The present invention concerns heteroaromatic analogues of 3- benzylmenadione derivatives, as well as processes for their preparation.

Unsymmetrical methylene-linked biaryl systems are important building blocks in medicinal chemistry. When applied to the 3-benzylmenadione series, no general or versatile synthetic strategy has been developed. In 1991 , a team from Takeda Pharmaceutical (formerly Takeda Chemical Industry) published the synthesis of numerous quinones bearing a 3-picolinyl group. One of these was the synthesis of 3- (3-picolinyl)menadione, one of the target molecules. This team inserted a bromomethyl or chloromethyl group in position 3 to achieve a direct coupling with a lithiated 3-pyridine (Ohkawa S, Terao S, TerashitaZ-l, Shibouta Y, Nishikawa K. Dual inhibitors of thromboxane A2 synthase and 5-lipoxygenase with scavenging activity of active oxygen species (AOS). Synthesis of a novel series of (3- pyridylmethyl)benzoquinone derivatives. J. Med. Chem. 1991, 34, 267-276. doi: 10.1021 /jm00105a042).

In the simple di(hetero)arylmethane series, benzyl halides were efficiently coupled with various aromatic and especially heteroaromatic boronic acids by a pallado-catalysed Suzuki coupling (Henry N, Enguehard-GueiffierC, Thery I, Gueiffier A. One-Pot Dual Substitutions of Bromobenzyl Chloride, 2-Chloromethyl-6- halogenoimidazo[1 ,2-a]pyridine and -[1 ,2-b]pyridazine by Suzuki-Miyaura Cross- Coupling Reactions. Eur. J. Org. Chem. 2008, 4824^827. doi:

10.1002/ejoc.200800544). But, no methylene-linked biaryl systems were built within the quinone series using the Suzuki coupling reaction.

The aim of the present invention is to provide new heteroaromatic analogues of 3-benzylmenadione derivatives that could be useful as ligands or components for active oxygen barriers in plastic polymers for food and drink preservation.

Another aim of the present invention is to provide new heteroaromatic analogues of 3-benzylmenadione derivatives that could be useful as therapeutic compounds. Another aim of the present invention is also to provide a new efficient process for the preparation of heteroaromatic analogues of 3-benzylmenadione derivatives with a satisfying yield.

The present invention thus relates to a compound having the formula (I): wherein:

• R ¹ is selected from the group consisting of: H, F, (Ci-C ₆ )alkoxy, and halo(Ci- C ₆ )alkyl; and

• R ² is a heteroaryl group, said heteroaryl group being optionally substituted with at least one substituent selected from the group consisting of:

. halogen,

. halo(Ci-C ₆ )alkyl,

. (Ci-C ₆ )alkoxy,

. CN,

. (Ci-Ce)alkyl,

. NR _a R _b , R _a and R _b , identical or different, being independently H or a (Ci- C ₆ )alkyl, such as NH ₂ ,

. (C2-C6)alkynyl, such as -CºC-,

. OR _c , R _c being a cycloheteroalkyl, preferably an oxetanyl group,

. NO ₂ ,

. SF ₃ ,

. SF ₅ ,

. -C(=0)-(Ci-C ₆ )alkyl,

. halo(Ci-C ₆ )alkoxy, and . (Ci-C ₆ )alkoxy, provided that the compound of formula (I) is different from the following compound: According to the invention, R ² is an optionally substituted heteroaryl group as defined above being different from the following heteroaryl groups, optionally substituted:

According to an embodiment, R ² is an optionally substituted heteroaryl group as defined above being different from the following heteroaryl groups, optionally substituted:

R ³ being selected from the group consisting of: halogen, halo(Ci-C ₆ )alkyl, (Ci- C ₆ )alkoxy, CN, (Ci-C ₆ )alkyl, NR _a R _b , R _a and R _b , identical or different, being independently H or a (Ci-C ₆ )alkyl, such as NH ₂ , (C2-C6)alkynyl, such as -CºC-,

OR _c , R _c being a cycloheteroalkyl, preferably an oxetanyl group, N0 ₂ , SF ₃ , SF ₅ , -C(=0)-(Ci-C ₆ )alkyl, halo(Ci-C ₆ )alkoxy, and (Ci-C ₆ )alkoxy.

The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The expression "C _t -C _z " means a carbon-based chain which can have from t to z carbon atoms, for example C ₁ -C ₃ means a carbon-based chain which can have from 1 to 3 carbon atoms.

The term "alkyl group" means: a linear or branched, saturated, hydrocarbon- based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms. By way of examples, mention may be made of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl groups. The term "aryl group" means: a cyclic aromatic group comprising between 6 and 10 carbon atoms. By way of examples of aryl groups, mention may be made of phenyl or naphthyl groups.

When an alkyl radical is substituted with an aryl group, the term "arylalkyl" or "aralkyl" radical is used. The "arylalkyl" or "aralkyl" radicals are aryl-alkyl- radicals, the aryl and alkyl groups being as defined above. Among the arylalkyl radicals, mention may in particular be made of the benzyl or phenethyl radicals.

The term "halogen" means: a fluorine, a chlorine, a bromine or an iodine.

The term "alkoxy group" means: an -O-alkyl radical where the alkyl group is as previously defined. By way of examples, mention may be made of -0-(Ci-C ₄ )alkyl groups, and in particular the -O-methyl group, the -O-ethyl group as -0-C ₃ alkyl group, the -O-propyl group, the -O-isopropyl group, and as -0-C ₄ alkyl group, the -O-butyl, -O-isobutyl or -O-tert-butyl group.

The term "haloalkyl group" means: an alkyl group as defined above, in which one or more of the hydrogen atoms is (are) replaced with a halogen atom. By way of example, mention may be made of fluoroalkyls, in particular CF ₃ or CHF ₂ .

The term "haloalkoxy group" means: an -O-haloalkyl group, the haloalkyl group being as defined above. By way of example, mention may be made of fluoroalkyls, in particular OCF ₃ or OCFF ₂ .

The abovementioned "alkyl" radicals can be substituted with one or more substituents. Among these substituents, mention may be made of the following groups: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy or carboxyalkyl.

The term "alkylthio" means: an -S-alkyl group, the alkyl group being as defined above.

The term "alkylamino" means: an -NH-alkyl group, the alkyl group being as defined above.

The term "aryloxy" means: an -O-aryl group, the aryl group being as defined above.

The term "arylalkoxy" means: an aryl-alkoxy- group, the aryl and alkoxy groups being as defined above.

The term "carboxyalkyl" means: an FlOOC-alkyl- group, the alkyl group being as defined above. As examples of carboxyalkyl groups, mention may in particular be made of carboxymethyl or carboxyethyl.

The term "heteroalkyl group" means: an alkyl group as defined above, in which one or more of the carbon atoms is (are) replaced with a heteroatom, such as O or N. The term "carboxyl" means: a COOH group.

The term "oxo" means: "=0".

The term "heterocycloalkyl group" means: a 4- to 10-membered, saturated or partially unsaturated, monocyclic or bicyclic group comprising from one to three heteroatoms selected from O, S or N; the heterocycloalkyl group may be attached to the rest of the molecule via a carbon atom or via a heteroatom. As an example, one may cite oxetanyl.

According to an embodiment, in formula (I), R 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.

As examples of heteroaryl groups, mention may be made of imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl and isoquinolinyl groups.

By way of a heteroaryl comprising 5 to 6 atoms, including 1 to 4 nitrogen atoms, mention may in particular be made of the following representative groups: pyrrolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl and 1 ,2,3-triazinyl.

Mention may also be made, by way of heteroaryl, of thiophenyl, oxazolyl, furazanyl, 1 ,2,4-thiadiazolyl, naphthyridinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2- a]pyridine, imidazo[2,1-b]thiazolyl, cinnolinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothiophenyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1 ,2,4-triazinyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolyl, 1 ,3,4-thiadiazolyl, thiazolyl, isothiazolyl, carbazolyl, and also the corresponding groups resulting from their fusion or from fusion with the phenyl nucleus.

According to an embodiment, the compounds of the invention are compounds having the formula (I) as defined above wherein R ¹ is H or F.

According to an embodiment, the compounds of the invention are compounds having the formula (I) as defined above wherein R ² is selected from the group consisting of: pyridinyl other than , pyrimidinyl other than quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, -CºC-, and CN.

According to an embodiment, the compounds of the invention are compounds having the formula (I) as defined above wherein R ² is selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, -CºC-, and CN, wherein said pyridinyl has the following formula: and wherein said pyrimidinyl has the following formula:

According to an embodiment, the compounds of the invention are compounds having the formula (I) as defined above wherein R ¹ is H or F, and R ² is selected from the group consisting of: pyridinyl other than , pyrimidinyl other than , quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, -CºC-, and CN.

As preferred compounds according to the invention, the followings may be mentioned:

54 55 56

The compounds of formula (I) according to the invention are for example used as drug-candidates or compounds with therapeutic properties, or as ligands or components for active oxygen barriers in plastic polymers for food and drink preservation.

The present invention also relates to a process for the preparation of a compound having the formula (I): wherein:

• R ¹ is selected from the group consisting of: H, F, (Ci-C ₆ )alkoxy, and halo(Ci- C ₆ )alkyl; and

• R ² is a heteroaryl group as defined above, said heteroaryl group being optionally substituted with at least one substituent selected from the group consisting of:

. halogen,

. halo(Ci-C ₆ )alkyl,

. (Ci-C ₆ )alkoxy,

. CN,

. (Ci-Ce)alkyl,

. NR _a R _b , R _a and R _b , identical or different, being independently H or a (Ci- C ₆ )alkyl, such as NH ₂ ,

. (C ₂ -C ₆ )alkynyl, such as -CºC-,

. OR _c , R _c being a cycloheteroalkyl, preferably an oxetanyl group,

. NO ₂ ,

. SF ₃ ,

. SF ₅ , . -C(=0)-(C ₁ -C ₆ )alkyl,

. halo(Ci-C ₆ )alkoxy,

. (Ci-C ₆ )alkoxy, said process comprising the preparation of a compound having the following formula (IV): wherein:

- R ¹ is selected from the group consisting of: H, F, (Ci-C ₆ )alkoxy, and halo(Ci- C ₆ )alkyl; and

- X is Cl or Br, by the chloromethylation or bromomethylation of a compound having the following formula (V): wherein R ¹ is selected from the group consisting of: H, F, (Ci-C ₆ )alkoxy, and halo(Ci-C ₆ )alkyl.

Depending on the nature of the R2 group, the compounds of formula (I) may be further submitted to a post-functionalization step, especially for modifying the nature of the possible substituent present on the heteroaryl group.

According to an embodiment, the chloromethylation or bromomethylation step as defined above is carried out with a mixture of hydrochloric acid or hydrobromic acid with paraformaldehyde (or aqueous formaldehyde) in the presence of a solvent selected from the group consisting of: water, acetic acid, and dioxane.

Preferably, the chloromethylation or bromomethylation step is carried out in a mixture of hydrochloric acid or hydrobromic acid and paraformaldehyde. According to an embodiment, the chloromethylation or bromomethylation step is carried out for a duration comprised from one hour to 24 hours, preferably for 3 hours.

According to an embodiment, the chloromethylation or bromomethylation step is carried out at a temperature comprised from 20°C to 100°C, preferably at 80°C.

Preferably, the chloromethylation or bromomethylation step mentioned above is a chloromethylation step. Therefore, preferably, the obtained compounds from the compounds of formula (V) as defined above are compounds having the following formula (IV-1):

R ¹ being as defined above in formula (IV).

Preferably, the chloromethylation step is carried out in a mixture of hydrochloric acid and paraformaldehyde.

According to an embodiment, the chloromethylation step is carried out for a duration comprised from one hour to 24 hours, preferably for 3 hours when R ¹ is H, or 18 hours R ¹ is F.

According to an embodiment, the chloromethylation step is carried out at a temperature comprised from 20°C to 100°C, preferably at 80°C when R ¹ is H, or 60°C when R ¹ is F.

According to an embodiment, the process of the invention further comprises the pallado-catalyzed Suzuki coupling of the compound of formula (IV) as defined above with a boronic acid compound having the formula (III) or (IN’): wherein R ² is as defined above in formula (I), in order to obtain a compound having the following formula (II): R ¹ and R ² being as defined above in formula (I).

According to an embodiment, the pallado-catalyzed coupling is carried out with a palladium catalyst selected from the group consisting of: Pd(PPh ₃ )4, PdCh, PdCl2(dppf), Pd(OAc)2 and PPh ₃ , and with a base selected from the group consisting of: Na ₂ C0 ₃ , K ₂ C0 ₃ , KOtBu, Cs ₂ C0 ₃ , NaOH, and NEt ₃ , or with K ₃ P0 ₄ in toluene.

Preferably, the pallado-catalyzed coupling is carried out with a palladium catalyst being Pd(PPh ₃ ) , and with a base being Na ₂ C0 ₃ .

Preferably, the amount of palladium catalyst is comprised from 2 to 5% in moles in comparison with the number of moles of compound of formula (IV) or (IV-1 ).

Preferably, the amount of base is comprised from 2 to 5 equivalents, and is preferably 2.1 equivalents.

According to an embodiment, the pallado-catalyzed coupling is carried out in the presence of a solvent selected from the group consisting of: dimethoxyethane

(DME)/water, tetrahydrofuran (THF)/water, dioxane/water, dimethylformamide

(DMF)/water, toluene/water, preferably in a mixture DME/water.

According to an embodiment, the pallado-catalyzed coupling is carried out for a duration comprised from 30 minutes to 6 hours, preferably for 1 hour.

According to an embodiment, the pallado-catalyzed coupling is carried out at a temperature comprised from 70°C to 150°C, preferably at 100°C.

According to an embodiment, the process of the invention further comprises an oxidative demethylation step of the compound of formula (II) as defined above in the presence of an oxidant, in order to obtain the compound of formula (I) as defined above.

Preferably, the oxidant is selected from the group consisting of: ceric ammonium nitrate (CAN), silver oxide (Ag0/Ag ₂ 0), OsCVNalC , oxone, BBr ₃ with O2 or open air, and boron trichloride/Tetra-n-butylammonium iodide (BCI ₃ /TBAI) with O2 or open air.

According to an embodiment, the oxidative demethylation step is carried out in the presence of a solvent selected from the group consisting of: a mixture of acetonitrile and water, dichloromethane for BBr ₃ or BCI ₃ /TBAI, preferably in a mixture of acetonitrile and water. According to an embodiment, the oxidative demethylation step is carried out for a duration comprised from 10 minutes to 6 hours, preferably for 1 hour.

According to an embodiment, the oxidative demethylation step is carried out at a temperature comprised from 4°C to 50°C, preferably at room temperature (22- 25°C).

According to an embodiment of the process according to the invention, the compound of formula (V) is prepared by reacting a compound having the following formula (VI): wherein R ¹ is selected from the group consisting of: H, F, (Ci-Ce)alkoxy, and halo(Ci-C ₆ )alkyl, with a reducing agent, followed by a methylation step, in order to obtain the compound of formula (V) as defined above.

The compound of formula (V) as defined above is thus obtained from the compound of formula (VI) by the implementation of a reduction step, followed by a methylation step.

According to an embodiment, the reducing agent is selected from the group consisting of: SnCh and HCI, and sodium dithionite.

According to an embodiment, the reduction step is carried out in the presence of a solvent selected from the group consisting of: MeOH, EtOH, or MeOH/water, EtOH/water for sodium dithionite, preferably in ethanol or methanol.

According to an embodiment, the reduction step is carried out for a duration comprised from one hour to 4 hours, preferably for 2 hours.

According to an embodiment, the reduction step is carried out at a temperature comprised from 15°C to 50°C, preferably at room temperature (22-25°C).

According to an embodiment, the methylation step is carried out with a methylation agent, said methylation agent being selected from the group consisting of: Me2SC>4, and ICH ₃ .

According to an embodiment, the methylation step is carried out in the presence of a solvent being acetone. According to an embodiment, the methylation step is carried out in the presence of a base selected from the group consisting of NaOH, and KOH.

According to an embodiment, the methylation step is carried out for a duration comprised from one hour to 16 hours, preferably for 4 hours.

According to an embodiment, the methylation step is carried out at a temperature comprised from 40°C to 60°C, preferably at 60°C.

According to an embodiment, R ² is selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, halo(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, and CN.

According to an embodiment, R ¹ is H or F.

The present invention also relates to a compound having the following formula

(II): wherein:

• R ¹ is selected from the group consisting of: H, F, (Ci-C ₆ )alkoxy, and halo(Ci- C ₆ )alkyl; and

• R ² is a heteroaryl group as defined above in formula (I), said heteroaryl group being optionally substituted with at least one substituent selected from the group consisting of:

. halogen,

. halo(Ci-C ₆ )alkyl,

. (Ci-C ₆ )alkoxy,

. CN,

. (Ci-Ce)alkyl,

. NR _a R _b , R _a and R _b , identical or different, being independently FI or a (Ci- C ₆ )alkyl, such as NFI ₂ ,

. (C2-C6)alkynyl, such as -CºC-,

. OR _c , R _c being a cycloheteroalkyl, preferably an oxetanyl group,

. N0 ₂ ,

. SF ₃ ,

. SF ₅ , . -C(=0)-(Ci-C ₆ )alkyl,

. halo(Ci-C ₆ )alkoxy,

. (Ci-C ₆ )alkoxy, provided that the compound of formula (II) is different from the following compound:

As compounds of formula (II), the followings may be mentioned:

59 60 The present invention also relates to a compound having the following formula

(IV): wherein R ¹ is selected from the group consisting of: H, F, (Ci-C ₆ )alkoxy, and halo(Ci-C ₆ )alkyl, provided that the compound of formula (IV) is different from the following compounds:

As compounds of formula (IV), the followings may be mentioned:

The present invention also relates to a compound having the following formula

(V): wherein R ¹ is selected from the group consisting of: F, (Ci-C ₆ )alkoxy, and halo(Ci-C ₆ )alkyl.

As compounds of formula (V), the followings may be mentioned: EXAMPLES

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. Muller, 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.

The compounds of formula (I) according to the invention are prepared according to the following general scheme: PREPARATION OF COMPOUNDS OF FORMULA (IP (bv Suzuki reaction between 2-methyl-3-chloromethyl-1,4,-dimethoxynaphtalene and boronic acids of formula (III))

The compounds of formula (II) wherein R ¹ =H are prepared according to the following reaction scheme: , y p or 2-methyl-3-chloromethyl- 6-fluoro-1 ,4-dimethoxynaphtalene 2

Synthesis of 2-(chloromethyl)-1 ,4-dimethoxy-3-methylnaphthalene: 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% aqueous HCI (50 ml.) were heated at 80 °C during 2 h. The mixture was cooled down, diluted with water and extracted three times with EtOAc. The reunited organic layers were washed with brine, dried over MgSC> 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. ¹ H NMR (400

MHz, CDCIs) d 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:

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 30min 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.

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

- 7.50 (m, 2H), 7.46 (ddd, J = 8.1 , 6.7, 1 .2 Hz, 1 H), 4.44 (s, 2H), 3.87 (s, 6H), 2.29 (s,

3H). ¹³ C NMR (126 MHz, CDCI ₃ ) d 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 ₂₃ H ₂₂ N0 ₂ : 344.1645. Found: 344.1659 (MH ⁺ ). Preparation of 3-((1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) pyridine (21’)

5 mol% Pd(PPh ₃ ), Eluant Cyclohexane:Ethyl acetate (1 :1 ), yellowish solid, 71% yield. ¹ H NMR (500 MHz, CDCI ₃ ) d 8.50 (dd, J = 2.3, 1.0 Hz, 1 H), 8.41 (dd, J = 4.8, 1 .6 Hz, 1 H), 8.12 - 8.04 (m, 2H), 7.63 - 7.42 (m, 2H), 7.39 - 7.32 (m, 1 H), 7.13 (ddd, J = 7.8, 4.8, 0.9 Hz, 1 H), 4.25 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.26 (s, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) d 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 ₁₉ H ₂₀ NO ₂ : 294.1489. Found: 294.1490 (MH ⁺ ).

Preparation of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) pyrimidine (22) 5 mol% Pd(PPh ₃ ), Eluant Cyclohexane:Ethyl acetate (1 :1), beige solid, 87% yield. ¹ H NMR (500 MHz, CDCI ₃ ) d 9.04 (s, 1 H), 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). ¹³ C NMR

(126 MHz, CDCIs) d 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 ₁₈ H ₁₉ N ₂ 0 ₂ : 295.1441. Found: 295.1450 (MH+).

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

3H), 2.26 (s, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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. ¹⁹ F NMR

(471 MHz, CDCIs) d -67.68. HRMS (ESI) calcd. for C ₂₀ H ₁₉ F ₃ NO ₂ : 362.1362. Found:

362.1368 (MH ⁺ ). Preparation of 5-((1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2- fluoropyridine (24)

2 mol% Pd(PPh ₃ ), Eluant Cyclohexane:Ethyl acetate (9:1), white solid, 89% yield. ¹ H NMR (400 MHz, CDCI ₃ ) d 7.94 - 7.70 (m, 3H), 7.40 - 7.19 (m, 3H), 6.54 (ddd, J= 8.4, 3.1 , 0.6 Hz, 1 H), 3.98 (s, 1 H), 3.63 (s, 3H), 3.61 (s, 3H), 2.03

(s, 3H). ¹⁹ F NMR (377 MHz, CDCI ₃ ) d -72.09 (d, J = 8.0 Hz). ¹³ C NMR (101 MHz, CDCh) d 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 ₁₉ H ₁₉ FN0 ₂ : 312.1394. Found: 312.1403 (MH ⁺ ).

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

5 mol% Pd(PPh ₃ ), Eluant Cyclohexane:Ethyl acetate (9:1), white solid, 87% yield. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.19 (dd, J= 2.6, 0.8 Hz, 1 H), 8.07 - 7.91 (m, 2H), 7.51 - 7.38 (m, 2H), 7.26 (dd, J = 8.2, 2.5 Hz, 1 H), 7.08 (dd, J =

8.2, 0.7 Hz, 1 H), 4.13 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 2.18 (s, 3H). ¹³ C NMR (101 MHz, CDCIs) d 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 ₁₉ H ₁₉ CIN0 ₂ : 328.1099. Found: 328.1102 (MH ⁺ ).

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

2 mol% Pd(PPh ₃ ), Eluant Cyclohexane:Ethyl acetate (8:2), white solid, 97% yield. ¹ H NMR (400 MHz, CDCI ₃ ) d 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). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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 ₁₈ H ₁₈ CIN ₂ 0 ₂ : 329.1051. Found: 329.1054 (MH ⁺ ). Preparation of 5-((1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2- (trifluoromethyl)pyrimidine (27) , , , , , , ,

NMR (377 MHz, CDCI ₃ ) d -70.15. HRMS (ESI) calcd. for CI ₇ HI ₂ F ₃ N ₂ 0 ₂ : 333.0845. Found: 333.0868 (MH ⁺ ).

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

J= 8.6, 0.7 Hz, 1 H), 4.16 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.85 (s, 3H), 2.28 (s, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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 ₂₀ H ₂₂ NO ₃ : 324.1594. Found: 324.1617 (MH+).

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

2 mol% Pd(PPh ₃ ) Eluant Cyclohexane:Ethyl acetate (s, 3H), 2.30 (s, 3H). HRMS (ESI) calcd. for

C ₁₉ H ₂₀ N ₂ NaO ₃ : 347.1366. Found: 347.1357 (MNa ⁺ ).

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

(30) 2 mol% Pd(PPh ₃ ) ₄ , Eluant Cyclohexane:Ethyl acetate (99:1 up to 98:2), translucid oil, 99% yield. ¹ H NMR (400 MHz, CDCIs) d 8.19 - 8.03 (m, 2H), 7.62 - 7.46 (m, 2H), 7.34 (dd, J = 1.8, 0.9 Hz, 1 H), 6.27 (dd, J = 3.2, 1 .9 Hz, 1 H), 5.85 (dq, J = 3.2, 1 .1 Hz, 1 H), 4.27 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.41 (s, 3H). ¹³ C NMR (101 MHz, CDCIs) d 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 ₁₈ H ₁₉ 0 ₃ : 283.1329. Found: 283.1334 (MH ⁺ ).

Post-modifications of Suzuki coupling products:

Preparation of 5-((1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) pyrimidine-2-carbonitrile (32) 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 MgS04 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. ¹ H NMR (400 MHz, CDCI ₃ ) d 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). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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 C17H12N3O2: 290.0924. Found: 290.0918 (MH ⁺ ).

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

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 5h 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 MgS04 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. ¹ H NMR (500 MHz, CDCI3) d 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). ¹³ C NMR (126 MHz, CDCI3) d 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 CieH^BrlShC^: 343.0077. Found: 343.0099 (MH ⁺ ).

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

2 mol% Pd(PPh ₃ ), Eluant Cyclohexane:Ethyl acetate , , ,

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 CI ₈ H _2O N ₃ 02: 310.1550. Found: 310.1539 (MH ⁺ ). M. p. = 198-200 °C. Preparation of 5-((7-fluoro-1 ,4-dimethoxy-3-methylnaphthalen-2-yl) methyl)-2-(trifluoromethyl)pyridine (58): 7.66 (dd, J = 10.3, 2.5 Hz, 1 H), 7.53 (d, J = 1.4 Hz, 2H), 7.28 (ddd, J = 9.2, 8.3, 2.6 Hz, 1 H), 4.30 (s, 2H), 3.84 (s, 6H), 2.24 (s, 3H). ¹³ C NMR (101 MHz, CDCh) d 162.4, 159.9, 151.0 (d, ⁵ J _C -F = 1.3 Hz), 150.3 (d, ⁴ _C -F = 5.4 Hz), 150.1 , 146.2 (q, ² J _C -F = 34.7 Hz), 140.0-138.9 (m), 136.8, 128.6, 128.3 (d, ³ JC-F = 8.6 Hz), 125.5 (d, ³ J _C -F = 7.2 Hz), 125.4 (d, ³ J _C -F = 9.0 Hz), 121.8 (q, ¹ J _C -F = 273.7 Hz), 120.4 (q, ⁴ J _C -F = 2.7 Hz), 116.6 (d, ² J _C -F = 25.4 Hz), 106.4 (d ² J _C -F = 22.4 Hz), 62.3, 61.7, 30.3, 12.7. ¹⁹ F NMR (377 MHz, CDCh): 6 -67.71 , -114.25 (ddd, J = 10.1 , 8.4, 5.6 Hz). HRMS (ESI+) calcd. for C2 _O HI ₈ F ₄ N0 : 380.126818. Found: 380.125589 (MH ⁺ ).

Preparation of 5-((7-fluoro-1 ,4-dimethoxy-3-methylnaphthalen-2-yl) methyl)benzo[d]thiazole (59): 7.70 (dd, J= 10.4, 2.5 Hz, 1 H), 7.34-7.25 (m, 2H), 4.43 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H). ¹³ C NMR (101 MHz, CDCh) 6 161.0 (d, ¹ JC-F = 245.2 Hz), 150.8 (d, ⁵ J _C -F = 1.1 Hz), 150.2 (d, ⁴ J _C -F = 5.3 Hz), 139.0, 130.3, 128.4, 128.3, 126.4 (2C), 126.2 (d, ⁴ J _C -F = 2.4 Hz), 125.23, 125.17 (d, ³ J _C -F = 8.9 Hz), 122.7, 121.7 (2C), 116.1 (d, ² J _C -F = 25.4 Hz), 106.3 (d, ² J _C -F = 22.3 Hz), 62.3, 61.6, 32.8, 12.7. ¹⁹ F NMR (377 MHz, CDCh): 6 -114.78 (ddd, J = 10.2, 8.5, 5.7 Hz). HRMS (ESI+) calcd. for C21H19FNO2S: 368.111504. Found: 368.110660 (MH ⁺ ). Preparation of 5-((1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) benzo[rf]thiazole (60): 7.48 (m, 2H), 7.31 (d, J = 8.2 Hz, 1 H), 4.46 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.31 (s, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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 C21H20NO2S:

350.120926. Found: 350.120240 (MH ⁺ ). M.p. = 139-141 °C.

Preparation of 6-((1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl) benzo[d]thiazole (61): 1 H), 4.43 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.28 (s, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) <5 153.5, 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 C21H20NO2S: 350.120926. Found: 350.121033 (MH ⁺ ).

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

2 mol% Pd(PPh ) Eluant c clohexane/eth l acetate , , , , , , ,

J = 8.8, 2.5 Hz, 1 H), 4.41 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.26 (s, 3H). ¹³ C NMR (101 MHz, CDCIs) <5 161.0 (d, ¹ J _C -F = 245.4 Hz), 153.8, 152.2, 150.8 (d, ⁴ J _C -F = 1.2

Hz), 150.2 (d, ³ JC-F = 5.3 Hz), 138.2, 134.7, 130.4, 128.3 (d, ³ J _C -F = 8.6 Hz), 127.1 ,

126.2 (d, ⁴ JC-F = 2.5 Hz), 125.3, 125.2, 123.4, 120.7, 116.2 (d, ² J _C -F = 25.4 Hz), 106.4 (d, ² JC-F = 22.3 Hz), 62.3, 61.7, 32.9, 12.7. ¹⁹ F NMR (CDCIs, 377 MHz): <5 -114.66 (ddd, J= 10.2, 8.4, 5.7 Hz). HRMS (ESI+) calcd. for C21H19NO2S: 368.111504. Found: 368.111827 (MH ⁺ ).

Preparation of 5-[(1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl]pyridin- 2-amine (63): un omogenous an was a e ropw se o a solution of 5-((1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-fluoropyridin e (108 mg, 0.35 mmol, 1 .0 equiv.) in anhydrous DMSO (500 mI_), 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 MgS0 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%). ¹ H NMR (CDCI ₃ , 400 MHz): <58.12- 8.04 (m, 2H), 7.88 (d, J = 1.8 Hz, 1 H), 7.53-7.46 (m, 2H), 7.37 (dd, J = 8.5, 2.4 Hz, 1 H), 6.66 (d, J = 8.5 Hz, 1 H), 5.55 (p, J = 5.8 Hz, 1 H), 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). ¹³ C { ¹ H} NMR (CDCIs, 126 MHz): <5 160.9, 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 C22H24NO4: 366.169985. Found: 366.169403 (MH ⁺ ).

5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-(oxet an-3- yloxy)pyrimidine (65): 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. ¹ H NMR (CDCI ₃ , 400 MHz): <58.29 (s, 2H), 8.11-8.03 (m,

2H), 7.55-7.47 (m, 2H), 5.53 (q, J= 6.2 Hz, 1 H), 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). ¹³ C { ¹ H} NMR (CDCI3, 101 MHz): <5 162.9, 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 C21H23N2O4: 367.165324. Found: 367.165015 (MH ⁺ ).

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)-2-(oxetan-3-yloxy)pyrimidine (66): 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 MRO0331 (85 mg, 83%) as a colorless oil. ¹ H NMR (CDCI ₃ , 400 MHz): <58.28 (s, 2H), 8.07 (dd, J = 9.2, 5.5 Hz, 1 H), 7.64 (dd, J = 10.3, 2.5 Hz, 1 H), 7.27 (ddd, J = 9.2, 8.3, 2.6 Hz, 1 H), 5.53 (p, J = 6.0 Hz, 1 H), 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). ¹³ C { ¹ H} NMR (CDCI ₃ , 101 MHz): <5 162.9, 161.1 (d, ¹ J _C -F = 245.9 Hz), 159.1 (2C), 151.0 (d, ⁵ J _C -F = 1.3 Hz), 150.1 (d, ⁴ JC-F = 5.4 Hz), 128.7, 128.3 (d, ³ J _C -F = 8.7 Hz), 127.4, 125.44 (d, ⁵ J _C -F = 1.1 Hz), 125.36 (d, ³ J _C -F = 8.9 Hz), 125.2 (d, ⁴ J _C -F 2.5 Hz), 116.6 (d, ² J _C -F = 25.4 Hz), 106.4 (d, ² JC-F = 22.4 Hz), 77.9 (2C), 70.1 , 62.3, 61.8, 27.2, 12.7. ¹⁹ F NMR (CDCI ₃ , 377 MHz): <5 -114.23 (ddd, J 10.1 , 8.4, 5.6 Hz). HRMS (ESI+) calcd. for C21H22FN2O4: 385.155812. Found: 385.156295 (MH ⁺ ).

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)-2-(oxetan-3-yloxy)pyridine (67): 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. ¹ H NMR (CDCI ₃ , 400 MHz): <58.07 (dd, J = 9.2, 5.6 Hz, 1 H), 7.86 (d, J = 1 .9 Hz, 1 H), 7.66 (dd, J = 10.4, 2.5 Hz, 1 H), 7.36 (dd, J = 8.5, 2.4 Hz, 1 H), 7.29-7.22 (m, 1 H), 6.67 (d, J = 8.5 Hz, 1 H), 5.55 (p, J = 5.8 Hz, 1 H), 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). ¹³ C { ¹ H} NMR (CDCIs, 101 MHz): <5161 .0 (d, ¹ J _C -F = 245.4 HZ), 160.9, 150.8 (d, ⁵ J _C -F = 1 .2 Hz), 150.0 (d, ⁴ JC-F = 5.4 Hz), 146.0, 139.2, 130.0, 129.0, 128.30, 128.27 (d, ³ J _C -F = 8.6 Hz), 125.8 (d, ⁴ JC-F = 2.5 Hz), 125.21 (d, ³ J _C -F = 8.8 Hz), 125.20, 116.2 (d, ² J _C -F = 25.4 Hz), 110.8, 106.3 (d, ² JC-F = 22.3 Hz), 78.4 (2C), 69.0, 62.2, 61.6, 29.4, 12.6. ¹⁹ F NMR (CDCI ₃ , 377 MHz): 6-114.64 (ddd, J = 10.2, 8.4, 5.7 Hz). HRMS (ESI+) calcd. for C ₂₂ H ₂₃ FN0 ₄ : 384.160563. Found: 384.161191 (MH ⁺ ). Preparation of 5-[(1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl]-2-[2-

(trimethylsilyl)ethynyl]pyrimidine (68’): , , 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 MgSC 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. ¹ H NMR (CDCIs, 400 MHz): <58.49 (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). ¹³ C { ¹ H} NMR (CDCI ₃ , 101 MHz): 6157.0 (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 C23H27S1N2O2: 391 .183631 . Found: 391 .181585 (MH ⁺ ).

Preparation of 5-[(1 ,4-dimethoxy-3-methylnaphthalen-2-yl)methyl]-2- ethynylpyrimidine (68): ’ at room temperature for 1.5 h. The mixture was quenched with a saturated aqueous solution of NH CI. The aqueous layers were extracted three times with diethyl ether. The organic extracts were dried over MgSC>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. ¹ H NMR (CDCI ₃ , 400 MHz): <58.50 (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, 1 H), 2.27 (s, 3H). ¹³ C { ¹ H} NMR (CDCI ₃ , 101 MHz): <5 157.1 , 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 C20H19N2O2: 319.144104. Found: 319.143171 (MH ⁺ ).

PREPARATION OF COMPOUNDS OF FORMULA (I) (by oxidative deprotection from the compounds of formula (II))

The compounds of formula (I) wherein R ¹ =H or F are prepared according to the following reaction scheme:

General procedure for the oxidative deprotection:

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/H2O 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 MgS04 and the solvent was removed under reduced pressure. Purification by silica gel chromatography was performed using the adequate eluent.

Preparation of 2-methyl-3-(pyridin-3-ylmethyl)naphthalene-1,4-dione (1”) Eluant Cyclohexane:Ethyl acetate (1 :1), yellow solid, 74% yield. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.54 - 8.51 (m, 1 H), 8.43 (dd, J = 4.8, 1 .6 Hz, 1 H), 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, 1 H), 7.18 (ddd, J = 7.8, 4.8, 0.9 Hz, 1 H), 4.01 (s, 2H), 2.25 (s, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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 C17H14NO2: 264.1019. Found: 264.1018 (MH ⁺ ).

Preparation of 2-methyl-3-(quinolin-3-ylmethyl)naphthalene-1,4-dione (1’) 7.64 (ddd, J = 8.4, 6.9, 1 .5 Hz, 1 H), 7.49 (ddd, J = 8.1 , 6.8, 1 .2 Hz, 1 H), 4.20 (s, 2H), 2.31 (s, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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 IHI ₆ N0 : 314.1176. Found: 314.1177 (MH ⁺ ). Preparation of 2-methyl-3-(pyrimidin-5-ylmethyl)naphthalene-1 ,4-dione , , , , , , ,

NMR (126 MHz, CDCI ₃ ) d 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. ¹⁹ F NMR (471 MHz, CDCI3) d - 67.81. HRMS (ESI) calcd. for CI ₈ HI ₃ F ₃ N0 ₂ : 332.0893. Found: 332.0915 (MH ⁺ ).

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

Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 97% yield. ¹ H NMR (500 MHz, CDCI ₃ ) d 8.13 (d, J = 2.6 Hz, 1 H), 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, 1 H), 6.84 (dd, J =

8.4, 3.0 Hz, 1 H), 4.00 (s, 2H), 2.27 (s, 3H). ¹³ C NMR (126 MHz, CDCI3) d 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. ¹⁹ F NMR (377 MHz, CDCI3) d -70.88 (d, J= 7.7

Hz). HRMS (ESI) calcd. for C1 ₇ H13FNO2: 282.0925. Found: 282.0920 (MH ⁺ ). Preparation of 2-((6-chloropyridin-3-yl)methyl)-3-methylnaphthalene-1 ,4- dione (5’)

Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 99% yield. ¹ H NMR (500 MHz, CDCI ₃ ) d 8.30 (d, J = 2.5 Hz, 1 H), 8.11 - 7.96 (m, 2H), 7.75 - 7.63 (m, 2H), 7.51 (dd, J = 8.2, 2.6 Hz, 1 H), 7.20 (d, J= 8.2 Hz, 1 H), 3.97 (s, 2H),

2.25 (s, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) d 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 C1 ₇ H13CINO2: 298.0629. Found: 298.0648 (MH ⁺ ).

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

Eluant Cyclohexane:Ethyl acetate (7:3), yellow solid, 93% yield. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.54 (s, 2H), 8.20 - 7.92 (m, 2H), 7.85 - 7.57 (m, 2H), 3.96 (s, 2H), 2.29 (s, 3H). ¹³ C NMR (101 MHz, CDCI3) d 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 C16H12CIN2O2: 299.0582. Found: 299.0596 (MH ⁺ ).

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

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. ¹⁹ F NMR (377 MHz, CDCI3) d -70.23. HRMS (ESI) calcd. for C17H12F3N2O2: 333.0845. Found:

333.0868 (MH ⁺ ). Preparation of 2-((6-methoxypyridin-3-yl)methyl)-3-methylnaphthalene- 1,4-dione (8)

Eluant Cyclohexane:Ethyl acetate (90:10), yellow solid, 3.91 (s, 2H), 3.88 (s, 3H), 2.24 (s, 3H). ¹³ C NMR (101 MHz, CDCIs) d 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 CI ₈ HI ₅ N0 ₃ : 294.112470. Found: 294.112517 (MH ⁺ ).

Preparation of 2-((2-methoxypyrimidin-5-yl)methyl)-3-methylnaphthalene- 1,4-dione (9) NMR (101 MHz, CDCI ₃ ) d 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 CI ₇ HI ₅ N ₂ 0 ₃ : 295.107719. Found: 295.108670 (MH ⁺ ).

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

Eluant Cyclohexane:Ethyl acetate (98:2), orange solid, 74% yield m.p: 83-84°C. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.21 - 7.95 (m, 1 H), 7.86 - 7.58 (m, 1 H), 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, 1 H), 2.28 (s, 2H). ¹³ C NMR (101 MHz, CDCI ₃ ) d 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) m.p. = 96-97 °C. ¹ H NMR (CDCI ₃ , 400 MHz): d 8.11-8.03 (m, 2H), 7.71-7.65 (m, 2H), 7.11 (dd, J = 4.5, 1.8 Hz, 1 H), 6.89 (d,

J = 4.5 Hz, 2H), 4.18 (s, 2H), 2.29 (s, 3H). ¹³ C NMR (CDCI3, 101 MHz): d 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 Ci ₆ Hi ₂ Na0 ₂ S [M + Na] ⁺ : 291 .045021 . Found 291 .045521 .

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

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 CI ₇ HI ₂ N ₃ 0 ₂ : 290.0924. Found: 290.0918 (MH ⁺ ).

Preparation of 2-((2-bromopyrimidin-5-yl)methyl)-3-methylnaphthalene- 1 ,4-dione (13) Eluant Cyclohexane:Ethyl acetate (75:25), yellow solid, 96% yield m.p: 165-166°C. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.48 (s, 2H), 8.11 - 8.00 (m, 2H), 7.80 - 7.60 (m, 2H), 3.94 (s, 2H), 2.28 (s, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) d

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 Ci ₆ Hi ₂ BrN ₂ 0 ₂ : 343.0077. Found: 343.0099 (MH ⁺ ).

Preparation of 2-((2-aminopyrimidin-5-yl)methyl)-3-methylnaphthalene- 1 ,4-dione (46): 2H), 6.46 (s, 2H), 3.73 (s, 2H), 2.18 (s, 3H). ¹³ C { ¹ H} NMR (CDCI ₃ , 126 MHz): <5184.6, 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 C16H14N3O2: 290.1081. Found: 280.1081 (MH ⁺ ). M.p. = degradation after 200 °C.

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

47 was isolated by purification by flash MHz): <5 8.65 (s, 1 H), 8.13 (dd, J = 8.5, 5.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.70 (dd, J = 8.5, 2.5 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.37 (td, J = 8.3, 2.4 Hz, 1 H), 4.09 (s, 2H), 2.29 (s, 3H). ¹³ C { ¹ H} NMR (CDCI ₃ , 101 MHz): <5 183.6, 183.4, 166.2 (d, ¹ J _C -F = 257.5 Hz), 150.5, 146.7 (q, ² J _C -F = 34.9 Hz), 145.5,

143.6 (d, ⁵ JC-F = 1.6 Hz), 137.5, 137.2, 134.4 (d, ³ J _C -F = 7.9 Hz), 130.0 (d, ³ J _C -F = 8.9 Hz), 128.7 (d, ⁴ JC-F = 3.2 Hz), 121.6 (q, ¹ J _C -F = 273.7 Hz), 121.2 (d, ² J _C -F = 22.5 Hz),

120.6 (d, ⁴ JC-F = 2.2 Hz), 113.4 (d, ² J _C -F = 23.5 Hz), 30.2, 13.7. ¹⁹ F NMR (CDCI ₃ , 377 MHz): <5 -67.80, -101.84 (td, J = 8.2, 5.3 Hz). HRMS (ESI+) calcd. for CI ₈ HI ₂ F ₄ N02: 350.079868. Found: 350.079641 (MH ⁺ ). M.p. = 122-124 °C.

Preparation of 3-(benzo[c/|thiazol-5-ylmethyl)-6-fluoro-2-methyl- naphthalene-1 ,4-dione (48):

48 was isolated by purification by flash (CDCI3, 400 MHz): <59.04 (s, 1 H), 8.13 (dd, J = 8.5, 5.2 Hz, 1 H), 7.95 (s, 1 H), 7.89 (d, J = 8.2 Hz, 1 H), 7.72 (dd, J = 8.5, 2.5 Hz, 1 H), 7.46-7.30 (m, 2H), 4.20 (s, 2H), 2.29 (s, 3H). ¹³ C { ¹ H} NMR (CDCI3, 101 MHz): <5 184.0, 183.6, 166.1 (d, ¹ J _C -F = 256.9 Hz), 155.3, 154.2, 145.2 (d, ⁵ J _C -F = 1.8 Hz), 145.2, 136.5, 134.7 (d, ³ J _C -F = 7.9 Hz), 132.4, 129.8 (d, ³ JC-F = 8.8 Hz), 128.8 (d, ⁴ J _C -F = 3.2 Hz), 126.8, 123.1 , 122.2, 120.9 (d, ² J _C -F = 22.6 Hz), 113.3 (d, ² J _C -F = 23.5 Hz), 32.4, 13.6. ¹⁹ F NMR (CDCI3, 377 MHz): <5 -102.4 (td, J = 8.3, 5.3 Hz). HRMS (ESI+) calcd. for C19H13FNO2S: 338.064554. Found: 338.063505 (MH ⁺ ). M.p. = 109-111 °C. Preparation of 2-(benzo[c/]thiazol-5-ylmethyl)-3-methylnaphthalene-1 ,4- dione (49):

49 was isolated by purification by flash chromatography 7.57 (m, 1 H), 7.36 (d, J= 8.1 Hz, 2H), 4.18 (s, 2H), 2.27

(s, 3H). ¹³ C { ¹ H} NMR (CDCI ₃ , 101 MHz): <5 185.3, 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 Ci ₉ Hi ₃ NNa0 ₂ S: 342.055920. Found: 342.055527 (MNa ⁺ ).

M.p. = 148-149 °C.

Preparation of 2-methyl-3-((6-(oxetan-3-yloxy)pyridin-3-yl)methyl) naphthalene-1 ,4-dione (50): 1 H), 5.48 (ddt, J = 9.6, 6.9, 2.6 Hz, 1 H), 4.97 (dd, J = 12.3, 9.8 Hz, 1 H), 4.82 (dd, d apparent because of HDO peak, J= 7.0 Hz, 1 H), 4.13 (s, 2H), 4.03 (dd, J= 13.1 , 2.4 Hz, 1 H), 3.80 (dd, J = 13.1 , 2.9 Hz, 1 H), 2.31 (s, 3H). ¹³ C { ¹ H} NMR (CD ₃ OD, 101 MHz): <5 185.9, 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. HRMS (ESI+) calcd. for C _2O HI ₈ N0 ₄ : 336.123034 Found: 336.123633 (MH ⁺ ). M.p. = 125-127 °C.

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

51 i l t d b ifi ti b fl h h t h 7.81 (s, 1 H), 7.71 (dd, J= 5.7, 3.3 Hz, 2H), 7.42 (d, = 7.8 Hz, 1 H), 4.19 (s, 2H), 2.29 (s, 3H). ¹³ C { ¹ H} NMR (CDCI3, 101 MHz): <5 185.3, 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 CI ₉ HI ₄ N0 ₂ S: 320.074032 Found: 320.074032 (MH ⁺ ). M.p. = 146-147 °C. Preparation of 3-(benzo[c/|thiazol-6-ylmethyl)-6-fluoro-2- methylnaphthalene-1 ,4-dione (52):

= 8.6, 5.2 Hz, 1 H), 8.04 (d, J = 7.5 Hz, 1 H), 7.80 (s, 1 H), 7.73 (dd, J = 8.6, 2.6 Hz, 1 H), 7.44-7.34 (m, 2H), 4.17 (s, 2H), 2.29 (s, 3H). ¹³ C { ¹ H} NMR (CDCI ₃ , 126 MHz): 6 184.0, 183.7, 166.1 (d, ¹ J _C -F = 257.0 Hz), 154.4, 152.2, 145.18, 145.17, 145.1 , 135.8, 134.6 (d, ³ JC-F = 7.8 Hz), 129.8 (d, ³ J _C -F = 8.8 Hz), 128.8 (d, ⁴ J _C -F = 3.1 Hz), 127.3, 123.8, 121.6, 120.9 (d, ² J _{C F} = 22.5 Hz), 113.4 (d, ² J _C -F = 23.5 Hz), 32.6, 13.6. ¹⁹ F NMR (CDCIs, 377 MHz): <5 -102.28 (td, J = 8.2, 5.3 Hz). HRMS (ESI+) calcd. for C ₁₉ H ₁₃ FNO ₂ S: 338.064554 Found: 338.064817 (MH ⁺ ). M.p. = 170-172 °C.

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

53 was isolated after precipitation in 7.90-7.82 (m, 2H), 5.45 (ddt, J = 9.7, 6.9, 3.2 Hz, 1 H), 4.88 (dd, J = 12.7, 9.8 Hz, 1 H), 4.65 (dd, _* 7= 12.7, 7.1 Hz, 1 H), 4.09 (s, 2H), 3.88 (dd, J= 13.0, 2.5 Hz, 1 H), 3.74 (dd, J= 13.0, 3.7 Hz, 1 H), 2.21 (s, 3H). ¹³ C { ¹ H} NMR (DMSO-cfe, 101 MHz): 6184.4, 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 ₁₉ H ₁₇ N ₂ O ₄ : 337.118684 Found: 337.118684 (MH ⁺ ). 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):

54 was isolated after reci itation in

J = 9.3, 5.4 Hz, 1 H), 7.72 (ddd, J = 8.8, 6.2, 2.7 Hz, 2H), 5.45 (ddt, J = 9.9, 6.8, 3.2 Hz, 1 H), 4.86 (dd, J = 12.6, 9.8 Hz, 1 H), 4.64 (dd, J = 12.7, 7.1 Hz, 1 H), 4.09 (s, 2H), 3.88 (dd, J = 13.0, 2.5 Hz, 1 H), 3.73 (dd, J = 13.0, 3.7 Hz, 1 H), 2.21 (s, 3H). ¹³ C { ¹ H} NMR (DMSO-cfe, 101 MHz): <5183.2, 182.7 (d, ⁴ J _C -F = 1 .2 Hz), 169.4, 165.3 (d, ¹ J _C -F = 254.0 Hz), 159.7, 148.0, 146.3, 141.3 (d, ⁵ J _C -F = 1.8 Hz), 134.3 (d, ³ J _C -F = 7.9 Hz), 129.7 (d, ³ JC-F = 9.2 Hz), 128.8 (d, ⁴ J _C -F = 3.0 Hz), 126.8, 121.2 (d, ² J _C -F = 22.6 Hz), 112.4 (d, ² JC-F = 23.4 Hz), 83.7, 60.7, 50.8, 26.0, 13.2. ¹⁹ F NMR (CD ₃ OD, 377 MHz): <5 -105.18 (td, J = 8.6, 5.3 Hz). HRMS (ESI+) calcd. for CI ₉ HI ₆ FN ₂ 0 ₄ : 355.108862 Found: 355.107660 (MH ⁺ ). M.p. = degradation after 165 °C.

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

8.5, 2.3 Hz, 1 H), 6.44 (d, J = 8.5 Hz, 1 H), 4.59 (s, 2H), 3.86 (s, 2H), 2.26 (s, 3H). ¹³ C

{ ¹ H} NMR (101 MHz, CDCI ₃ ) <5185.3, 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):

2H), 3.99 (s, 2H), 3.09 (s, 1 H), 2.28 (s, 3H). ¹³ C { ¹ H} NMR (CDCI ₃ , 126 MHz): <5184.8, 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 CI ₈ HI ₃ N ₂ 0 : 289.097154 Found:

289.096682 (MH ⁺ ). 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))

The compounds of formula (II) wherein R ¹ =F are prepared according to the following reaction scheme:

Synthesis of 6-fluoro precursors: Acetone, 60 C overnight

63%

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

According to the previously published method (T. Miiller, 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. ¹ H NMR (CDCIs, 400 MHz): <58.07 (dd, J = 9.2, 5.6 Hz, 1 H), 7.88 (dd, J = 10.6,

2.7 Hz, 1 H), 7.32 (ddd, J = 9.2, 8.3, 2.7 Hz, 1 H), 6.64 (s, 1 H), 3.95 (s, 3H), 3.89 (s, 3H), 2.48 (s, 3H). ¹³ C NMR (CDCI ₃ , 101 MHz): <5 160.4 (d, ¹ J _C -F = 243.9 Hz), 150.9 (d, 4JC-F = 5.1 Hz), 147.1 (d, ⁵ J _C -F = 1.4 Hz), 126.1 (d, ³ J _C -F = 8.8 Hz), 125.8 (d, 5JC-F = 0.8 Hz), 124.8 (d, ⁴ J _C -F = 2.5 Hz), 124.2 (d, ³ J _C -F = 8.7 HZ), 116.3 (d, 2JC-F = 25.2 Hz), 108.0, 106.3 (d, ² J _C -F = 22.5 Hz), 61.2, 55.5, 16.1. ¹⁹ F NMR (CDCIs, 377 MHz): d -116.24 (ddd, J = 10.3, 8.4, 5.5 Hz). HRMS calculated for C13H14FO2 [M + H] ⁺ : 221 .097234. Found 221 .097121 . Preparation Of 3-(chloromethyl)-6-fluoro-1,4-dimethoxy-2- methylnaphthalene

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 MgSC>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. ¹ H NMR (CDCI ₃ , 400 MHz): 68.07 (dd, J = 9.2, 5.5 Hz, 1 H), 7.68 (dd, J = 10.2, 2.5 Hz, 1 H), 7.29 (ddd, J = 9.2, 8.2, 2.6 Hz, 1 H), 4.89 (s,

2H), 4.02 (s, 3H), 3.87 (s, 3H), 2.52 (s, 3H). ¹³ C NMR (CDCI ₃ , 101 MHz): <5 161.1 (d, ¹ JC-F = 246.0 Hz), 150.9 (d, ⁴ J _C -F = 5.4 Hz), 150.7 (d, ⁵ J _C -F = 1.3 Hz), 128.2 (d, ³ J _C -F = 8.7 Hz), 128.0, 126.3 (d, ⁵ J _C -F = 0.6 Hz), 125.6 (d, ⁴ J _C -F = 2.5 Hz), 125.3 (d, ³ J _C -F = 8.8 Hz), 117.1 (d, ² JC-F = 25.3 Hz), 106.7 (d, ² J _C -F = 22.4 Hz), 63.1 , 61.6, 38.9. ¹⁹ F NMR (CDCIs, 377 MHz): <5 -114.27 (m). HRMS calculated for CI ₄ HI ₅ CIF0 ₂ [M + H] ⁺ :

269.073912. Found 269.073883.

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

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 MgSC , and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to afford the expected product. Boronic acid of Compound of

Yield formula (III) formula (II)

Preparation of 2-fluoro-5-((7-fluoro-1 ,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)pyridine (34) 1 H), 8.07 (s, 1 H), 7.69 (dd, J = 10.3, 2.5 Hz, 1 H), 7.52 (td, J= 8.2, 2.3 Hz, 1 H), 7.28 (td, J= 9.2, 2.6 Hz, 1 H), 6.80 (dd, J= 8.4, 2.9 Hz, 1 H), 4.22 (s, 2H), 3.86 (d, J= 1.7 Hz, 6H), 2.27 (s, 3H). ¹³ C NMR (CDCIs, 101 MHz): <5 162.4 (d, ¹ JC-F = 237.3 Hz), 161.0 (d, ¹ J _C -F = 246.4 Hz), 150.9 (d, ⁵ J _C -F = 2.0 Hz), 150.1 (d, ⁴ JC-F = 5.4 Hz), 146.9 (d, ³ J _C -F = 14.5 Hz), 141.0 (d, ³ J _C -F = 7.7 Hz), 133.3 (d, ⁴ J _C -F = 4.6 Hz), 129.4, 128.3 (d, ³ J _C -F= 8.7 Hz), 125.6 (d, ⁴ J _C -F= 2.5 Hz), 125.3, 125.2 (d, ³ JC-F= 9.1 Hz), 116.3 (d, ² J _C -F= 25.4 Hz), 109.3 (d, ² J _C -F= 37.5 Hz), 106.3 (d, ² J _C -F = 22.4 Hz), 62.2, 61.6, 29.4, 12.6. ¹⁹ F NMR (CDCI ₃ , 377 MHz): <5-114.42 (ddd, J= 10.1, 8.4, 5.7 Hz). HRMS calculated for CI ₉ HI ₈ F ₂ N0 ₂ [M + H] ⁺ : 330.130012. Found 330.131085.

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)picolinonitrile (35) Thi i l ifi i fl h <58.60 (d, J = 1.36 Hz, 1 H), 8.08 (dd, J = 9.2, 5.6 Hz,

1 H), 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). ¹³ C NMR (CDCI ₃ , 101 MHz): <5 161.1 (d, ¹ JC-F= 246.1 Hz), 151.3, 151.0 (d, ⁵ J _C -F = 1.3 Hz), 150.2 (d, ⁴ _C -F= 5.4 HZ), 140.3, 136.5, 131.6, 128.4, 128.22 (d, ³ J _C -F= 8.7 Hz), 128.15, 125.5 (d, ⁵ JC-F= 1.1 Hz), 125.4 (d, ³ JC-F = 8.9 Hz), 125.2 (d, ⁴ J _C -F = 2.5 Hz), 117.4, 116.6 (d, ² J _C -F = 25.4 Hz), 106.3 (d, ² JC-F= 22.4 Hz), 62.2, 61.7, 30.6, 12.7. ¹⁹ F NMR (CDCI ₃ , 377 MHz): <5 -114.04 (ddd, J= 10.1, 8.4, 5.6 Hz). HRMS calculated for C _2O HI ₈ FN ₂ 0 [M + H] ⁺ : 337.134682. Found 337.135223.

Preparation of 2-chloro-5-((7-fluoro-1 ,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)pyrimidine (36) (s, 2H), 8.06 (dd, J= 9.2, 5.6 Hz, 1H), 7.63 (dd, J = 10.2, 2.5 Hz, 1 H), 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). ¹³ C NMR (CDCI ₃ , 101 MHz): <5161.1 (d, ¹ J _C -F= 246.2 Hz), 159.4, 159.3 (2C), 151.1 (d, ⁴ J _C -F= 1.3 Hz), 150.1 (d, ⁴ J _C -F= 5.4 Hz), 132.3, 128.2 (d, ³ J _C -F = 8.7 Hz), 127.8, 125.5 (d, ⁵ J _C -F= 0.5 Hz), 125.4 (d, ³ J _C -F= 8.9 Hz), 124.9 (d, ⁵ J _C -F= 2.5 Hz), 116.6 (d, ² JC-F= 25.4 Hz), 106.3 (d, ² J _C -F= 22.4 Hz), 62.2, 61.7, 27.3, 12.7. ¹⁹ F NMR (CDCIs, 377 MHz): <5 -113.94 (ddd, J= 10.1, 8.4, 5.6 Hz). HRMS calculated for

C18H17CIFN2O2 [M + H] ⁺ : 347.095710. Found 347.097652. Preparation of 2-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)furan (38)

This compound were isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from 1/0 to 99/1, v/v, UV) with 83% yield (colourless oil). ¹ H NMR (CDCI ₃ , 400 MHz): <58.09 (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, 1 H), 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, =3.4Hz, 6H), 2.36 (s, 3H). ¹³ C NMR

(CDCh, 101 MHz): 6161.0 (d, ¹ J _C -F= 245.2 HZ), 154.0, 150.5 (d, ⁵ J _C -F= 1.4 Hz), 150.2 (d, ⁴ JC-F = 5.4 Hz), 141.3, 128.4, 128.3 (d, ³ J _C -F = 8.7 Hz), 126.3 (d, ⁴ J _C -F 2.4 Hz), 125.3, 125.2 (d, ³ _C-F = 8.9 Hz), 116.2 (d, ² J _C -F= 25.4 Hz), 110.4, 106.4 (d, ² J _C -F= 22.3 Hz), 106.0, 62.5, 61.6, 26.5, 12.4. ¹⁹ F NMR (CDCI ₃ , 377 MHz): 6-114.95 (ddd, J = 10.4, 8.4, 5.7 Hz). HRMS calculated for CI ₈ HI ₈ F0 ₃ [M + H] ⁺ : 301.123449. Found

301.123811.

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)-2-(trifluoromethyl)pyrimidine (37) J = 9.2, 5.6 Hz, 1 H), 7.64 (dd, J = 10.2, 2.5 Hz, 1 H), 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). ¹³ C NMR (CDCIs, 101 MHz): 6161.2 (d, ¹ J _C-F = 246.3 Hz), 157.6 (2C), 154.9 (q, ² J _C-F = 36.9 Hz), 151.2 (d, ⁵ J _C-F = 1.3 Hz), 150.2 (d, ⁴ J _C-F = 5.3 Hz), 136.1, 128.6 (d, ³ J _C-F = 8.7 Hz), 127.4, 125.7, 125.5 (d, ³ J _C-F = 8.9 Hz), 124.9 (d, ⁴ J _C-F = 2.5 Hz), 119.8 (d, ¹ Jc- _F = 275.7 Hz), 116.8 (d, ² J _C-F = 25.4 Hz), 106.4 (d, ² J _C-F = 22.5 Hz), 62.2, 61.8, 28.1, 12.8. ¹⁹ F NMR (CDCI ₃ , 377 MHz): 6 -70.12, -113.87 (ddd, J= 10.1, 8.4, 5.6 Hz). Post-modifications of Suzuki coupling products:

Preparation of 5-((7-fluoro-1,4-dimethoxy-3-methylnaphthalen-2- yl)methyl)pyrimidine-2-carbonitrile (40) 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. ¹ H NMR (CDCI ₃ , 400 MHz): 68.63 (s, 2H), 8.09 (dd, J = 9.2, 5.6 Hz, 1 H), 7.64 (dd, J = 10.2, 2.5 Hz, 1 H), 7.30 (ddd, J= 9.1 , 8.4, 2.6 Hz, 1 H), 4.25 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.27 (s, 3H). ¹³ C NMR (CDCI ₃ , 101 MHz): 6 161 .3 (d, ¹ JC-F = 246.7 Hz), 157.8 (2C), 151.3 (d, ⁵ J _C -F = 1.3 Hz), 150.3 (d, ⁴ J _C -F = 5.5 Hz), 143.2, 136.9, 128.3 (d, ³ J _C -F = 8.7 Hz), 127.1 , 125.8, 125.5 (d, ³ J _C -F = 8.9 Hz), 124.7 (d, ⁴ JC-F = 2.5 Hz), 117.0 (d, ² J _C -F = 25.4 Hz), 115.8, 106.4 (d, ² J _C -F = 22.5 Hz), 62.3, 61.9, 28.4, 12.9. ¹⁹ F NMR (CDCI3, 377 MHz): 6 -113.65 (ddd, J = 9.9, 8.4, 5.6 Hz). HRMS calculated for C19H17FN3O2 [M + H] ⁺ : 338.129931. Found 338.131588.

PREPARATION OF COMPOUNDS OF FORMULA m (by oxidative deprotection from the compounds of formula (II))

The compounds of formula (I) wherein R ¹ =F are prepared according to the following reaction scheme: General procedure for the oxidative deprotection:

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 MgSC>4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to afford the desired product. Preparation of 6-fluoro-3-((6-fluoropyridin-3-yl)methyl)-2- methylnaphthalene-1,4-dione (14)

(dd, J = 8.6, 5.1 Hz, 2H), 7.70 (dd, J = 8.5, 2.6 Hz, 1 H), 7.66 (dd, J = 8.1 , 2.4 Hz, 1 H), 7.36 (td, J = 8.4, 2.6 Hz, 1 H), 6.83 (dd, J = 8.4, 3.0 Hz, 1 H), 3.98 (s, 2H), 2.27 (s, 3H). ¹³ C NMR (CDCh, 101 MHz): <5 183.8, 183.5 (d, ⁴ J _C -F = 1 .4 Hz), 166.2 (d, ¹ J _C -F = 257.3 Hz), 162.6 (d, ¹ JC-F = 238.5 Hz), 147.4 (d, ³ J _C -F = 14.6 Hz), 145.1 , 144.3 (d, ⁵ J _C -F = 1.0 Hz), 141 .5 (d, ³ JC-F = 7.8 Hz), 134.5 (d, ³ J _C -F = 7.9 Hz), 131.3 (d, ⁴ J _C -F = 4.6 Hz), 129.9 (d, ³ JC-F = 8.9 Hz), 128.7 (d, ⁴ J _C -F = 3.3 Hz), 121.1 (d, ² J _C -F = 22.6 Hz), 113.3 (d, ² J _C -F = 23.5 Hz), 109.7 (d, ² J _C -F = 37.5 Hz), 29.2, 13.5. ¹⁹ F NMR (CDCh, 377 MHz): <5 -70.7 (m), -102.03 (td, J = 8.3, 5.3 Hz). HRMS calculated for CI ₇ HI ₂ F ₂ N0 ₂ [M + H] ⁺ : 300.083061. Found 300.083945.

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

(CDCh, 400 MHz): <58.62 (d, J = 1 .6 Hz, 1 H), 8.11 (dd, J = 8.6, 5.2 Hz, 1 H), 7.68 (td, J = 8.4, 7.6, 2.3 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1 H), 7.37 (td, J = 8.3, 2.6 Hz, 1 H), 4.07 (s, 2H), 2.27 (s, 3H). ¹³ C NMR (CDCI ₃ , 101 MHz): d 183.4, 183.3 (d, ⁴ J _C -F = 1.5 Hz),

166.1 (d, ¹ JC-F = 257.6 Hz), 151.5, 145.7, 143.2 (d, ⁴ J _C -F = 1.9 Hz), 138.1 , 137.1 , 134.3 (d, ³ JC-F = 8.0 Hz), 132.1 , 130.0 (d, ³ J _C -F = 8.9 Hz), 128.7 (d, ⁴ J _C -F = 3.3 Hz), 128.5,

121.2 (d, ² JC-F = 22.5 Hz), 117.2, 113.3 (d, ² J _C -F = 23.5 Hz), 30.3, 13.6. ¹⁹ F NMR (CDCh, 377 MHz): <5 -101 .69 (td, J= 8.2, 5.3 Hz). HRMS calculated for CI ₈ HI ₂ FN ₂ 0 ₂

[M + H] ⁺ : 307.087732. Found 307.088742. Preparation of 6-fluoro-3-(furan-2-ylmethyl)-2-methylnaphthalene-1 ,4- dione (18)

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).

¹ H NMR (CDCIs, 400 MHz): 68.12 (dd, J = 8.6, 5.3 Hz,

1 H), 7.73 (dd, J = 8.6, 2.6 Hz, 1 H), 7.35 (td, J = 8.3, 2.7

Hz, 1 H), 7.27 (dd, = 1.8, 0.7 Hz, 1 H), 6.27 (dd, J= 3.2, 1 .9 Hz, 1 H), 6.08 (dd, = 3.2, 0.8 Hz, 1 H), 4.03 (s, 2H), 2.29 (s, 3H). ¹³ C NMR (CDCIs, 101 MHz): 6184.1 , 183.0 (d, ⁴ JC-F = 1.4 Hz), 166.1 (d, ¹ J _C -F = 256.8 Hz), 151.0, 145.4, 142.6 (d, ⁵ J _C -F = 2.0 Hz), 141.7, 134.7 (d, ³ J _C -F = 7.9 Hz), 129.8 (d, ³ J _C -F = 8.9 Hz), 128.9 (d, ⁴ J _C -F 3.3 Hz), 120.8 (d, ² JC-F = 22.6 Hz), 113.3 (d, ² J _C -F = 23.5 Hz), 110.6, 106.9, 25.7, 13.2. ¹⁹ F NMR (CDCIs, 377 MHz): 6 -102.49 (td, J = 8.3, 5.3 Hz). HRMS calculated for CieHisFOs [M + H] ⁺ : 271 .076499. Found 271 .078115.

Preparation of 3-((2-chloropyrimidin-5-yl)methyl)-6-fluoro-2- methylnaphthalene-1,4-dione (16) J = 8.6, 5.2 Hz, 1 H), 7.69 (dd, J = 8.5, 2.6 Hz, 1 H), 7.38 (td, J = 8.3, 2.6 Hz, 1 H), 3.96 (s, 2H), 2.30 (s, 3H). ¹³ C NMR (CDCIs, 101 MHz): 6 183.4, 183.2 (d, ⁴ J _C -F = 1.5 Hz), 166.2 (d, ¹ JC-F = 258.6 Hz), 160.0, 159.7 (2C), 145.5, 142.9 (d, ⁵ J _C -F = 1.9 Hz), 134.3 (d, ³ JC-F = 7.9 Hz), 130.4, 130.0 (d, ³ J _C -F = 8.9 Hz), 128.6 (d, ⁴ J _C -F = 3.3 Hz), 121.3 (d, ² JC-F = 22.5 Hz), 113.4 (d, ² J _C -F = 23.6 Hz), 27.2, 13.7. ¹⁹ F NMR (CDCIs, 377 MHz): 6 -101.54 (td, J = 8.2, 5.2 Hz). HRMS calculated for CieHuCIFNsOs [M + H]+: 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)

68.76 (s, 2H), 8.15 (dd, J = 8.6, 5.2 Hz, 1 H), 7.71 (dd, J = 8.4, 2.6 Hz, 1 H), 7.41 (td, J= 8.3, 2.6 Hz, 1 H), 4.06 (s, 2H), 2.33 (s, 3H). ¹³ C NMR (CDCI3, 101 MHz): <5 183.20, 183.18, 166.3 (d, ¹ J _C -F = 258.1 Hz), 158.1 (2C), 146.0, 143.6, 142.2, 134.9, 134.2 (d, ³ JC-F = 7.9 Hz), 130.2 (d, ³ J _C -F = 8.9 Hz), 128.7 (d, ⁴ J _C -F = 3.3 Hz), 121.5 (d, ² J _C -F = 22.6 Hz), 115.7, 113.5 (d, ² J _C -F = 23.6 Hz), 28.3, 13.8. ¹⁹ F NMR (CDCI3, 377 MHz): <5 -101 .19 (td, J= 8.2, 5.3 Hz). HRMS calculated for C17H11FN3O2 [M + H] ⁺ : 308.082981 .

Found 308.084056.

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

<58.81 (s, 2H), 8.14 (dd, J = 8.6, 5.2 Hz, 1 H), 7.70 (dd, J = 8.4, 2.6 Hz, 1 H), 7.39 (td, J = 8.3, 2.7 Hz, 1 H), 4.07 (s, 2H), 2.33 (s, 3H). ¹³ C NMR (CDCI ₃ , 101 MHz): <5 183.3, 183.2 (d, ⁴ JC-F = 1.4 Hz), 166.3 (d, ¹ J _C -F = 257.9 Hz), 158.0, 155.4 (q, ² J _C -F = 37.1 Hz), 145.8, 142.6 (d, ⁵ J _C -F = 1.8 Hz), 134.3 (d, ³ J _C -F = 8.2 Hz), 134.2, 130.1 (d, ³ J _C -F = 8.9 Hz), 128.7 (d, ⁴ JC-F = 3.3 Hz), 121.4 (d, ² J _C -F = 22.5 Hz), 119.6 (d, ¹ J _C -F = 275.3 Hz), 113.5 (d, ² JC-F = 23.6 Hz), 28.0, 13.7. ¹⁹ F NMR (CDCI ₃ , 377 MHz): <5 -70.24, -101.44 (td, J= 8.2, 5.3 Hz). HRMS calculated for C17H11F4N2O2 [M + H]+: 351 .075117. Found 351.075663.

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

M.p. = 60-62 °C. ¹ H NMR (CDCI ₃ , 400 MHz): <58.10 (dd, J = 8.6, 5.3 Hz, 1 H), 7.73 (dd, J = 8.6, 2.6 Hz, 1 H), 7.34 (td, J = 8.3, 2.7 Hz, 1 H), 7.11 (dd, J = 4.9, 1.4 Hz, 1 H), 6.92-6.85 (m, 2H), 4.17 (s, 2H), 2.29 (s, 3H). ¹³ C NMR (CDCI ₃ , 101 MHz): <5 184.1 , 183.2 (d, ⁴ J _C -F = 1.4 Hz), 166.1 (d, ¹ J _C -F = 256.9 Hz), 144.6 (d, ⁵ JC-F = 1.9 Hz), 144.4, 139.7, 134.6 (d, ³ J _C -F = 7.9 Hz), 129.7 (d, ³ J _C -F = 8.8 Hz), 128.8 (d, ⁴ JC-F = 3.2 Hz), 127.0, 125.9, 124.3, 120.8 (d, ² J _C -F = 22.6 Hz), 113.3 (d, ² J _C -F = 23.2 Hz), 27.1 , 13.2. ¹⁹ F NMR (CDCI ₃ , 377 MHz): <5 -102.36 (td, = 8.3, 5.3 Hz). HRMS calculated for C16H12FO2S [M + H] ⁺ : 287.053655. Found 287.054700. Comparative example

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).

The following reaction was carried out:

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

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 bioloaical results

Regioisomeric compounds were synthetized using the process of WO 2020/252414 based on organozinc intermediates. MRO0397 and MR00407 were obtained with very low yields (Scheme 2, Table):

X = N, MRO0397 (30%) X = C, MR00407 (15%)

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. MRO0418 was isolated with a second fluorinated compound and MRO0419 with 4 other fluorinated compounds. The structures of the (non separated) side-products were not elucidated.

X = N, MRO0418 X = C, MRO0419

The method according to the invention is thus the most efficient synthetic pathway to synthetize MRO0418 and MRO0419. With this method, MRO0418 was obtained with total 84% yield in 2 steps from MD705. MRO0419 was synthetized in 2 steps from MD705 with total 67% yield in 2 steps

The first primary screening, performed with the Plasmodium falciparum NF54 strain and the rat L6 myoblast cell line, showed that both MRO0418 and MRO0419 displayed more potent and specific antimalarial activities than the regioisomers MRO0397 and MR00407, respectively: