enantioselective synthesis methods and the use thereof

The present invention relates to 4-aminoalcohol quinoline derivatives, as well as the synthesis methods and the uses of such derivatives. Document references in brackets [ ] are listed on the end of the description.

Human malaria is one of the most important diseases in the world, with a corresponding mortality of more than 1 million deaths per year [1]. Four species of Plasmodium are responsible for malaria in human beings and among these P. falciparum is the most dangerous.

Antifolates such as pyrimethamine, trimethoprim, and sulphonamides, and quinolin-containing drugs such as quinine, mefloquine, halofantrine, chloroquine and primaquine are two principal classes of antimalarial drugs that have been developed during the past 50 years [2]. Newer antimalarial agents such as antibiotics (doxycycline), the hydroxynaphtoquinone derivatives (atovaquone, lumefantrine) and artemisinin (active principle of Artemesia annua) were introduced during this period [3]. Due to the efficiency decrease of classical medication towards the rapid extension of Plasmodium falciparum chloroquine- resistant strains, there is a need to develop new and effective antimalarial drugs [4]. Extensive work has been done to synthesize chloroquine analogs but much less in regard to mefloquine derivatives.

Consequently, mefloquine and its derivatives still remain very attractive synthetic targets. Mefloquine hydrochloride (Lariam®) is a highly active blood schizontocide against multi-drug resistant falciparum malaria strains. This quinoline methanol derivative presents two asymmetric carbon atoms. Karle et al. showed that the (+)-enantiomer of the mefloquine is more potent than the (-)- enantiomer by a factor of 1.69 (IC ₅₀ values against Sierra Leone and Indochina P. falciparum strains) [5]. Mefloquine and its synthesis were first described by Ohnmacht et al. [6] in 1971 . In 1974, a more detailed account of the synthesis along with anti-malarial activity of the mefloquine isomers is given by Carroll and Blackwell [7]. More recently, Xie et al. reported a new and enantioselective synthesis of the (1 1 ,12S)-mefloquine hydrochloride using a proline-catalyzed asymmetric direct aldol reaction and a Beckmann rearrangement as key steps. The experimental analysis confirmed the a ine as (1 1 R.12S) [8].

(+)-enantiomer (-)-enantiomer

(+)-(11R, 12S) (-M11 S, 12R)

Mefloquine Enantiomer Structures.

However, mefloquine is commonly used clinically as a racemic mixture of (±)-(R*,S*)-a-2-piperidinyl-2 ₎ 8-bis(trifluoromethyl)-4-quinolinemethanol which consists of individual enantiomers (+)-(1 1 R, 2S)-a-2-piperidinyl-2,8- bis(trifluoromethyl)-4-quinoIinemethanol and (-)-(1 1 S,12R)-a-2-piperidinyl-2,8- bis(trifluoromethyl)-4-quinolinemethanol. Mefloquine remains the drug of choice for U.S. military deployments in such regions, primarily because its longer half-life (compared to those of Malarone or doxycycline) [9] allows weekly administration, thereby making compliance less problematic.

However, undesirable side effects on the central nervous system (CNS) have been associated with mefloquine use. These include disturbed sleep, heightened anxiety, panic attacks, depression and psychosis [10,1 1].

It has been found that the (-)-enantiomer of mefloquine binds to CNS adenosine receptors, while the (+)-enantiomer is without significant activity at this binding site. Moreover, blocking of central adenosine receptors by the (-)- enantiomer is believed to result in neuropsychiatric symptoms associated with mefloquine [12]. Further evidence suggests that the neurotoxicity of mefloquine appears to be related to with the piperidine ring [13]. Previously, it was reported that the opening of the piperidine ring at the 4-position of the quinoline scaffold is associated with an improved potency and a selectivity relative to mefloquine.

Dow et at. described the antimalarial potential together with the physicochemical properties of several libraries describing racemic mixtures of mefloquine non-piperidine analogs [ 14 ]. According to these authors, the mefloquine neurological effects could be limited by a lower permeability of the blood-brain barrier of new mefloquine analogs through physicochemical properties modifications. From their library, an active series of diamines has been identified showing a similar metabolic stability and a lower permeability than mefloquine. The main modification of the mefloquine derivatives concerns the 4-position of the quinoline scaffold to synthesize 4-aminoalcoholquinoline [1 1 , 15 ]. Racemic mixtures of mefloquine analogs were synthesized and evaluated for other biological properties such as treatment of tuberculosis [16], bacterial infections and, treatment of movement disorders (Parkinson's or Alzheimer's diseases) due to their binding affinity to adenosine A2 receptor [ 7].AIthough several other approaches to reduce mefloquine neurotoxicity have been proposed to obtain less neurotoxic derivatives showing an antimalarial activity, no effective solution to solve at one time the problems of potency, reduced blood-brain barrier penetration, and metabolic stability has been found.

It was in this context that the present inventors found enantiopure 4- aminoalcoholquinolines mefloquine analogs which present interesting physiochemical properties.

The present invention was made in view of the prior art described above, and the object of the present invention is to provide:

- new antimalarial compounds with a strong antimalarial activity as well as antibacterial activity with few neurological side effects; and

- a new enantioselective pathway to mefloquine amino-analogs allowing the access of such compounds. To this end, there is provided a compound of formula (I):

in which Y is one selected from formulae (II) to (III) :

HCL HO,,

(II)

in which Z is selected from formulae (IV) to (VI): wherein:

n = 0, 1 or 2;

Ri and f¾ are independently selected from a hydrogen atom, a straight or branched C1 - C9 chain alkyl group, containing or not a heteroatom which is not substituted or substituted by an aryl group, an aryl group, an alkylaryl group and a substituted or non-substituted C3-C7 cyclic alkyl group, or NR†R ₂ is an enantiomeric, diastereomeric or racemic group represented by formula (VII)

- R3 and R ₄ are independently selected from a hydrogen atom, a chain alkyl group C1 -C9 containing or not a heteratom which is not substituted or substituted by an aryl group; a cyclic alkyl groups; and aromatic groups; or

R5, R6 and R ₇ are independently selected from: a hydrogen atom; a heteroatom, a branched or straight-chain C1 -C9 alkyl group containing or not a heteroatom which is not substituted or substituted by an aryl group, a cyclic amine or a heterocycle; a C3-C7 cyclic alkyl group; R ₈ , R ₉ and Rio are independently selected from: a hydrogen atom; a straight or branched chain C1-C9 alkyl group; an aryl group; a C3-C7 cyclic alkyl group; a side chain containing an aromatic group; and a side chain containing a heterocyclic group; and

X is a carbon atom or a nitrogen atom.

Preferably, NR^ is one of a n-hexylamino group, a n-heptylamino group octylamino group, a n-octylamino group, n- nonylamino group or represented by formula (VII) wherein: X=N; R ₈ and R ₁₀ are a hydrogen atom; and R ₉ is a naphthalen-1-ylmethyl group.

Preferably, Y is represented by formula (III). This means, the compounds of formula (I) are (S)-enantiomers. The present inventors found that 4- aminoquinoline derivatives of the present invention particularly having (S)- structure show not only excellent antimalarial activities but very limited side effects.

Preferably, formula (I) is one of ( ^f S -2-(benzylamino)-1-(2,8- bis(trifluoromethyl)quinolin-4-yl)ethanol, (S)-ethyl-4-(4-(2-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(hydroxyethyl)piperazin -1 -yl)butanoate, (SJ-1 - (2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(pentylamino)ethan ol, (S 1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(hexylamino)ethanol, (S 1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(heptylamino)ethanol, (S)-1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(octylamino)ethanol, (S -1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(nonylamino)ethanol, (S 1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(piperazine substituted)ethanol, ^¾)-tert-butyl- (3-(4-(3((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-

(hydroxyethyl)amino)propyl)piperazin-1-yl)propyl)carbamat e or (S)-1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(4-(naphthalen-1-ylmeth yl)piperazin-1- yl)ethanol.

Preferably yet, formula (I) is one selected from fSJ-1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(pentylamino)ethanol, (S)-1-{2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(hexylamino)ethanol, (S 1 -(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(heptylamino)ethanol, fSJ-1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(octylamino)ethanol.

Preferably still, formula (I) is fSJ-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2- (pentylamino)ethanol.

The present invention further relates to a process for providing a compound of formula (I):

wherein Y is represented by formula (II) as defined above. The process comprises in the following order:

preparation of 2,8-bis(trifluoromethyl)-4-vinylquinoline; preparation of (f?)-1 -[2,8-bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2- diol by adding an asymmetric dihydroxylation catalyst to said 2,8- bis(trifluoromethyl)-4-vinylquinoline;

preparation of (f?)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl) quinoline (2a) starting from said ( )-1-[2,8-bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol; and

addition of Z selected from formulae (IV) to (VI) as defined above to said (f?)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline.

The present invention also relates to a process for providing a compound of formula (I):

wherein Y is represented by formula (III) as defined above. The process comprises in the following order:

- preparation of 2,8-bis(trifluoromethyl)-4-vinylquinoline; - preparation of (S)-1 -[2,8-bis(trifluoromethyl)quinolin-4-y[]ethan-1 ,2-dio[ by adding an asymmetric dihydroxylation catalyst to said 2,8-bis(trifluoromethyl)-4- vinylquinoline;

- preparation of (S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl) quinoline starting from said (S)-1-[2,8-bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol; and

- addition of Z selected from formulae (IV) to (VI) as defined above to said (S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline.

Preferably, said 2,8-bis(trifluoromethyl)-4-vinylquinoline is prepared by reacting a 4-bromo-2,8-bis(trifiuoromethyl)quinorine with vinylstannane using the Pd(PPh ₃ ) 2 Cl ₂ as catalyst.

Preferably yet, the asymmetric dihydroxylation catalysts is one of AD-mix a and AD-mix β. Also, (R) -1 -[2,8-bis(trifluoromethyl)qu ^' inolin-4-yl]ethan-1 ,2-diol and (S) -1-[2,8-bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol are prepared by reacting said 2,8-bis(trifluoromethyl)-4-vinylquinoline (3) with respectively AD-mix β and AD-mix a in a solution of t-BuOH/H ₂ 0 at 0°C.

It is preferable that K ₂ Os0 ₂ (OH) ₄ is further added to prepare (S)-1 -[2,8- bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol or said (R) -1 -[2,8- bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol.

Preferably still, starting from respectively (SJ-1 -[2,8- bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol (4b) or (R)-1 -[2,8- bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol (4a), said respectively (S 4-(oxiran- 2-yl)-2,8-bis(trifluoromethyl) quinoline and (7? 4-(oxiran-2-yl)-2,8- bis(trifluoromethyl) quinoline are prepared by a process comprising steps of:

- formation of the cyclic orthoester by acid catalyzed trans-esterification;

- generation of halohydrins ester via regioselective opening of acetoxonium ion by addition of tributyldimethylsilyl chloride; and

- cyclization to epoxide by base mediated saponification in methanol.

The process according to the present invention enables to provide an enantiopure, synthetic, and straightforward route to prepare 4-aminoquinolines derivatives through the enantiopure 4-oxirane synthesis. The preparation of (S)-or fRj-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline is carried out from 4- vinylquinoline in two steps via a Sharpless asymmetric dihydroxyiation with retention of configuration. The key-intermediate enantiopure 4-(oxiran-2-yl)-2,8- bis(trifluoromethyl)quinoline has been easily diversified, on position 4, through a regioselective S 2 ring opening mechanism with various amines, to provide the corresponding enantiopure 4-aminoquinolines (R) or (S) with excellent yield. In consequent, the fabrication cost of the antimalarial and antibacterial drugs can be drastically reduced.

The present invention also relates to a compound of formula (I) for the use as a drug. In particular, the compound (I) or a salt pharmaceutically acceptable thereof may be used as or as an antimalarial agent and/or as an antibacterial agent.

Alternatively, the present invention is also intended to provide a pharmaceutical composition comprising the compound of the formula (I). According to the present invention, compounds with excellent antimalarial activity and antibacterial activity can be obtained. Particularly, when Y of the compounds of formula (I) is represented by the formula (III), in other words, the compounds are (S)- enantiomers, they show excellent antimalarial activities with very limited side effects.

The compounds of the present invention have also antibacterial activity equivalent or superior to mefloquine. In particular, when Y of the formula (I) is represented by the formula (II) (when the compounds are (R)- enantiomers), they tend to be more active. These molecules may be used as antibiotics.

The compounds according to the present invention display a stronger antimalarial activity than mefloquine and /or chloroquine. In particular, (S)- enantiomers are shown to be more portent than their counterparts.

In the present invention, the term "pharmaceutically acceptable salt" means a non-toxic, substantially non-irritating base or acid addition salts of the compound of the formula (I). The base addition salts comprise salts including a cation which is an alkali metal or alkaline earth metal, such as sodium, potassium, calcium, magnesium or ammonium, or salts with organic amines such as benzathine, choline diethanolamine, ethylenediamine, meglumine benethamine, diethylamine, piperazine and tromethamine etc. The acid addition salts may be inorganic or organic salts such as salts of sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, methansulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid and cinnamic acid.

According to the present invention, the term "alkyl" either on its own or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated. For example, "C1 -C9" means one to nine carbons. Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec- butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds, such as vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 ,4- pentadienyl), ethynyl, 1 - and 3-propynyl, 3-butynyl.

According to the invention, the term "aryl" is understood as meaning an aromatic radical having 6 to 14 carbon atoms, preferably phenyl. Examples of aryl groups are phenyl, xenyl, naphthyl, and anthracyl. Examples of substituted groups are: a heteroatom, a halogen, a branched or straight-chain C1 -C9 alkyl group containing or not a heteroatom which is not substituted or substituted by an aryl group, a cyclic amine or a heterocycle; a C3-C7 cyclic alkyl group. For examples, hydroxyphenyl, aminophenyl, halogenophenyl, alkylphenyl, alkylaminophenyl, alkylalcoholphenyl, alkylnaphtyl, alkylalcoholnaphtyl, alkylaminonaphtyl.

The term "heteroatom" according to the present invention means oxygen, sulphur, or nitrogen. Examples of a straight or branched chain alkyl group C1 -C9 group containing a heteroatom are : NHC ₅ Hn, NHC ₆ H ₃ , NHC ₇ H ₁₅ , OC5H-11 , OC ₇ H ₁₅ , C ₅ H ₁₀ NH2, C ₇ H ₁₄ NH ₂ , C5H10SH, C ₇ H ₁₄ SH.

In the context of the present invention, the term "enantiomeric group" means that the group represented by formula (VII) is a piperazine or a piperidine in which the carbons bearing the Rs or R10 substituent's possess a R or S configuration (Rs or R10 is a hydrogen atom).

In the context of the present invention, the term "diastereomeric group" means that the group represented by formula (VII) is a piperazine or a piperidine in which the carbons bearing the Rs and R10 substituent's possess a R or S configuration (Rs and R10 are not hydrogen atoms).

In the context of the present invention, the term "racemic group" means that the carbons bearing the R ₈ and/or R ₀ substituent's are in the form of a mixture of R or S configuration.

The present invention will be described in further detail with reference to the accompanying drawings wherein:

Fig. 1 shows ¹ H NMR Analysis of the Diastereomeric Esters 8a and 8b;

Fig. 2 shows a View of the Crystal Structure of (R)-2a with our Numbering

Scheme, Displacement Ellipsoids Are Drawn at the 30% Probability Level. Example 1. Synthesis of Compounds of formula (I)

According to the present invention, he synthesis of (R)- and (S)-4 aminoalcoholquinoline mefloquine analogs 1 (Compounds of formula (I)) was carried out via enantiopure key intermediate 2 (4-oxirane) synthesis as indicated below. This enantioselective epoxide can be diversified on position 4, through a regioselective SN2 ring opening mechanism. The preparation of 4-oxirane 2 was carried out from 4-vinylquinoline 3 either in one step by a Jacobsen epoxidation or in two steps via a Sharpless asymmetric dihydroxylation (diol 4) [18].

The 4-vinylquinoline 3 may be prepared from any one of 4-bromoquinoline 6a and 4-sulfoxyquinoline (4-tosyloxy- 6b or 4-trifluorooxy-quinoline 6c). Among this group, the 4-bromoquinoline 6a is preferred. The 4-bromoquinoline 6a is easily accessible by reaction of 4-hydroxyquinoline 5 with phosphorus oxybromide at 150 °C. Sulfonates 6b and 6c are prepared from the same alcohol 5 by action of triflic anhydride (50% yield) and p-toluenesulfonic acid (96% yield), respectively. These different precursors will be used as electrophile in transition- metal-catalyzed cross couplings.

6a 6c

As the cross-coupling reaction, although any one of Hiyama, Stille and Suzuki reactions may be used, the Stille coupling as described hereinbelow is the most preferred reaction. Using the reaction conditions reported by literature [19], a Hiyama coupling has been performed with vinyltrimethoxysilane and 2,8-trifluoromethyl-4- bromoquinoline 6a on water using sodium hydroxide as the activator at 120 °C. Normally, this process should give good results in presence of low quantity of diacetate palladium (1 mol %). In this case, 4-vinylquinoline 3 is formed in 14% yield after 16 h of reaction time.

To further reduce time reaction and to increase the yield, the Stille coupling reaction with vinyltributylstannane as a vinylating reagent may be used. The cross-coupling reaction conditions (solvents, catalysts, substrates and bases) are shown in Table 1 .

Table 1. Stille Coupling Conditions to Prepare Alkene 3.

TBAB Base Yield

Entry ⁸ Pd catalyst (mol %) Solvenf Purity (%)

(eq.) (eq.) (%) ^rf

1 Pd(PPh ₃ )2CI ₂ (10) 1 - MeCN ^c 46 98

2 Pd(PPh ₃ )2CI ₂ (10) 1 - MeCN 65 nd 3 Pd(PPh ₃ )2CI ₂ (10) 1 - Toluene 7 nd 4 Pd(PPh ₃ )2CI ₂ (10) 1 - DMF 13 nd 5 Pd(PPh ₃ ) ₂ CI ₂ (10) - MeCN 43 99 6 Pd(PPh ₃ ) ₄ (10) 1 2 MeCN 9 nd

Pd(PPh ₃ ) ₂ CI ₂ (10) +

7

PPh ₃ (20) 1 - MeCN 16 96

Pd ₂ (dba) ₃ (10) + PPh ₃

8

(20) 1 - MeCN 84 72

9 Pd(OAc) ₂ (10) 1 - MeCN 60 83 10 Pd(PPh ₃ ) ₂ CI ₂ (10) 1 2 MeCN 75 100 11 Pd ₂ (dba) ₃ (10) 1 2 MeCN 88 68 12 Pd(PPh ₃ )2CI ₂ (5) 1 2 MeCN 48 96 ^a All reactions were performed with 1 eq. of 6a and 2 eq. of Bu ₃ SnCH=CH2.

b Performed using dry solvents.

c Performed using a degassed solvent.

d yield obtained after flash chromatography.

e Determined by HPLC analysis. The reaction conditions described by Comins et a/. , slightly modified [20] was used.

The 4-bromoquinoline 6a was reacted with vinylstannane using the Pd(PPh ₃ ) ₂ Cl2 as catalyst and tetrabutylammonium bromide as additive in reflux of dried acetonitrile (entry 1 , table 1). The 4-vinyl product has been obtained in 46% yield with a purity of 98% determined by HPLC. The starting material was totally converted but the reaction suffered of instability of the catalyst, which was observable through the precipitation of black palladium over the course of the reaction. Thus, when the same reaction was performed using oven dried glassware and distilled acetonitrile: a yield increase of 20% was observed (entry 2). The comparison between three solvents (dimethylformamide, toluene and acetonitrile) shows that acetonitrile affords the best yields (entries 2-5). Without adding tetrabutylammonium bromide (TBAB), a 43% yield (vs. 65%) of the corresponding cross-coupled product 3 was obtained (entry 5). Indeed, TBAB is able to stabilize colloidal palladium nanoparticules that act as catalysts.

Other Pd complexes may be used as catalysts (see entries 8 and 9 of table 1 ). The addition of an inorganic base like K ₂ CO ₃ increases reaction yield (entries 10 vs. 2). The best yield with a satisfactory purity is obtained using Pd(PPh ₃ )2CI ₂ , TBAB, distilled acetonitrile and K ₂ CO ₃ (75%, entry 10). When 4- bromoquinoline 6a was used in the place of 4-tosyloxyquinoline 6b and 4- trifluorooxyquinoline 6b in the optimal conditions previously described, the yields increased in an important way by 42 and 60%, respectively.

The vinylquinoline 3 was prepared in good yield (82%) by a direct Suzuki-

Miyaura cross-coupling reaction of 4-bromoquinoline 6a with dibutyl vinylboronate.

^B(OBu) ₂

71% This step has been performed in the presence of Pd(PPh3) ₄ as a catalyst and a 4 M aqueous solution of KOH solution [21 ]. The Suzuki-Miyaura-type reaction was expanded with potassium vinyltrifluoroborate and 4-bromoquinoline 6a as coupling partner by using PdCI ₂ (dppf) CH ₂ CI ₂ as the catalyst, Cs ₂ C0 ₃ as the base, and THF-H ₂ 0 as the solvent system [22]. Consequently, this new palladium-catalyzed cross-coupling reaction led to the expected 4-vinylquinoline 3 with a 71 % yield.

After optimization of the 4-vinylquinoline 3 preparation, a two step process synthesis based on an asymmetric dihydroxylation chemistry followed by a stereospecific cyclization is realized.

The cyclization can be obtained according to different literature procedures:

(i) a base-mediated ring closure via selective hydroxyl activation, generally in a mesylate or tosylate form [23];

(ii) a formation of acetoxy halides and epoxide via the Sharpless acetoxonium ion [24] ; or

(iii) a Mitsunobu reaction [25].

Among these procedures, the Sharpless asymmetric dihydroxylation method followed by a cyclization via Sharpless acetoxonium ion is mostly preferred in the present invention. The optimized conditions of the Sharpless asymmetric dihydroxylation starting from the 2,8-bis(trifluoromethyl)-4- vinylquinoline (3) are given in table 2. According to the final enantiomeric alcohol expected 4a (R) or 4b (S) the vinylquinoline 3 is put to react with commercially available AD-mix a or AD-mix β, in a solution of i-BuOH/H ₂ 0 at OX, with eventual addition of K ₂ Os0 ₂ (OH) ₄ and MeS0 ₂ NH ₂ (see table 2). Alternatively, divers asymmetric dihydroxylation catalysts may be used on behalf of AD-mix as far as they fulfills the same function as the AD-mix. Table 2. Reagents and Conditions Used to Prepare Enantiopure Diol 4a and 4b

AD-mix Time % (Absolute

Entry K ₂ Os0 ₂ (OH)4 eS0 ₂ NH ₂ Yield (%)

(g) (h) ee ^c configuration)

1 a (1.4)a - 1 mmol 26 37 nd" - -

2 β (1.4)» - 1 mmol 30 43 nd - -

3 a (2.5) - 1 mmol 28 36 nd - -

4 a (6.4) - 1 mmol 47 26 96 + 62 4b (S)

5 β (1 -4) 1 mol % 1 mmol 24 78 98 - 52 4a (R)

6 3 (1.4) 1 mol % - 19 68 97 - 52 4a (f?)

7 a (1.4) 1 mol % - 18 78 96 + 62 4b (S) a 1 g of AD-mix a corresponds to 1.0 mol % of (DHQ)2-PHAL, 3 mmol of K3Fe(CN) ₆ , 3 mmol of K2CO3, 0.4 mol % of K ₂ Os0 ₂ (OH) ₄ .

⁶ 1 g of AD-mix β corresponds to 1.0 mol % of (DHQD) ₂ -PHAL, 3 mmol of K ₃ Fe(CN)6, 3 mmol of K ₂ C0 ₃ , 0.4 mol % of K ₂ Os0 ₂ (OH) ₄ .

c Enantiomeric excesses were determined by HPLC (Chiralpak IB column, heptane//-PrOH 90:10; 1mL/min, 210 nm) tr (R) = 26 min, t _r (S) = 33 min;

d not determined.

ec 0.25, DCM.

fConfiguration of the major enantiomer was determined by analyzing ¹ H NMR spectra of the Mosher monoesters and/or with crystallographic epoxide spectra.

The first asymmetric dihydroxylation were carried out with 1.4 g of AD-mix a or β added to 1 equivalent of methylsulfonamide (entries 1 , 2 of table 2) as described by Kolb ef a/. [26] The corresponding oxiranes 4a or 4b were obtained with 40% yield average. In order to increase the yield, quantities of AD-mix a have been increased: doubled (entry 3 of table 2) or multiplied by four (entry 4). Addition of 1 mol % of K ₂ Os02(OH) ₄ to 1.4 g of AD-mix increased significantly the yield (78% vs. 43% entries 5, 2). Furthermore, the inventors found that the presence of methylsulfonamide is not required for the advancement of the reaction (entry 5, 6). Finally, the treatment of vinylquinoline 3 with 1.4 g of AD-mix β in the presence of 1 mol % of oxidant f ₂ 0s0 ₂ (OH)4 provided the corresponding (/?)-diol ([oc] _D ²⁰ -52 (c 0.25; DCM)) in 68% yield and 97% enantiomeric excess (ee). The (S)-diol ([ ] _D ²⁰ +62 (c 0.25; DCM)) was prepared from 1.4 g of AD-mix a in the presence of 1 mol % of oxidant K ₂ 0s02(OH) ₄ in 78% yield and 96% ee. The Mosher's MTPA (methoxy(trifluoromethyl)phenylacetyl) method was used as a tool to determine the absolute configuration of chiral alcohols and primary amines since this process does not require crystallization of compounds [ 27 ]. In MTPA esters, the aromatic substituent (phenyl group) generates a diamagnetic anisotropy effect due to the ring current induced by the external magnetic field. The proton NMR signals of the alcohol moiety facing the phenyl group on the preferred conformation are moved to a higher magnetic field (high field shift). In ester (S,X), the protons of group Ri feel a diamagnetic anisotropy effect, and hence their ¹ H NMR signals show high-field shifts whereas R2 does not. Conversely, in the ester (R, X), R2 is above the benzene plane of the MTPA moiety, and hence the protons of group R2 show high-field shifts. The parameter Δδ reflecting the anisotropy is defined as Δδ = 5(S,X) - 5(R,X).

high field shift

The corresponding Mosher's monoester 8 was prepared, from the diol 4a (R), using (S)-a-methoxy-a-trifluoromethyl-phenylacetic acid or (R)-a-methoxy-a- trifluoromethyl-phenylacetic acid. To this purpose, the alcohol 7 as indicated below was obtained with a 39% yield after selective primary alcohol protection of compound 4a with f-butyldimethylsilylchloride in DMF, at room temperature. Subsequently, the two diastereomeric esters 8a (R,R) and 8b (S,R) as indicated below, were synthesized by reaction of 7 with the corresponding (R)- and (S)- Mosher's MTPA in dichloromethane with a 49% yield. , HO,

OTBDMS

(R)-MTPA, EDCI,

DMAP, DCM, RT

49%.

¹ H NMR analyses of the diastereomeric esters allowed to establish without ambiguity the absolute configuration of the diols by combining the anisotropy effects discussed above with the definition of Δδ parameter. The MTPA moiety and the methine proton of the secondary alcohol moiety are placed in the up in the front side and in the rear side, respectively. The substituent R ₂ showing positive Δδ values is placed at the right side, while the substituent Ri showing negative Δδ values is at the left side. So, the absolute configuration ( =R) of our alcohol has been determined (see Figure 1).

Concerning the epoxide formation by ring closure via Sharpless acetoxonium ion, a "one-pot" method was used. This is described by Sharpless for the stereospecific conversion of each R or S 1 ,2-diols into their corresponding epoxides ^f30] . This process involves three successive steps:

(i) formation of the cyclic orthoester by acid catalyzed transesterification;

(ii) generation of halohydrins ester via regioselective opening acetoxonium ion by addition of tributyldimethylsilyl chloride; and

(iii) cyclization to epoxide by base mediated saponification in methanol.

This conversion of the diol 4a to the oxirane 2a was accomplished with global retention of configuration because this process involves two successive inversions at the same stereocenter:

(i) inversion at the halide receiving stereocenter at the time of halohydrins ester formation and (ii) second inversion at the halide center while cyclization to epoxide ( as indicated below).

One-pot Stereospecific Conversion of the 1 ,2-diol 4a into Epoxyde 2a via a Chlorhydrine ester

All three operations were carried out in one reaction vessel without isolation of any intermediates but each step was followed and validated by GCMS. Thus, the slightly modified Sharpless conditions applied to the conversion of diols 4a and 4b give the corresponding oxiranes 2a and 2b with retention of configuration according to optical rotation of each compound (Table 3).

Yield ee Absolute

4 2

(%) ( ) ^» configurations

a a 68 92 -52 R

b b 57 96 +45 S

a Enantiomeric excess was determined by GC.

" c O.25, MeOH.

cAbsolute configuration was determined with

crystallographic epoxide spectra.

Table 3. Substrate Scope of Enantioselective Epoxydation In order to confirm the structure and the absolute configuration of the synthesized quinoline epoxides 2, X-rays studies for the two derivatives were performed. Suitable crystals for compound (-)-2a were obtained. Its molecular structure, depicted in Figure 2, confirms the structure in the solid state as anticipated on the basis of IR and NMR data. Moreover, the configuration of (-)-2a was determined by observing and calculating the F(+)/F(-) ratios of Bijvoet pairs using the mean F value of each independent reflection. ¹²⁸¹ Based on these results, the absolute configuration at C-1 1 in (-)-2a is determined to be R. And consequently (-)-2a confirmed that the (+)-enantiomer-2b presents the S-absolute configuration. Furthermore, these results indirectly confirm the stereochemistry of each R or S quinolin-4-yl-ethanediol precursors 4 (see figure 2).

Finally, the treatment of oxirane 2a or 2a with diverse amines, in a regioselective SN2 nucleophilic ring opening mechanism, provided the corresponding enantiopure 4-aminoquinolines 1 ((R) or (S)) with good yield (35- 96%) and ees generally superior to 92%. No epimerization at the stereogenic carbon was observed, as determined by chiral HPLC analysis, using the opposite enantiomer as a standard.

The present invention is intended to provide an enantiopure, synthetic, and straightforward route to prepare 4-aminoquinolines derivatives through the enantiopure 4-oxirane 2 synthesis. The preparation of the enantiopure 4-oxirane 2 was carried out from 4-vinylquinoline 3 in two steps via a Sharpless asymmetric dihydroxylation with retention of configuration. As a result, the enantiopure 4- oxirane 2 has been easily diversified, on position 4, through a regioselective SN2 ring opening mechanism with various amines, to provide the corresponding enantiopure 4-aminoquinolines 1 (( ) or (S)) with good yield (35-96%) and ees generally superior to 92%.

Example 2 General methods for the preparation of precursors

All starting materials and reagents were obtained from commercial suppliers and were used without further purification. Reactions requiring anhydrous conditions were performed under a blanket of argon. All solvents were purified via literature procedures or used without further purification. Flash column chromatography was carried out on Kielselgel 60 (40-63 pm) ASTM (Merck). Routine monitoring of reactions was performed using Merck silica gel 60 F254 plates, thin layer chromatography (TLC) and visualized under UV light (254 nm), with ethanolic phosphomolybdic acid (PMA). Nuclear magnetic resonance (NMR) spectra were recorded using Bruker 600 MHz NMR instrument ( ¹ H NMR at 600 MHz and ¹³ C NMR at 150 MHz) and Bruker 300 MHz NMR instrument ( ¹ H NMR at 300 MHz and ¹³ C NMR at 75 MHz). Chemical shifts are expressed in parts per million (δ, ppm) downfield from tetramethylsilane and are referenced to the deuterated solvent. ¹ H NMR and ¹³ C NMR data were reported in the order of chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qt = quintuplet, m = multiplet), integration, coupling constants in hertz (Hz). High Performance Liquid Chromatography (HPLC) was carried out on a Shimadzu LC- 20AD equipped with a Chiralpak IB column. Specific rotations were measured on a Jasco P1010 polarimeter. High-resolution mass spectra were obtained from a Micromass-Waters Q-TOF Ultima spectrometer. Infrared spectra were recorded with a Jasco FTIR-4200 and are reported using the frequency of absorption (cm- ¹ ). Gas Chromatography-Mass Spectrometry (GCMS) was carried out on a Shimadzu GCMS-QP2010S equipped with a SLB-5ms. Microwave used is a CEM discovered-SP.

4-bromo-2,8-bis(trifluoromethyl)quinoline (6a)

Phosphorous oxybromide (4 g, 14.2 mmol), under argon atmosphere, was heated to 90 °C until complete dissolution of the solid. 4-hydroxyquinoline 5 (4.08 g, 14.2 mmol) was added to this hot solution and the bath temperature was increased to 150 °C. After 6 h, the resulting mixture was cooled to room temperature. The reaction mixture was quenched by addition of ice-cold water and the precipitated formed was filtered and washed with water to afford the expected compound 6a (4.70 g, 96%) as a white solid. R _f 0.79 (cyclohexane/Et ₂ 0 5:1); mp: 60 °C; ¹ H NMR (300 MHz, CDCI ₃ ) δ 7.82 (t, J = 7.9 Hz, 1 H), 8. (s, 1 H), 8.22 (d, J = 7.3 Hz, 1 H), 8.46 (d, J = 8.6 Hz, 1 H), NMR data were in agreement with the lit.: ^[13] ; ¹³ C NMR (125 MHz, CDCI ₃ ) δ 120.9 (q, J = 276.0 Hz), 122.0 (q, J = 2.0 Hz), 123.6 (q, J = 273.8 Hz), 128.9, 129.4, 129.8 (q, J = 30.8 Hz), 130.5 (q, J = 5.3 Hz), 131.5, 138.5, 144.5, 148.6 (q, J = 36.1 Hz); IR u _ma x=1577, 1422, 1302, 1 136, 1098, 1010, 876, 824 cm ^"1 ; GCMS (m/z): 343; HRMS calcd for C ₁₁ H ₄ BrF ₆ NNa (M+Na) ⁺ 365.9329, found 365.9346. -bis(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate (6b)

To a solution of 4-hydroxyquinoline 5 (1.5 g, 5.34 mmol) in toluene/aqueous solution of LiOH (5%, w/v) (22 ml_; 1 :1 , v/v) was added dropwise anhydride triflique (1.1 ml_, 6.41 mmol), at 0 °C. The resulting mixture was allowed to warm to room temperature and was stirred during 3 h. The reaction mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure to afford 6b (1.12 g, 50 %) as a colorless oil. ¹ H NMR (300 MHz, CDCI ₃ ) δ 7.86 (s, 1 H), 7.95 (t, J = 8.0 Hz, 1 H), 8.34 (d, J = 7.8 Hz, 1 H), 8.37 (d, J = 7.8 Hz, 1 H); ¹³ C NMR (75 MHz, CDCI ₃ ) δ 109.4 (q, J = 1.7 Hz), 1 18.9 (q, J = 320.5 Hz), 120.4 (q, J = 275.5 Hz), 122.0 (q, J = 273.6 Hz), 125.1 , 129.1 (q, J = 27.3 Hz), 129.4, 130.8 (q, J = 5.0 Hz), 145.6, 149.4 (q, J = 36.8 Hz), 154.0.

2,8-bis(trifluoromethyl)quinolin-4-yl 4-methylbenzenesulfonate (6c)

To a solution of 4-hydroxyquinoline 5 (500 mg, 1 .78 mmol) in acetone (4 mL) was added an aqueous solution of NaOH 2N until pH=1 1 , and p-toluenesulfonyl chloride (680 mg, 3.56 mmol) at 0 °C. The reaction mixture was stirred during 12 h then was warmed to room temperature and the solvent was reduced under pressure. The resulting residue was washed with water and filtered to afford compound 6c (746 mg, 96 %) as a white solid, mp: 107 °C; H NMR (300 MHz, CDC ) δ 7.86 (s, 1 H), 7.95 (t, J = 7.9 Hz, H), 8.34 (d, J = 7.8 Hz, 1 H), 8.37 (d, J = 7.8 Hz, 1 H); ¹³ C NMR (75 MHz, CDCI ₃ ) δ 21.7, 109.4, 120.6 (q, J = 275.6 Hz), 123.2 (q, J = 273.8 Hz), 123.6, 126.1 , 127.9, 130.0 (q, J = 5.2 Hz), 130.4, 131.4 (q, J = 3.9 Hz), 145.3, 147.0, 149.1 (q, J = 36.0 Hz), 154.6; HRMS calcd for C ₁₈ HiiF ₆ N0 ₃ SNa (M+Na) ⁺ 458.0262, found 458.0270. -bis(trifluoromethyl)-4-vinylquinoline (3)

Method A: To a solution of 6a (100 mg, 0.29 mmol), TBAB (93 mg, 0.29 mmol), K ₂ CO3 (80 mg, 0.58 mmol), and Pd(PPh ₃ ) ₂ CI ₂ (20 mg, 10 mol %) in dry MeCN (580 pL), was added tributylvinyltin (102 pL, 0.35 mmol), under argon atmosphere. The tube was scelled and the mixture was stirred at 90 °C. After 4 h, the reaction was cooled to room temperature then was filtered through a pad of celite and washed with MeCN. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (cyclohexane/Et ₂ 0 5:1 ) to afford 3 (64 mg, 75%) as a white solid. R _f 0.34 (cyclohexane/Et ₂ 0 5:1); mp: 76 °C; ¹ H NMR (300 MHz, CDCI ₃ ) δ 5.83 (dd, J = 11.1 , 0.7 Hz, 1 H), 6.09 (dd, J = 17.3, 0.7 Hz, 1 H), 7.43 (dd, J = 17.3, 1 1.1 Hz, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 7.86 (s, 1 H), 8.15 (d, J = 6.9 Hz, 1 H), 8.33 (d, J = 8.6 Hz, 1 H); ¹³ C NMR (75 MHz, CDCI ₃ ) δ 1 14.1 (q, J = 2.1 Hz), 121 .3 (q, J = 275.5 Hz), 123.2, 123.6 (q, J = 273.6 Hz), 127.0, 127.9, 127.8, 129.0 (q, J = 5.5 Hz), 129.2 (q, J = 30.5 Hz), 131 .0, 144.0, 146.2, 148.4 (q, J = 35.6 Hz), NMR data were in agreement with the lit.: ^[121 ; IR u _max = 1590, 1426, 1303, 1134, 1108, 888, 833 cm ^'1 ; GCMS (m/z): 291 ; HRMS calcd for Ci ₃ H ₇ F ₆ NNa (M+Na) ⁺ 314.0380, found 314.0390.

Method B: To a solution of 6a (1.16 mmol) in toluene/aqueous solution of KOH (4M) (9 mL; 8:1 , v/v) was added dibutyl vinylboronate (1.28 mmol) and Pd(PPh ₃ ) ₄ (0.035 mmol), under under nitrogen. The reaction mixture was stirred at reflux during 24 h. The reaction was cooled to room temperature and was washed with water (20 mL), then was washed with toluene (2 x 20 mL). The organic layer was separated, washed with an aqueous 1 M NaOH solution, and a brine solution, then dried over Na2S0 ₄ , and evaporated under reduced pressure. The residue was purified by column chromatography (cyclohexane/ether 5:1 ) to afford 3 (82%) as a white solid.

Method C: To a suspension of potassium vinyltrifluoroborate (1.16 mmol), cesium carbonate (3.5 mmol), PdCI ₂ (dppf) CH2Cl ₂ (0.1 16 mmol), and 6a (1.16 mmol) in THF (15 mL) was added water (1.5 mL), under a nitrogen atmosphere. The reaction mixture was stirred at reflux during 24 h. The reaction was cooled to room temperature, and water was added (25 mL) and extracted with diethyl ether (3 x 25 mL). The combined organic layers were washed with brine and then dried over Na2S0 ₄ , filtered and was concentrated under reduced pressure. The residue was purified by column chromatography (cyclohexane/ether 5:1) to afford 3 (71 %) as a white solid.

(R)-1 -[2,8-bis(trifluoromethyl)quinolin-4-yl]ethan-1 ,2-diol (4a)

To a solution of AD-mix-β (4.8 g) and K ₂ Os0 ₂ (OH) ₄ (12.7 mg, 1 mol %) in t- BuOH/H ₂ 0 (34.4 mL; 1 :1 v/v) was added 3 (1 g, 3.44 mmol) at 0 °C and stirred during 12 h. The reaction was quenched at 0 °C by addition of Na ₂ S0 ₃ (5.16 g), then was warmed to room temperature and stirred for 30 min. The reaction mixture was extracted with EtOAc, dried with anhydrous Na ₂ S0 ₄ and evaporated under reduced pressure. The residue was precipitated in cyclohexane, filtered on buchner to afford 4a (945 mg, 84%, GCMS: 00%, and 98% ee) as a white solid. HPLC analysis (Chiralpak IB column, heptane/ -PrOH, 95:5; flow 1.0 mL/min, tt{R) = 26.8 min, f^S) = 32.9 min); [a] _D ²⁰ -52° (c 0.25, DCM); mp: 30-135 °C; ¹ H NMR (300 MHz, CDCI ₃ ) δ 3.77 (dd, J = 11.6, 4.2 Hz, 1 H), 3.89 (dd, J = 1 1.6, 5.2 Hz, H), 5.62 (dd, J - 5.9, 4.4 Hz, 1 H), 7.83 (t, J = 7.9 Hz, 1 H), 8.15 (s, 1 H), 8.23 (d, J = 7.2 Hz, 1 H), 8.54 (d, J - 8.5 Hz, 1 H); ¹³ C NMR (75 MHz, CDCI ₃ ) 5 67.9, 71.7, 116.3 (q, J = 2.1 Hz), 122.9 (q, J = 274.8 Hz), 125.1 (q, J = 272.8 Hz), 128.4, 129.3, 130.0 (q, J = 5.6 Hz), 130.1 (q, J = 29.7 Hz), 144.8, 149.2 (q, J = 34.9 Hz), 153.4; IR u _max = 3266, 2937, 1605, 1587, 1308, 1128, 1102, 838 cm ^"1 ; GCMS (m/z): 325; HRMS calcd for C ₁₃ H ₉ F ₆ N0 ₂ Na (M+Na) ⁺ 348.0435, found 348.0420.

( -1 -[2,8-bis(trifluoromethyl)quinolin-4-yl]ethane-1 ,2-diol (4b)

According to the same procedure that 4a, the product 4b was prepared starting from 3 (640 mg) to obtain 4b (558 mg, 78%, 97% ee) as a white solid. HPLC analysis (Chiralpak IB column, heptane//-PrOH, 95:5; flow 1 .0 mL/min, t^R) = 26.8 min, tr{S) = 31.8 min); mp: 130-135 °C; [oc] _D ²⁰ +62 (c 0.25, DCM); ¹ H NMR (300 MHz, CDCI ₃ ) δ 3.77 (dd, J = 1 1.6, 4.2 Hz, 1 H), 3.89 (dd, J = 1 1.6, 5.2 Hz, 1 H), 5.62 (dd, J = 5.9, 4.4 Hz, 1 H,), 7.83 (t, J = 7.9 Hz, 1 H), 8.15 (s, 1 H), 8.23 (d, J = 7.2 Hz, 1 H), 8.54 (d, J = 8.5 Hz, 1 H); ¹³ C NMR (75 MHz, CDCI ₃ ) δ 67.9, 71.7, 116.3 (q, J = 2.1 Hz), 122.9 (q, J = 274.8 Hz), 125.1 (q, J = 272.8 Hz), 128.4, 129.3, 130.0 (q, 1 H, J = 5.6 Hz), 130.1 (q, J = 29.7 Hz), 144.8, 149.2 (q, J = 34.9 Hz), 153.4; IR u _max = 3266, 2937, 1605, 1587, 1308, 1 128, 1102, 838 cm ^"1 ; GCMS (m/z): 325; HRMS calcd for (M+Na) ⁺ 348.0435, found 348.0440.

(R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((tert- butyldimethylsilyl)oxy)ethanol (7)

To a solution of 4a (140 mg, 0.43 mmol) in dry DMF (5 ml_), under argon atmosphere, was added TDBMSCI (64.8 mg, 0.43 mmol), and imidazole (29.2 mg, 0.43 mmol). The mixture was stirred at room temperature for 24 h. The solution was concentrated under reduced pressure, and then the residue was dissolved in EtOAc and was washed with water, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH 99:1) to afford 7 (74 mg, 39%, 99% ee) as a colorless oil. HPLC analysis (Chiralpak IB column, heptane//-PrOH 99:1 ; flow 1 mL/min, t,(R) = 13.9 min, US) = 16.6 min); [a] _D ²¹ -41.1 (c 0.25, DCM); R, 0.88 (DCM/MeOH 99:1); ¹ H NMR (300 MHz, CDCI ₃ ) δ 0.03 (s, 3H), 0.06 (s, 3H), 0.90 (s, 9H), 3.67 (dd, J = 10.3, 7.4 Hz, 1 H), 4.03 (dd, J = 10.3, 3.7 Hz, 1 H), 5.57 (dd, J = 7.2, 3.4 Hz, 1 H), 7.74 (t, J = 8.0 Hz, 1 H), 8.10 (s, 1 H), 8.15 (d, J = 7.2 Hz, H), 8.24 (d, J = 8.2 Hz, 1 H); ¹³ C NMR (75 MHz, CDCI ₃ ) 18.2, 25.8, 67.5, 70.3, 1 15.2 (q, J = 2.05 Hz), 121.3 (q, J = 275.1 Hz), 123.5 (q, J = 273.6 Hz), 126.8, 127.0, 127.2, 128.7 (q, J = 5.5 Hz), 129.2 (q, J = 32.7 Hz), 143.6, 148.5 (q, J = 36.8 Hz), 149.2; IR u _max = 2956, 2932, 2861 , 1604, 1586, 1431 , 1308, 1144, 1 108, 837, 807 cm ^-1 ; HRMS calcd for C ₉ H23F ₆ NO ₂ SiNa (M+Na) ⁺ 462.1300, found 462.1320. (R)-(R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((ierf- butyldimethylsilyl)oxy)ethyl-3,3,3-trifluoro-2-methoxy-2-phe nylpropanoate

(8a

To a solution of 7 (43 mg, 0.098 mmol) in dry DCM (1 mL), under argon atmosphere, was added at 0 °C (/?)(+)-MTPA (27 mg, 0.12 mmol), EDCI (37.5 mg, 0.2 mmol), and DMAP (3.6 mg, 0.029 mmol). The mixture was stirred at room temperature for 24 h. The solution was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH 99:1) to afford 8a (38 mg, 58%, 95% ee) as a yellow oil. The ee was determined by H NMR. [oc] _D ²⁴ - 19.2 (c 0.25, DCM); R _f 0.82 (DCM/MeOH 99:1); ¹ H NMR (600 MHz, CDCI ₃ ) δ - 0.044 (s, 3H), -0.041 (s, 3H), 0.81 (s, 9H), 3.65 (d, J = 0.68 Hz, 3H), 3.99 (dd, J = 1 1.4, 4.0 Hz, 1 H), 4.05 (dd, J = 11.4, 6.8 Hz, 1 H), 6.77 (dd, J = 6.8, 4.0 Hz, 1 H), 7.49-7.36 (m, 5H), 7.57 (s, H), 7.77 (t, J = 7.9 Hz, 1 H), 8.21 (d, J = 7.2 Hz), 8.32 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150 MHz, CDCI ₃ ) δ -5.6 (2C), 18.1 , 25.6, 55.8, 65.1 , 74.3, 115.4 (q, J = 1.8 Hz), 120.9 (q, J = 275.6 Hz), 123.2 (q, J = 288.7 Hz), 123.4 (q, J = 273.7 Hz), 126.4, 126.9 (3C), 127.7, 128.6, 129.1 (q, J = 5.1 Hz), 129.7 (q, J = 30.4 Hz), 130.1 , 131.7, 143.8, 145.0, 148.2 (q, J = 35.5 Hz), 165.9; IR u _max = 2955, 2930, 2857, 1755, 1605, 1312, 1147, 1 112, 1018, 837 cm ^"1 ; HRMS calcd for C ₂ 9H3oF9 O ₄ SiNa (M+Na) ⁺ 678.1698, found 678.1688.

R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((fert- butyldimethylsilyl)oxy)ethyl-3,3,3-trifluoro-2-methoxy-2-phe nylpropanoate

8b According to the same procedure that 8a, the product 8b was prepared starting from 7 (41 mg) to obtain 8b (30 mg, 49%, 98% ee) as a yellow oil. The ee was determined by ¹ H NMR. [a] _D ²⁴ -36.7 (c O.25, DCM); R _f 0.82 (DCM/MeOH 99:1); ¹ H NMR (600 MHz, CDCI ₃ ) δ -0.12 (s, 3H), -0.1 (s, 3H), 0.74 (s, 9H), 3.49 (d, J = 1.2 Hz, 3H), 3.98 (dd, J = 1 1.2, 4.6 Hz, 1 H), 4.02 (dd, J = 11.1 , 5.9 Hz, 1 H), 6.80 (t, J = 5.19 Hz, 1 H), 7.57-7.32 (m, 5H), 7.81 -7.78 (m, 2H), 8.22 (d, J = 7.2 Hz, 1 H), 8.37 (d, J = 8.5 Hz, 1 H); ¹³ C NMR (150 MHz, CDCI ₃ ) δ -5.9, -5.8, 18.0, 25.5, 55.3, 65.0, 73.9, 1 15.8 (q, J = 1.9 Hz), 121.0 (q, J = 275.6 Hz), 123.3 (q, J = 289.0 Hz), 123.4 (q, J = 273.8 Hz), 126.5, 127.2, 127.4, 127.7, 128.6 , 129.2 (q, J = 5.6 Hz), 129.7 (q, J = 30.7 Hz), 129.9, 131.4, 143.8, 145.4, 148.1 (q, J = 35.5 Hz), 165.9; IR Umax= 2955, 2930, 2857, 1755, 1605, 1312, 1 147, 1 1 12, 1018, 837 cm ^'1 ; HRMS calcd for C29H ₃ oF ₉ N0 ₄ SiNa (M+Na) ⁺ 678.1698, found 678.1688.

(ft)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (2a)

To a solution of 4a (800 mg, 0.62 mmol) in dry DCM (8.8 ml_), under argon atmosphere, was added trimethylorthoacetate (236 μΙ_, 1.85 mmol) and PTSA (5.3 mg, 0.031 mmol). The mixture was stirred for 4h at room temperature. The volatiles were removed in vacuo, and the flask pumped on high vacuum to remove excess MeOH. The residue was dissolved in dry DCM (8.8 ml_), under argon, and was cooled to 0 °C. Trimethylsilyl chloride (234 μί, 1.85 mmol) was added dropwise. The reaction was warmed to room temperature and was stirred during 12 h. The volatiles were removed in vacuo, and the residue was dissolved in MeOH (8.8 mL). K ₂ CO ₃ (254.8 mg, 1.85 mmol) was added, and the mixture was stirred for 5h. The reaction was poured onto saturated aqueous solution of NH ₄ CI, extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO , filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (cyclohexane/Et ₂ 0 1 :1), to afford 2a (513 mg, 68%, 92% ee) as a yellow solid. HPLC analysis (Chiraipak IB column, heptane//-PrOH, 99:1 ; flow 1.0 mL/min, t^S) = 15.1 min, t^R) = 17.4 min); [a] _D ²⁰ -52 (c 0.25, DCM); R _f 0.36 (cyclohexane/Et ₂ 0 1 :1); mp: 84 °C; ¹ H NMR (300 MHz, CDCI ₃ ) δ 2.83 (dd, J = 5.7, 2.5 Hz, 1 H), 3.42 (dd, J = 5.7, 4.2 Hz, 1 H), 4.55 (dd, J = 3.6, 2.7 Hz, 1 H), 7.79 (t, J = 7.9 Hz, 1H), 7.81 (s, 1 H), 8.20 (d, J = 7.2 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150 MHz, CDCI ₃ ): 49.2, 50.8, 113.3 (q, J = 2.0 Hz), 121.1 (q, J = 275.5 Hz), 123.4 (q, J = 273.6 Hz), 127.0, 127.4, 127.6, 129.1 (q, J = 5.5 Hz), 129.4 (q, J = 30.5 Hz), 143.3, 146.8, 148.7 (q, J = 35.5 Hz), 149.5, NMR data were in agreement with the lit.: ^{[ 2]} ; IR u _max = 1606, 1587, 1431 , 1308, 1276, 1213, 1102, 1069, 895, 982, 822 cm ^"1 ; GCMS: 307; HRMS calcd for C ₁₃ H ₇ F ₆ NONa (M+Na) ⁺ , 330.0330 found 330.0314.

(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (2b)

According to the same procedure that 2a, the product 2b was prepared starting from 4b (800 mg) to obtain 2b (437 mg, 57%, 96% ee) as a yellow solid. HPLC analysis (Chiraipak IB column, heptane/ -PrOH, 99:1 ; flow 1.0 mL/min, f,(S) = 14.9 min, tr(R) = 17.4 min); [a] _D ²⁰ +45 (c O.25, DCM); R 0.36 (cyclohexane/Et ₂ 0 1 :1); mp: 84 °C; ¹ H NMR (300 MHz, CDCI3) δ 2.83 (dd, J = 5.7, 2.5 Hz, 1H), 3.42 (dd, J = 5.7, 4.2 Hz, 1 H), 4.55 (dd, J = 3.6, 2.7 Hz, 1 H), 7.79 (m, 2H), 8.20 (d, J = 7.2 Hz, 1 H), 8.39 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150 MHz, CDCI ₃ ): 49.2, 50.8, 113.3 (q, J = 2.0 Hz), 121.1 (q, J = 275.5 Hz), 123.4 (q, J = 273.6 Hz), 127.0, 127.4, 127.6, 129.1 (q, J = 5.5 Hz), 129.4 (q, J = 30.5 Hz), 143.3, 146.8, 148.7 (q, J = 35.5 Hz), 149.5, NMR data were in agreement with the lit.: ¹¹²¹ ; IR u _ma x= 1606, 1587, 1431 , 1308, 1276, 1213, 1102, 1069, 895, 982, 822 cm ^-1 ; GCMS: 307; HRMS calcd for Ci ₃ H ₇ F ₆ NONa (M+Na) ⁺ , 330.0330 found 330.0314. Example 3 General method for the preparation of compounds according to the present invention

In the following examples, only a part of the compounds according to the invention is presented. However, the invention is not limited to such compositions as far as the composition fall within the scope of the present claims.

Method D:

To a solution of 2a or 2b (1 eq) in /-PrOH (0.05 M) was added the appropriate amine (3eq). The mixture was stirred for 24 h at 90 °C. The volatiles were removed in vacuo. The crude was then purified by column chromatography.

Method E:

To a solution of 2a or 2b (1 eq) in EtOH absolu (0.05 M) was added the appropriate amine (3eq). The mixture was heated by microwaves for 15 min at 130 °C (150 W, 275 psi, stirring). The volatiles were removed under reduced pressure. The crude was then purified by column chromatography.

( ? -2-(benz lamino)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)ethanol (1a)

Using method D, the crude was purified by column chromatography

(EtOAc/MeOH/NH ₄ OH 90:5:5), to afford 1a (44 mg, 66%, 95% ee) as a white solid. HPLC analysis (Chiralpak IB column, heptane/EtOH, 90:10; flow 0.5 mL/min, t^R) = 16.8 min, tr(S) = 18.9 min); [oc] _D ²⁷ -34.5 (c 0.25, DMSO); R _/ 0.78 (EtOAc/MeOH/NH ₄ OH 80:10:10); mp: 163 °C; H NMR (300 MHz, CDCI ₃ ) 52.78 (dd, J = 12.4, 6.9 Hz, 1 H), 2.88 (dd, J = 12.5, 3.9 Hz, 1 H), 3.72, (s, 2H), 5.61 (m, 1 H), 7.20 (m, 5H), 7.85 (t, J = 8.0 Hz, 1 H), 8.12 (s, 1 H), 8.32 (d, J = 7.3Hz, 1 H), 8.55 (d, J = 8.6 Hz, 1 H); ¹³ C NMR (150 MHz, CDCI ₃ ) δ 52.3, 55.4, 68.1 , 114.7, 121.5 (q, J = 275.4 Hz), 123.3 (q, J = 273.1 Hz), 126.4, 126.7, 126.9 (q, J = 28.5 Hz), 127.4, 127.7, 127.9, 129.1 , 129.4 (q, J = 5.5 Hz), 140.5, 142.5, 146.6 (q, J - 34.1 Hz), 155.0; IR u _max = 1603, 1587, 1430, 1310, 1300, 1 127, 1106, 903, 881 , 835 crrT ¹ ; HRMS calcd for C20H17F6N2O (M+H) ⁺ 415.1245, found 415.1265.

(S)-2-(benzylamino)-1 -(2,8-bis(trifluoromethyl)quinoiin-4-yl)ethanol (1f)

Using method D, the crude was purified by column chromatography

(EtOAc/MeOH/NH ₄ OH 90:5:5), to afford 1f (59 mg, 89%, 98% ee) as a white solid. HPLC analysis (Chiralpak IB column, heptane/EtOH, 90:10; flow 0.5 mL/min, tr(R) = 16.8 min, WS) = 18.9 min); [a] _D ²⁷ +46.3 (c 0.25, DMSO); R, 0.78 (EtOAc/MeOH/NH ₄ OH 80:10:10); mp: 163 °C; ¹ H NMR (300 MHz, CDCI3) ό ^" 2.78 (dd, J = 12.4, 6.9 Hz, 1 H), 2.88 (dd, J = 12.5, 3.9 Hz, 1 H), 3.72, (s, 2H), 5.61 (m, 1 H), 7.20 (m, 5H), 7.85 (t, J = 8.0 Hz, 1 H), 8.12 (s, 1 H), 8.32 (d, J = 7.3Hz, 1 H), 8.55 (d, J = 8.6 Hz, 1 H); ¹³ C NMR (150 MHz, CDCI ₃ ) δ 52.3, 55.4, 68.1 , 1 14.7, 121.5 (q, J = 275.4 Hz), 123.3 (q, J = 273.1 Hz), 126.4, 126.7, 126.9 (q, J = 28.5 Hz), 127.4, 127.7, 127.9, 129.1 , 129.4 (q, J = 5.5 Hz), 140.5, 142.5, 146.6 (q, J = 34.1 Hz), 155.0; IR u _max = 1603, 1587, 1430, 1310, 1300, 1 127, 1 106, 903, 881 , 835 cm ^-1 ; HRMS calcd for C ₂ oHi7F ₆ N ₂ 0 (M+H) ⁺ 415.1245, found 415.1265.

(R)-ethyl-4-(4-(2-(2,8-bis(trifluoromet yl)quinolin-4-yl)-2- (hydroxyethy l)piperazin-1 -yl)butanoate (1 b)

Using method D, the crude was purified by column chromatography (DCM/MeOH 90: 10), to afford 1b (29 mg, 35%, 89% ee) as a yellow oil. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA 90:10:0.1 ; flow 1 mL/min, R) = 9.0 min, tr(S) = 20.6 min); [a] _D ²⁴ -70.7 (c 0.25, DCM); R _f 0.43 (DCM/MeOH 90:10); ¹ H NMR (300 MHz, CDCI ₃ ) δ 1.26 (t, J = 7.1 Hz, 3H), 1.88-1.78 (m, 2H), 2.85-2.26 (m, 14H), 4.13 (q, J = 7.2 Hz, 2H), 5.54 (dd, J = 10.5, 3.2 Hz, 1 H), 7.72 (t, J = 7.1 Hz, 1 H), 8.12-8.14 (m, 2H); ¹³ C NMR (150 MHz, CDCI ₃ ) δ 14.2, 22.1 , 32.2, 53.0, 57.5, 60.3, 64.5, 65.1 , 1 14.5 (q, J = 1.8 Hz), 121.2 (q, J = 275.6 Hz), 123.5 (q, J = 273.9), 126.6, 126.J, 127.0, 128.7 (q, J = 5.2 Hz), 129.6 (q, J = 29.8Hz), 143.6, 148.7 (q, J = 34.9 Hz), 151.1 , 173.5; IR u _max = 2941 , 2818, 1731 , 1604, 1585, 1430, 1308, 1 140, 1108, 907 cm ^'1 ; HRMS calcd for C23H28F6 3O3 (M+H) ⁺ 508.2035, found 508.2056. (S)-ethyl-4-(4-(2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2- oate (1g)

Using method D, the crude was purified by column chromatography (DCM/MeOH 90:10), to afford 1g (31 mg, 38%, 97% ee) as a yellow oil. HPLC analysis (Chiralpak IB column, heptane/ /-PrOH/EDA 90:10:0.1 ; flow 1 mL/min, tr{R) =9.1 min, tr(S) = 20.1 min); [a] _D ²³ +78.2 (c 0.25, DCM); R _f 0.43 (DCM/MeOH 90:10); ¹ H NMR (300 MHz, CDCI ₃ ) δ 1.26 (t, J = 7.1 Hz, 3H), 1.88-1.78 (m, 2H), 2.85-2.26 (m, 14H), 4.13 (q, J = 7.2 Hz, 2H), 5.54 (dd, J = 10.5, 3.2 Hz, 1 H), 7.72 (t, J = 7.1 Hz, 1 H), 8.12-8.14 (m, 2H); ³ C NMR (150 MHz, CDCI ₃ ) δ 14.2, 22.1 , 32.2, 53.0, 57.5, 60.3, 64.5, 65.1, 114.5 (q, J= 1.8 Hz), 121.2 (q, J = 275.6 Hz), 123.5 (q, J = 273.9), 126.6, 126.J, 127.0, 128.7 (q, J = 5.2 Hz), 129.6 (q, J = 29.8Hz), 143.6, 148.7 (q, J = 34.9 Hz), 151.1, 173.5; IR u _max = 2941, 2818, 1731, 1604, 1585, 1430, 1308, 1140, 1108, 907 cm ^-1 ; HRMS calcd for C23H28F6N3O3 (M+H) ⁺ 508.2035, found 508.2056.

(R-1 -(2,8-bis(trifiuoromethyl)quinolin-4-yl)-2-(pentylamino)etha nol (1 c)

Using method D, the crude was purified by column chromatography (DCM/MeOH 90:10), to afford 1c (56 mg, 88%, 94% ee) as a white solid. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA, 99:1:0.1; flow 1 mL/min, t^R) = 21.5 min, t^S) = 25.3 min); [a] _D ²⁶ -50.3 (c 0.25, MeOH); R _f 0.53 (DCM/MeOH 90:10); mp: 120 °C; ¹ H NMR (300 MHz, MeOD) δ 0.92 (t, J = 6.5 Hz, 3H), 1.36- 1.21(m, 4H), 1.65-1.47 (m, 2H), 2.72-2.64 (m, 2H), 2.83 (dd, J = 12.30, 9.32 Hz, 1H), 2.99 (dd, J = 12.63, 2.20 Hz, 1H), 5.68 (dd, J = 9.0, 2.0 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1Hz), 8.15 (s, 1H), 8.26 (d, J = 7.0 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H); ¹³ C NMR (150 MHz, MeOD) δ 14.4, 23.6, 30.2, 30.6, 50.5, 57.2, 69.4, 115.7 (q, J = 1.96 Hz), 122.9 (q, J = 274.6 Hz), 125.1 (q, J = 272.6 Hz),128.0, 128.8, 129.1, 130.3 (q, J = 60.1 Hz), 130.3 (q, J= 5.7 Hz), 144.9, 149.4 (q, J= 34.8 Hz), 154.7; IR u _m ax= 2934, 2841, 2357, 1604, 1586, 1432, 1303, 1119, 1104, 889, 835 cm ^'1 ; HRMS calcd for C _ia H ₂ iF ₆ N ₂ O (M+H) ⁺ 395.1558, found 395.1544.

( -1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(pentylamino)et hanol (1h)

1h Using method D, the crude was purified by column chromatography (DCM/MeOH 90:10), to afford 1h (56 mg, 93%, 99% ee) as a white solid. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA, 99:1 :0.1 ; flow 1 mL/min, t^R) = 22.2 min, f,(S) = 25.3 min); [a] _D ²⁶ +49.8 (c 0.25, MeOH); R, 0.53 (DCM/MeOH 90:10); mp: 120 °C; ¹ H NMR (300 MHz, MeOD) δ 0.92 (t, J = 6.5 Hz, 3H), 1.36- 1.21(m, 4H), 1.65-1.47 (m, 2H), 2.72-2.64 (m, 2H), 2.83 (dd, J = 12.30, 9.32 Hz, 1 H), 2.99 (dd, J = 12.63, 2.20 Hz, 1H), 5.68 (dd, J = 9.0, 2.0 Hz, 1 H), 7.87 (t, J = 7.9 Hz, 1 Hz), 8.15 (s, 1H), 8.26 (d, J = 7.0 Hz, 1 H), 8.53 (d, J = 8.6 Hz, 1 H); ³ C NMR (150 MHz, MeOD) δ 14.4, 23.6, 30.2, 30.6, 50.5, 57.2, 69.4, 115.7 (q, J = 1.96 Hz), 122.9 (q, J = 274.6 Hz), 125.1 (q, J = 272.6 Hz),128.0, 128.8, 129.1 , 130.3 (q, J = 60.1 Hz), 130.3 (q, J = 5.7 Hz), 144.9, 149.4 (q, J = 34.8 Hz), 154.7; IR u _max = 2934, 2841 , 2357, 1604, 1586, 1432, 1303, 1119, 1104, 889, 835 cm ^"1 ; HRMS calcd for C ₁₈ H ₂ iF ₆ N ₂ O (M+H) ⁺ 395.1558, found 395.1544. ( -1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(hexylamino)eth anol (1d)

Using the method D the crude was purified by column chromatography (DCM/MeOH, 90:10), to afford 1d (58 mg, 88%, 97% ee) as a white solide. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA, 99:1 :0.1 ; flow 1 mL/min, tr(R) = 18.5 min, t,{S) = 21.4 min); [a] _D ²⁶ -47.5 (c 0.25, MeOH); R _f 0.58 (DCM/MeOH 90:10); mp: 108 °C; H NMR (600 MHz, MeOD) δ 0.91 (t, J = 6.9 Hz, 3H), 1.43-1.42 (m, 6H), 1.62-1.49 (m, 2H), 2.76-2.59 (m, 2H), 2.82 (dd, J = 12.6, 9.1 Hz, 1 H), 2.99 (dd, J = 12.6, 2.9 Hz, 1 H), 5.68 (dd, J = 9.0, 2.5 Hz, 1H), 7.88 (t, J = 7.2 Hz, 1 H), 8.15 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.53 (d, J = 8.6 Hz); ¹³ C NMR (150 MHz, MeOD) δ 14.4, 23.7, 28.1 , 30.5, 32.9, 50.5, 57.3, 69.4, 115.7 TqTJ ^" = 2.3 Hz), 122.9 (q, J = 274.4 Hz), 125.2 (q, J = 272.8 Hz), 128.0, 128.8, 129.1, 130.3 (q, J = 5.4 Hz), 130.3 (q, J = 30.3 Hz), 144.9, 149.4 (q, J = 35.8 Hz), 154.8; IR u _max = 2928, 2858, 1603, 1586, 1432, 1304, 1 1 19, 1 103, 886, 837 cm HRMS calcd for C19H22F6N2O (M+H) ⁺ 409.1726, found 409. 732.

(S)-1 -(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(hexylamino)ethan ol (1 i)

Using the method D, the crude was purified by column chromatography (DCM/MeOH, 90:10), to afford 1f (56mg, 85%, 97% ee) as a white solide. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA, 99: 1 :0.1 ; flow 1 mL/min, UR) = 19.1 min, t^S) = 21.4 min); [a] _D ²⁷ +54.0 (c 0.25, MeOH); R _f 0.58 (DCM/MeOH 90:10); mp: 108 °C; ¹ H NMR (600 MHz, MeOD) δ 0.91 (t, J = 6.9 Hz, 3H), 1.43-1 .42 (m, 6H), 1.62-1.49 (m, 2H), 2.76-2.59 (m, 2H), 2.82 (dd, J = 12.6, 9.1 Hz, 1 H), 2.99 (dd, J - 12.6, 2.9 Hz, 1 H), 5.68 (dd, J = 9.0, 2.5 Hz, 1 H), 7.88 (t, J = 7.2 Hz, 1 H), 8.15 (s, 1 H), 8.26 (d, J = 8.6 Hz, 1 H), 8.53 (d, J = 8.6 Hz); ¹³ C NMR (150 MHz, MeOD) δ 14.4, 23.7, 28.1 , 30.5, 32.9, 50.5, 57.3, 69.4, 115.7 (q, J = 2.3 Hz), 122.9 (q, J = 274.4 Hz), 125.2 (q, J = 272.8 Hz), 128.0, 128.8, 129.1 , 130.3 (q, J = 5.4 Hz), 130.3 (q, J = 30.3 Hz), 144.9, 149.4 (q, J = 35.8 Hz), 154.8; IR u _max = 2928, 2858, 1603, 1586, 1432, 1304, 1 19, 1 103, 886, 837 cm ^"1 ; HRMS calcd for Ci ₉ H ₂ 2F6N ₂ O (M+H) ⁺ 409.1726, found 409.1732.

( ?)-1- 2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(heptylamino)ethano l (1t)

Using the method D, the crude was purified by column chromatography (DCM/MeOH, 90:10), to afford 1t (1 10 mg, 79% 90%ee) as a white solide. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA, 99:1 :0.1 ; flow 1 mL/min, t^R) = 17.2min, t^S) = 19.6 min); [a] _D ²³ -83 (c 0.25, MeOH); H NMR (600 MHz, MeOD) δ 0,89 (t, sJ2i/20 = 7,1 Hz, 3H, H21) ; 1 ,38-1 ,24 (m, 8H, H17,18,19,20,) ; 1 ,59-1 ,51 (m, 2H, Hie) ; 2,75-2,62 (m, 2H, H15) ; 2,83 (dd, 2Jua/i4b = 12,6 Hz, 3Ji4a i3 = 9,1 Hz, 1 H, Hi4a) ; 3,00 (dd, 2Ji4b/i4a = 12,7 Hz, 3Ji4b/i3 = 3,0 Hz, 1 H, Hub) ; 5,69 (dd, 3 i3/i4a = 9,1 Hz, 3Ji3/i4b = 2,7 Hz, 1 H, H13) ; 7,87 (t, 3j7/e,e = 7,9 Hz, 1 Hz, H7) ; 8,15 (s, 1 H, H3) ; 8,25 (d, ₃ Js/7 = 7,2 Hz, 1 H, He) ; 8,53 (d, sJe/7 = 8,3 Hz, 1 H, He); ³ C NMR(150 MHz, MeOD) δ 14,4 (C21) ; 23,6 (C20) ; 28,3 (C17) ; 30,3 (C16.18) ; 32,9 (C19) ; 50,4 (C15) ; 57,1 (C14) ; 69,2 (C13) ; 115,6 (q, 3J = 1 ,4 Hz, C3) ; 122,8 (q, 1J = 274,3 Hz, C12) ; 125,1 (q, 1 J = 272,9 Hz, C11) ; 128,0 (C5) ; 128,7 (C7) ; 129,1 (C6) ; 130,2 (q, 2J = 29,8 Hz, C9) ; 130,2 (q, 3J = 5,2 Hz, C8) ; 144,8 (C10) ; 149,3 (q, 2J = 34,9 Hz, C2) ; 154,6 (C4); IR umax 2927, 2853, 1604, 1586, 1303, 1119, 1103, 890, 836 cm-i HRMS calcd for C20H25F6N2O (M+H) ₊ 423,1881 , found 423,1871

(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(heptylam ino)ethanol (1u)

Using the method D, the crude was purified by column chromatography (DCM/MeOH, 90:10), to afford 1u (100 mg, 0,32 mmol, 1 eq.) as a white solide. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA, 99:1 :0.1 ; flow 1 mL/min, tr(R) = 19.5min, f^S) = 17.3 min); [a] _D ²³ +83 (c 0.25, MeOH); ¹ H and ¹³ C NMR, IR and HRMS same as 1t. R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(octylamino)e thanol (1v)

1v Using the method D, the crude was purified by column chromatography (DCM/MeOH, 90: 10), to afford 1v (108 mg, 75%, 94%ee) as a white solide. HPLC analysis (Chiralpak IB column, heptane/ -PrOH/EDA, 99:1 :0.1 ; flow 1 mL/min, tr{R) = 16.7min, i^S) = 19.1 min); [a] _D ²³ -77 (c 0.25, MeOH); ¹ H NMR (600 MHz, MeOD) δ 0,89 (t, 3 22/21 = 7,1 Hz, 3H, H22) ; 1 ,38-1 ,23 (m, 10H, Hi7,i3,i9,2o,2i) ; 1 ,58- 1 ,51 (m, 2H, Hie) ; 2,74-2,63 (m, 2H, H15) ; 2,82 (dd, 2Jua/i4b = 12,6 Hz, sJi4a/i3 = 9,1 Hz, 1 H, Hi4a) ; 2,99 (dd, 2Ji4b i a = 12,6 Hz, 3Ji4b/i3 = 3,0 Hz, 1 H, Hu-c/s) ; 5,68 (dd, 3 is/i4a = 9,0 Hz, sJi3/i4 = 2,7 Hz, 1 H, His) ; 7,87 (t, 3J7/6,s = 8,0 Hz, 1 Hz, H?) ; 8,15 (s, 1 H, H3) ; 8,25 (d, zJm = 7,2 Hz, 1 H, Hs) ; 8,53 (d, 3J6/7 = 8,4 Hz, 1 H, He).; ¹³ C NMR(150 MHz, MeOD) δ 13,0 (C22) ; 22,3 (Cai) ; 26,9 (C17) ; 29,0 (Cis,i9) ; 29,1 (C16) ; 31 ,6 (C20) ; 49,0 (C15) ; 55,8 (Cu) ; 67,9 (C13) ; 1 14,2 (q, 3J = 1 ,4 Hz, C3) ; 121 ,4 (q, 1 J = 274,6 Hz, C12) ; 123,7 (q, 1 J = 272,8 Hz, C11) ; 126,6 (Cs) ; 127,3 (C7) ;

127.8 (C6) ; 128,8 (q, 2J = 30,0 Hz, C9) ; 128,8 (q, zJ = 5,1 Hz, Cs) ; 143,4 (C10) ;

147.9 (q, 2J = 35,1 Hz, C2) ; 153,3 (C ₄ ).; IR u max 2924, 2853, 1604, 1468, 1306, 1 119, 1 101 , 892, 836 cm-i HRMS clcd for C21H26F6N2O (M+H) ₊ 437,20 , found

437,2028 -(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(octylamino)ethan ol (1w)

1w

Using the method D, the crude was purified by column chromatography (DCM/MeOH, 90:10), to afford 1w (108 mg, 75%, 94%ee) as a white solide. HPLC analysis (Chiralpak IB column, heptane//-PrOH/EDA, 99: 1 :0.1 ; flow 1 mL/min, UR) = 17.0min, US) = 19.1 min); [a] _D ²³ +77 (c 0.25, MeOH); ¹ H and ¹³ C NMR, IR and HRMS same as 1 w. («).ferf-butyl-(3-(4-(3((2-(2,8-bis(trifluoromethyl)quinoli n-4-yl)-2- (hydroxyethyl)amino)propyl)piperazin-1 -yl)propyl)carbamate (1 e)

Using the method D, the crude was purified by column chromatography (EtOAc/MeOH/N H ₄ OH , 80:10:10), to afford 1e (88mg, 90%, 93% ee) as a colorless oil. HPLC analysis (Chiralpak IB column, MfBE/EDA 100:0.3; flow 1 mL/min, R) = 6.2 min, US) = 7.2 min); [a] _D ²⁴ -49.6 (c 0.25, DCM); R _f 0.29 (EtOAc/MeO H/N H ₄ 0 H 80:10:10); ¹ H NMR (300 MHz, MeOD) δ 1.38 (s, 9H), 1.64-1.59 (m, 2H), 1.67 (dt, J = 13.40, 6.76 Hz, 2H), 2.51-2.24 (m, 12H), 2.85- 2.57 (m, 2H), 2.72 (dd, J = 12.41 , 9.1 1 Hz, 1 H), 3.05 (dd, J = 12.51 , 2.77 Hz, 1 H), 3.1 1 (m, 1 H), 5.52 (dd, J = 8.4, 2.1 Hz, 1 H), 7.67 (t, J = 7.9 Hz, 1 H), 8.1 1-8.09 (m, 2H), 8.23 (d, J = 8.5 Hz, 1 H); ¹³ C NMR (150 MHz, MeOD) δ 26.2, 26.5, 28.3, 39.8, 48.0, 52.8, 53.2, 55.8, 56.5, 56.6, 67.7, 78.8, 114.5 (q, J = 1 .6 Hz), 121.2 (q, J = 275.6 Hz), 123.4 (q, J = 273.8 Hz), 126.5, 126.9, 127.0, 128.6 (q, J = 5.6 Hz), 129.3 (q, J = 29.9 Hz), 143.5, 148.4 (q, J = 35.5 Hz), 152.0, 156.1 ; IR u _max = 2940, 1433, 1307, 1 132, 1 104, 885, 838 cm ^"1 ; HRMS calcd for C28H40F6N5O3 (M+H) ⁺ 608.3035, found 608.3035.

(S)-feri-butyl-(3-(4-(3((2-(2,8-bis(trifluoromethyl)quino lin-4-yl)-2- (hydroxyethyl)amino)propyl)piperazin-1-yl)propyl)carbamate (1j)

Using the method D, the crude was purified by column chromatography

(EtOAc/MeOH/NH ₄ OH, 80:10:10), to afford 1j (96mg, 98%, 92% ee) as a colorless oil. HPLC analysis (Chiralpak IB column, MfBE/EDA 100:0.3; flow 1 mL/min, t^R) = 6.2 min, r^S) = 7.2 min); [a] _D ²⁴ +50.6 (c 0.25, DCM); R _f 0.29 (EtOAc/MeOH/NH ₄ OH 80:10:10); ¹ H NMR (300 MHz, MeOD) δ 1.38 (s, 9H), 1 .64-1 .59 (m, 2H), 1.67 (dt, J = 13.40, 6.76 Hz, 2H), 2.51-2.24 (m, 12H), 2.85- 2.57 (m, 2H), 2.72 (dd, J = 12.41 , 9.11 Hz, 1 H), 3.05 (dd, J = 12.51 , 2.77 Hz, 1 H), 3.1 1 (m, 1 H), 5.52 (dd, J = 8.4, 2.1 Hz, 1 H), 7.67 (t, J - 7.9 Hz, 1 H), 8.1 1 -8.09 (m, 2H), 8.23 (d, J = 8.5 Hz, 1 H); ¹³ C NMR (150 MHz, MeOD) δ 26.2, 26.5, 28.3, 39.8, 48.0, 52.8, 53.2, 55.8, 56.5, 56.6, 67.7, 78.8, 114.5 (q, J = 1.6 Hz), 121.2 (q, J = 275.6 Hz), 123.4 (q, J = 273.8 Hz), 126.5, 126.9, 127.0, 128.6 (q, J = 5.6 Hz), 129.3 (q, J = 29.9 Hz), 143.5, 148.4 (q, J = 35.5 Hz), 152.0, 156.1 ; IR u _max = 2940, 1433, 1307, 1 132, 1 104, 885, 838 cm ^"1 ; HRMS calcd for C28H ₄ oF ₆ N ₅ O ₃ (M+H) ⁺ 608.3035, found 608.3035.

-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(piperazin-1 -yl)ethanol (1 k)

Using the method D, the crude was purified by column chromatography

(EtOAc/MeOH/NH4OH, 80:10:10), to afford 1 k (76 %) as a white solid. HPLC analysis (Chiralpak IB column, MtBE/EDA 100:0.3; flow 1 mL/min, tr(R) = 6.2 min, tr(S) = 7.2 min); [a]D20 -49 (c 0.25, MeOH); Rf 0.28 (EtOAc/MeOH/NH4OH 80:10:10); 1 H NMR (300 MHz, MeOD) δ 2.72-2.54 (m, 6H), 2.94-2.78 (m, 4H), 5.74 (dd, J = 7.0, 4.8 Hz, 1 H), 7.83 (t, J = 8.0, Hz, 1 H), 8.16 (s, 1 H), 8.20 (d, J = 7.2 Hz, 1 H), 8.49 (d, J = 8.3 Hz, 1 H). 13C NMR (75 MHz, MeOD) δ 46.3, 55.2, 66.9, 68.1 , 1 15.8 (q, J = 1.9 Hz), 122.8 (q, J = 274.8 Hz), 125.1 (d, J = 272.9 Hz), 128.1 , 128.5, 129.4, 130.2 (q, J = 5.5 Hz), 130.2 (q, J = 17.5 Hz), 144.7, 149.3 (q, J = 34.8 Hz), 155.1 ; IR umax= 1607, 1429, 1309, 1 195, 1091 , 1029, 849; HRMS calcd for C17H18F6N3O (M+H)+, 394.1339 found 394.1354

(S)-1 -(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(piperazin-1 -yl)ethanol (11)

Using the method E, the crude was purified by column chromatography (EtOAc/MeOH/NH ₄ OH, 80:10:10), to afford 1e (quant.) as a white solid. HPLC analysis (Chiralpak IB column, MfBE/EDA 100:0.3; flow 1 mL/min, tr(R) = 6.2 min, US) = 7.2 min); [a] _D ²⁰ +48 (c 0.25, MeOH). ¹ H and ¹³ C NMR, IR and HRMS same as 1k.

(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-fluor ophenyl)amino)ethanol

Using method D,the crude was purified by column chromatography (cyclohexane/ether, 40:60), to afford 1e (67%, 90 %ee) as a yellow oil. HPLC analysis (Chiralpak IB column, heptane/-PrOH 95:5; flow 1 mL/min, tr(R) = 23.3 min, tr{S) = 25.9 min); [ ] _D ²⁰ +16 (c 0.25, MeOH); R _f 0.38 (cyclohexane/ether, 40:60); ¹ H NMR (300 MHz, MeOD) δ 3.42 (dd, J = 13.6, 7.0 Hz, 1 H), 3.52 (dd, J = 13.6, 4,8 Hz, 1 H), 5.71 (dd, J = 6.8, 4.9 Hz, 1 H), 6.61-6.53 (m, 2H), 6.86-6.74 (m, 2H), 7.70 (t, J = 8.0 Hz, 1 H), 8.15 (s, 1H), 8.22 (d, J = 7.0 Hz,1 H), 8.47 (d, J = 8.6 Hz, 1 H). ¹³ C NMR (75 MHz, MeOD) δ 52.8, 69.4, 115.2 (d, J = 7.5 Hz), 116.1 (q, J = 2.0 Hz), 116.3 (d, J = 22.5 Hz), 122.9 (d, J = 274.7 Hz), 125.1 (d, J = 272.9 Hz), 128.4, 129.4, 130.1 (q, J = 5.5 Hz), 130.1 (q, J = 30.0 Hz), 144.8, 146.0, 149.3 (q, J = 34.7 Hz), 15 1604, 1509, 1310, 1214, 1099, 822; HRMS calcd for 1.0806 found 441.0814 (R)-1-(2 -bis(trifluoromethyl)quinolin-4-yl)-2-((4-fluorophenyl)amino )ethanol

Using method D, the crude was purified by column chromatography (cyclohexane/ether, 40:60), to afford 1e (72 %, 90 %ee) as yellow oil. HPLC analysis (Chiralpak IB column, heptane//-PrOH 95:5; flow 1 mL/min, t^R) = 22.0 min, S) = 25.4 min); [a] _D ²⁰ -24 (c 0.25, MeOH); ¹ H and ¹³ C NMR, IR and HRMS same as 1 m.

( )-3-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyeth yl)amino)phenol

Using method D, the crude was purified by column chromatography (DCM/MeOH, 95:5), to afford 1e (29 %, 91 %ee) as a yellow oil. HPLC analysis (Chiralpak IB column, heptane//-PrOH 86:15; flow 1 mL/min, tr(R) = 21.1 min, f^S) = 24.8 min);

[ ] _D ²¹ +4 (c 0.25, MeOH); R _f 0.24 (DCM/MeOH, 95:5); ¹ H NMR (300 MHz, MeOD) δ 3.46 (dd, J = 13.7, 7.0 Hz, 1 H), 3.54 (dd, J = 13.7, 5.1 Hz, 1 H), 5.74 (dd, J = 6.7, 5.3 Hz, 1 H), 6.20-6.12 (m, 3H), 6.97-6.89 (m, 1 H), 7.80 (t, J = 7.9 Hz, 1 H), 8.18 (s, 1 H), 8.25 (d, J = 7.2 Hz,1 H), 8.48 (d, J = 8.6 Hz, 1 H). ¹³ C NMR (75 MHz, MeOD) δ 52.8, 69.2, 101 .2, 105.8, 106.3, 1 16.0 (q, J = 2.6 Hz), 128.4, 129.6, 130.2 (q, J = 5.6 Hz), 131 .0. HRMS calcd for Ci ₉ Hi4F ₆ N2O ₂ Na (M+Na) ⁺ , 439.0857 found 439.0857 (R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((2-fluoroph enyl)amino)ethanol

Using method D, the crude was purified by column chromatography (cyclohexane/ether 40:60), to afford 1e (39 %, 48 %ee) as yellow oil. HPLC analysis (Chiralpak IB column, heptane//-PrOH 95:5; flow 1 mL/min, t^R) = 23.5 min, tr(S) = 26.5 min); [a] _D ²¹ -19 (c 0.17, MeOH); R _f 0.46 (cyclohexane/ether 40:60); ¹ H NMR (300 MHz, MeOD) δ 3.52 (dd, J = 13.7, 6.9 Hz, 1 H), 3.63 (dd, J = 13.7, 4.8 Hz, 1 H), 5.75 (dd, J = 6.7, 4.8 Hz, 1 H), 6.60-6.51 (m, 1 H), 6.69-6.61 (m, 1 H), 6.93-6.80 (m, 2H), 7.80 (t, J = 7.9 Hz, 1 H), 8.15 (s, 1 H), 8.23 (d, J = 7.1 Hz, 1 H), 8.52 (d, J = 8.5 Hz, 1 H). ¹³ C NMR (75 MHz, MeOD) δ 51.6, 69.5, 1 13.8 (d, J = 3.1 Hz), 1 15.4 (d, J = 19.0 Hz), 1 16.1 (q, J = 2.2 Hz), 1 18.1 (d, J = 7.2 Hz), 125.6 (d, J = 3.4 Hz), 128.5, 129.4, 130.2 (q, J = 5.3 Hz); IR u _max = 1064, 1506, 1311 , 1097, 998, 884; HRMS calcd for 441.0814 found 441 .0814

(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((2-fluoroph enyl)amino)ethanol

Using the method D, the crude was purified by column chromatography (cyclohexane/ether 40:60), to afford 1e (29 %, 80 %ee) as a yellow oil. HPLC analysis (Chiralpak IB column, heptane//-PrOH 95:5; flow 1 mL/min, i^R) = 24.0 min, triS) = 25.5 min); ¹ H and ¹³ C NMR, IR and HRMS same as 1 p. (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(4-(naphthal en-1- ylmethyl)piperazin-1 -y l)ethanol (1 s)

^CF 3

Using the method E, the crude was purified by column chromatography (cyclohexane/EtOAc 40:60), to afford 1e (90 %, 86 %ee) as a colorless oil. HPLC analysis (Chiralpak IB column, heptane/ -PrOH 90:10; flow 1 mL/min, t^R) = 10.5 min, tr(S) = 1 1 .8 min); [a] _D ²⁰ +36 (c 0.25, MeOH); R _f 0.70 (DCM/MeOH 95:5); ¹ H NMR (300 MHz, CDCI ₃ ) δ 2.95-2.39 (m, 10H), 3.96 (s, 2H), 5.53 (dd, J = 10.4,

3.0 Hz, 1 H), 7.59-4.40 (m, 4H), 7.66 (t, J = 7.9 Hz, 1 H), 7.80 (dd, J = 6.8, 2.5 Hz, 1 H), 7.87 (dd, J = 7.1 , 2.3 Hz, 1 H), 8.13 (d, J = 8.0, 2H), 8.23 (s, 1 H), 8.19 (d, J =

7.2 Hz,1 H), 8.33 (d, J = 7.7 Hz, 1 H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 53.0, 60.9, 64.4, 65.0, 114.4 (d, J = 4.1 Hz), 121.3 (d, J = 275.6 Hz), 123.5 (q, J = 273.5 Hz), 124.6, 125.0, 125.5, 125.6, 126.4, 126.7, 126.9, 127.3, 128.0, 128.3, 128.6 (q, J =

5.1 Hz), 128.9, 129.3 (q, J = 30.2 Hz), 132.4, 133.6, 133.8, 143.5, 148.5 (q, J = 35.0 Hz), 151.3; IR u _max = 2817, 1602, 1512, 1430, 1307, 1 133, 1105, 1005, 904,

826; HRMS calcd for Cas^eFeNsO (M+H) ⁺ , 534.1980 found 534.2006.

Example 4 Biological tests

4-1. Plasmodium falciparum susceptibility assays

4-1-1. Method

The in vitro activities of the compounds according to the present invention were tested over a concentration range of 0.78 to 400 nM against P. falciparum strains W2 and 3D7. These strains are resistant or susceptible to chloroquine respectively. Additionally, W2 is sensitive while 3D7 displays a decreased susceptibility to mefloquine. The traditional labeled hypoxanthine method was used to assess antimalarial activity, as described by Desjardins et al. [29 ]. Chloroquine and mefloquine were routinely included as positive controls as well as negative controls using solvent. The resulting IC ₅ oS were calculated using Pk-6 - Fit software [30]. Growth inhibition (I) and corresponding drug concentrations (C) were fitted according to a sigmoid model, described as:

I = (lmax.C)/(C ^> + ICso')

where Imax is the maximum growth inhibition and gamma the sigmoid factor of the curve.

Alternatively, IC ₅ oS were also determined on P. falciparum 3D7 strain over a concentration range of 0 to 580 nM using SYBR Green labeling [31 , 32] Bennet et al., 2004 ; Bacon et al., 2007]. IC ₅ os were subsequently derived using ICEstimator 1.2 (available at: http://www.antimalarial-icestimator.net/). For both techniques, chloroquine and mefloquine were routinely included as positive controls as well as negative controls using solvent.

4-1 -2. Results

IC50S for the various products are reported in Table 4. Enantiomers with a (S)-absolute configuration were found to be more active than their (R)- counterparts by a factor ranging from 2 to15-fold, according to the compound and the strain considered (Table 4). Compound (S)-1 -(2,8-bis(trifluoromethyl)quinolin- 4-yl)-2-(pentylamino)ethanol 1h was the most active of all, whatever the strain tested, followed by (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2- (hexylamino)ethanol 1i. Compounds (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2- (heptylamino)ethanol 1 u and (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2- (octylamino)ethanol 1w displayed similar ICsos, around 30 nmol/L. All (S)- enantiomers displayed lower ICsos than the racemic mixture of mefloquine, whatever the strain.

C Como _p u _r om _p a _re

h _t E _{I t} oemxa _p

Table 4. In vitro antimalarial activity of 4-aminoalcohol quinolone enantiomers.

Compounds IC ₅₀ (3D7) ^{a b} IC ₅₀ (3D7) ^b

Φ Chloroquine 12-36 nM 345-625 nM

> (Λ

■E Φ Mefloquine 52. 2nM 26.5 nM

Racemic compound 54.3nM N.D.

of 1c and 1h

Racemic compound 30.91 nM N.D.

of 1d and 1 i

1a 104.5nM 41 .1 nM

1f 35.1 nM 19.1 nM c

Ό ,- 1c 74.7 nM 38.2 nM t. c

o o 1h 8.33 nM 6.98 nM

O C CO Φ 1 d 205.0 nM 142 nM

CO g 1 i 14.5 nM 9.40 nM

1t 254.0 nM N.D.

1u 33.0 nM N.D.

1 v 290.0 nM N.D.

1w 31.1 nM N.D.

1s 165.9nM ^a N.D.

N.D.: Not determined

a: as determined by the SYBR Green method

b: as determined by the labeled hypoxanthine method

4-2. Antibacterial test

4-2-2. Method

The minimum inhibitory concentrations (MICs) were determined according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI) [28]. The different strains were seeded in 96-well plates at a rate of 10 ⁵ -10 ⁶ colonies forming units per ml per well in Mueller-Hinton adjusted for cations (Ca ²⁺ 25 mg / L and Mg ²⁺ 12.5 mg / L). The different molecules to be tested were diluted to half in series to obtain final concentrations in wells ranging from 0.0625pg / mL to 128 g/ mL. After incubation for 8 to 24 h (48 h for Enterococcus faecalis) at 37°C, the MIC was determined as the product concentration of the first well with no visual signs of bacterial growth (no disorder in the well). The results are shown in table 5, according to which excellent antibacterial properties can be observed in the compounds according to the present invention.

4-2-2. Results

The results obtained during these tests show that nearly all antibacterial compounds have activity equivalent or superior to mefloquine in relation to the gram-positive bacteria.

In contrast, the compounds have no activity against P. aeruginosa which are Gram-negative, these results are not surprising because in the literature, it is indicated that mefloquine and its analogues have no activity against such bacteria.

But more surprising, some of the compounds show activity against bacteria E. coli also gram-negative. Unlike malaria control activities, there is little difference between the antibacterial activity of enantiomers R- and S-. The R- enantiomers are slightly more active for certain compounds except in the case of compounds 1d, 1i and 1a, 1f where the compound R- shows much greater activity.

The minimum inhibitory concentration of compound 1d is 16 μg/mL of E. coli while the MIC of its enantiomer 1 i is greater than 128 μg/mL. The same difference is observed in the case of molecules 1a and 1f but this time in gram- positive bacteria, the compound 1a in the configuration R- has a MIC of 4 or 8 μg/mL depending on the strain while the S-enantiomer has MIC of greater than 128 g/mL With the exception of the compound 1f, all S- conformation molecules are bactericidal. These molecules may be used as antibiotics.

Table5. The antibacterial effects of the compounds

SAAM = Staphylococcus aureus Amiens (clinical strains resistant to methiciliin) a: Collection de I'institut Pasteur

: Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

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