 2H), 8.10-7.96 (m, 2H), 7.67 (dd, J=5.8, 3.3 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 2H), 2.25 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 184.91, 184.33, 164.61, 159.22, 144.51, 143.77, 133.81, 133.76, 132.01, 131.82, 126.51, 126.48, 124.86, 54.91, 26.75, 13.37. HRMS (ESI) calcd. for C.sub.17H.sub.15N.sub.2O.sub.3: 295.107719. Found: 295.108670 (MH.sup.+).

Preparation of 2-(furan-2-ylmethyl)-3-methylnaphthalene-1,4-dione (10)

[0192] ##STR00109##

Eluant Cyclohexane:Ethyl acetate (98:2), orange solid, 74% yield. m.p: 83-84? C. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.21-7.95 (m, 1H), 7.86-7.58 (m, 1H), 7.27 (dd, J=1.9, 0.9 Hz, OH), 6.26 (dd, J=3.2, 1.9 Hz, OH), 6.07 (dd, J=3.2, 0.9 Hz, OH), 4.03 (s, 1H), 2.28 (s, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 185.34, 184.06, 151.27, 145.02, 142.41, 141.62, 133.62, 133.58, 132.21, 132.05, 126.56, 126.41, 110.55, 106.79, 25.57, 13.11.

Preparation of 2-methyl-3-(thiophen-2-ylmethyl)naphthalene-1,4-dione (11)

[0193] ##STR00110##

m.p.=96-97? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.11-8.03 (m, 2H), 7.71-7.65 (m, 2H), 7.11 (dd, J=4.5, 1.8 Hz, 1H), 6.89 (d, J=4.5 Hz, 2H), 4.18 (s, 2H), 2.29 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): 5 185.3, 184.2, 144.4, 144.1, 139.9, 133.61, 133.59,132.1,132.0, 126.9, 126.5, 126.4, 125.8, 124.2, 27.0, 13.1. HRMS calculated for C.sub.16H.sub.12NaO.sub.2S [M+Na].sup.+: 291.045021. Found 291.045521.

Preparation of 5-((3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)pyrimidine-2-carbonitrile (12)

[0194] ##STR00111##

Eluant Cyclohexane:Ethyl acetate (7:3), yellow solid, 87% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.76 (s, 2H), 8.10-7.99 (m, 2H), 7.81-7.61 (m, 2H), 4.06 (s, 2H), 2.31 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 184.50, 184.17, 158.11, 145.67, 143.40, 142.05, 135.19, 134.23, 134.09, 132.00, 131.62, 126.77, 126.69, 115.68, 28.20, 13.72. HRMS (ESI) calcd. for C.sub.17H.sub.12N.sub.3O.sub.2: 290.0924. Found: 290.0918 (MH.sup.+).

Preparation of 2-((2-bromopyrimidin-5-yl)methyl)-3-methylnaphthalene-1,4-dione (13)

[0195] ##STR00112##

Eluant Cyclohexane:Ethyl acetate (75:25), yellow solid, 96% yield. m.p: 165-166? C. .sup.1H NMR (400 MHz, CDCl.sub.3) 5 8.48 (s, 2H), 8.11-8.00 (m, 2H), 7.80-7.60 (m, 2H), 3.94 (s, 2H), 2.28 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) ? 184.67, 184.23, 159.56, 151.26, 145.20, 142.67, 134.09, 134.00, 132.03, 131.73, 131.14, 126.69, 126.66, 27.24, 13.61. HRMS (ESI) calcd. for C.sub.16H.sub.12BrN.sub.2O.sub.2: 343.0077. Found: 343.0099 (MH.sup.+).

Preparation of 2-((2-aminopyrimidin-5-yl)methyl)-3-methylnaphthalene-1,4-dione (46)

[0196] ##STR00113##

46 was isolated by purification by flash chromatography on silica gel (dichloromethane/methanol, 9/1, v/v, UV) with 60% yield as an orange solid. .sup.1H NMR (CDCl.sub.3, 500 MHz): ? 8.12 (s, 2H), 8.01-7.96 (m, 2H), 7.84-7.80 (m, 2H), 6.46 (s, 2H), 3.73 (s, 2H), 2.18 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 126 MHz): ? 184.6, 184.2, 162.4, 144.8, 143.8, 133.9, 133.8, 131.7, 131.5, 125.9, 125.8, 119.5, 26.1, 13.0. HRMS (ESI+) calcd. for C.sub.16H.sub.14N.sub.3O.sub.2: 290.1081. Found: 280.1081 (MH.sup.+). M.p.=degradation after 200? C.

Preparation of 6-fluoro-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)naphthalene-1,4-dione (47)

[0197] ##STR00114##

47 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3 then pentane/diethyl ether, 8/2, v/v, UV) with 61% yield as a yellow solid. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.65 (s, 1H), 8.13 (dd, J=8.5, 5.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.70 (dd, J=8.5, 2.5 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.37 (td, J=8.3, 2.4 Hz, 1H), 4.09 (s, 2H), 2.29 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 183.6, 183.4, 166.2 (d, .sup.1J.sub.C-F=257.5 Hz), 150.5, 146.7 (q, .sup.2J.sub.C-F=34.9 Hz), 145.5, 143.6 (d, .sup.5J.sub.C-F=1.6 Hz), 137.5, 137.2, 134.4 (d, .sup.3J.sub.C-F=7.9 Hz), 130.0 (d, .sup.3J.sub.C-F=8.9 Hz), 128.7 (d, .sup.4J.sub.C-F=3.2 Hz), 121.6 (q, .sup.1J.sub.C-F=273.7 Hz), 121.2 (d, .sup.2J.sub.C-F=22.5 Hz), 120.6 (d, .sup.4J.sub.C-F=2.2 Hz), 113.4 (d, .sup.2J.sub.C-F=23.5 Hz), 30.2, 13.7. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-67.80, ?101.84 (td, J=8.2, 5.3 Hz). HRMS (ESI+) calcd. for C.sub.18H.sub.12F.sub.4NO.sub.2: 350.079868. Found: 350.079641 (MH.sup.+). M.p.=122-124? C.

Preparation of 3-(benzo[d]thiazol-5-ylmethyl)-6-fluoro-2-methyl-naphthalene-1,4-dione (48)

[0198] ##STR00115##

48 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3, v/v, UV) and by recrystallization in ethanol with 91% yield as a yellow solid. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 9.04 (s, 1H), 8.13 (dd, J=8.5, 5.2 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.72 (dd, J=8.5, 2.5 Hz, 1H), 7.46-7.30 (m, 2H), 4.20 (s, 2H), 2.29 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 184.0, 183.6, 166.1 (d, .sup.1J.sub.C-F=256.9 Hz), 155.3, 154.2, 145.2 (d, .sup.5J.sub.C-F=1.8 Hz), 145.2, 136.5, 134.7 (d, .sup.3J.sub.C-F=7.9 Hz), 132.4, 129.8 (d, .sup.3J.sub.C-F=8.8 Hz), 128.8 (d, .sup.4J.sub.C-F=3.2 Hz), 126.8, 123.1, 122.2, 120.9 (d, .sup.2J.sub.C-F=22.6 Hz), 113.3 (d, .sup.2J.sub.C-F=23.5 Hz), 32.4, 13.6. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-102.4 (td, J=8.3, 5.3 Hz). HRMS (ESI+) calcd. for C.sub.19H.sub.13FNO.sub.2S: 338.064554. Found: 338.063505 (MH.sup.+). M.p.=109-111? C.

Preparation of 2-(benzo[d]thiazol-5-ylmethyl)-3-methylnaphthalene-1,4-dione (49)

[0199] ##STR00116##

49 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.97 (s, 1H), 8.06 (dt, J=5.7, 3.1 Hz, 2H), 7.95 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.83-7.57 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 4.18 (s, 2H), 2.27 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 185.3, 184.6, 154.8, 153.9, 145.0, 144.8, 136.6, 133.6 (2C), 132.1 (2C), 132.0, 126.7, 126.5, 126.4, 123.1, 122.0, 32.3, 13.4. HRMS (ESI+) calcd. for C.sub.19H.sub.13NNaO.sub.2S: 342.055920. Found: 342.055527 (MNa.sup.+). M.p.=148-149? C.

Preparation of 2-methyl-3-((6-(oxetan-3-yloxy)pyridin-3-yl)methyl) naphthalene-1,4-dione (50)

[0200] ##STR00117##

50 was isolated by solubilisation in ethanol with 85% yield as a yellow solid. .sup.1H NMR (CD.sub.3OD, 400 MHz): ? 8.47 (s, 1H), 8.36 (dd, J=9.1, 1.8 Hz, 1H), 8.12-8.04 (m, 2H), 7.82-7.75 (m, 2H), 7.42 (d, J=9.0 Hz, 1H), 5.48 (ddt, J=9.6, 6.9, 2.6 Hz, 1H), 4.97 (dd, J=12.3, 9.8 Hz, 1H), 4.82 (dd, d apparent because of HDO peak, J=7.0 Hz, 1H), 4.13 (s, 2H), 4.03 (dd, J=13.1, 2.4 Hz, 1H), 3.80 (dd, J=13.1, 2.9 Hz, 1H), 2.31 (s, 3H). .sup.13C {.sup.1H} NMR (CD.sub.3OD, 101 MHz): ? 185.9, 185.6, 161.1, 150.6, 147.3, 143.4, 137.8, 135.0, 134.9, 133.4, 133.1, 132.4, 127.3, 127.2, 111.0, 86.2, 62.4, 53.2, 29.7, 13.4. H RMS (ESI+) calcd. for C.sub.20H.sub.18NO.sub.4: 336.123034 Found: 336.123633 (MH.sup.+). M.p.=125-127? C.

Preparation of 2-(benzo[d]thiazol-6-ylmethyl)-3-methylnaphthalene-1,4-dione (51)

[0201] ##STR00118##

51 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) with 78% yield as a yellow solid. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.95 (s, 1H), 8.15-8.06 (m, 2H), 8.04 (d, J=8.3 Hz, 1H), 7.81 (s, 1H), 7.71 (dd, J=5.7, 3.3 Hz, 2H), 7.42 (d, J=7.8 Hz, 1H), 4.19 (s, 2H), 2.29 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 101 MHz): ? 185.3, 184.7, 154.3, 152.4, 144.9, 144.7, 135.9, 134.8, 133.65, 133.64, 132.1, 132.0, 127.3, 126.6, 126.4, 123.6, 121.5, 32.4, 13.5. HRMS (ESI+) calcd. for C.sub.19H.sub.14NO.sub.2S: 320.074032 Found: 320.074032 (MH.sup.+). M.p.=146-147? C.

Preparation of 3-(benzo[d]thiazol-6-ylmethyl)-6-fluoro-2-methylnaphthalene-1,4-dione (52)

[0202] ##STR00119##

52 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) as a yellow solid with 42% yield. .sup.1H NMR (CDCl.sub.3, 500 MHz): ? 8.96 (s, 1H), 8.13 (dd, J=8.6, 5.2 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.80 (s, 1H), 7.73 (dd, J=8.6, 2.6 Hz, 1H), 7.44-7.34 (m, 2H), 4.17 (s, 2H), 2.29 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 126 MHz): ? 184.0, 183.7, 166.1 (d, .sup.1J.sub.C-F=257.0 Hz), 154.4, 152.2, 145.18, 145.17, 145.1, 135.8, 134.6 (d, .sup.3J.sub.C-F=7.8 Hz), 129.8 (d, .sup.3J.sub.C-F=8.8 Hz), 128.8 (d, .sup.4J.sub.C-F=3.1 Hz), 127.3, 123.8, 121.6, 120.9 (d, .sup.2J.sub.C-F=22.5 Hz), 113.4 (d, .sup.2J.sub.C-F=23.5 Hz), 32.6, 13.6. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-102.28 (td, J=8.2, 5.3 Hz). HRMS (ESI+) calcd. for C.sub.19H.sub.13FNO.sub.2S: 338.064554 Found: 338.064817 (MH.sup.+). M.p.=170-172? C.

Preparation of 2-methyl-3-((2-(oxetan-3-yloxy)pyrimidin-5-yl)methyl)naphthalene-1,4-dione (53)

[0203] ##STR00120##

53 was isolated after precipitation in dichloromethane with 39% yield as a yellow solid. .sup.1 H NMR (DMSO-d.sub.6, 400 MHz): ? 9.24 (d, J=2.5 Hz, 1H), 9.04 (d, J=2.4 Hz, 1H), 8.07-7.95 (m, 2H), 7.90-7.82 (m, 2H), 5.45 (ddt, J=9.7, 6.9, 3.2 Hz, 1H), 4.88 (dd, J=12.7, 9.8 Hz, 1H), 4.65 (dd, J=12.7, 7.1 Hz, 1H), 4.09 (s, 2H), 3.88 (dd, J=13.0, 2.5 Hz, 1H), 3.74 (dd, J=13.0, 3.7 Hz, 1H), 2.21 (s, 3H). .sup.13C {.sup.1H} NMR (DMSO-d.sub.6, 101 MHz): ? 184.4, 183.7, 169.3, 159.7, 148.0, 146.0, 141.1, 134.1, 134.0, 131.8, 131.5, 127.0, 126.0, 83.6, 60.7, 50.8, 25.9, 13.2. HRMS (ESI+) calcd. for C.sub.19H.sub.17N.sub.2O.sub.4: 337.118684 Found: 337.118684 (MH.sup.+). M.p.=degradation after 165? C.

Preparation of 6-fluoro-2-methyl-3-((2-(oxetan-3-yloxy)pyrimidin-5-yl)methyl)naphthalene-1,4-dione (54)

[0204] ##STR00121##

54 was isolated after precipitation in dichloromethane with 98% yield as a yellow solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): ?9.23 (d, J=2.5 Hz, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.14 (dd, J=9.3, 5.4 Hz, 1H), 7.72 (ddd, J=8.8, 6.2, 2.7 Hz, 2H), 5.45 (ddt, J=9.9, 6.8, 3.2 Hz, 1H), 4.86 (dd, J=12.6, 9.8 Hz, 1H), 4.64 (dd, J=12.7, 7.1 Hz, 1H), 4.09 (s, 2H), 3.88 (dd, J=13.0, 2.5 Hz, 1H), 3.73 (dd, J=13.0, 3.7 Hz, 1H), 2.21 (s, 3H). .sup.13C {.sup.1H}NMR (DMSO-d.sub.6, 101 MHz): ? 183.2, 182.7 (d, .sup.4J.sub.C-F=1.2 Hz), 169.4, 165.3 (d, .sup.1J.sub.C-F=254.0 Hz), 159.7, 148.0, 146.3, 141.3 (d, .sup.5J.sub.C-F=1.8 Hz), 134.3 (d, .sup.3J.sub.C-F=7.9 Hz), 129.7 (d, .sup.3J.sub.C-F=9.2 Hz), 128.8 (d, .sup.4J.sub.C-F=3.0 Hz), 126.8, 121.2 (d, .sup.2J.sub.C-F=22.6 Hz), 112.4 (d, .sup.2J.sub.C-F=23.4 Hz), 83.7, 60.7, 50.8, 26.0, 13.2. .sup.19F NMR (CD.sub.3OD, 377 MHz): ?-105.18 (td, J=8.6, 5.3 Hz). HRMS (ESI+) calcd. for C.sub.19H.sub.16FN.sub.2O.sub.4: 355.108862 Found: 355.107660 (MH.sup.+). M.p.=degradation after 165? C.

Preparation of 2-[(6-aminopyridin-3-yl)methyl]-3-methyl-1,4-dihydronaphthalene-1,4-dione (55)

[0205] ##STR00122##

0 55 was isolated by purification by flash chromatography on silica gel (ethyl acetate) with 68% yield as an orange solid. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.08 (dt, J=5.9, 3.0 Hz, 2H), 7.95 (s, 1H), 7.76-7.60 (m, 2H), 7.35 (dd, J=8.5, 2.3 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H), 4.59 (s, 2H), 3.86 (s, 2H), 2.26 (s, 3H). .sup.13C {.sup.1H} NMR (101 MHz, CDCl.sub.3) ? 185.3, 184.7, 156.8, 146.6, 144.9, 144.2, 138.9, 133.6, 132.1, 131.9, 126.4, 126.3, 109.1, 28.9, 13.2.

Preparation of 2-[(2-ethynylpyrimidin-5-yl)methyl]-3-methyl-1,4-dihydronaphthalene-1,4-dione (56)

[0206] ##STR00123##

56 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) as an orange solid with 70% yield. .sup.1H NMR (CDCl.sub.3, 500 MHz): ? 8.63 (s, 2H), 8.13-7.99 (m, 2H), 7.81-7.61 (m, 2H), 3.99 (s, 2H), 3.09 (s, 1H), 2.28 (s, 3H). .sup.13C {.sup.1H} NMR (CDCl.sub.3, 126 MHz): ? 184.8, 184.3, 157.4 (2C), 150.5, 145.3, 142.8, 134.1, 134.0, 132.1, 131.8, 131.4, 126.7 (2C), 81.7, 75.9, 27.9, 13.6. HRMS (ESI+) calcd. For C.sub.18H.sub.13N.sub.2O.sub.2: 289.097154 Found: 289.096682 (MH.sup.+). M.p.=160-162? C.

Preparation of Compounds of Formula (II) (by Suzuki Reaction Between 6-Fluoro-3-Chloromethyl-1,4-Dimethoxynaphtalene and Boronic Acids of Formula (III))

[0207] The compounds of formula (II) wherein R.sup.1?F are prepared according to the following reaction scheme:

##STR00124##

Synthesis of 6-fluoro precursors

[0208] ##STR00125##

Preparation of 6-fluoro-1,4-dimethoxy-2-methylnaphthalene

[0209] ##STR00126##

According to the previously published method (T. Mller, L. Johann, B. Jannack, M. Bruckner, D. A. Lanfranchi, H. Bauer, C. Sanchez, V. Yardleyll, C. Deregnaucourt, J. Schrevel, M. Lanzer, R. H. Schirmer, E. Davioud-Charvet, J. Am. Chem. Soc. 2011, 133, 30, 11557-11571), this compound was purified by flash chromatography on silica gel (Toluene, UV) with 63% yield (beige solid). m.p.=52-53? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.07 (dd, J=9.2, 5.6 Hz, 1H), 7.88 (dd, J=10.6, 2.7 Hz, 1H), 7.32 (ddd, J=9.2, 8.3, 2.7 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.48 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 160.4 (d, .sup.1J.sub.C-F=243.9 Hz), 150.9 (d, .sup.4J.sub.C-F=5.1 Hz), 147.1 (d, .sup.5J.sub.C-F=1.4 Hz), 126.1 (d, .sup.3J.sub.C-F=8.8 Hz), 125.8 (d, .sup.5J.sub.C-F=0.8 Hz), 124.8 (d, .sup.4J.sub.C-F=2.5 Hz), 124.2 (d, .sup.3J.sub.C-F=8.7 Hz), 116.3 (d, .sup.2J.sub.C-F=25.2 Hz), 108.0, 106.3 (d, .sup.2J.sub.C-F=22.5 Hz), 61.2, 55.5, 16.1. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-116.24 (ddd, J=10.3, 8.4, 5.5 Hz). HRMS calculated for C.sub.13H.sub.14FO.sub.2 [M+H].sup.+: 221.097234. Found 221.097121.

Preparation of 3-(chloromethyl)-6-fluoro-1,4-dimethoxy-2-methylnaphthalene

[0210] ##STR00127##

A solution of 6-fluoro-1,4-dimethoxy-2-methylnaphthalene (250 mg, 1.14 mmol, 1 eq) and paraformaldehyde (538 mg, 17.03 mmol, 15 eq) in 37% aqueous hydrochloric acid (9 mL) was stirred at 60? C. overnight. The reaction mixture was cooled down, diluted with water, and extracted with ethyl acetate. The organic phase was dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Toluene/cyclohexane, 9/1, v/v, UV) to afford the expected product (200 mg, 66%, white solid). m.p.=100-102? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.07 (dd, J=9.2, 5.5 Hz, 1H), 7.68 (dd, J=10.2, 2.5 Hz, 1H), 7.29 (ddd, J=9.2, 8.2, 2.6 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H), 3.87 (s, 3H), 2.52 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 161.1 (d, .sup.1J.sub.C-F=246.0 Hz), 150.9 (d, .sup.4J.sub.C-F=5.4 Hz), 150.7 (d, .sup.5J.sub.C-F=1.3 Hz), 128.2 (d, .sup.3J.sub.C-F=8.7 Hz), 128.0, 126.3 (d, .sup.5J.sub.C-F=0.6 Hz), 125.6 (d, .sup.4J.sub.C-F=2.5 Hz), 125.3 (d, .sup.3J.sub.C-F=8.8 Hz), 117.1 (d, .sup.2J.sub.C-F=25.3 Hz), 106.7 (d, .sup.2J.sub.C-F=22.4 Hz), 63.1, 61.6, 38.9. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-114.27 (m). HRMS calculated for C.sub.14H.sub.15CIFO.sub.2 [M+H].sup.+: 269.073912. Found 269.073883.

General procedure for the Suzuki coupling between 2-(chloromethyl)-6-fluoro-1,4-dimethoxy-3-methylnaphthalene and heteroarylboronic acid

[0211] In a flame dried sealable tube, under argon, 2-(chloromethyl)-6-R-1,4-dimethoxy-2-methylnaphthalene (1 eq), boronic acid (1.2 eq), sodium carbonate (2.1 eq) were introduced successively in a mixture of dimethoxyethane and water (ratio 2/1, v/v). The solvent was degassed and tetrakis(triphenylphosphine)palladium (0.02 eq) was added in the solution. The tube was sealed and stirred at 100? C. for 1 h. The reaction mixture was diluted with water and extracted 3 times with dichloromethane. The organic layer was washed with brine, dried over MgSO.sub.4, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to afford the expected product.

TABLE-US-00003 Boronic acid of formula (III) Compound of formula (II) Yield [00128] [00129] 71% [00130] [00131] 70% [00132] [00133] 70% [00134] [00135] 83% [00136] [00137] 73%

Preparation of 2-fluoro-5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyridine (34)

[0212] ##STR00138##

This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 9/1, v/v, UV) with 71% yield (colourless oil). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.10 (dd, J=9.3, 5.7 Hz, 1H), 8.07 (s, 1H), 7.69 (dd, J=10.3, 2.5 Hz, 1H), 7.52 (td, J=8.2, 2.3 Hz, 1H), 7.28 (td, J=9.2, 2.6 Hz, 1H), 6.80 (dd, J=8.4, 2.9 Hz, 1H), 4.22 (s, 2H), 3.86 (d, J=1.7 Hz, 6H), 2.27 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 162.4 (d, .sup.1J.sub.C-F=237.3 Hz), 161.0 (d, .sup.1J.sub.C-F=246.4 Hz), 150.9 (d, .sup.5J.sub.C-F=2.0 Hz), 150.1 (d, .sup.4J.sub.C-F=5.4 Hz), 146.9 (d, .sup.3J.sub.C-F=14.5 Hz), 141.0 (d, .sup.3J.sub.C-F=7.7 Hz), 133.3 (d, .sup.4J.sub.C-F=4.6 Hz), 129.4, 128.3 (d, .sup.3J.sub.C-F=8.7 Hz), 125.6 (d, .sup.4J.sub.C-F=2.5 Hz), 125.3, 125.2 (d, .sup.3J.sub.C-F=9.1 Hz), 116.3 (d, .sup.2J.sub.C-F=25.4 Hz), 109.3 (d, .sup.2J.sub.C-F=37.5 Hz), 106.3 (d, .sup.2J.sub.C-F=22.4 Hz), 62.2, 61.6, 29.4, 12.6. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-114.42 (ddd, J=10.1, 8.4, 5.7 Hz). HRMS calculated for C.sub.1H.sub.18F.sub.2NO.sub.2 [M+H].sup.+: 330.130012. Found 330.131085.

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)picolinonitrile (35)

[0213] ##STR00139##

This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 70% yield (white solid). m.p.=132-134? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ?68.60 (d, J=1.36 Hz, 1H), 8.08 (dd, J=9.2, 5.6 Hz, 1H), 7.65 (dd, J=10.3, 2.5 Hz, 1H), 7.59-7.45 (m, 2H), 7.32-7.23 (m, 1H), 4.29 (s, 2H), 3.91-3.79 (m, 6H), 2.23 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 161.1 (d, .sup.1J.sub.C-F=246.1 Hz), 151.3, 151.0 (d, .sup.5J.sub.C-F=1.3 Hz), 150.2 (d, .sup.4J.sub.C-F=5.4 Hz), 140.3, 136.5, 131.6, 128.4, 128.22 (d, .sup.3J.sub.C-F=8.7 Hz), 128.15, 125.5 (d, .sup.5J.sub.C-F=1.1 Hz), 125.4 (d, .sup.3J.sub.C-F=8.9 Hz), 125.2 (d, .sup.4J.sub.C-F=2.5 Hz), 117.4, 116.6 (d, .sup.2J.sub.C-F=25.4 Hz), 106.3 (d, .sup.2J.sub.C-F=22.4 Hz), 62.2, 61.7, 30.6, 12.7. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-114.04 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS calculated for C.sub.20H.sub.18FN.sub.2O.sub.2[M+H].sup.+: 337.134682. Found 337.135223.

Preparation of 2-chloro-5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (36)

[0214] ##STR00140##

This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 70% yield (white solid). m.p.=139-141? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ?8.41 (s, 2H), 8.06 (dd, J=9.2, 5.6 Hz, 1H), 7.63 (dd, J=10.2, 2.5 Hz, 1H), 7.26 (td, J=8.8, 2.6 Hz, 1H), 4.15 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 2.25 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 161.1 (d, .sup.1J.sub.C-F=246.2 Hz), 159.4, 159.3 (2C), 151.1 (d, .sup.4J.sub.C-F=1.3 Hz), 150.1 (d, .sup.4J.sub.C-F=5.4 Hz), 132.3, 128.2 (d, .sup.3J.sub.C-F=8.7 Hz), 127.8, 125.5 (d, .sup.5J.sub.C-F=0.5 Hz), 125.4 (d, .sup.3J.sub.C-F=8.9 Hz), 124.9 (d, .sup.5J.sub.C-F=2.5 Hz), 116.6 (d, .sup.2J.sub.C-F=25.4 Hz), 106.3 (d, .sup.2J.sub.C-F=22.4 Hz), 62.2, 61.7, 27.3, 12.7. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-113.94 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS calculated for C.sub.18H.sub.17CIFN.sub.2O.sub.2[M+H].sup.+: 347.095710. Found 347.097652.

Preparation of 2-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)furan (38)

[0215] ##STR00141##

This compound were isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from I/O to 99/1, v/v, UV) with 83% yield (colourless oil). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.09 (dd, J=9.2, 5.6 Hz, 1H), 7.68 (dd, J=10.4, 2.6 Hz, 1H), 7.32 (br d, J=1.1 Hz, 1H), 7.26 (ddd, J=9.1, 8.3, 2.6 Hz, 1H), 6.26 (dd, J=3.1, 1.9 Hz, 1H), 5.87-5.82 (m, 1H), 4.23 (s, 2H), 3.87 (d, J=3.4 Hz, 6H), 2.36 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 161.0 (d, .sup.1J.sub.C-F=245.2 Hz), 154.0, 150.5 (d, .sup.5J.sub.C-F=1.4 Hz), 150.2 (d, .sup.4J.sub.C-F=5.4 Hz), 141.3, 128.4, 128.3 (d, .sup.3J.sub.C-F=8.7 Hz), 126.3 (d, .sup.4J.sub.C-F=2.4 Hz), 125.3, 125.2 (d, .sup.3J.sub.C-F=8.9 Hz), 116.2 (d, .sup.2J.sub.C-F=25.4 Hz), 110.4, 106.4 (d, .sup.2J.sub.C-F=22.3 Hz), 106.0, 62.5, 61.6, 26.5, 12.4. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-114.95 (ddd, J=10.4, 8.4, 5.7 Hz). HRMS calculated for C.sub.18H.sub.18FO.sub.3 [M+H].sup.+: 301.123449. Found 301.123811.

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(trifluoromethyl)pyrimidine (37)

[0216] ##STR00142##

This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 73% yield (colourless oil). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.69 (s, 2H), 8.08 (dd, J=9.2, 5.6 Hz, 1H), 7.64 (dd, J=10.2, 2.5 Hz, 1H), 7.28 (ddd, J=9.1, 8.4, 2.6 Hz, 1H), 4.27 (s, 2H), 3.85 (d, J=12.1 Hz, 6H), 2.28 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 161.2 (d, .sup.1J.sub.C-F=246.3 Hz), 157.6 (2C), 154.9 (q, .sup.2J.sub.C-F=36.9 Hz), 151.2 (d, .sup.5J.sub.C-F=1.3 Hz), 150.2 (d, .sup.4J.sub.C-F=5.3 Hz), 136.1, 128.6 (d, .sup.3J.sub.C-F=8.7 Hz), 127.4, 125.7, 125.5 (d, .sup.3J.sub.C-F=8.9 Hz), 124.9 (d, .sup.4J.sub.C-F=2.5 Hz), 119.8 (d, .sup.1J.sub.C-F=275.7 Hz), 116.8 (d, .sup.2J.sub.C-F=25.4 Hz), 106.4 (d, .sup.2J.sub.C-F=22.5 Hz), 62.2, 61.8, 28.1, 12.8. .sup.19F NMR (CDC.sub.3, 377 MHz): ?-70.12, ?113.87 (ddd, J=10.1, 8.4, 5.6 Hz).

Post-Modifications of Suzuki Coupling Products

[0217] ##STR00143##

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine-2-carbonitrile (40)

[0218] ##STR00144##

A solution of 36 (100 mg, 0.29 mmol, 1 eq) in DMSO (1.0 mL) was added a solution of sodium cyanide (28.26 mg, 0.58 mmol, 2 eq) and DABCO (6.81 mg, 0.058 mmol, 0.2 eq) in DMSO (1 mL) and water (0.4 mL). The reaction mixture was stirred at 50? C. for 72 h. The reaction mixture was diluted with water and extracted twice with diethyl ether. Reunited organic layers were washed with brine and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v) to afford 40 as a white solid (19 mg, 20%). m.p.=167-169? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.63 (s, 2H), 8.09 (dd, J=9.2, 5.6 Hz, 1H), 7.64 (dd, J=10.2, 2.5 Hz, 1H), 7.30 (ddd, J=9.1, 8.4, 2.6 Hz, 1H), 4.25 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.27 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 161.3 (d, .sup.1J.sub.C-F=246.7 Hz), 157.8 (2C), 151.3 (d, .sup.5J.sub.C-F=1.3 Hz), 150.3 (d, .sup.4J.sub.C-F=5.5 Hz), 143.2, 136.9, 128.3 (d, .sup.3J.sub.C-F=8.7 Hz), 127.1, 125.8, 125.5 (d, .sup.3J.sub.C-F=8.9 Hz), 124.7 (d, .sup.4J.sub.C-F=2.5 Hz), 117.0 (d, .sup.2J.sub.C-F=25.4 Hz), 115.8, 106.4 (d, .sup.2J.sub.C-F=22.5 Hz), 62.3, 61.9, 28.4, 12.9. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-113.65 (ddd, J=9.9, 8.4, 5.6 Hz). HRMS calculated for C.sub.19H.sub.17FN.sub.3O.sub.2[M+H].sup.+: 338.129931. Found 338.131588.

Preparation of Compounds of Formula (1) (by Oxidative Deprotection from the Compounds of Formula (11))

[0219] The compounds of formula (1) wherein R.sup.1?F are prepared according to the following reaction scheme:

##STR00145##

General Procedure for the Oxidative Deprotection:

[0220] To a solution of 3-R-6-R-1,4-dimethoxy-2-methylnaphetalene (1 eq) in acetonitrile was added dropwise a solution of ceric ammonium nitrate (2.2 eq) in water. The solution was stirred at room temperature for 15 min. The reaction mixture was diluted with water and extracted twice with dichloromethane. The organic layer was washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure.

[0221] The crude residue was purified by flash chromatography on silica gel to afford the desired product.

TABLE-US-00004 Compound of formula (I) Yield [00146] 71% [00147] 85% [00148] 72% [00149] 15% [00150] 75% [00151] 96%

Preparation of 6-fluoro-3-((6-fluoropyridin-3-yl)methyl)-2-methylnaphthalene-1,4-dione (14)

[0222] ##STR00152##

0 4 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from 4/1 to 7/3, v/v, UV) with 71% yield (yellow solid). m.p.=141-143? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ?8.12 (dd, J=8.6, 5.1 Hz, 2H), 7.70 (dd, J=8.5, 2.6 Hz, 1H), 7.66 (dd, J=8.1, 2.4 Hz, 1H), 7.36 (td, J=8.4, 2.6 Hz, 1H), 6.83 (dd, J=8.4, 3.0 Hz, 1H), 3.98 (s, 2H), 2.27 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 183.8, 183.5 (d, .sup.4J.sub.C-F=1.4 Hz), 166.2 (d, .sup.1J.sub.C-F=257.3 Hz), 162.6 (d, .sup.1J.sub.C-F=238.5 Hz), 147.4 (d, .sup.3J.sub.C-F=14.6 Hz), 145.1, 144.3 (d, .sup.5J.sub.C-F=1.0 Hz), 141.5 (d, .sup.3J.sub.C-F=7.8 Hz), 134.5 (d, .sup.3J.sub.C-F=7.9 Hz), 131.3 (d, .sup.4J.sub.C-F=4.6 Hz), 129.9 (d, .sup.3J.sub.C-F=8.9 Hz), 128.7 (d, .sup.4J.sub.C-F=3.3 Hz), 121.1 (d, .sup.2J.sub.C-F=22.6 Hz), 113.3 (d, .sup.2J.sub.C-F=23.5 Hz), 109.7 (d, .sup.2J.sub.C-F=37.5 Hz), 29.2, 13.5. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-70.7 (m), ?102.03 (td, J=8.3, 5.3 Hz). HRMS calculated for C.sub.17H.sub.12F.sub.2NO.sub.2 [M+H].sup.+: 300.083061. Found 300.083945.

Preparation of 5-((7-fluoro-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)picolinonitrile (15)

[0223] ##STR00153##

0 15 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from 4/1 to 7/3, v/v, UV) with 85% yield (yellow solid). m.p.=153-154? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.62 (d, J=1.6 Hz, 1H), 8.11 (dd, J=8.6, 5.2 Hz, 1H), 7.68 (td, J=8.4, 7.6, 2.3 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.37 (td, J=8.3, 2.6 Hz, 1H), 4.07 (s, 2H), 2.27 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 183.4, 183.3 (d, .sup.4J.sub.C-F=1.5 Hz), 166.1 (d, .sup.1J.sub.C-F=257.6 Hz), 151.5, 145.7, 143.2 (d, .sup.4J.sub.C-F=1.9 Hz), 138.1, 137.1, 134.3 (d, .sup.3J.sub.C-F=8.0 Hz), 132.1, 130.0 (d, .sup.3J.sub.C-F=8.9 Hz), 128.7 (d, .sup.4J.sub.C-F=3.3 Hz), 128.5, 121.2 (d, .sup.2J.sub.C-F=22.5 Hz), 117.2, 113.3 (d, .sup.2J.sub.C-F=23.5 Hz), 30.3, 13.6. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-101.69 (td, J=8.2, 5.3 Hz). HRMS calculated for C.sub.18H.sub.12FN.sub.2O.sub.2 [M+H].sup.+: 307.087732. Found 307.088742.

Preparation of 6-fluoro-3-(furan-2-ylmethyl)-2-methylnaphthalene-1,4-dione (18)

[0224] ##STR00154##

18 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from 4/1 to 7/3, v/v, UV) with 14% yield (sticky yellow dark solid). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.12 (dd, J=8.6, 5.3 Hz, 1 H), 7.73 (dd, J=8.6, 2.6 Hz, 1H), 7.35 (td, J=8.3, 2.7 Hz, 1H), 7.27 (dd, J=1.8, 0.7 Hz, 1H), 6.27 (dd, J=3.2, 1.9 Hz, 1H), 6.08 (dd, J=3.2, 0.8 Hz, 1H), 4.03 (s, 2H), 2.29 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 184.1, 183.0 (d, .sup.4J.sub.C-F=1.4 Hz), 166.1 (d, .sup.1J.sub.C-F=256.8 Hz), 151.0, 145.4, 142.6 (d, .sup.5J.sub.C-F=2.0 Hz), 141.7, 134.7 (d, .sup.3J.sub.C-F=7.9 Hz), 129.8 (d, .sup.3J.sub.C-F=8.9 Hz), 128.9 (d, .sup.4J.sub.C-F=3.3 Hz), 120.8 (d, .sup.2J.sub.C-F=22.6 Hz), 113.3 (d, .sup.2J.sub.C-F=23.5 Hz), 110.6, 106.9, 25.7, 13.2. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-102.49 (td, J=8.3, 5.3 Hz). HRMS calculated for C.sub.16H.sub.12FO.sub.3 [M+H].sup.+: 271.076499. Found 271.078115.

Preparation of 3-((2-chloropyrimidin-5-yl)methyl)-6-fluoro-2-methylnaphthalene-1,4-dione (16)

[0225] ##STR00155##

16 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 72% yield (yellow solid). m.p.=167-168? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.53 (s, 2H), 8.13 (dd, J=8.6, 5.2 Hz, 1H), 7.69 (dd, J=8.5, 2.6 Hz, 1H), 7.38 (td, J=8.3, 2.6 Hz, 1H), 3.96 (s, 2H), 2.30 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 183.4, 183.2 (d, .sup.4J.sub.C-F=1.5 Hz), 166.2 (d, .sup.1J.sub.C-F=258.6 Hz), 160.0, 159.7 (2C), 145.5, 142.9 (d, .sup.5J.sub.C-F=1.9 Hz), 134.3 (d, .sup.3J.sub.C-F=7.9 Hz), 130.4, 130.0 (d, .sup.3J.sub.C-F=8.9 Hz), 128.6 (d, .sup.4J.sub.C-F=3.3 Hz), 121.3 (d, .sup.2J.sub.C-F=22.5 Hz), 113.4 (d, .sup.2J.sub.C-F=23.6 Hz), 27.2, 13.7. .sup.19F NMR (CDCl.sub.3, 377 MHz): ? -101.54 (td, J=8.2, 5.2 Hz). HRMS calculated for C.sub.16H.sub.11CIFN.sub.2O.sub.2[M+H].sup.+: 317.048760. Found 317.049497.

Preparation of 5-((7-fluoro-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)pyrimidine-2-carbonitrile (20)

[0226] ##STR00156##

20 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 75% (yellow solid). m.p.=187-188? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.76 (s, 2H), 8.15 (dd, J=8.6, 5.2 Hz, 1H), 7.71 (dd, J=8.4, 2.6 Hz, 1H), 7.41 (td, J=8.3, 2.6 Hz, 1H), 4.06 (s, 2H), 2.33 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 183.20, 183.18, 166.3 (d, .sup.1J.sub.C-F=258.1 Hz), 158.1 (2C), 146.0, 143.6, 142.2, 134.9, 134.2 (d, .sup.3J.sub.C-F=7.9 Hz), 130.2 (d, .sup.3J.sub.C-F=8.9 Hz), 128.7 (d, .sup.4J.sub.C-F=3.3 Hz), 121.5 (d, .sup.2J.sub.C-F=22.6 Hz), 115.7, 113.5 (d, .sup.2J.sub.C-F=23.6 Hz), 28.3, 13.8. .sup.19F NMR (CDCl.sub.3, 377 MHz): ? -101.19 (td, J=8.2, 5.3 Hz). HRMS calculated for C.sub.17H.sub.11FN.sub.3O.sub.2[M+H].sup.+: 308.082981. Found 308.084056.

Preparation of 6-fluoro-2-methyl-3-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)naphthalene-1,4-dione (17)

[0227] ##STR00157##

17 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 7/3, v/v, UV) with 96% yield (yellow solid). m.p.=195-197? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.81 (s, 2H), 8.14 (dd, J=8.6, 5.2 Hz, 1H), 7.70 (dd, J=8.4, 2.6 Hz, 1H), 7.39 (td, J=8.3, 2.7 Hz, 1H), 4.07 (s, 2H), 2.33 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 183.3, 183.2 (d, .sup.4J.sub.C-F=1.4 Hz), 166.3 (d, .sup.1J.sub.C-F=257.9 Hz), 158.0, 155.4 (q, .sup.2J.sub.C-F=37.1 Hz), 145.8, 142.6 (d, .sup.5J.sub.C-F=1.8 Hz), 134.3 (d, .sup.3J.sub.C-F=8.2 Hz), 134.2, 130.1 (d, .sup.3J.sub.C-F=8.9 Hz), 128.7 (d, .sup.4J.sub.C-F=3.3 Hz), 121.4 (d, .sup.2J.sub.C-F=22.5 Hz), 119.6 (d, .sup.1J.sub.C-F=275.3 Hz), 113.5 (d, .sup.2J.sub.C-F=23.6 Hz), 28.0, 13.7. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-70.24, ?101.44 (td, J=8.2, 5.3 Hz). HRMS calculated for C.sub.17H.sub.11F.sub.4N.sub.2O.sub.2 [M+H].sup.+: 351.075117. Found 351.075663.

Preparation of 6-fluoro-2-methyl-3-(thiophen-2-ylmethyl)naphthalene-1,4-dione (19)

[0228] ##STR00158##

M.p.=60-62? C. .sup.1H NMR (CDCl.sub.3, 400 MHz): ?8.10 (dd, J=8.6, 5.3 Hz, 1H), 7.73 (dd, J=8.6, 2.6 Hz, 1H), 7.34 (td, J=8.3, 2.7 Hz, 1H), 7.11 (dd, J=4.9, 1.4 Hz, 1H), 6.92-6.85 (m, 2H), 4.17 (s, 2H), 2.29 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 184.1, 183.2 (d, .sup.4J.sub.C-F=1.4 Hz), 166.1 (d, .sup.1J.sub.C-F=256.9 Hz), 144.6 (d, .sup.5J.sub.C-F=1.9 Hz), 144.4, 139.7, 134.6 (d, .sup.3J.sub.C-F=7.9 Hz), 129.7 (d, .sup.3J.sub.C-F=8.8 Hz), 128.8 (d, .sup.4J.sub.C-F=3.2 Hz), 127.0, 125.9, 124.3, 120.8 (d, .sup.2J.sub.C-F=22.6 Hz), 113.3 (d, .sup.2J.sub.C-F=23.2 Hz), 27.1, 13.2. .sup.19F NMR (CDCl.sub.3, 377 MHz): ?-102.36 (td, J=8.3, 5.3 Hz). HRMS calculated for C.sub.16H.sub.12FO.sub.2S [M+H].sup.+: 287.053655. Found 287.054700.

COMPARATIVE EXAMPLE

[0229] It was shown that the order of the steps is essential for the process of the invention for the preparation of the intermediate compounds of formula (IV).

[0230] The following reaction was carried out:

##STR00159##

[0231] By carring out a chloromethylation step from menadione, the compound of formula (IV) could not be obtained.

[0232] Moreover, the yield for this chloromethylation step was lower in comparison with the yield for this step in the preparation of compounds of formula (IV) from compounds of formula (V).

Comparative Biological Results

[0233] Regioisomeric compounds were synthetized using the process of WO 2020/252414 based on organozinc intermediates. MR00397 and MR00407 were obtained with very low yields (Scheme 2, Table):

##STR00160##

[0234] The synthesis of pyridinyl/pyrimidinyl derivatives of formula (I) according to the invention was investigated using the same method. Unfortunately, both molecules were obtained in inseparable mixtures. The mixtures were allowed to react with CAN. MR00418 was isolated with a second fluorinated compound and MR00419 with 4 other fluorinated compounds. The structures of the (non separated) side-products were not elucidated.

##STR00161##

[0235] The method according to the invention is thus the most efficient synthetic pathway to synthetize MR00418 and MR00419. With this method, MR00418 was obtained with total 84% yield in 2 steps from MD705. MR00419 was synthetized in 2 steps from MD705 with total 67% yield in 2 steps

[0236] The first primary screening, performed with the Plasmodium falciparum NF54 strain and the rat L6 myoblast cell line, showed that both MR00418 and MR00419 displayed more potent and specific antimalarial activities than the regioisomers MR00397 and MR00407, respectively:

TABLE-US-00005 NF54 IC50 L6 IC50 (nM) (?M) MRO0418 (invention) 6 179.3 MRO0397 567 N.D. MRO0419 (invention) 65 48.3 MRO0407 84 N.D. plasmodione 8 141.7