Disubstituted ferrocene compounds and their therapeutic use

Abstract

The present invention relates to compounds of formula (I) for use in the prevention and / or treatment of viral infections, wherein R1, R2 and R3 are as defined in claim 1.

Description

DescriptionTitle: Disubstituted ferrocene compounds and their therapeutic useTECHNICAL FIELD

[0001] The present invention relates to disubstituted ferrocene compounds and to their use as a medicament, notably in the treatment of viral infections.BACKGROUND

[0002] Despite advances in biology and medicine in the 20thand 21stcentury, viral infections still represent a major health problem. While recent decades have been notably marked by HIV and influenza viruses, the recent COVID-19 pandemic has shown a lack of preparedness against emerging viruses.

[0003] With respect to the COVID-19 pandemic, vaccines against SARS-CoV-2 have made it possible to resume a normal lifestyle and different treatments are in clinical trials. These are often based on inhibitors of 3CLPR0, one of the key proteases of SARS-CoV2. Antiviral treatments such as the Molnupiravir, the Lopinavir-Ritonavir or the Nirmatrelvir-Ritonavir combinations have also been used.

[0004] Among other emerging viruses which are now widely monitored, four are arboviruses transmitted by arthropods such as mosquitoes: ZIKV (ZIKA virus), CHIKV (chikungunya virus), DENV (dengue virus) and USUV (Usustu virus). The WHO has classified ZIKV on its list of global health threats in 2019. Indeed, while these infections have long remained confined to tropical regions, climatic and demographic changes have led to the spread of these diseases to other regions of the world, including Europe. While the symptoms are often those of influenza, the progression to severe forms, including neurological sequelae, has become frequent. For these arboviruses, the development of vaccines is particularly complex, in particular due to the variability of the immune response depending on the type of virus, the age of the patient and potential pre-exposures to viral infections.

[0005] On the other hand, while the development of antiviral compounds has received much attention, few compounds have reached the stage of clinical trials, and even fewer have been marketed. In addition, most of these compounds have complex structures and their preparation involves multi- step synthetic procedures making their industrial large-scale production difficult.

[0006] Thus, there is a need to broaden the antiviral therapeutic arsenal by developing small original molecules, easy to prepare, to prevent or treat viral infections, in particular to counter the appearance of emerging viruses or their variants.SUMMARY OF THE INVENTION

[0007] The present invention aims to satisfy the above needs. The inventors have identified a class of compounds that, surprisingly, have antiviral properties against a broad range of viruses. These compounds are readily prepared from simple starting materials by known chemical reactions, and thus may advantageously be produced in sufficient amounts to allow large scale use.

[0008] Thus, there is proposed a compound of Formula I:wherein Ri, R2 and Rs are as defined herein, and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment of a viral infection.

[0009] In other words, the present invention relates to a method of treatment of a viral infection, comprising administering to patient in need thereof a therapeutically effective amount of a compound of Formula I as defined herein.

[0010] According to another aspect of the invention, there is proposed a pharmaceutical composition comprising a compound of Formula I as defined herein, in admixture with one or more pharmaceutically acceptable excipient.

[0011] The present invention also proposes disubstituted ferrocene compounds of Formula IA,Rr and R2 being as defined herein, and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof, with the provisio that the compound of Formula IA is not a racemic mixture of the following structures:Brief description of the figures

[0012] Other features, details and advantages will be shown in the following detailed description and on the figures, on which:Figure 1

[0013] Figure 1 represents the reduction of viral infection in Huh7 cells infected by HCoV-229E and treated with ferrocene compounds h to he (20 pg / mL), according to example 3A. Data are expressed on the y-axis as percentage compared to the untreated cells (control). Bars represent the mean ± SD (standard deviation) from three independent experiments.Figure 2

[0014] Figure 2 represents a graph showing the cellular viability of Huh7 cells treated with different concentrations of ferrocene compounds I1 to I10 and he, according to example 3A. Data are represented as the mean ± SD from three independent experiments. The x-axis indicates the concentration of ferrocene compounds, expressed in pM and the y-axis shows the reduction in cell viability based on quantitation of ATP, expressed as the percentage of reduction compared to a control (non-treated cells).Figure 3

[0015] Figure 3 represents the reduction of viral infection in Huh7 cells infected by HCoV-229E and treated with different non-toxic concentrations of ferrocene compounds h to I10 and he according to example 3A. The x-axis indicates the concentration of ferrocene compounds, expressed in pM andthe y-axis shows the percentage of infection, relative to a control (non-treated cells). Data are represented as the mean ± SD from three independent experiments.Figure 4

[0016] Figure 4 represents the results of a preliminary study, according to example 3A, of the mode of action on the compound I4, I9 and I10 in the treatment of Huh7 cells infected by HCov-229E. Figure 4A shows a schematic representation of HCoV-229E inactivation assay performed to characterize the virucidal activity of tested compounds. The black parts of the arrows representing the presence of the antiviral compounds. Figure 4B shows the results obtained under the experimental conditions shown in Figure 4A. Data are represented as the mean ± SD from three independent experiments. Figure 4C shows a schematic representation of time-of-drug-addition assay used to characterize antiviral activity of tested compounds on HCoV-299E infection. The black parts of the arrows representing the presence of the antiviral compounds. Isoquercitrin (25 pM) and Remdesivir (0.1 pM) were used as positive controls. Figure 4D shows the results obtained under the experimental conditions shown in Figure 4C. Data are represented as the mean of infected cells ± SD from three independent experiments. **** p-value < .0001 ; *** p-value < .001 ; ** p-value < .01 ; * p-value < .05; n.s = not significant.Figure 5

[0017] Figure 5 represents the results of a preliminary study, according to example 3B, of the antiviral activity of the compounds I4 and I10 against SARS-CoV-2 in human A549-ACE2 cells. Figure 5A shows the cytotoxicity of I4 and I10 on A549-ACE2 cells. The x-axis indicates the concentration of ferrocene compound, expressed in pM and the y-axis shows the reduction in cell viability based on quantitation of ATP, expressed as the percentage of reduction compared to a control (non-treated cells). Data are represented as the mean ± SD from three independent experiments. Figure 5B shows the RNA relative expression level by RT-qPCR (y-axis), for each ferrocene compound. Bars indicate the mean ± SD from three independent experiments. Figure 5C shows the viral progeny, assessed after 24h 24 by performing PFU assay. The y-axis represents SARS-CoV-2 viral progeny expressed in PFU / mL, for each ferrocene compound. Bars indicate the mean ± SD from three independent experiments. Untreated cells were used as positive control. Figure 5D shows the percentage of infected cells (y-axis) for each ferrocene compound. Untreated cells were used as positive control of infection and mock infected cells were used as negative control. Bars indicate the mean ± SD from three independent experiments.Figure 6

[0018] Figure 6 represents the results of a study, according to example 3D, of the antiviral activity of the compound I7 against zika virus (ZIKV) in Vero E6 cells. Figure 6A shows the reduction in ZIKV infectivity at different experimental conditions. The x-axis represents different experimental conditions, and the y-axis shows the percentage of infected cells compared to a control (non-treated infected cells). Compound I7 at 20 pM was mixed with ZIKVGFPand incubated at 37°C for 2 hours, then diluted 50-fold to a subtherapeutic concentration before adding to Vero cells. PLA2 at 1 pg / mLserved as a positive control, and Q3G at 25 pM served as negative controls. Flow cytometry was used 24 hours post-infection to determine the percentages of GFP-positive cells compared to a control (non-treated infected cells). The results are presented as means ± SEM from three independent experiments, each conducted in triplicate. Statistical analysis was performed using oneway ANOVA (****p<0.0001 ; n.s = not significant). Figure 6B shows the targeting of the late stage of the ZIKV replication cycle by compound I7. Positive controls were included for comparison: Q3G at 25 pM to inhibit viral entry and Plitidepsin at 0.1 pM to block viral replication. Flow cytometry was again used to determine the percentages of GFP-positive cells compared to a control (non-treated infected cells). The results, also presented as means ± SEM, are based on three independent experiments, each conducted in triplicate. Values are expressed relative to the vehicle-treated cells. Statistical analyses were conducted using one-way ANOVA and Dunnett’s test (****p<0.0001 ; n.s = not significant).

[0019] DETAILLED DESCRIPTION

[0020] The invention will now be described in more detail.

[0021] A first object of the present invention is a compound of Formula I:wherein:Ri and R3 are each independently chosen from H, (C6-10 )aryl or 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more groups, in particular by one, two or three groups, selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• (C1-C6)alkylC(=O)-, optionally substituted by one or more fluorine atoms,• -C(OH)ReRf• Halogen,• -NO2,• -CN, and• (C1-C6)alkoxy, optionally substituted by one or more fluorine atoms,• (C1-C6)thioalkoxy, optionally substituted by one or more fluorine atoms, and• -SF, -S(O)F, -SO2F or-SF5,It being understood that one of R1 or R3 is H, the other one being different from H,R2 is chosen from -C(=O)NRaRb or -NRcC(=0)Rd,Ra, Rb, being each independently chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (C6- C10)aryl-SO2-, (C6-10 )aryl-(C1-C6)alkyl-,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re, Rf each independently chosen from H, CF3, and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment of a viral infection.

[0022] Thus, the present invention concerns the use for the prevention and / or treatment of a viral infection of disubstituted ferrocenes having two types of substitution patterns, i.e. 1 ,3-disubstituted ferrocenes and 1 ,1 ’-disubstituted ferrocenes.1,3-disubstituted ferrocene 1,1 ’-disubstituted ferrocene

[0023] The term “ (C6-10 )aryl” refers to an aromatic group consisting of 6 to 10 carbon atoms in its ring. Examples of such groups include, but are not limited to, phenyl or naphthyl and the like.

[0024] The term “5 to 10 membered heteroaryl” refers to an aromatic mono- or polycyclic radical of 5 to 10 atoms having at least one aromatic ring containing one, two or three heteroatoms independently selected from oxygen, nitrogen and sulfur, with the remaining ring atoms being carbon. Examples of such groups include, but are not limited to, pyridyl, furyl, imidazolyl, pyrrolyl and the like.

[0025] The expression “(C1-C6)alkyl” refers to a linear or branched alkyl group comprising 1 to 6 carbon atoms. With “linear (C1-C6)alkyl group" is meant methyl, ethyl, propyl, butyl, pentyl or hexyl. With “branched (C1-C6)alkyl group” is meant a linear alkyl group as defined above comprising substituents selected from the list of linear alkyl groups defined above, said linear alkyl groups being also capable of branching. Among the branched alkyl groups can be cited, as non-limiting examples, a tert-butyl, a sec-butyl or an isopropyl group. A (C1-C6)alkyl group may in particular be a (C1-C4)alkyl group, notably a (C1-C3)alkyl group.

[0026] With “(C1-C6)alkyl and (C1-C6)alkylC(=O)- optionally substituted by one or more fluorine groups" is meant that one or more hydrogen atoms of (C1-C6)alkyl are replaced with a fluorine atom. Examples of such groups include -CF3 and CF3C(=O)-.

[0027] The halogen may be chosen from fluorine, chlorine, bromine or iodine. In particular halogen may be fluorine or chlorine.

[0028] As used herein, the term “(C1-C6)alkoxy” means (C1-C6)alkyl-O-, wherein (C1-C6)alkyl is as defined above. As examples, mention can be made of methoxy, ethoxy or isopropoxy. As an example of a (C1-C6)alkoxy substituted by one or more fluorine atoms can be cited -OCF3.

[0029] As used herein, the term “(C1-C6)thioalkoxy” means (C1-C6)alkyl-S-, wherein (C1-C6)alkyl is as defined above. As an example of a (C1-C6)thioalkoxy substituted by one or more fluorine atoms can be cited -SCF3.

[0030] It is recognized that compounds of the present invention may exist in various stereoisomeric forms. Indeed, 1 ,3-disubstituted ferrocenes of Formula I are chiral and may be present in the (SP) or (RP) configuration, or mixtures thereof.

[0031] In addition, R1, R2 and / or R3 as defined above may comprise one or more asymmetric centers, said asymmetric centers may be present in the (S) or (R) configuration, or mixtures thereof.

[0032] As such, the compounds of the present invention include both diastereomers and enantiomers. The compounds are normally prepared as racemates and can conveniently be used as such, but individual enantiomers can be isolated or synthesized by conventional techniques if so desired. Such racemates and individual enantiomers and mixtures thereof form part of the present invention.

[0033] It is well known in the art how to prepare and isolate such optically active forms. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as resolution of racemic forms, normal, reverse-phase, and chiral chromatography, recrystallization, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose.

[0034] As used herein, “pharmaceutically acceptable salts” includes salts of compounds of the present invention derived from the combination of such compounds with non-toxic acid or base addition salts.

[0035] Acid addition salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as well as organic acids such as acetic, citric, propionic, tartaric, glutamic, salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, and benzoic acid, and related inorganic and organic acids.

[0036] Base addition salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, phosphates, hydrogenophosphates, dihydrogenophosphates and the like, as well as salts derived from basic organic amines such asaliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.

[0037] In addition to pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of the compounds, in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.

[0038] The pharmaceutically acceptable salts of compounds of the present invention can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, dimethylsulfoxide, ethyl acetate and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Such solvates are within the scope of the present invention.

[0039] The compound of Formula I for use as defined above, may be such that R3 is H.

[0040] In this embodiment, R1 is as defined herein, but is different from H, the compound of Formula I being a 1 ,3-disubstituted ferrocene compound.

[0041] The compound of Formula I for use as defined above may be such that R1 or R3 is pyridyl or thienyl, in particular unsubstituted pyridyl or thienyl.

[0042] Pyridyl may be attached to the ferrocene moiety on position 2, 3 or 4 of the pyridyl group, in particular on position 4. Thienyl may be attached to the ferrocene moiety on position 2 or 3 of the thienyl group, in particular on position 3.

[0043] The compound of Formula I for use as defined above, may be such that R1 or R3 is phenyl, said phenyl being optionally substituted, in particular by 1 to 3 groups as defined above.

[0044] In an embodiment, the compound of Formula I for use as defined above is such that R1 or R3 is chosen from phenyl, 4-fluorophenyl, 4-CF3-phenyl, 3-CF3-phenyl, 2-CF3-phenyl, 4-nitrophenyl and 3,4-difluorophenyl, 4-pyridyl, 3,4,5-trifluorophenyl, 4-CHF2-phenyl, 4-CF3C(O)-phenyl, 4-CF3O- phenyl, 4-CF3S-phenyl, 4-CF3CH(OH)-phenyl or 4-F5S-phenyl.In an embodiment, the compound of Formula I for use as defined above is such that R? is chosen from -C(=O)NRaRb or -NRcC(=0)Rd,Ra, Rb, being each independently chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (C6- C10)aryl-SO2-, (C6-10 )aryl-(C1-C6)alkyl-, or one of Raor Rb being H and the other of Raor Rb being chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (C6-10 )aryl-S02-, (C6-C10)aryl-(C1- Ce)alkyl-,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re, Rf each independently chosen from H, CF3.

[0045] In an embodiment, the compound of Formula I for use as defined above is such that R2is chosen from -C(=O)NiPr2, -C(=O)NEt2, -C(=O)NHEt, -C(=O)NEtMe, -C(=O)NEtBu, -NHC(=O)Et, - C(=O)NEtBn, -C(=O)N(CH3)(OCH3), or C(=O)NEt(SO2CH3).

[0046] In an embodiment, the compound of Formula I for use as defined above, is such that:R1 or R3is phenyl, said phenyl being optionally substituted by one or more groups, in particular by one, two or three groups, selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• Halogen,• -NO2,• -OCF3,• -SCF3,• -C(O)CF3,• -C(OH)H(CF3), or• -SF5.R2is chosen from -C(=O)NRaRb or -NRcC(=0)Rd,Rabeing (C1-C6)alkyl,Rb being chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (C6-10 )aryl(C1-C6)alkyl -,Rcbeing H,Rd being chosen from H or (C1-C6)alkyl.

[0047] The compound for use as defined above may in particular be chosen from:

[0048] In an embodiment, the compound for use as defined above may be in the form of a mixture of stereoisomeric forms, in particular in the form of a racemic mixture.

[0049] Compounds disclosed herein can be prepared starting with commercially available starting materials and utilizing synthetic techniques and procedures known to those skilled in the art. Compounds may be purified by classic techniques such as chromatographic separation. Stereochemically pure compounds may be obtained, for instance, by resolution of racemic mixtures or separation of stereoisomers using chiral HPLC.

[0050] For instance, the 1 ,1 ’-disubstituted and racemic 1 ,3-disubstituted ferrocene compounds of Formula I, may be obtained through procedures as described by Erb et.al. (Adv. Synth. Cat., 2020, 362, p.832 - “Functionalization of 3-lodo-N,N-Diisopropylferrocene-Carboxamide, a Pivotal Substrate to Open the Chemical Space to 1 ,3-Disubstituted Ferrocenes”).

[0051] The compounds of Formula I as defined above are useful in the prevention or treatment of a viral infection. In particular, the compounds of Formula I may have broad spectrum antiviral activity and may advantageously be active against a variety of different viruses.

[0052] With "Treatment" is meant the action of treating a declared pathology, the symptoms of which are visible. With "Prevention" is meant the action of preventing a disease from occurring.

[0053] Without wishing to be bound to any theory, and with reference to the examples below and figures provided herein, it is believed that the antiviral properties of the compounds of Formula I may reside both in the inhibition of virus replication and in the inhibition of entry of the virus into the cell.

[0054] The compounds of Formula I as defined herein may in particular be useful for the treatment and / or prevention of a viral infection caused by a virus belonging to the class of single-stranded RNA- positive viruses.

[0055] Single-stranded RNA-positive viruses are viruses that have a positive sense single-stranded RNA (+ssRNA) genome. The skilled person may refer to group IV the Baltimore classification to identify specific viruses that belong to the class of single-stranded RNA-positive viruses.

[0056] In an embodiment, the viral infection is caused by a virus belonging to:• the picornaviruses virus family, in particular the Hepatitis A virus, an enterovirus, a rhinovirus, the poliovirus, and foot-and-mouth virus,• the flaviviruses virus family, in particular the dengue virus, the yellow fever virus, the West Nile virus, the Japanese encephalitis virus, the Zika virus, the Usutu virus and the Tick-Borne encephalitis virus,• the alphaviruses virus family, in particular the Chikungunya virus, the Mayaro virus, the Ross River virus, and the Venezuelan Equine Encephalitis virus,• the hepaciviruses virus family, in particular the Hepatitis C virus,• the hepeviruses virus family, in particular the Hepatitis E virus,• the coronaviruses virus family, in particular HCov or SARS virus, more in particular HCoV- 229E, SARS-CoV or SARS-CoV-2,• the Filoviridae virus family, in particular the Ebola virus,• the Paramyxoviridae virus family, in particular the Respiratory Syncytial virus,• the Rhabdoviridae virus family, and / or• the Orthomyxoviridae virus family, in particular Influenzavirus A, Influenzavirus B and Influenzavirus C.

[0057] In particular, the viral infection is caused by a virus chosen from Zika virus, Dengue virus, Chikungunya virus, Ross River virus, HCoV229E virus and SARS-CoV-2.

[0058] In an embodiment, the present invention relates to a compound for use as defined above, wherein the viral infection is caused by a virus belonging to the flaviviruses virus family and wherein the compound of formula I is chosen from compounds h to I27 as defined above, the virus belonging to the flaviviruses virus family being in particular dengue virus or Zika virus.

[0059] In another embodiment, the present invention relates to a compound for use as defined above, wherein the viral infection is caused by a virus belonging to the flaviviruses virus family and wherein the compound of formula I is chosen from compounds h, I7, I10, he, I17, he, I20 I21 , I22, I23, I24, I25, I26 and I27, said compound being in particular compound I10, the virus belonging to the flaviviruses virus family being notably Zika virus,I10

[0060] In another embodiment, the present invention relates to a compound for use as defined above, wherein the viral infection is caused by a virus belonging to the coronaviruses virus family and wherein the compound of formula (I) is chosen from compounds h to I27 as defined above, in particular said compound being chosen from h, I2, I3, I4, I5, le I7, Is, I9, I10 and he, more in particular chosen from I4 or I10.

[0061] The compound of Formula I may be used as a combination of at least two compounds of Formula I.

[0062] In this embodiment, two or more, in particular 2 or 3, compounds of Formula I may be coadministered to a patient.

[0063] The term "co-administered" as used herein refers to the administration of a first compound of Formula I and at least one additional compound of Formula I, different from the first, either sequentially in any order or simultaneously, by the same administration method or a combination of different administration methods. The use of a combination of two or more compounds of Formula I may allow to fine tune the antiviral activity of the antiviral agents and may for example constitute a means to provide more efficient broad spectrum antiviral activity.

[0064] The compound of Formula I may be used in combination with another antiviral agent, in particular interferon.

[0065] In this embodiment, the compound of Formula I may be co-administered to a patient in combination with another antiviral agent. Amongst other antiviral agents can be cited the Bemnifosbuvir (AT-752) or Favipiravir, polymerase inhibitors, and Paxlovid, 3CL protease inhibitor.

[0066] The compound for use according to the invention may be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers. Suitable unit forms of administration include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, and forms of sublingual and buccal administration.

[0067] A second object of the present invention is a pharmaceutical composition comprising a compound of Formula I as defined above, in admixture with one or more pharmaceutically acceptable excipients.

[0068] For the purposes of the present invention, the expression “pharmaceutically acceptable” is understood to mean what is useful in the preparation of a pharmaceutical composition which is of sufficient purity and quality for human use or veterinary use.

[0069] "Pharmaceutically acceptable excipients" are understood to mean substances which are nontoxic, biologically tolerable and biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or used as a vehicle, carrier or diluent to facilitate the administration of an agent and which is compatible therewith.

[0070] A third object of the present invention is a compound of Formula IA:wherein:Rr is (C6-10 )aryl or 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more groups, in particular by one, two or three groups, selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• (C1-C6)alkylC(=O)-, optionally substituted by one or more fluorine atoms,• -C(OH)Re'Rr• Halogen,• -NO2,• -CN, and• (C1-C6)alkoxy, optionally substituted by one or more fluorine atoms,• (C1-C6)thioalkoxy, optionally substituted by one or more fluorine atoms, and• -SF, -S(O)F, -SO2F or -SF5,R2 is chosen from -C(=O)NRaRb or -NRcC(=0)Rd ,Ra , Rb , being each independently chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (Ce- C10)aryl-SO2-, (C6-10 )aryl-(C1-C6)alkyl,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re’, Rr each independently chosen from H, CF3, and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof, with the provisio that the compound of Formula IA is not a racemic mixture of the following structures:In a further embodiment, the compound of Formula IA is additionally not a racemic mixture of the following structure:Within the context of Rr, R2 and R3 , generic groups are defined by the definitions given above for R1, R2 and R3.In an embodiment, the compound of Formula IA as defined above is such that R2 is chosen from - C(=O)NRaRb or -NRcC(=0)Rd ,Ra , Rb , being each independently chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (C6- C10)aryl-SO2-, (C6-10 )aryl-(C1-C6)alkyl-, or one of Raor Rb being H and the other of Raor Rb being chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (C6-10 )aryl-S02-, (C6-10 )aryl-(C1- Ce)alkyl-,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re’, Rr each independently chosen from H, CF3.

[0071] In an embodiment, the invention relates to a compound of Formula IA as described above, wherein:Rr is phenyl, said phenyl being optionally substituted by one or more groups selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• (C1-C6)alkylC(=O)-, optionally substituted by one or more fluorine atoms,• -C(OH)Re'Rr• Fluorine,• -NO2,• -CN,• -OCF3,• -SCF3,• -C(O)CF3,• -C(OH)H(CF3), or• -SFs.R2 is chosen from -C(=O)NRaRb or -NRcC(=0)Rd ,Ra , Rb , being each independently chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, (C6-C10)aryl-SO2-, (C6-10 )aryl-(C1-C6)alkyl,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re’, Rr each independently chosen from H, CF3.

[0072] In an embodiment, the invention relates to a compound of Formula IA as described above, wherein the following structures are excluded:In a further embodiment, the compound of Formula IA is additionally not the following structure:

[0073] The following examples serve to illustrate the invention without intending to limit its scope in any manner.EXAMPLESGeneral synthesis procedures

[0074] General protocol A for the Suzuki-Miyaura cross-couplingThe required iodoferrocene derivative (1.00 equiv), boronic acid (4.00 equiv), Pd(dba)2 (5 mol%), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos; 20 mol%) and CsF (2.00 equiv) were placed in a dried Schlenk tube which was subjected to three cycles of vacuum / argon. Anhydrous and degassed toluene (0.100 mol / L respect to the iodoferrocene) was added, and the reaction mixture was stirred for 14 h at 110 °C in a pre-heated oil bath. The reaction mixture was cooled to 20 °C before being diluted with water and extracted with ethyl acetate. The combined organic layers were dried over MgSCM, filtrated on cotton wool and concentrated under reduced pressure on a rotaryevaporator to give the crude product. This was purified by column chromatography over SiC>2, using petroleum ether-ethyl acetate (proportions given for each product) to give the title product.

[0075] General protocol B for the / V-alkylation of A / -ethyl-3-(4-(trifluoromethyl)phenyl)-ferrocene- carboxamideSodium hydride (60% in oil, 98.0 mg, 2.25 mmol, 3.00 equiv) was added portionwise to a solution of A / -ethyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (301 mg, 0.750 mmol, 1.00 equiv) in a tetrahydrofuran / / V, / V-dimethylformamide mixture (4:1 , 5 mL) at 20 °C and the reaction mixture was stirred for 15 min. The desired alkyl halide (3.00 equiv) was added to the reaction mixture which was stirred at 20 °C for 2 h. Water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSCU, filtrated over cotton wool and concentrated under reduced pressure on a rotary evaporator to give the crude product. This was purified by column chromatography over silica, eluting with petroleum ether-ethyl acetate (eluent given in the product description) to give the title product.Solvents and reagents were sourced from commercial sources.Tetrahydrofuran was distilled over sodium / benzophenone under argon. Dichloromethane and toluene were distilled over CaH2 under argon. / V, / V-Dimethylformamide and 2, 2,6,6- tetramethylpiperidine were distilled under vacuum over CaH2. All organolithium reagents were titrated before use.Column chromatography separations were achieved on silica gel (40-63 pm). All Thin Layer Chromatographies were performed on aluminum backed plates pre-coated with silica gel (Merck, Silica Gel 60 F254). They were visualized by exposure to UV light.Melting points were measured on a Kofler bench. IR spectra were taken on a Perkin-Elmer Spectrum 100 spectrometer.1H,13C and19F Nuclear Magnetic Resonance (NMR) spectra were recorded either on a (i) Bruker AV III 300 MHz spectrometer fitted with a BBFO probe at 300 MHz, 75 MHz and 282 MHz, on a (ii) Bruker AV III 400 MHz spectrometer fitted with a BBFO probe at 400 MHz, 100 MHz and 376 MHz or on a (ii) Bruker AV III HD 500 MHz spectrometer fitted with a BBFO probe at 500 MHz, 126 MHz and 470 MHz, respectively.1H chemical shifts (6) are given in ppm relative to the solvent residual peak and13C chemical shifts are relative to the central peak of the solvent signal. Cp refers to the unsubstituted cyclopentadienyl ring of ferrocene.

[0076] Example 1 - Synthesis of 1 ,1 ’-disubstituted ferrocene derivatives.1 ,1 ’-Disubstituted derivatives were prepared according to the reaction scheme below (Erb et al. Adv. Synth. Cat., 2020, 362, 832):The starting material 1 ’-iodo- / V, / V-diisopropylferrocenecarboxamide was obtained according to the procedure as described by Kadari et.al. (Synthesis, 2020, 52, 3153 - “Remote Deprotometalation- lodolysis of N,N-Diisopropyl-2-trimethylsilylferrocenecarboxamide: A New Route Toward 1 ,1'- Disubstituted Ferrocenes”).

[0077] A / ,A / -Diisopropyl-T-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (he - WE- 1457)By following the general protocol A, using 1 ’-iodo- / V, / V-diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and 4-(trifluoromethyl)phenylboronic acid (380 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 95:5 to 90:10) as a red oil (132 mg, 58%).Rf (eluent: petroleum ether-ethyl acetate 85:15) = 0.32. vmax (film) / crrr12968, 1614, 1460, 1422, 1370, 1317, 1160, 1107, 1089, 1062, 828, 805.1H NMR (400 MHz, CDCI3): δ (ppm) 7.60 (d, J = 8.1 Hz, 2H, ArCH), 7.52 (d, J = 8.1 Hz, 2H, ArCH), 4.72 (s, 2H, FcCH), 4.49 (s, 2H, FcCH), 4.34 (br s, 1 H, CH), 4.31 (d, 2H, FcCH), 4.12 (s, 2H, FcCH), 3.40 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.07 (br s, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 168.7 (s, C=O), 143.3 (s, ArC), 128.1 (q, J = 32.7 Hz, ArC), 126.3 (s, 2 x ArCH), 125.4 (q, J = 3.7 Hz, 2 x ArCH), 124.5 (q, J = 270.2 Hz, CF3), 84.4 (s, FcC), 83.3 (s, FcC), 72.0 (s, 2 x FcCH), 71 .8 (s, 2 x FcCH), 70.4 (s, 2 x FcCH), 69.0 (s, 2 x FcCH), 49.9 (s, CH), 46.4 (s, CH), 21 .1 (s, 4 x CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.4.

[0078] / V, / V-Diisopropyl-T-(4-fluorophenyl)ferrocenecarboxamide (Iv - WE-2674)By following the general protocol A, using 1 ’-iodo- / V, / V-diisopropylferrocenecarboxamide2(220 mg, 0.500 mmol) and 4-fluorophenylboronic acid (280 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 20:1 to 10:1) as an orange oil (184 mg, 90%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.42. Vmax (film) / crrr12957, 1601 , 1523, 1369, 1318, 1223, 1157, 1043, 1032, 831 , 805, 752, 730.1H NMR (500 MHz, CDCI3): δ (ppm) 7.49-7.45 (m, 2H, ArCH), 7.00-5.95 (m, 2H, ArCH), 4.62 (t, J = 1.8 Hz, 2H, FcCH), 4.41 (t, J = 1.8 Hz, 2H, FcCH), 4.38 (br s, 1 H, CH), 4.32 (t, J = 1.7 Hz, 2H, FcCH), 4.12 (t, J = 1.7 Hz, 2H, FcCH), 3.41 (br s, 1 H, CH), 1.48 (br s, 6H, CH3), 1.10 (br s, 6H, CH3).13C{1H} NMR (125 MHZ, CDCI3): δ (ppm) 169.1 (s, C=O), 161.3 (d, J = 245.0 Hz, ArC), 134.6 (d, J = 3.0 Hz, ArC), 127.8 (d, J = 7.9 Hz, 2 x ArCH),115.4 (d, J = 21 .4 Hz, 2 x ArCH), 86.0 (s, FcC), 82.7 (s, FcC), 71 .8 (s, 2 x FcCH), 71 .1 (s, 2 x FcCH),70.4 (s, 2 x FcCH), 68.6 (s, 2 x FcCH), 49.8 (s, CH), 46.4 (s, CH), 21.2 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) -116.7.

[0079] / V, / V-Diisopropyl-T-phenylferrocenecarboxamide (hs - WE-2679)By following the general protocol A, using 1 ’-iodo- / V, / V-diisopropylferrocenecarboxamide2(220 mg, 0.500 mmol) and phenylboronic acid (244 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 20:1) as an orange oil (181 mg, 92%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.57 (double elution). Vmax (film) / crrr12955, 1601 , 1451 , 1369, 1317, 1201 , 1030, 805, 752, 729.1H NMR (500 MHz, CDCI3): δ (ppm) 7.50 (d, J = 7.4 Hz, 2H, ArCH), 7.28 (t, J = 7.7 Hz, 2H, ArCH), 7.19 (t, J = 7.4 Hz, 1 H, ArCH), 4.67 (s, 2H, FcCH), 4.46 (br s, 1 H, CH), 4.42 (s, 2H, FcCH), 4.34 (s, 2H, FcCH), 4.13 (s, 2H, FcCH), 3.41 (br s, 1 H, CH), 1.50 (br s, 6H, CH3), 1.09 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 169.3 (s, C=O), 138.7 (s, ArC), 128.5 (s, 2 x ArCH), 126.4 (s, 2 x ArCH), 126.3 (s, ArCH), 86.7 (s, FcC), 82.3 (s, FcC), 71 .9 (s, 2 x FcCH), 71 .2 (s, 2 x FcCH), 70.6 (s, 2 x FcCH), 68.6 (s, 2 x FcCH), 49.8 (s, CH),46.4 (s, CH), 21.2 (s, 4 x CH3).

[0080] / V, / V-Diisopropyl-T-(4-nitrophenyl)ferrocenecarboxamide (I19 - WE-2676)By following the general protocol A, using 1 ’-iodo- / V, / V-diisopropylferrocenecarboxamide2(220 mg, 0.500 mmol) and 4-nitrophenylboronic acid (334 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10 to 80:20) as a red solid (70 mg, 32%).Rf (eluent: petroleum ether-ethyl acetate 80:20) = 0.35. Mp 165-166 °C. Vmax (film) / crrr12965, 2930, 1615, 1593, 1508, 1457, 1331 , 1316, 1200, 1159, 1111 , 1046, 849, 840, 818, 805, 755.1H NMR (500 MHz, CDCI3): δ (ppm) 8.14 (d, J = 8.9 Hz, 2H, ArCH), 7.62 (d, J = 8.9 Hz, 2H, ArCH), 4.79 (t, J = 1.9 Hz, 2H, FcCH), 4.58 (t, J = 1.9 Hz, 2H, FcCH), 4.30 (t, J = 1.9 Hz, 2H, FcCH), 4.27 (br s, 1 H, CH), 4.14 (t, J = 1.9 Hz, 2H, FcCH), 3.42 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.08 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.8 (s, C=O), 147.6 (s, ArC), 145.9 (s, ArC), 126.4 (s, 2 x ArCH), 123.9 (s, 2 x ArCH), 83.7 (s, FcC), 83.0 (s, FcC), 72.7 (s, 2 x FcCH), 72.0 (s, 2 x FcCH), 70.6 (s, 2 x FcCH), 69.5 (s, 2 x FcCH), 50.1 (s, CH), 46.5 (s, CH), 21 .1 (s, 4 x CH3).

[0081] / V, / V-Diisopropyl-T-(3,4-difluorophenyl)ferrocenecarboxamide (bo - WE-2675)By following the general protocol A, using 1 ’-iodo- / V, / V-diisopropylferrocenecarboxamide2(220 mg, 0.500 mmol) and 3,4-difluorophenylboronic acid (316 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 20:1 to 10:1) as an orange oil (186 mg, 87%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.35. Umax (film) / crrr12967, 1602, 1527, 1464, 1425, 1359, 1317, 1266, 1201 , 1032, 817, 805, 770, 731.1H NMR (500 MHz, CDCI3): δ (ppm) 7.31 (ddd, J = 11 .7, 7.6, 2.2 Hz, 1 H, ArCH), 7.21 (dddd, J = 8.5, 4.2, 2.2, 1 .4 Hz, 1 H, ArCH), 7.06 (dt, J = 10.2, 8.4 Hz, 1 H, ArCH), 4.61 (t, J = 1.9 Hz, 2H, FcCH), 4.43 (t, J = 1.9 Hz, 2H, FcCH), 4.34 (br s, 1 H, CH), 4.31 (t, J = 1.9 Hz, 2H, FcCH), 4.13 (t, J = 1.9 Hz, 2H, FcCH), 3.41 (br s, 1 H, CH), 1.50 (br s, 6H, CH3), 1.09 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.8 (s, C=O), 150.5 (dd, J = 247.1 , 12.7 Hz, ArC), 149.0 (dd, J = 247.1 , 12.7 Hz, ArC), 136.3 (dd, J = 6.0, 3.9 Hz, ArC), 122.1 (dd, J = 5.7, 3.3 Hz, ArCH), 117.3 (d, J = 17.4 Hz, ArCH), 115.0 (d, J = 17.7 Hz, ArCH), 84.7 (s, FcC), 83.3 (s, FcC), 71 .9 (s, 2 x FcCH), 71 .5 (s, 2 x FcCH), 70.3 (s, 2 x FcCH), 68.7 (s, 2 x FcCH),49.9 (s, CH), 46.4 (s, CH), 21 .2 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) -138.4 (d, J =20.9 Hz), -141.5 (d, J = 20.9 Hz).

[0082] Example 2 - Synthesis of 1 ,3-disubstituted ferrocene derivatives.

[0083] Example 2A - Synthesis of 3-aryl- / V, / V-diisopropylferrocenecarboxamide derivatives1 ,3-Disubstituted derivatives having a A / , / V-diisopropylcarboxamide substituent were prepared from 3-iodo- / V, / V-diisopropylferrocenecarboxamide according to the reaction scheme below (Erb et al., Adv. Synth. Cat., 2020, 362, 832):By following the general protocol A, using 3-iodo-A / ,A / -diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and 4-fluorophenylboronic acid (280 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10 to 80:20) as an orange oil (136 mg, 66%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.18. vmax (film) / crrr12966, 1606, 1523, 1443, 1369, 1324, 1218, 1157, 1105, 1040, 1001 , 833, 820, 805.1H NMR (400 MHz, CDCI3): δ (ppm) 7.44(dd, J = 5.3, 8.6 Hz, 2H, ArCH), 7.00 (t, J = 8.6 Hz, 2H, ArCH), 5.02 (s, 1 H, FcCH), 4.68 (s, 1 H, FcCH), 4.66 (s, 1 H, FcCH), 4.63 (br s, 1 H, CH), 4.11 (s, 5H, Cp), 3.46 (br s, 1 H, CH), 1.47 (br s, 6H, CH3), 1.27 (br, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 169.2 (s, C=O), 161.7 (d, J = 246.6 Hz, ArC), 134.2 (d, J = 2.9 Hz, ArC), 127.6 (d, J = 7.9 Hz, 2 x ArCH), 115.5 (d, J = 21.6 Hz, 2 x ArCH), 85.6 (s, FcC), 82.3 (s, FcC), 71.5 (s, Cp), 70.4 (s, FcCH), 68.6 (s, FcCH), 67.1 (s, FcCH), 49.8 (s, CH), 46.58 (s, CH), 21.3 (4 x CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -116.2.

[0085] / V, / V-Diisopropyl-3-phenylferrocenecarboxamide (Is - WE-1560)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and phenylboronic acid (244 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10 to 80:20) as an orange oil (166 mg, 85%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.30. Umax (film) / cm“12965, 1603, 1464, 1442, 1368, 1321 , 1282, 1212, 1159, 1105, 1041 , 818, 807, 761.1H NMR (400 MHz, CDCI3): δ (ppm) 7.49 (d, J = 7.6 Hz, 2H, ArCH), 7.31 (t, J = 7.5 Hz, 2H, ArCH), 7.21 (t, J = 7.2 Hz, 1 H, ArCH), 5.07 (s, 1 H, FcCH), 4.74 (s, 1 H, FcCH), 4.68 (s, 1 H, FcCH), 4.65 (br s, 1 H, CH), 4.11 (s, 5H, Cp), 3.47 (br s, 1 H, CH), 1 .48 (br s, 6H, CH3), 1 .28 (s, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 169.2 (s, C=O), 138.3 (s, ArC), 128.6 (s, 2 x ArCH), 126.5 (s, ArCH), 126.3 (s, 2 x ArCH), 86.3 (s, FcC), 82.3 (s, FcC), 71.5 (s, Cp), 70.5 (s, FcCH), 68.7 (s, FcCH), 67.2 (s, FcCH), 49.8 (s, CH), 46.4 (s, CH), 21.3 (s, 4 X CH3).

[0086] / V, / V-Diisopropyl-3-(4-nitrophenyl)ferrocenecarboxamide (k - WE-1563)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and 4-nitrophenylboronic acid (334 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10 to 70:30) as a red solid (100 mg, 46%).Rf (eluent: petroleum ether-ethyl acetate 70:30) = 0.65. Mp 163-164 °C. Umax (film) / crrr12964, 2931 , 1625, 1594, 1508, 1468, 1442, 1343, 1321 , 1284, 1152, 1103, 1040, 844, 819, 808, 754.1H NMR (400 MHz, CDCI3): δ (ppm) 8.16 (d, J = 8.7 Hz, 2H, ArCH), 7.58 (d, J = 8.7 Hz, 2H, ArCH), 5.16 (s, 1 H, FcCH), 4.81 (s, 1 H, FcCH), 4.79 (s, 1 H, FcCH), 4.56 (br s, 1 H, CH), 4.13 (s, 5H, Cp), 3.47 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.27 (br s, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 168.3 (s, C=O), 147.2 (s, ArC), 146.0 (s, ArC), 126.2 (s, 2 x ArCH), 124.1 (s, 2 x ArCH), 84.7 (s, FcC), 82.4(s, FcC), 72.0 (s, Cp), 71.6 (s, FcCH), 69.4 (s, FcCH), 67.6 (s, FcCH), 50.0 (s, CH), 46.5 (s, CH), 21.3 (s, 4 X CH3).

[0087] 3-(3,4-Difluorophenyl)-A / ,A / -diisopropylferrocenecarboxamide (la - WE-1561)By following the general protocol A, using 3-iodo-A / ,A / -diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and 3,4-difluorophenylboronic acid (316 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10 to 80:20) as an orange oil (160 mg, 75%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.34. Umax (film) / crrr12966, 2931 , 1603, 1528, 1453, 1369, 1327, 1264, 1202, 1106, 1040, 817, 807, 771 , 761.1H NMR (400 MHz, CDCI3): δ (ppm) 7.28-7.23 (m, 1 H, ArCH), 7.19-7.17 (m, 1 H, ArCH), 7.14-7.07 (m, 1 H, ArCH), 5.01 (s, 1 H, FcCH), 4.67-4.66 (m, 2H, FcCH), 4.60 (br s, 1 H, CH), 4.12 (s, 5H, Cp), 3.46 (br s, 1 H, CH), 1.47 (br s, 6H, CH3), 1.26 (br s, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 168.6 (s, C=O), 150.5 (dd, J = 13.1 , 247.7 Hz, ArC), 149.1 (dd, J = 12.6, 247.6 Hz, ArC), 135.8 (dd, J = 3.7, 5.9 Hz, ArC), 121.9 (dd, J = 3.5, 5.7 Hz, ArCH), 117.4 (d, J = 17.3 Hz, ArCH), 114.8 (d, J = 17.8 Hz, ArCH), 84.3 (s, FcC), 82.9 (s, FcC), 71.6 (s, Cp), 70.6 (s, FcCH), 68.7 (s, FcCH), 67.1 (s, FcCH), 49.8 (s, CH), 46.5 (s, CH), 21.3 (s, 4 X CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -138.0 (d, J = 21.3 Hz), -140.9 (d, J = 21.3 Hz).

[0088] / V, / V-Diisopropyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (I10 - KA-31)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and 4-trifluoromethylphenylboronic acid (379 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 80:20) as an orange oil (156 mg, 68%).Rf (eluent: petroleum ether-ethyl acetate 80:20) = 0.25. vmax (film) / crrr12967, 1614, 1467, 1445, 1320, 1284, 1160, 1119, 1105, 1067, 1039, 842, 821 , 807.1H NMR (500 MHz, CDCI3): δ (ppm) 7.55 (br s, 4H, ArCH), 5.12 (s, 1 H, FcCH), 4.77 (s, 1 H, FcCH), 4.72 (s, 1 H, FcCH), 4.61 (br s, 1 H, CH), 4.12 (s, 5H, Cp), 3.46 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.25 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.7 (C=O), 142.8 (s, ArC), 128.3 (q, J = 32.2 Hz, ArC), 126.2 (s, 2 x ArCH), 125.6 (q, J = 2.4 Hz, 2 x ArCH), 124.5 (q, J = 272.2 Hz, CF3), 84.0 (s, FcC), 83.4 (FcC), 71.7 (Cp), 70.9 (FcCH), 69.1 (FcCH), 67.3 (FcCH), 49.9 (CH), 46.5 (CH), 21.3 (4 x CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.4 (s).

[0089] A / ,A / -Diisopropyl-3-(2-(trifluoromethyl)phenyl)ferrocenecarboxamide (In - WE-1572)By following the general protocol A, using 3-iodo-A / ,A / -diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and 2-(trifluoromethyl)phenylboronic acid (380 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10 to 80:20) as an orange oil (185 mg, 81 %).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.47. Umax (film) / crrr12968, 2932, 1611 , 1602, 1470, 1455, 1434, 1367, 1344, 1307, 1161 , 1120, 1101 , 1034, 830, 772, 758.1H NMR (400 MHz, CDCI3): δ (ppm) 8.01 (d, J = 7.9 Hz, 1 H, ArCH), 7.61 (d, J = 7.9 Hz, 1 H, ArCH), 7.53 (t, J = 7.9 Hz, 1 H, ArCH), 7.35 (t, J = 7.9 Hz, 1 H, ArCH), 4.89 (s, 1 H, FcCH), 4.74 (s, 1 H, FcCH), 4.62 (s, 1 H, FcCH), 4.49 (br s, 1 H, CH), 4.26 (s, 5H, Cp), 3.46 (br s, 1 H, CH), 1.51 (br s, 6H, CH3), 1.21 (br s, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 168.8 (s, C=O), 137.5 (s, ArC), 133.6 (s, ArCH),131.2 (s, ArCH), 128.7 (q, J = 30.2 Hz, ArC), 126.7 (s, ArCH), 126.2 (q, J = 5.7 Hz, ArCH), 124.4 (q, J = 274.1 Hz, CF3), 86.6 (s, FcC), 83.0 (s, FcC), 71.8 (s, Cp), 71.3 (q, J = 1.9 Hz, 1 H, FcCH), 70.8 (q, J = 2.9 Hz, 1 H, FcCH), 70.6 (s, FcCH), 50.0 (s, CH), 46.4 (s, CH), 21 .3 (s, 4 x CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -57.1.

[0090] / V, / V-Diisopropyl-3-(3-(trifluoromethyl)phenyl)ferrocenecarboxamide (112 - WE- 1554)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide (220 mg, 0.500 mmol) and 3-(trifluoromethyl)phenylboronic acid (380 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10 to 80:20) as an orange oil (165 mg, 72%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.31. Umax (film) / crrr12967, 1611 , 1456, 1314, 1162, 1121 , 1092, 10472, 895, 820, 801 , 762.1H NMR (400 MHz, CDCI3): δ (ppm) 7.69 (s, 1 H, ArCH), 7.66 (d, J = 7.5 Hz, 1 H, ArCH), 7.46 (d, J = 7.5 Hz, 1 H, ArCH), 7.41 (t, J = 7.5 Hz, 1 H, ArCH), 5.10 (s, 1 H, FcCH), 4.76 (s, 1 H, FcCH), 4.71 (s, 1 H, FcCH), 4.61 (br s, 1 H, CH), 4.13 (s, 5H, Cp), 3.47 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.26 (br s, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 168.8 (s, C=O), 139.8 (s, ArC), 131.0 (q, J = 32.2 Hz, ArC), 129.4 (s, ArCH), 129.1 (s, ArCH),124.3 (q, J = 271.9 Hz, CF3), 123.1 (q, J = 3.4 Hz, ArCH), 122.7 (q, J = 3.5 Hz, ArCH), 84.5 (s, FcC),83.3 (s, FcC), 71.7 (s, Cp), 70.8 (s, FcCH), 69.0 (s, FcCH), 67.2 (s, FcCH), 49.9 (s, CH), 46.5 (s, CH), 21 .3 (4 x CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.8.

[0091] 3-(3,4.5-Trifluorophenyl) diisopropylferrocenecarboxamide (I21 - WE-2680)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide1(220 mg, 0.500 mmol) and 3,4,5-trifluorophenylboronic acid (352 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 20:1) as an orange oil (43 mg, 19%).Rf (eluent: petroleum ether-ethyl acetate 80:20) = 0.54. Vmax (film) / crrr12957, 1610, 1536, 1442, 1340, 1325, 1251 , 1040, 821 , 806, 741.1H NMR (500 MHz, CDCI3): δ (ppm) 7.08-7.02 (m, 2H, ArCH), 4.99 (t, J = 1.4 Hz, 1 H, FcCH), 4.69 (dd, J = 2.5, 1.3 Hz, 1 H, FcCH), 4.65 (dd, J = 2.5, 1.3 Hz, 1 H, FcCH), 4.57 (br s, 1 H, CH), 4.14 (s, 5H, Cp), 3.46 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.25 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.6 (s, C=O), 151.5 (ddd, J = 249.1 , 10.1 , 4.4 Hz, 2 x ArC), 138.3 (dt, J = 250.6, 15.5 Hz, ArC), 135.4 (m, ArC), 109.8 (dd, J = 16.7, 5.1 Hz, 2 x ArCH), 83.7 (s, FcC), 83.2 (s, FcC), 71.8 (s, Cp), 70.9 (s, FcCH), 68.7 (s, FcCH), 67.1 (s, FcCH), 50.0 (s, CH), 46.6 (s, CH), 21 .3 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) -134.7 (d, J = 20.1 Hz, 2F), -163.4 (t, J = 20.4 Hz, 1 F).

[0092] 3-(4-(Difluoromethyl)phenyl)- diisopropylferrocenecarboxamide (I22 - WE-2704)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide1(176 mg, 0.400 mmol) and 4-(difluoromethyl)phenylboronic acid (275 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 10:1 to 9:1) as an orange oil (139 mg, 79%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.20. Vmax (film) / crrr12967, 1614, 1459, 1445, 1370, 1323, 1284, 1218, 1057, 1039, 1016, 819, 807,730.1H NMR (500 MHz, CDCI3): δ (ppm) 7.56 (d, J = 8.2 Hz, 2H, ArCH), 7.44 (d, J = 8.2 Hz, 2H, ArCH), 6.63 (t, J = 56.4 Hz, 1 H, CHF2), 5.11 (t, J = 1 .5 Hz, 1 H, FcCH), 4.76 (dd, J = 2.6, 1 .5 Hz, 1 H, FcCH), 4.71 (dd, J = 2.6, 1 .5 Hz, 1 H, FcCH), 4.63 (br s, 1 H, CH), 4.12 (s, 5H, Cp), 3.47 (brs, 1 H, CH), 1.49 (br s, 6H, CH3), 1.26 (brs, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 169.0 (s, C=O), 141.5 (s, ArC), 132.3 (t, J = 22.3 Hz, ArC), 126.3 (s, 2 x ArCH), 125.9 (t, J = 6.0 Hz, 2 x ArCH), 114.9 (t, J = 238.3 Hz, CHF2), 84.7 (s, FcC), 83.0 (s, FcC), 71 .7 (s, Cp), 70.8 (s, FcCH), 69.0 (s, FcCH), 367.3 (s, FcCH), 49.9 (s, CH), 46.5 (s, CH), 21 .3 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) -110.2.

[0093] 3-(4-(2,2,2-Trifluoroacetyl)phenyl)-A / ,A / -diisopropylferrocenecarboxamide (I23 - WE-2706)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide1(176 mg, 0.400 mmol) and 4-(2,2,2-trifluoroacetyl)phenylboronic acid pinacol ester (480 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 80:20) with 2% NEts as a red glue (166 mg, 85%).Rf (eluent: petroleum ether-ethyl acetate 80:20) = 0.25. Umax (film) / crrr12958, 1600, 1466, 1444, 1324, 1095, 821 , 751.1H NMR (500 MHz, CDCI3): δ (ppm) 8.00 (d, J = 7.9 Hz, 2H, ArCH), 7.60 (d, J = 8.6 Hz, 2H, ArCH), 5.18 (t, J = 1 .5 Hz, 1 H, FcCH), 4.83 (dd, J = 2.6, 1 .5 Hz, 1 H, FcCH), 4.79 (dd, J = 2.6, 1.5 Hz, 1 H, FcCH), 4.58 (br s, 1 H, CH), 4.14 (s, 5H, Cp), 3.47 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.25 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 179.8 (q, J = 34.8 Hz, C=O), 168.4 (s, C=O), 148.0 (s, ArC), 130.6 (s, 2 x ArCH), 127.5 (s, ArC), 126.2 (s, 2 x ArCH), 117.0 (q, J = 291.2 Hz, CF3), 84.6 (s, FcC), 82.6 (s, FcC), 72.0 (s, Cp), 71.7 (s, FcCH), 69.4 (s, FcCH), 67.6 (s, FcCH), 50.0 (s, CH), 46.5 (s, CH), 21 .3 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) -71 .2.

[0094] 3-(4-(Trifluoromethoxy)phenyl)- / V, / V-diisopropylferrocenecarboxamide (I24 - WE-2703)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide1(176 mg, 0.400 mmol) and 4-(trifluoromethoxy)phenylboronic acid (329 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 10:1 to 9:1) as an orange solid (152 mg, 80%).Rf (eluent: petroleum ether-ethyl acetate 10:1) = 0.37. Mp 65-66 °C. Umax (film) / crrr13003, 2967, 2243, 1612, 1522, 1474, 1443, 1339, 1251 , 1206, 1148, 1104, 1040, 920, 823, 805, 732, 724.1H NMR (500 MHz, CDCI3): δ (ppm) 7.49 (d, J = 8.9 Hz, 2H, ArCH), 7.15 (d, J = 8.9 Hz, 2H, ArCH), 5.05 (t, J = 1 .5 Hz, 1 H, FcCH), 4.70 (dd, J = 2.6, 1 .5 Hz, 1 H, FcCH), 4.68 (dd, J = 2.6, 1 .5 Hz, 1 H, FcCH), 4.64 (br s, 1 H, CH), 4.12 (s, 5H, Cp), 3.47 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.27 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.9 (s, C=O), 147.8 (s, ArC), 137.4 (s, ArC), 127.4 (s, 2 x ArCH), 121.2 (s, 2 x ArCH), 120.6 (q, J = 256.9 Hz, CF3), 84.8 (s, FcC), 82.8 (s, FcC), 71.6 (s, Cp), 70.6 (s, FcCH), 68.8 (s, FcCH), 67.2 (s, FcCH), 49.9 (s, CH), 46.5 (s, CH), 21 .3 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) -57.8.

[0095] 3-(4-(Trifluoromethylsulfanyl)phenyl)-A / ,A / -d / / sopropy / ferrocenecarfaoxam / de (125 - WE-2707)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide1(176 mg, 0.400 mmol) and 4-(trifluoromethylsulfanyl)phenylboronic acid (355 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 10:1 to 9:1) as an orange oil (103 mg, 52%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.24. Vmax (film) / crrr12957, 1607, 1595, 1454, 1443, 1326, 1152, 1115, 1104, 1039, 821 , 807, 754.1H NMR (500 MHz, CDCI3): δ (ppm) 7.57 (d, J = 8.3 Hz, 2H, ArCH), 7.51 (d, J = 8.3 Hz, 2H, ArCH), 5.09 (t, J = 1.5 Hz, 1 H, FcCH), 4.75 (dd, J = 2.6, 1.5 Hz, 1 H, FcCH), 4.72 (dd, J = 2.6, 1.5 Hz, 1 H, FcCH), 4.60 (br s, 1 H, CH), 4.12 (s, 5H, Cp), 3.47 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.25 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.8 (s, C=O), 142.1 (ArC), 136.6 (s, 2 x ArCH), 129.6 (q, J = 308.2 Hz, CF3), 127.0 (s, 2 x ArCH), 121.6 (s, ArC), 84.0 (FcC), 83.5 (s, FcC), 71.7 (s, Cp), 71.0 (s, FcCH), 69.0 (s, FcCH), 67.3 (s, FcCH), 50.0 (s, CH), 46.5 (s, CH), 21.3 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) - 42.9.

[0096] 3-(4-(Pentafluorosulfanyl)phenyl)-A / ,A / -diisopropylferrocenecarboxamide (I26 - WE-2724)By following the general protocol A, using 3-iodo- / V, / V-diisopropylferrocenecarboxamide1(176 mg, 0.400 mmol) and 4-(pentafluorosulfanyl)phenylboronic acid (250 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 10:1 to 9:1) as an orange solid (185 mg, 89%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.35. Mp 60-64 °C. Vmax (film) / crrr12967, 1600, 1444, 1370, 1324, 1095, 1040, 819, 761.1H NMR (500 MHz, CDCI3): δ (ppm) 7.67 (d, J = 8.8 Hz, 2H, ArCH), 7.52 (d, J = 8.5 Hz, 2H, ArCH), 5.11 (t, J = 1 .5 Hz, 1 H, FcCH), 4.76 (dd, J = 2.6, 1 .5 Hz, 1 H, FcCH), 4.73 (dd, J = 2.6, 1.5 Hz, 1 H, FcCH), 4.59 (br s, 1 H, CH), 4.13 (s, 5H, Cp), 3.47 (br s, 1 H, CH), 1.49 (br s, 6H, CH3), 1.25 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.6 (s, C=O), 151.8 (quint, J = 17.2 Hz, ArC), 143.0 (s, ArC), 126.3 (quint, J = 4.6 Hz, 2 x ArCH), 125.9 (s, 2 x ArCH), 83.7 (s, FcC), 83.2 (s, FcC), 71.8 (s, Cp), 71.1 (s, FcCH), 69.3 (s, FcCH), 67.4 (s, FcCH), 49.9 (s, CH), 46.5 (s, CH), 21 .3 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) 86.2- 84.1 (m, 1 F), 63.4-62.8 (m, 4F).

[0097] Example 2B - Synthesis of various 3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide derivativesA variety of secondary carboxamides, tertiary carboxamides and acylsulfonamides was prepared according to the reaction scheme below:Staring material / V-cumyl- / V-ethyl-2-iodoferrocenecarboxamide was prepared according to Metallinos et.al. (Adv. Synth. Catal., 2003, 345, 370 - “(-)-Sparteine-Mediated Directed ortho Metalation of N- Cumyl-N-Ethyl Ferrocenecarboxamide. Versatile Routes to Planar Chiral Ferrocenecarboxamides, Amines, Esters and Phosphines”).

[0098] / V-Cumyl- / V-ethyl-3-iodoferrocenecarboxamide (WE-1499-1) / V-Cumyl- / V-ethyl-3-iodoferrocenecarboxamide was prepared according to Erb et. al. (Adv. Synth. Cat., 2020, 362, 832) from / V-cumyl- / V-ethyl-2-iodoferrocenecarboxamide (1.50 g, 3.00 mmol) using 2,2,6,6-tetramethylpiperidine (557 pL, 3.30 mmol) and nBuLi (2.40 mL, 3.30 mmol) and was isolatedas an orange solid (645 mg, 43%). It was found unstable upon heating and storage, losing the cumyl moiety to give A / -ethyl-3-iodoferrocenecarboxamide as an orange oil.

[0099] N-Cumyl-N-ethyl-3-iodoferrocenecarboxamide (WE-1499-1)Rf(eluent: cyclohexane-iPrOAc 78:22) = 0.48. Mp 111 -112 °C. Vmax (film) / crrr13309, 2971 , 1622, 1549, 1433, 1376, 1306, 1277, 1260, 1195, 1105, 821 , 763.1H NMR (300 MHz, CDCI3): δ (ppm) 7.39-7.29 (m, 4H, ArCH), 7.18 (m, 1 H, ArCH), 4.84 (t, J = 1.2 Hz, 1 H, FcCH), 4.64 (dd, J = 1.4, 2.5 Hz, 1 H, FcCH), 4.51 (dd, J = 1.4, 2.5 Hz, 1 H, FcCH), 4.09 (s, 5H, Cp), 3.72 (m, 2H, CH2), 1.74 (s, 3H, CH3), 1 .72 (s, 3H, CH3), 1 .35 (t, J = 7.0 Hz, 3H, CH3).

[0100] / V-Ethyl-3-iodoferrocenecarboxamide (WE-1499-2)Rf (eluent: petroleum ether-ethyl acetate 60:40) = 0.36. Vmax (film) / crrr13306 (br), 2970, 2930, 1626, 1538, 1437, 1374, 1318, 1291 , 1200, 1145, 1106, 1001 , 873, 822, 752.1H NMR (500 MHz, CDCI3): δ (ppm) 5.70 (br s, 1 H, NH), 4.89 (t, J = 1.2 Hz, 1 H, FcCH), 4.69 (dd, J = 1.4, 2.3 Hz, 1 H, FcCH), 4.57 (dd, J = 1.2, 2.4 Hz, 1 H, FcCH), 4.22 (s, 5H, Cp), 3.40 (m, 2H, CH2), 1.21 (t, J = 7.3 Hz, 3H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 168.7 (s, C=O), 77.4 (s, FcC), 76.9 (s, FcCH), 74.2 (s, FcCH), 72.8 (s, Cp), 69.2 (s, FcCH), 39.6 (s, FcC), 34.7 (s, CH2), 15.4 (s, CH3).

[0101] / V-Ethyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (h - WE-1579)By following the general protocol A, using / V-cumyl- / V-ethyl-3-iodoferrocenecarboxamide (401 mg, 0.800 mmol) and 4-(trifluoromethyl)phenylboronic acid (608 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 70:30 to 50:50) as an orange solid (199 mg, 62%).Rf (eluent: petroleum ether-ethyl acetate 60:40) = 0.30. Mp 66-68 °C. Vmax (film) / crrr13309 (br), 1615, 1539, 1321 , 1268, 1161 , 1105, 1068, 1015, 840, 823.1H NMR (400 MHz, CDCI3): δ (ppm) 7.58 (d, J = 8.7 Hz, 2H, ArCH), 7.55 (d, J = 8.7 Hz, 2H, ArCH), 5.71 (t, J = 5.2 Hz, 1 H, NH), 5.21 (s, 1 H, FcCH), 4.84 (s, 2H, FcCH), 4.09 (s, 5H, Cp), 3.45 (quint, J = 6.4 Hz, 2H, CH2), 1.25 (t, J = 7.1 Hz, 3H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 169.5 (s, C=O), 142.3 (s, ArC), 128.6 (q, J = 32.6 Hz, ArC), 126.2 (s, 2 x ArCH), 125.6 (q, J = 3.6 Hz, 2 x ArCH), 124.4 (q, J = 271.8 Hz, CF3), 85.7 (s, FcC), 77.9 (s, FcC), 71.6 (s, Cp), 69.3 (s, FcCH), 68.9 (s, FcCH), 66.8 (s, FcCH), 34.7 (s, CH2), 15.4 (s, CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.5.

[0102] A / -Ethyl-A / -methyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (h - WE-1704)By following the general protocol B, using iodomethane (140 pL), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 50:50) as an orange solid (212 mg, 68%).Rf (eluent: petroleum ether-ethyl acetate 50:50) = 0.42. Mp 111-112 °C. Umax (film) / crrr12931 , 1606, 1496, 1398, 1321 , 1287, 1158, 1118, 1106, 1063, 1011 , 840, 823.1H NMR (400 MHz, CDCI3): δ (ppm) 7.58 (d, J = 8.5 Hz, 2H, ArCH), 7.55 (d, J = 8.5 Hz, 2H, ArCH), 5.18 (s, 1 H, FcCH), 4.80 (m, 2H, FcCH), 4.12 (s, 5H, Cp), 3.57 (q, J = 6.8 Hz, 2H, CH2), 3.13 (br s, 3H, CH3), 1.23 (t, J = 7.3 Hz, 3H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 169.6 (s, C=O), 142.7 (s, ArC), 128.3 (q, J = 32.3 Hz, ArC), 126.2 (s, 2 x ArCH), 125.5 (q, J = 3.6 Hz, 2 x ArCH), 124.4 (q, J = 271 .1 Hz, CF3), 84.5 (s, FcC), 80.7 (s, FcC), 71.7 (s, Cp), 69.9 (s, FcCH), 69.4 (s, FcCH), 67.8 (s, FcCH), 44.4 (s, CH2), 36.4 (s, CH3), 13.3 (s, CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.4.

[0103] A / -A / -Diethyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (l3- WE-1707)By following the general protocol B, using iodoethane (181 pL) and with heating at 50 °C for 1 h after addition of the alkyl halide, the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 60:40) as an orange oil (223 mg, 69%).Rf (eluent: petroleum ether-ethyl acetate 60:40) = 0.45. Umax (film) / crrr12975, 1614, 1484, 1321 , 1265, 1161 , 1105, 1066, 1014, 841 , 823.1H NMR (400 MHz, CDCI3): δ (ppm) 7.58 (d, J = 8.6 Hz, 2H, ArCH), 7.55 (d, J = 8.6 Hz, 2H, ArCH), 5.18 (s, 1 H, FcCH), 4.80 (s, 1 H, FcCH), 4.78 (s, 1 H, FcCH), 4.12 (s, 5H, Cp), 3.54 (br s, 4H, CH2), 1.25 (t, J = 6.2 Hz, 6H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 169.0 (s, C=O), 142.7 (s, ArC), 128.4 (q, J = 32.6 Hz, ArC), 126.2 (s, 2 x ArCH), 125.6 (q, J = 3.5 Hz, 2 x ArCH), 124.5 (q, J = 271 .3 Hz, CF3), 84.4 (s, FcC), 81.0 (s, FcC), 71.7 (s, Cp), 71.3 (s, FcCH), 69.4 (s, FcCH), 67.8 (s, FcCH), 42.7 and 41.2 (s, 2 x CH2), 14.9 and 13.1 (s, 2 x CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.5.

[0104] / V-n-Butyl- / V-ethyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (b - WE-1706)By following the general protocol B, using 1 -iodobutane (256 pL) and with heating at 50 °C for 14 h after addition of the alkyl halide, the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 70:30 to 60:40) as an orange oil (189 mg, 55%).Rf (eluent: petroleum ether-ethyl acetate 50:50) = 0.75. Vmax (film) / crrr12960, 2933, 1614, 1482, 1321 , 1279, 1161 , 1106, 1060, 1014, 841 , 822.1H NMR (400 MHz, CDCI3): δ (ppm) 7.58 (d, J = 8.5 Hz, 2H, ArCH), 7.55 (d, J = 8.5 Hz, 2H, ArCH), 5.17 (s, 1 H, FcCH), 4.79 (s, 1 H, FcCH), 4.77 (s, 1 H, FcCH), 4.11 (s, 5H, Cp), 3.54 (br s, 2H, CH2), 3.46 (br s, 2H, CH2), 1 .64 (quint, J = 7.8 Hz, 2H, CH2), 1 .37 (sex, J = 7.5 Hz, 2H, CH2), 1 .24 (t, J = 6.7 Hz, 3H, CH3), 0.97 (t, J = 7.3 Hz, 3H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 169.1 (s, C=O), 142.7 (s, ArC), 128.3 (q, J = 32.3 Hz, ArC), 126.6 (s, 2 x ArCH), 125.6 (q, J = 3.5 Hz, 2 x ArCH), 124.4 (q, J = 271.6 Hz, CF3), 84.4 (s, FcC), 81.1 (s, FcC), 71.7 (s, Cp), 71.3 (s, FcCH), 69.4 (s, FcCH), 67.8 (s, FcCH), 48.3 and 46.1 (s, CH2), 43.3 and 41.7 (s, CH2), 31.6 and 29.9 (s, CH2), 20.4 (s, CH2), 14.8 and 12.9 (s, CH3), 14.1 (s, CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.5.

[0105] / V-Benzyl- / V-ethyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (h3- WE-1708)By following the general protocol B, using benzyl bromide (267 pL), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 70:30 to 60:40) as an orange oil (270 mg, 73%).Rf (eluent: petroleum ether-ethyl acetate 60:40) = 0.59. Vmax (film) / crrr12977, 2933, 1614, 1478, 1446, 1321 , 1248, 1162, 1119, 1106, 1066, 841 , 823, 750.1H NMR (400 MHz, CDCI3): δ (ppm) 7.53 (br s, 4H, ArCH), 7.40 (br s, 2H, ArCH), 7.31 (m, 3H, ArCH), 5.21 (br s, 1 H, FcCH), 4.81 (br s, 2H, CH2), 4.77 (br s, 2H, FcCH), 4.11 (s, 5H, Cp), 3.54 (br s, 2H, CH2), 1.24 (t, J = 6.8 Hz, 3H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 170.2 (s, C=O), 142.5 (s, ArC), 137.9 (s, ArC), 128.9 (s, 2 x ArCH), 128.4 (q, J = 32.5 Hz, ArC), 127.5 (s, 3 x ArCH), 126.2 (s, 2 x ArCH), 125.6 (q, J = 3.3 Hz, 2 x ArCH), 124.4 (q, J = 271.2 Hz, CF3), 84.8 (s, FcC), 79.7 (s, FcC), 71.7 (s, Cp), 71.5 (s, FcCH), 69.7 (s, FcCH), 68.2 (s, FcCH), 51.8 (s, CH2), 42.1 (s, CH2), 12.6 (s, CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.5.

[0106] A / -Ethyl-A / -methylsulfonyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (I14 - WE-1711)A solution of nBuLi in hexanes (1.4 M, 320 pL, 0.450 mmol, 0.900 equiv) was added dropwise to a solution of A / -ethyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (200 mg, 0.500 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) at 0 °C. After addition, the reaction mixture was stirred at the same temperature for 15 min. Methanesulfonyl chloride (140 pL, 114 mg, 1.00 mmol, 2.00 equiv) was added and the reaction mixture was warmed to 20 °C and stirred for 14 h. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSCM, filtrated over cotton wool and concentrated under reduced pressure on a rotary evaporator to give the crude product. This was purified by column chromatography over silica, eluting with petroleum ether-ethyl acetate (70:30 to 50:50) to give the title product as an orange oil (43 mg, 18%).Rf (eluent: petroleum ether-ethyl acetate 60:40) = 0.78. vmax (film) / crrr11652, 1616, 1427, 1343, 1321 , 1234, 1154, 1106, 1054, 1014, 963, 899, 828, 754.1H NMR (500 MHz, CDCI3): δ (ppm) 7.61 (d, J = 8.7 Hz, 2H, ArCH), 7.58 (d, J = 8.7 Hz, 2H, ArCH), 5.34 (s, 1 H, FcCH), 4.99 (s, 2H, FcCH), 4.20 (s, 5H, Cp), 4.03 (q, J = 7.1 Hz, 2H, CH2), 3.39 (s, 3H, CH3), 1.36 (t, J = 7.1 Hz, 3H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 174.0 (s, C=O), 141.5 (s, ArC), 129.0 (q, J = 32.6 Hz, ArC), 126.4 (s, 2 x ArCH), 125.7 (q, J = 3.3 Hz, 2 x ArCH), 124.3 (q, J = 271.5 Hz, CF3), 87.1 (s, FcC), 76.0 (s, FcC), 72.7 (s, Cp), 72.1 (s, FcCH), 70.1 (s, FcCH), 69.8 (s, FcCH), 43.8 (s, CH2), 43.5 (s, CH3), 16.1 (s, CH3).19F{1H} NMR (470 MHz, CDCI3): δ (ppm) -62.5.

[0107] Example 2C - Synthesis of / V-methoxy- / V-methyl-3-(4-(trifluoromethyl)phenyl)- ferrocenecarboxamide / V-Methoxy- / V-methyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide hs was prepared according to the reaction scheme below:

[0108] Methyl 3-(4-(trifluoromethyl)phenyl)ferrocenecarboxylate (WE-1943)By following the general protocol A, using methyl 3-iodoferrocenecarboxylate (185 mg, 0.50 mmol) and 4-(trifluoromethyl)phenylboronic acid (285 mg), the title product was obtained after column chromatography (petroleum ether-ethyl acetate, 90:10) as an orange solid (135 mg, 69%).Rf (eluent: petroleum ether-ethyl acetate 80:20) = 0.63. Mp 135-136 °C. Vmax (film) / cm-13111 , 2952, 1698, 1615, 1474, 1448, 1324, 1248, 1156, 1132, 1106, 1067, 1013, 843, 826, 775.1H NMR (400 MHz, CDCI3): δ (ppm) 7.59 (d, J = 8.5 Hz, 2H, ArCH), 7.56 (d, J = 8.5 Hz, 2H, ArCH), 5.33 (t, J = 1 .4 Hz, 1 H, FcCH), 5.01 (dd, J = 1 .3, 2.7 Hz, 1 H, FcCH), 4.90 (t, J = 1 .6, 2.6 Hz, 1 H, FcCH), 4.10 (s, 5H, Cp), 3.84 (s, 3H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 171.8 (s, C=O), 142.1 (s, ArC), 128.9 (q, J = 32.9 Hz, ArC), 126.3 (s, 2 x ArCH), 125.6 (q, J = 3.6 Hz, 2 x ArCH), 124.4 (q, J = 272.1 Hz, CF3), 86.6 (s, FcC), 72.6 (s, FcC), 71.6 (s, FcCH and Cp), 69.9 (s, FcCH), 68.5 (s, FcCH), 51.9 (s, CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.5.

[0109] A / -Methoxy-A / -methyl-3-(4-(trifluoromethyl)phenyl)ferrocenecarboxamide (I15 - WE-1999)A solution of iPrMgCI in tetrahydrofuran (2 M, 1 .20 mL, 2.40 mmol, 6.00 equiv) was added dropwise to a solution of methyl 3-(4-(trifluoromethyl)phenyl)ferrocenecarboxylate (135 mg, 0.400 mmol, 1.00 equiv) and / V-methylhydroxylamine hydrochloride (117 mg, 1 .20 mmol, 3.00 equiv) in tetrahydrofuran (5 mL) at -20 °C. After addition, the reaction mixture was stirred at the same temperature for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layer was dried over MgSCM, filtrated over cotton wool and concentrated under reduced pressure on a rotary evaporator to give the crude product. This was purified by column chromatography over silica, eluting with petroleum ether-ethyl acetate (60:40 to 50:50) to give the title product as an orange oil (144 mg, 86%).Rf (eluent: petroleum ether-ethyl acetate 60:40) = 0.24. Vmax (film) / crrr12938, 1615, 1472, 1438, 1321 , 1161 , 1118, 1105, 1064, 842, 823, 750.1H NMR (400 MHz, CDCI3): δ (ppm) 7.61 (d, J = 8.4 Hz, 2H, ArCH), 7.56 (d, J = 8.4 Hz, 2H, ArCH), 5.45 (t, J = 1.4 Hz, 1 H, FcCH), 5.10 (dd, J = 1.3, 2.7 Hz, 1 H, FcCH), 4.88 (dd, J = 1.6, 2.5 Hz, 1 H, FcCH), 4.10 (s, 5H, Cp), 3.78 (s, 3H, CH3), 3.34 (s, 3H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 170.6 (s, C=O), 142.5 (s, ArC), 128.5 (q, J = 32.4 Hz, ArC), 126.3 (s, 2 x ArCH), 125.6 (q, J = 3.7 Hz, 2 x ArCH), 124.4 (q, J = 271.3 Hz, CF3), 85.8 (s,FcC), 75.2 (s, FcC), 72.6 (s, FcCH), 71 .6 (s, Cp), 70.0 (s, FcCH), 69.4 (s, FcCH), 61 .4 (s, CH3), 33.6 (s, CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.4.

[0110] Example 2D - Synthesis of A / -(3-(4-(trifluoromethyl)phenyl)ferrocenyl)propionamideA / -(3-(4-(Trifluoromethyl)phenyl)ferrocenyl)propionamide was prepared using a Curtius rearrangement according to the scheme below (Erb et. al., Adv. Synth. Cat., 2020, 362, 832):

[0111] 3-(4-(T rifluoromethyl)phenyl)ferrocenecarboxylic acid (WE-1948)3-(4-(Trifluoromethyl)phenyl)ferrocenecarboxylic acid was prepared from methyl 3-(4- (trifluoromethyl)phenyl)ferrocenecarboxylate (1.28 g, 3.30 mmol) and sodium hydroxide (660 mg, 16.5 mmol) and was isolated as an orange solid (1 .22 g, 99%).Rf (eluent: petroleum ether-ethyl acetate 50:50) = 0.51. Mp 219-220 °C. Umax (film) / cm12856 (br), 1657, 1617, 1483, 1325, 1255, 1156, 1121 , 1107, 1068, 931 , 837, 823.1H NMR (500 MHz, CDCI3): δ (ppm) 7.62 (d, J = 8.2 Hz, 2H, ArCH), 7.58 (d, J = 8.2 Hz, 2H, ArCH), 5.39 (t, J = 1 .3 Hz, 1 H, FcCH), 5.08 (dd, J = 1.0, 2.3 Hz, 1 H, FcCH), 4.98 (dd, J = 1.3, 2.3 Hz, 1 H, FcCH), 4.17 (s, 5H, Cp). The carboxylic acid signal is not observed.13C{1H} NMR (125 MHz, CDCH): δ (ppm) 177.6 (s, C=O), 141.9 (s, ArC), 128.9 (q, J = 32.4 Hz, ArC), 126.4 (s, 2 x ArCH), 125.7 (q, J = 3.0 Hz, 2 x ArCH), 124.4 (q, J = 272.1 Hz, CF3), 87.5 (s, FcC), 72.1 (s, FcCH), 72.0 (s, Cp), 70.7 (s, FcCH), 69.0 (s, FcCH). One FcC is missing or overlapping.19F{1H} NMR (470 MHz, CDCH): δ (ppm) -62.5.

[0112] 3-(4-Trifluoromethylphenyl)ferrocenoyl azide (WE-1955)3-(4-(Trifluoromethyl)phenyl)ferrocenoyl azide was prepared from 3-(4- (trifluoromethyl)phenyl)ferrocenecarboxylic acid (674 mg, 1.80 mmol), triethylamine (1.25 mL, 9.00 mmol) and diphenylphosphoryl azide (426 pL, 1 .98 mmol) and was isolated as an orange solid (682 mg, 95%).Rf (eluent: petroleum ether-ethyl acetate 80:20) = 0.55. Mp 119-120 °C. Vmax (film) / crrr12149, 1678, 1615, 1462, 1434, 1331 , 1223, 1198, 1161 , 1106, 1075, 1042, 996, 907, 8369, 822.1H NMR (500 MHz, CDCI3): δ (ppm) 7.59 (d, J = 8.9 Hz, 2H, ArCH), 7.57 (d, J = 8.9 Hz, 2H, ArCH), 5.34 (t, J = 1 .3 Hz, 1 H, FcCH), 5.02 (dd, J = 1.3, 2.7 Hz, 1 H, FcCH), 5.01 (dd, J = 1.3, 2.7 Hz, 1 H, FcCH), 4.15 (s, 5H, Cp).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 176.9 (s, C=O), 141.5 (s, ArC), 129.0 (q, J = 32.5 Hz, ArC), 126.4 (s, 2 x ArCH), 125.7 (q, J = 3.6 Hz, 2 x ArCH), 124.3 (q, J = 271 .8 Hz, CF3), 88.1 (s, FcC), 73.6 (s, FcC), 72.1 (s, Cp), 71.8 (s, FcCH), 71.2 (s, FcCH), 68.6 (s, FcCH).19F{1H} NMR (470 MHz, CDCI3): δ (ppm) -62.5.

[0113] 1-(tert-Butoxycarbonyl)amino-3-(4-(trifluoromethyl)phenyl)ferrocene (WE-1958)1-(te / Y-Butoxycarbonyl)amino-3-(4-(trifluoromethyl)phenyl)ferrocene was prepared from 3-(4- (trifluoromethyl)phenyl)ferrocenoyl azide (399 mg, 1.00 mmol) and te / Y-butanol (239 pL, 2.50 mmol) and was isolated as an orange solid (380 mg, 85%).Rf (eluent: petroleum ether-ethyl acetate 90:10) = 0.53. Mp 117-118 °C. Vmax (film) / crrr13298, 2985, 1691 , 1613, 1551 , 1367, 1323, 1283, 1250, 1157, 1120, 1104, 1063, 875, 843, 818.1H NMR (400 MHz, CDCI3): δ (ppm) 7.50 (s, 4H, ArCH), 5.81 (br s, 1 H, NH), 5.10 (s, FcCH), 4.61 (s, 1 H, FcCH), 4.50 (dd, J = 1.7, 2.4 Hz, 1 H, FcCH), 4.04 (s, 5H, Cp), 1.53 (s, 9H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 153.3 (s, C=O), 143.7 (s, ArC), 127.7 (q, J = 32.4 Hz, ArC), 125.9 (s, 2 x ArCH), 125.4 (q, J = 3.6 Hz, 2 x ArCH), 124.6 (q, J = 270.5 Hz, CF3), 97.6 (s, FcC), 80.6 (s, C(CH3)3), 79.4 (s, FcC), 71 .0 (s, Cp), 62.8 (s, FcCH), 62.0 (s, FcCH), 59.5 (s, FcCH), 28.5 (s, C(CH3)3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.4.

[0114] A / -(3-(4-(Trifluoromethyl)phenyl)ferrocenyl)propionamide (b - WE-1964)Trifluoroacetic acid (214 pL, 319 mg, 2.80 mmol, 5.00 equiv) was added dropwise to a solution of 1 - (te / Y-butoxycarbonyl)amino-3-(4-(trifluoromethyl)phenyl)ferrocene (250 mg, 0.56 mmol, 1.00 equiv) in tetrahydrofuran (2 mL) and the reaction mixture was stirred at 40 °C for 15 min. Volatiles were removed under reduced pressure using a rotary evaporator to give the crude product. This was triturated in petroleum ether to afford the trifluoroacetate salt (210 mg), directly used in the next step.Propionyl chloride (98.0 pL, 103 mg, 1.12 mmol, 2.00 equiv) and triethylamine (234 pL, 170 mg, 1.38 mmol, 3.00 equiv) were added to a solution of the previous trifluoroacetate salt in dichloromethane (5 mL). After 30 min at room temperature, ethyl acetate was added and the reaction mixture was washed with an aqueous solution of HCI (1 M), a saturated aqueous solution of K2CO3, and brine. The combined organic layers were dried over MgSCU, filtrated over cotton wool and concentrated under reduced pressure using a rotary evaporator to give the crude product. This was purified by column chromatography over silica, eluting with petroleum ether-ethyl acetate (70:30 to 60:40) to give the title product as an orange solid (139 mg, 61 % over 2 steps).Rf (eluent: petroleum ether-ethyl acetate 70:30) = 0.25. Mp 169-170 °C. vmax (film) / cm“13288 (br), 2980, 1655, 1613, 1557, 1486, 1379, 1321 , 1157, 1117, 1104, 1067, 841 , 817.1H NMR (400 MHz, CDCI3): δ (ppm) 7.50 (s, 4H, ArCH), 6.71 (br s, 1 H, NH), 5.25 (s, 1 H, FcCH), 4.76 (s, 1 H, FcCH), 4.53 (s, 1 H, FcCH), 4.03 (s, 5H, Cp), 2.31 (q, J = 7.6 Hz, 2H, CH2), 1.24 (t, J = 7.6 Hz, 3H, CH3).13C{1H} NMR (100 MHz, CDCI3): δ (ppm) 172.2 (s, C=O), 143.5 (s, ArC), 127.9 (q, J = 32.3 Hz, ArC), 125.9 (s, 2 x ArCH), 125.4 (q, J = 3.7 Hz, 2 x ArCH), 121.8 (q, J = 271.7 Hz, CF3), 96.2 (s, FcC), 79.8 (s, FcC), 71.1 (s, Cp), 63.1 (s, FcCH), 62.6 (s, FcCH), 60.3 (s, FcCH), 30.5 (s, CH2), 9.9 (s, CH3).19F{1H} NMR (376 MHz, CDCI3): δ (ppm) -62.4.

[0115] Example 2D - Synthesis of 3-(4-(2,2,2-Trifluoro-1 -hvdroxyethyl)phenyl)- / V, / V- diisopropylferrocenecarboxamide (127 - WE-2732)Sodium borohydride (37.8 mg, 0.99 mmol, 3.00 equiv) was added portionwise to a solution of 3-(4- (2,2,2-trifluoroacetyl)phenyl)- / V, / V-diisopropylferrocenecarboxamide (160 mg, 0.33 mmol, 1.00 equiv) in methanol at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSCM, filtrated over cotton wool and concentrated under vacuum using a rotary evaporator to give the crude product. This was purified by column chromatography over silica, eluting with petroleumether-ethyl acetate (80:20 to 70:30) to give the title product as an orange solid (138 mg, 85%, 1 :1 mixture of diastereoisomers).Rf (eluent: petroleum ether-ethyl acetate 80:20) = 0.30. Mp 97-100 °C. vmax (film) / crrr13225 (br), 2958, 1589, 1476, 1448, 1371 , 1338, 1258, 1150, 1122, 1040, 815.1H NMR (500 MHz, CDCI3): δ (ppm) 7.49-7.46 (m, 2H, ArCH), 7.44-7.42 (m, 2H, ArCH), 5.04-5.02 (m, 2H, FcCH and CH(OH)), 4.73 (dd, J = 4.0, 2.2 Hz, 1 H, FcCH), 4.69 (br s, 1 H, CH), 4.65 (dd, J = 3.9, 2.4 Hz, 1 H, FcCH), 4.18 and 4.09 (br s, 1 H, OH), 4.09 and 4.07 (s, 5H, Cp), 3.46 (br s, 1 H, CH), 1 .48 (br s, 6H, CH3), 1 .25 (br s, 6H, CH3).13C{1H} NMR (125 MHz, CDCI3): δ (ppm) 169.6 and 169.5 (s, C=O), 139.5 and 139.4 (s, ArC), 132.9 and 132.8 (s, ArC), 127.8 (s, 2 x ArCH), 126.4 and 126.3 (2 x ArCH), 124.6 (q, J = 282.7 Hz, CF3), 85.6 and 85.5 (s, FcC), 82.0 and 81.9 (s, FcC), 72.6 and 72.5 (q, J = 32.2 Hz, CH(OH)), 71.6 (s, Cp), 70.4 (s, FcCH), 69.3 and 69.2 (s, FcCH), 67.5 and 67.4 (s, FcCH), 49.9 and 46.6 (s, 2 x CH), 21 .3 (s, 4 x CH3).19F{1H} NMR (282 MHz, CDCI3): δ (ppm) -78.2.

[0116] Example 3 Biological Assays

[0117] General protocols for biological testing

[0118] Cells

[0119] Huh 7 human-derived hepatoma cells, obtained from the American Type Culture Collection (ATCC), were cultured in Dulbecco’s Modified Eagle Medium (DMEM, PAN Biotech) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1 % penicillin / streptomycin and 0.1 % amphotericin (PAN Biotech). A549 lung carcinoma cells expressing human ACE2 (InvivoGen) were maintained in DMEM supplemented with 10% FBS, 1 % penicillin / streptomycin, 0.1 % amphotericin B and 0.5 pg / ml puromycin. Vero E6 cells were purchased from ATCC and cultured in Essential Minimal Eagle’s Medium (MEM, PAN Biotech) containing 5% FBS, 1 % penicillin / streptomycin and 0.1 % amphotericin B. All cells were cultured at 37°C in 5% CO2 incubator.

[0120] Viruses and reagents

[0121] A recombinant HCoV-229E strain expressing the luciferase gene was produced as previously described (Van den worm et al, PLoS One., 2012, 7, e32857). SARS-CoV-2 virus was isolated in 2020 from a nasopharyngeal swab of a COVID-19 PCR-positive patient in Reunion Island. The virus was amplified on Vero E6 cells and viral titer was measured by plaque forming unit (PFU) assay. The recombinant Zika virus expressing green fluorescent protein (ZIKVGFP) was sourced as previously described (Gadea et al, Virology., 2016, 497, 157-162). The antiviral compounds evaluated, including Quercetin-3-p-D-glucoside (Q3G) and PLA2, were purchased from Sigma-Aldrich (Saint-Quentin- Fallavier, France), and Plitidepsin was obtained from AURUM Pharmatech (Frisco, USA). All stock solutions of these compounds were prepared in sterile dimethyl sulfoxide (DMSO), also acquired from Sigma-Aldrich, ensuring consistency in solution preparation and experimental conditions.Assessment of mitochondrial activity and viability using MTS and ATP assays

[0122] Cells were plated in 96-well plates at a density of 20,000 cells per well and incubated for 24 hours, cells were treated with a series of ferrocene dilutions, ranging from 250 pM to 3 pM, to assess the compound's effect on cell viability. The mitochondrial activity was measured using the MTS assay (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, CellTiter 96® AQueous One Solution Cell Proliferation Assay, Promega). Forty-eight hours after ferrocene treatment, the supernatant was removed, and the CellTiter 96® AQueous One Solution Reagent was added to each well. The plates were incubated for 1 hour at 37°C, allowing for the reduction of MTS to formazan by metabolically active cells. The absorbance of formazan was then measured at 490 nm to determine cell viability. The ATP assay was utilized to evaluate cellular ATP levels as an indicator of viable cell number. Forty-eight hours following treatment, the culture medium was aspirated, and cells were washed with 1X PBS. The ATP reagent was added directly to the cells, which were then lysed mechanically. After a 2-minute incubation, luminescence was measured to quantify ATP, indicative of cell viability.

[0123] Renilla luciferase assay

[0124] Twenty-four hours after HCoV-229E infection, Huh7 cells were lysed to measure luciferase activity using Renilla luciferase assay system (Promega) according to the supplier’s instructions. Luminescence was measured using FLUOstar Omega spectrophotometer.

[0125] Treatments and cells infections by HCOV-229E

[0126] The effects of antiviral compounds on viral infection were assessed by seeding cells until reaching 80% confluence. Cells were then incubated with the compounds at different concentrations or left untreated (control cells) and infected with HCoV-229E virus at a multiplicity of infection (MOI) of 0.05 or with SARS-CoV-2 virus at a MOI of 0.01. Twenty-four hours after infection, cells were harvested for further investigations.

[0127] Treatments and cells infections by ZIKV

[0128] Human epithelial cells (A549) or Vero E6 cells were seeded in 96-well plates at a concentration of 20,000 cells per well. Following a 24-hour incubation period, the cells underwent treatment with various concentrations of ferrocenes, ranging from 250 pM to 3 pM. Subsequent to the ferrocene treatment, cells were infected with Zika virus expressing green fluorescent protein (ZIKVGFP) at a multiplicity of infection (MOI) of 1. Twenty-four hours post-infection, the levels of GFP-positive cells were quantitatively assessed using flow cytometry.Flow cytometry assay

[0129] Cells were treated with trypsin and fixed in 4 % paraformaldehyde. Percentage of infection are revealed by flow cytometry using Cytoflex (Beckman). The percentage of GFP-positive cells was assessed using Cytexpert software (version 9.00, La Jolla, CA, USA).

[0130] Virus inactivation assay

[0131] Effect of compounds on HCoV-229E particles was evaluated by pre-incubating HCoV-229E strain with the compounds during 2 h at 37°C. Then mixtures were 25-fold diluted for achieving a concentration without effect on viral infection (non-therapeutic concentration) and added on Huh 7 cells seeded in 6-well plates. As controls, HCoV-229E particles were pre-incubated without compounds (positive control of infection) and Huh-7 were infected without pre-incubation with a 25- fold dilution of compounds (control of non-therapeutic concentration). After 12 h of infection, cells were lysed and luminescence assay was performed as described above.

[0132] Time of addition assay

[0133] To investigate the mechanism of action of compounds and identify which stage of the virus cycle is targeted, we conducted a time-of-drug addition assay. This assay dissected the approximately 24-hour infectious cycle under different experimental conditions. In the control condition, cells were simultaneously infected and treated with compounds forthe entire 24-hour cycle. In a second experimental setup, compounds were administered only during the first 2 hours postinfection, targeting the viral entry phase with Quercetin-3-p-D-glucoside (Q3G) at 25 pM serving as a positive control. The final condition involved treating cells with compounds two hours post-infection, focusing on the replication phase, with plitidepsin at 0.1 pM as a positive control to evaluate effects on viral translation inhibition.

[0134] Immunofluorescence

[0135] Twenty-four hours post-infection cells were fixed in 4% paraformaldehyde (PFA) and then stained with a 1 :500 dilution of human anti-SARS-CoV-2 spike monoclonal antibody (clone B38 cov2rbdc2-mab1 , InvivoGen) and observed under a Nikon eclipse Ti2 confocal microscope. The percentage of infected cells was calculated from 3 captured images representing different and randomized optical fields for each experiment. Experiments were performed 3 times.

[0136] Quantitative real-time PCR

[0137] Relative quantification was performed with the QuantiNova SYBR Green mix (Qiagen) 24 h post-infection. All samples were assessed in triplicate from three independent experiments. Total RNA was extracted with the RNeasy mini kit (Qiagen) according to the supplier’s instructions. Total RNA was reverse-transcribed using the the QuantiTect reverse transcription kit (Qiagen) and subjected to quantification with the following primers : Forward 5’-ATGAGCTTAGTCCTGTTG-3’ and Reverse 5’-CTCCCTTTGTTGTGTTGT-3’. Results were normalized relative to GAPDH (Forward 5’-CACCCATGGCAAATTCC-3’ and Reverse 5’-TGGGATTTCCATTGATGACAAG-3’) with the AACt method as previously described (Gaudry at al., Int. J. Mol. Sci. , 2018, 19, 1093).

[0138] Plaque forming units assay

[0139] Supernatant from 24 h infected cells were harvested and stored at -80°C for PFU assay. A 70% confluent monolayer of Vero E6 cells in 24-wells plate was incubated during 2 h with 100 pL of a ten-fold serial dilution of the supernatant. Then, DMEM containing 1 % carboxymethyl cellulose (CMC) was added to each well and incubated at 37°C under 5% CO2. Three days later, infected cells were carefully washed twice with PBS and fixed for 10 min with 4% PFA. Then, cells were washed and stained with crystal violet. Plaques were counted and expressed as PFU / mL.

[0140] IC50 and CC50 determination and Statistical analysis

[0141] Nonlinear regression was employed to generate sigmoidal dose-response curves for determining inhibitory concentrations (IC50) and cytotoxic concentrations (CC50). Statistical analysis was performed using GraphPad prism software (version 9.0; GraphPad software, La Jola, CA, USA). One-way ANOVA with Kruskal-Wallis test and Dunn’s multiple comparisons test was used. Two-way ANOVA with Tukey’s multiple comparisons test was used for statistical analysis (**** p-value < 0.0001 ; *** p-value < 0.001 ; ** p-value < 0.01 ; * p-value < 0.05; n.s = not significant).

[0142] Example 3A - Evaluation of anti-HCoV-229 properties of compounds h to he.

[0143] Compounds h-he were tested against HCoV-229 on Huh7 cells. Huh7 cells were treated with different compounds (h to he) and simultaneously infected with HCoV-229E at a MOI of 0.05. Twenty- four hours post-infection cells were lysed to measure luciferase activity.

[0144] The tests showed that all compounds were able to reduce the viral charge by more than 90% (Figure 1).

[0145] CC50 (half maximal cytotoxic concentration) and IC50 (half maximal inhibitory concentration) were determined. For the CC50 determination, Huh7 cells treated with different concentrations of ferrocene compounds h to I10 and he, during 48h, and cell viability was measured by Cell Titer gio assay. Nonlinear regression was performed to calculate CC50. For the IC50 determination, Huh7 cells infected by HCoV-229E were treated with different non-toxic concentrations of ferrocene compounds h to I10 and he (MOI 0.05) the percentage of infection was evaluated using luciferase assay. Nonlinear regression was performed to calculate IC50.The results are shown in the table below and in Figures 2 and 3:

[0146] Mechanistical aspects

[0147] To have a deeper understanding of which stage of HCoV-229E infection can be affected by the compounds, we performed an inactivation assay and a time-of-drug-addition-assay (Figure 4) on three selected compounds h, h and I10. First of all, to evaluate if I4, I9 and I10 have a virucidal effect we conducted a virus inactivation assay (Figure 4A). For this purpose, 104PFU of HCoV-229E were pre-incubated with I4, I9 and I10 at the 20 pM during 2 h at 37°C and then diluted 25 times before infecting Huh7 cells. Venom phospholipase A2 (PLA2, concentration), known for its virucidal activity (Andrei et al., Cell Mol Life Sci., 2021 , 78(23)) was used as a positive control. A huge decrease of infection was observed when HCoV-229E was pre-incubated with PLA2 whereas any differences were shown with I4, 19 and I10 pre-incubation (Figure 4B). These results demonstrate that I4, 19 and I10 have not a virucidal effect but should rather affect HCoV-299E life cycle. On the other hand, a time- of-drug-addition-assay was carried out to identify which stage of the HCoV-229E infection cycle could be affected by the I4, I9 and I10 (Figure 4C). Isoquercitrin and remdesivir, two well-known antiviral molecules acting on entry and replication steps respectively, were used as controls at 0.25 pM and 0.1 pM respectively. When cells received a pre-treatment with isoquercitrin, a drastic decrease of infection was observed, whereas when isoquercitrin was added after virus infection, no differences were observed compared to untreated cells (Figure 4D). Treatment with remdesivir after virus infection led to a much higher reduction of infection compared to cells receiving pre-treatment of remdesivir. Thereby, these results validate our time-of-drug-addition-assay for investigating entry or replication stage. Concerning I4, I9 and I10, we observed a significant decrease of infection level by almost 90 % when I4, 19 and I10 were added to the cells during the whole experiment (Figure 4D). For I4 and I9, data indicates a difference between pre-treatment and post-treatment with a much-marked inhibition reduction when they were added after infection. For I10 results were less obvious as there is no difference between pre-treatment and post-treatment. Taken together, the findings suggest that I4, I9 and I10 should act on replication stage of HCoV-229E.

[0148] Example 3B - Evaluation of anti-SARS-CoV-2 propertiesIt was examined whether I4, and 110 exerted antiviral activity against SARS-CoV-2 (Figure 5). Human lung carcinoma A549 cells overexpressing ACE2 receptor were used for SARS-CoV-2 infection. Cytotoxicity of I4, I9 and 110 on A549-ACE2 cells was first evaluated (Figure 5A). A549 cells expressing ACE2 receptor were treated with serial dilution of I4, or 110 for 48 h. Cytotoxicity was evaluated using Cell Titer gio assay. Nonlinear regression was performed to calculate CC50. As shown, I4, and 110 have close CC50 around 90 pM . The same non cytotoxic concentration was chosen for both compounds (20 pM) and used for the next experiments. Cells were treated with I4, and 110 and infected with SARS-CoV-2. To evaluate infection level, RNA relative expression level by RT-qPCR was measured (Figure 5B). A549 cells expressing ACE2 receptor were treated with I4 and 110 and infected with SARS-CoV-2 at 0.01 MOI during 24 h. (B) Total RNA was extracted and SARS- CoV-2 viral RNA was quantified by RT-qPCR, with the human GAPDH housekeeping gene transcript used for normalization.SARS-CoV-2 viral progeny was measured by PFU assay (Figure 5C) and percentage of infected cells was measured by immunofluorescence (Figure 5D).All experiments led to the same results that 110 and I4 elicit antiviral effect with an infection decrease around 80% and 60% respectively. Taken together, these results show that I4, and 110 present antiviral activity against SARS-CoV-2.

[0149] Example 3C - Comparative exempleThe anti-HCoV-229 properties of the compounds according to the invention were compared with a 1 ,2-disubstituted derivative having the same substituents.Comparative 1 ,2-disubstituted compound WE-1455 was less active than the corresponding 1 ,T- and 1 ,3-disubstituted compound according to the invention.

[0150] Example 3D - Evaluation of anti^ZIKV activity

[0151] Compounds h, I7, I10, he, I17, he, I20-27, were tested against ZIKV on Vero E6 cells. Vero E6 cells were treated with different compounds and simultaneously infected with ZIKVGFPat a MOI of 1. Twenty-four hours post-infection cells were subjected to flow cytometry to evaluate the percentage of fluorescence.

[0152] CC50 (half maximal cytotoxic concentration) and IC50 (half maximal inhibitory concentration) were determined. For the CC50 determination, Vero E6 cells treated with different concentrations of ferrocene compounds during 48h, and cell viability was measured by Cell Titer gio assay and MTS assay. Nonlinear regression was performed to calculate CC50. For the IC50 determination, Vero E6 cells infected by ZIKVGFPwere treated with different non-toxic concentrations of ferrocene compounds. The percentage of infection was evaluated using flow cytometry assay Nonlinear regression was performed to calculate IC50. The results are shown in the table below:

[0153] Mode of action against ZIKV

[0154] To elucidate the antiviral mechanism of I7 against Zika virus (ZIKV), we assessed its impact on cell-free virions (inactivation assay performed on Vero E6 cells). Specifically, ZIKVGFPvirions were pre-incubated with I7 for two hours, then diluted thirtyfold before the infection procedure to negate any residual antiviral activity of the molecule during cell exposure, thus minimizing potential interactions with host cellular components. Control substances included Pla2, serving as a positive control known for its direct effects on cell-free virions, and Quercetin-3-p-D-glucoside (Q3G), acting as a negative control which influences the virus indirectly through cellular mechanisms. Both controls were utilized at concentrations demonstrating antiviral efficacy without inducing cytotoxicity. Subsequent to molecular treatment, the levels of infection were quantified via flow cytometry.

[0155] Results indicated a significant reduction in infection levels, with I7 achieving up to 90% inhibition of ZIKV infection, a decrease paralleled by the direct antiviral action of Pla2 on viral particles (Figure 6A). This suggests that I7 interacts directly with ZIKV particles to substantially diminish viral infectivity. Nevertheless, I7 may also modulate other stages of the viral life cycle.

[0156] A time-of-drug addition assay was then performed on Vero E6 cells to determine the specific phase of the ZIKV cycle affected by I7. The assay involved treating cells with I7 either simultaneously with ZIKVGFPfor the initial two hours (entry phase) or post-infection for the same duration (post-entry phase), along with a continuous exposure condition covering the entire experimental timeframe.

[0157] Notably, I7 significantly reduced ZIKV infection levels when added during the post-entry phase, mirroring the inhibitory effects observed with Plitidepsin, a control molecule effective against post-entry viral processes (Figure 6B).

[0158] In conclusion, these findings affirm that the I7 molecule possesses a dual mechanism against ZIKV, capable of both directly neutralizing viral particles and interfering with subsequent stages of the viral infection cycle

[0159] ConclusionThe experimental data show that the compounds according to the invention show anti-viral activity against several viruses. In addition, the compounds show low cytotoxicity.It has been shown that 1 ,3-disubstituted derivatives (I4 (WE-1579) and 110 (KA-31)) and 1 ,1 ’disubstituted derivatives (116 (WE-1457)) according to the invention show superior activities against HCoV-229 as compared to the corresponding 1 ,2-disubstituted derivative (WE-1455).Additionally, the compound I7 not only acts directly on the viral particle but also intracellularly, impacting the replication phase of the Zika virus, showcasing its dual mechanism of action. These results suggest that the compounds as disclosed herein may advantageously be used as broadspectrum antiviral agents, offering significant therapeutic potential across a diverse range of viral pathogens.

Claims

CLAIMS1 . A compound of Formula (I):wherein:Ri and R3 are each independently chosen from H, (C6-10 )aryl or 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more groups selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• (C1-C6)alkylC(=O)-, optionally substituted by one or more fluorine atoms,• -C(OH)ReRf• Halogen,• -NO2,• -CN, and• (C1-C6)alkoxy, optionally substituted by one or more fluorine atoms,• (C1-C6)thioalkoxy, optionally substituted by one or more fluorine atoms, and• -SF, -S(O)F, -SO2F or -SF5,It being understood that one of R1 or R3 is H, the other one being different from H,R2 is chosen from -C(=O)NRaRb or -NRcC(=0)Rd,Ra, Rb, being each independently chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl- SO2-, (C6-10 )aryl-SO2-, (C6-10 )aryl(C1-C6)alkyl -,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re, Rf each independently chosen from H, CF3, and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment of a viral infection.

2. The compound for use according to claim 1 , wherein R1 or R3 is:• pyridyl or thienyl, in particular unsubstituted pyridyl or thienyl, or• phenyl, said phenyl being optionally substituted, notably by 1 to 3 groups as defined in claim 1 , or• chosen from phenyl, 4-fluorophenyl, 4-CF3-phenyl, 3-CF3-phenyl, 2-CF3-phenyl, 4- nitrophenyl and 3,4-difluorophenyl, 4-pyridyl, 3,4,5-trifluorophenyl, 4-CHF2-phenyl, 4-CF3C(O)-phenyl, 4-CF3O-phenyl, 4-CF3S-phenyl, 4-CF3CH(OH)-phenyl or 4-F5S- phenyl.

3. The compound for use according to any one of claims 1 or 2, wherein R2 is chosen from - CONiPr2, -C(=O)NEt2, -C(=O)NHEt, -C(=O)NEtMe, -C(=O)NEtBu, -NHC(=O)Et, - C(=O)NEtBn, -C(=O)N(CH3)(OCH3), or C(=O)NEt(SO2CH3).

4. The compound for use according to any one of claims 1 to 3, wherein:Ri or R3is phenyl, said phenyl being optionally substituted by one or more groups selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• Halogen, or• NO2,• -OCF3,• -SCF3,• -C(O)CF3,• -C(OH)H(CF3), or• -SF5,R2 is chosen from -C(=O)NRaRb or -NRcC(=0)Rd,Rabeing (C1-C6)alkyl,Rb being chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-SO2-, ((C6-10 )aryl-(Ci-C6)alkyl-,Rcbeing H,Rd being chosen from H or (C1-C6)alkyl.

5. The compound for use according to any one of claims 1 to 4, which is chosen from:

6. The compound for use according to any of claims 1 to 5, wherein the compound of formula (I) is in the form of a mixture of stereoisomeric forms, in particular in the form of a racemic mixture.

7. The compound for use according to any one of claims 1 to 6, wherein the viral infection is caused by a single-stranded RNA-positive virus, in particular chosen from a virus belonging to:• the picornaviruses virus family, in particular the Hepatitis A virus, an enterovirus, a rhinovirus, the poliovirus, and foot-and-mouth virus,• the flaviviruses virus family, in particular the dengue virus, the yellow fever virus, the West Nile virus, the Japanese encephalitis virus, the Zika virus, the Usutu virus and the Tick-Borne encephalitis virus,• the alphaviruses virus family, in particular the Chikungunya virus, the Mayaro virus, the Ross River virus, and the Venezuelan Equine Encephalitis virus,• the hepaciviruses virus family, in particular the Hepatitis C virus,• the hepeviruses virus family, in particular the Hepatitis E virus,• the coronaviruses virus family, in particular HCov or SARS virus, more in particular HCOV-229E, SARS-CoV or SARS-CoV-2,• the Filoviridae virus family, in particular the Ebola virus,• the Paramyxoviridae virus family, in particular the Respiratory Syncytial virus,• the Rhabdoviridae virus family, and / or• the Orthomyxoviridae virus family, in particular Influenzavirus A, Influenzavirus B and Influenzavirus C.

8. The compound for use according to claim 7, wherein the viral infection is caused by a virus chosen from Zika virus, Dengue virus, Chikungunya virus, Ross River virus, HCoV229E virus and SARS-CoV-2.

9. The compound for use according to any one of claims 1 to 8, wherein the viral infection is caused by a virus belonging to the flaviviruses virus family and wherein the compound of formula (I) is chosen from compounds h to I27 as defined in claim 5.

10. The compound for use according to any one of claims 1 to 8, wherein the viral infection is caused by a virus belonging to the coronaviruses virus family and wherein the compound of formula (I) is chosen from compounds h to I27 as defined in claim 5.

11. The compound for use according to any one of claims 1 to 10, wherein a combination of at least two compounds of formula (I) is used.

12. The compound for use according to any one of claims 1 to 11 , wherein the compound of Formula (I) is used in combination with another antiviral agent, in particular interferon.

13. A pharmaceutical composition comprising a compound of Formula (I) as defined in any of claims 1 to 12, in admixture with one or more pharmaceutically acceptable excipient.

14. A compound of Formula (IA)wherein:Rr is (C6-10 )aryl or 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more groups selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• (C1-C6)alkylC(=O)-, optionally substituted by one or more fluorine atoms,• -C(OH)ReRf• Halogen,• -NO2,• -CN, and• (C1-C6)alkoxy, optionally substituted by one or more fluorine atoms,• (C1-C6)thioalkoxy, optionally substituted by one or more fluorine atoms, and• -SF, -S(O)F, -SO2F or -SF5,R2 is chosen from -C(=O)NRaRb or -NRcC(=0)Rd ,Ra, Rb , being each independently chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl- SO2-, (C6-10 )aryl-SO2-, (C6-10 )aryl-(C1-C6)alkyl,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re’, Rr being each independently chosen from H, CF3, and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof, with the provisio that the compound of Formula (IA) is not a racemic mixture of one of the following structures:

15. The compound according to claim 14, wherein:Rr is phenyl, said phenyl being optionally substituted by one or more groups selected from:• (C1-C6)alkyl, optionally substituted by one or more fluorine atoms,• (C1-C6)alkylC(=O)-, optionally substituted by one or more fluorine atoms,• -C(OH)Re'Rr• Fluorine,• -NO2,• -CN,• -OCF3,• -SCF3,• -C(O)CF3,• -C(OH)H(CF3), or• -SFs,R2is chosen from -C(=O)NRaRb or -NRcC(=0)Rd ,Ra , Rb , being each independently chosen from H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl- SO2-, (C6-10 )aryl-S02-, (C6-10 )aryl-(C1-C6)alkyl,Rc, Rd being each independently chosen from H or (C1-C6)alkyl,Re’, Rr being each independently chosen from H, CF3.

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