NEW AZAIN DOLDER Derivatives as Antiviral Agents

Description

FIELD OF THE INVENTION

[0001] The present invention relates to compounds derived from 7-azaindole useful as AXL kinase inhibitors for the treatment of infections. Their preparation process is also described. TECHNOLOGICAL BACKGROUND

[0002] AXL is a Receptor Tyrosine Kinase (RTK) belonging to the TAM family composed of TYRO-3, AXL and MER. Initially discovered and demonstrated in patients with chronic myeloid leukemia (CML), the involvement of the AXL receptor in viral infections such as dengue, Zika virus, Chikungunya or Ebola fever has been described in the literature (Chen, J. et al. Nature Microbiology, 2018, 3, pp.302-309; Fedeli, C. et al. Journal of Virology, 2018, 92:e01613-17; Hastings, AK et al., iScience, 2019, 13 pp.339-350; Meertens, L. et al., Cell Reports, 2017, 18, 3, pp.324-333). This receptor, by interacting via the Gas6 adaptor with the phosphatidylserines present in viral envelopes, promotes the attachment of enveloped viruses to their cellular target. AXL thus stimulates viral endocytosis.AXL engagement during this interaction stimulates phosphorylation of the intracytoplasmic domain of AXL and activates associated signaling pathways. These signals neutralize interferon production and associated antiviral responses, promoting the escape of these viruses from host immune control.

[0003] To date, several kinase inhibitors active against AXL exist (Myers et al., J. Med. Chem. (2015), 59(8): 3593-3608), but none are truly selective or specific for this kinase. In the vast majority of cases, activity against AXL is secondary to the primary activity sought against MET or MER due to the sequence similarity between these RTKs. This is notably the case for Bosutinib or Cabozantinib, which are multi-target kinase inhibitors or MTKIs ( MultiTargeted Kinase Inhibitors) already on the market, or for BMS777607 (currently in clinical phase 2). This is also the case for the 7-azaindole derivative NPS-1034, which has a relatively broad inhibition profile, inhibiting a wide panel of kinases such as AXL / DDR1 / FLT3 / KIT / MEK / MET / ROS1 and TIE1. Bosutinib

[0004] Cabozantinib

[0005] BMS-777607

[0006] NPS-1034

[0007] Another AXL kinase inhibitor is Bemcentinib (also known as R428 or BGB324), currently in clinical trials. This compound, which is structurally very different from currently available kinase inhibitors, has also been shown to be active against other kinases such as ABL / KIT / JAK2-3 / LCK / PDGFRB / TIE2. R428 / BGB324

[0008] US 2003 / 207910 describes 6-aza-indoles as antiviral compounds. KR 2012 0061011 describes 7-aza-indoles as inhibitors of Phospho Inositide 3 Kinase.

[0009] There is therefore a need for new AXL inhibitory compounds that are more selective and effective against viral infections.

[0010] The present invention thus provides novel 7-azaindole derivatives that strongly inhibit AXL kinase, for use as antiviral agents.

[0011] Due to this very specific inhibition profile, unique to date for this type of structure, these compounds can be used in therapy in the treatment of infections caused by viruses using the AXL receptor to multiply. In order to combat viral infections, by inhibiting the phosphorylation of AXL, these compounds will act on the one hand by blocking the endocytosis of enveloped viruses in their cellular target, and on the other hand by neutralizing the intracellular signals controlled by AXL known to inhibit the production of interferons and antiviral responses of the host. The inhibitors of the present invention can thus be used for the treatment of diseases in which AXL is involved, in particular viral infections and in particular viral entry into cells. SUMMARY OF THE INVENTION

[0012] The present invention thus relates to a compound of formula (I): in which X represents a hydrogen atom or a halogen atom, Y is selected from a hydrogen atom, a group -CN, -CH 2 OH, -CH=NOH, -CO 2 H, an optionally mono- or polysubstituted aryl, an optionally mono- or polysubstituted heteroaryl, and -L-(CH 2 )pW, L represents -C(O)NH-, -CH 2 NH-, -NHC(O)-, -CH 2 N=CH-, -CH=N-, -NHC(O)NH- or - CH 2 NHC(O)-, p is an integer from 0 to 2, when L represents -CH 2 NH-, -NHC(O)-, -CH 2 N=CH-, -CH=N-, -NHC(O)NH- or - CH 2 NHC(O)-, W is selected from: a hydrogen atom, a C 1 -C 6 alkyl , preferably methyl, C 6 -C 10 aryl optionally mono- or polysubstituted, advantageously with 1 to 3 groups independently selected from halogen, hydroxyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl, and 5-10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl being optionally mono- or polysubstituted,advantageously it is optionally substituted by 1 to 4 groups independently chosen from: ∘ a halogen atom, ∘ a hydroxyl, ∘ an oxo group ∘ a C 1 -C 6 alkoxyl, ∘ a C 1 -C 6 alkyl, in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and ∘ a C 6 -C 10 aryl optionally substituted by a halogen atom and / or a C 1 -C 6 alkyl; when L represents -C(O)NH-, W is chosen from: an optionally mono- or polysubstituted phenyl, advantageously it is optionally substituted by a halogen atom, a hydroxyl group, a C 1 -C 6 alkyl, or a C 1 -C 6 alkoxyl group, and a 5-10 membered heteroaryl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 substituents independently chosen from: ∘ a halogen atom, ∘ a hydroxyl, ∘ an oxo group,∘ a C 1 -C 6 alkoxyl group, ∘ a C 1 -C 6 alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and ∘ a C 6 -C 10 aryl optionally substituted by a halogen atom and / or a C 1 -C 6 alkyl; Z represents -CH 2 Q or -O(CH 2 ) m T, Q represents -OH, -SO 2 R 1 , -NR 2 R 3 , or -R 4 R 4 represents C 1 -C 6 alkyl, R 2 and R 3 each independently represent C 1 -C 6 alkyl, and R 4 represents a 5-7 membered heterocycloalkyl, comprising from 1 to 2 heteroatoms independently selected from N, O and S, said heterocycloalkyl being optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C(O)-C 1 -C 6 alkyl and C(O)O-C ​​1 -C 6 alkyl, m is 1 or 2, T is -O(CH 2 ) n CH 3 or -R 5 n is 0 or 1 R 5 is a heterocycloalkyl of 5 to 7 groups comprising 1 to 2 heteroatoms independently chosen from N, O and S,said heterocycloalkyl being optionally substituted by 1 to 3 substituents independently chosen from a C1-C6 alkyl, a C1-C6 C(O)-alkyl and a C1-C6 C(O)O-alkyl; a pharmaceutically acceptable salt thereof or a mixture thereof, for its use in the prevention and / or treatment of viral infections.

[0013] The present invention also relates to a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient, for use in the prevention or treatment of viral infections. DETAILED DESCRIPTION

[0014] Generally, the following terms and definitions are used.

[0015] The term "peptide coupling" in the present invention refers to the reaction for forming an amide bond -NH-C(O)-. The techniques used in this reaction are common to peptide syntheses, i.e. they proceed by activating a carboxylic acid to react with an amine. The peptide coupling reactions used in the present invention are thus derived from peptide syntheses, and directly applicable to the subject matter of the present invention.

[0016] Peptide coupling reactions are well known to those skilled in the art, and may in particular be carried out using a coupling agent such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC), or N-hydroxy-5-norbornene-2,3-dicarodiimide), or a benzotriazole (such as O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(7-azabenzotriazol-1-yl)-1,2,3-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU), O-benzotriazol-1-yl-tetramethyl tetrafluoroborate (TBTU)), or an N-hydroxybenzotriazole (HOBT) / EDCI mixture, in a solvent such as chloroform, dichloromethane, dichloroethane, ethyl acetate, dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO),N-methyl pyrrolidinone (NMP), preferably at a temperature between 20°C and 150°C.,

[0017] Alternatively, peptide coupling takes place by first activating the carboxylic acid by transformation into the acyl chloride (especially in the presence of thionyl chloride or acetyl chloride) or a corresponding anhydride (e.g. in the presence of acetic or isopropyl anhydride), followed by reaction with the desired amine, preferably in the presence of a base to neutralize the acid released during the reaction (especially HCl in the case of an acyl chloride).

[0018] The term C(O) is equivalent to "C=O".

[0019] The term "alkyl" or "alkyl group" in the present invention means a linear or branched saturated aliphatic group containing 1 to 6 carbon atoms, if not explicitly stated. Examples of alkyl groups covered by the subject of the present invention are methyl, ethyl, propyl, butyl, tert-butyl, isopropyl groups.

[0020] In some embodiments, it is specified that one or more hydrogen atoms of the alkyl group are optionally replaced by a fluorine atom. In this case, preferably, 1 to 3 hydrogen atoms at most are involved. An example is the CH 2 CF 3 group.

[0021] The term "aryl group" or "aryl" in the present invention means an aromatic cyclic group (mono- or polycyclic) containing between 6 and 10 carbon atoms. Examples of aryl groups covered by the subject of the present invention are phenyl, naphthyl, preferably phenyl.

[0022] The term "heteroaryl group" or "heteroaryl" in the present invention means a 5- to 10-membered (mono- or polycyclic) aromatic ring group containing between 2 and 9 carbon atoms and between 1 and 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are furan, pyrrole, thiophene, thiazole, isothiazole, imidazole, oxazole, isoxazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, quinoline, indole, quinoxaline, benzofuran, dihydrobenzofuran, benzodioxole, benzotriazole, benzimidazole, preferably selected from pyrrole, imidazole, thiophene, pyridine, pyrimidine, benzofuran, benzodioxole, indole and benzimidazole.

[0023] The term "heterocycloalkyl" or "heterocycloalkyl group" in the present invention means a 5-7 membered aliphatic cyclic group, having one or more (preferably 1 to 2) heteroatoms independently selected from nitrogen, oxygen or sulfur, such as morpholine, piperidine, piperazine, pyrrolidine, homopiperazine (1,4-diazacycloheptane). Preferably, it is morpholine or piperazine.

[0024] The term "halogen atom" in the present invention means a fluorine, chlorine, bromine or iodine atom. Preferably, it is chlorine or fluorine, especially fluorine.

[0025] The term "alkoxyl group" or "alkoxyl" in the present invention refers to an alkyl group bonded to an oxygen atom. Examples of alkoxyl groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy. Preferably, it is a methoxy or ethoxy group.

[0026] The term "aryloxy group" in the present invention means an aryl group bonded to an oxygen atom. Examples of aryloxy groups are phenyloxy groups.

[0027] The term "hydroxyl group" or "hydroxyl" in the present invention means: OH.

[0028] The term "oxo group" refers to the substituent: =O.

[0029] The expression "optionally substituted aryl or heteroaryl group" in the present invention refers to an aryl or heteroaryl group optionally substituted by one or more (preferably 1 to 3, more preferably 1 or 2) substituents independently selected from: a halogen atom, a nitro group (NO₂), a cyano group (CN), a C₁-C₆ alkoxy group, a C₅-C₁₀ aryloxy group, a C₁-C₆ alkyl group in which one or more hydrogen atoms are optionally replaced by a fluorine atom, a heteroaryl group, a hydroxyl group, an oxo group, a C₁-C₆ -CONHalkyl group, a C₁-C₆ -NHCOalkyl group, and an NR₂R₃ group in which R₂ and R₃ independently represent a C₁ alkyl group 1 -C 6 , or a C 6 -C 10 aryl group optionally substituted by a halogen atom and / or a C 1 -C 6 alkyl group.

[0030] Preferably, the substituents in the expression "optionally substituted aryl or heteroaryl group" are independently selected from: a halogen atom, in particular a fluorine or a chlorine, a hydroxyl, an oxo group, a C1-C6 alkoxyl, in particular a methoxy, a C1-C6 alkyl, wherein one or more hydrogen atoms are optionally replaced by a fluorine atom, preferably a methyl group or CH2CF3, and a C6-C10 aryl group optionally substituted by a halogen atom (in particular a fluorine or a chlorine) and / or a C1-C6 alkyl group, for example a fluorophenyl (preferably 4-fluorophenyl) or a methylfluorophenyl (for example 4-fluoro-2-methylphenyl);

[0031] The term "7-azaindole" in the present invention refers to the 1H-pyrrolo[2,3-b]pyridine motif:

[0032] In the present invention, "pharmaceutically acceptable" means something useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and that is acceptable for veterinary as well as human pharmaceutical use.

[0033] In the present invention, the expression "pharmaceutical composition" designates any composition consisting of an effective dose of at least one compound of the invention and at least one pharmaceutically acceptable excipient. Such excipients are selected, depending on the pharmaceutical form and the desired method of administration, from the excipients usually known to those skilled in the art.

[0034] "Pharmaceutically acceptable salts" of a compound are understood to mean salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: (1) hydrates and solvates, (2) pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like;or formed with pharmaceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like, or (3) the salts pharmaceutically acceptable base addition compounds formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion;is coordinated with a pharmaceutically acceptable organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. ;

[0035] The term "mixtures of enantiomers" in the present invention means any mixture of enantiomers. The mixture may be racemic, i.e. 50 / 50 of each enantiomer by weight (w / w), or non-racemic, i.e. enriched in one or other of the enantiomers, for example so as to obtain an enantiomeric excess greater than or equal to 95%, preferably greater than or equal to 98%, more preferably greater than 99%.

[0036] The expression "mixtures of diastereomers" in the present invention refers to any mixture of diastereomers regardless of the proportion.

[0037] The term "treatment" applies to all types of animals, preferably mammals and more preferably humans. In the case of treatment of a non-human animal, the term will refer to veterinary treatment.

[0038] The present invention relates to compounds of formula (I): in which X represents a hydrogen atom or a halogen atom, Y is selected from a hydrogen atom, a group -CN, -CH 2 OH, -CH=NOH, -CO 2 H, an optionally mono- or polysubstituted aryl, an optionally mono- or polysubstituted heteroaryl, and -L-(CH 2 )pW, L represents -C(O)NH-, -CH 2 NH-, -NHC(O)-, -CH 2 N=CH-, -CH=N-, -NHC(O)NH- or - CH 2 NHC(O)-, p is an integer from 0 to 2, when L represents -CH 2 NH-, -NHC(O)-, -CH 2 N=CH-, -CH=N-, -NHC(O)NH- or - CH 2 NHC(O)-, W is selected from: a hydrogen atom, a C 1 -C 6 alkyl , preferably methyl, C 6 -C 10 aryl optionally mono- or polysubstituted, advantageously with 1 to 3 groups independently selected from halogen, hydroxyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl, and 5-10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl being optionally mono- or polysubstituted,advantageously it is optionally substituted by 1 to 4 groups independently chosen from: ∘ a halogen atom, ∘ a hydroxyl, ∘ an oxo group ∘ a C 1 -C 6 alkoxyl, ∘ a C 1 -C 6 alkyl, in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and ∘ a C 6 -C 10 aryl optionally substituted by a halogen atom and / or a C 1 -C 6 alkyl; when L represents -C(O)NH-, W is chosen from: an optionally mono- or polysubstituted phenyl, advantageously it is optionally substituted by a halogen atom, a hydroxyl group, a C 1 -C 6 alkyl, or a C 1 -C 6 alkoxyl group, and a 5-10 membered heteroaryl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 substituents independently chosen from: ∘ a halogen atom, ∘ a hydroxyl, ∘ an oxo group,∘ a C1-C6 alkoxyl group, ∘ a C1-C6 alkyl in which one or more hydrogen atoms are optionally replaced by a fluorine atom, and ∘ a C6-C10 aryl possibly substituted by a halogen atom and / or a C1-C6 alkyl; Z represents -CH 2 Q or -O(CH 2 ) m T, Q represents -OH, -SO 2 R 1 , -NR 2 R 3 , or -R 4 R 4 represents C 1 -C 6 alkyl, R 2 and R 3 each independently represent C 1 -C 6 alkyl, and R 4 represents a 5-7 membered heterocycloalkyl, comprising from 1 to 2 heteroatoms independently selected from N, O and S, said heterocycloalkyl being optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C(O)-C 1 -C 6 alkyl and C(O)O-C ​​1 -C 6 alkyl, m is 1 or 2, T is -O(CH 2 ) n CH 3 or -R 5 n is 0 or 1 R 5 is a 5- to 7-membered heterocycloalkyl comprising 1 to 2 heteroatoms independently selected from N, O and S,said heterocycloalkyl being optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C(O)-C 1 -C 6 alkyl and C(O)O-C ​​1 -C 6 alkyl; a pharmaceutically acceptable salt thereof or a mixture thereof, for use in the prevention and / or treatment of viral infections.

[0039] The compound of formula (I) according to the invention may be in the form of a stereoisomer or a mixture of stereoisomers, such as tautomers, enantiomers or diastereoisomers.

[0040] In a first embodiment, the compounds of the invention are of formula (Ia):

[0041] In a second embodiment, the compounds of the invention are of formula (Ib):

[0042] In a third embodiment, the compounds of the invention are of formula (Ic):

[0043] In a fourth embodiment, the compounds of the invention have the formula (Id):

[0044] In formulas (la), (Ib), (Ic) and (Id), the substituents X, Y and Z are as defined above and below.

[0045] In a particular embodiment, in the compounds of the invention, Z represents -CH₂R₄ or -O(CH₂)mR₅. Preferably, in this embodiment, R₄ and R₅ independently represent a piperazine, morpholine, or homopiperazine group, optionally substituted by a C₁-C₆ alkyl group or a C(O)O(C₁-C₆)-alkyl group. In this embodiment, m preferably represents 2.

[0046] In a particular embodiment, Z represents -CH 2 OH, -CH 2 SO 2 CH 3, -OCH 2 OCH 2 CH 3, -OCH 2 CH 2 OCH 3, -N(CH 2 CH 3) 2, Or

[0047] In a preferred embodiment, Z represents -CH2R4 in which R4 represents a piperazine group, optionally substituted by a C1-C6 alkyl, in particular a methyl.

[0048] In one particular embodiment, X represents a halogen, in particular fluorine.

[0049] In one particular embodiment, X represents a hydrogen.

[0050] In a particular embodiment, Y represents -H, -CN, -CH2OH, -CH=NOH, aryl or heteroaryl optionally mono- or polysubstituted, or -L-(CH2)pW.

[0051] In an advantageous embodiment, Y represents an optionally mono- or polysubstituted aryl or heteroaryl, or -L-(CH2)pW.

[0052] In the case where Y represents an optionally mono- or polysubstituted aryl or heteroaryl, it is preferably an optionally mono- or polysubstituted aryl, in particular a phenyl, especially unsubstituted.

[0053] In an even more advantageous embodiment, Y represents L-(CH 2 )pW. In the case where Y represents -L-(CH 2 )pW, preferably, p is then equal to 0, 1 or 2.

[0054] Advantageously, when Y represents L-(CH 2 )pW, L represents -C(O)NH-, -CH 2 NH-, - NHC(O)-, -NHC(O)NH- or -CH 2 NHC(O)-, preferably -CH 2 NH-, -NHC(O)- or -NHC(O)NH-

[0055] In the embodiment where Y represents -L-(CH 2 )pW, W advantageously represents a C 6 -C 10 aryl or 5-10 linker heteroaryl containing 1 to 2 heteroatoms independently chosen from N, S and O, said aryl or heteroaryl being optionally mono- or polysubstituted.

[0056] In a preferred embodiment, W represents a C 6 -C 10 aryl, in particular a phenyl, unsubstituted or monosubstituted, preferably by a hydroxyl.

[0057] In another preferred embodiment, W represents a 5- or 6-membered heteroaryl containing 1 to 2 heteroatoms independently chosen from N, S, and O, particularly N, such as pyrazole, pyridine, or imidazole. Advantageously, said heteroaryl is optionally substituted by 1 to 4, preferably 1 or 2 groups independently chosen from: a halogen atom, in particular fluorine, an oxo group, a C 1 -C 6 alkyl, in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, in particular methyl, and a C 6 -C 10 aryl optionally substituted by a halogen atom (in particular fluorine) and / or a C 1 -C 6 alkyl, for example methyl, a fluorophenyl (preferably 4-fluorophenyl) or a methylfluorophenyl (for example 4-fluoro-2-methylphenyl).

[0058] Preferably, W represents pyrazole, 3-oxo-2,3-dihydro-1H-pyrazole, pyridine, 2(1H)-pyridinone, 4(1H)-pyridinone or imidazole, in particular 2(1H)-pyridinone or imidazole, optionally substituted by 1 to 4, preferably 1 or 2 groups independently selected from: a C 1 -C 6 alkyl, in particular a methyl, and a C 6 -C 10 aryl optionally substituted by a C 1 -C 6 alkyl, for example a methyl.

[0059] In particular, W is then chosen from: preferably

[0060] In an advantageous embodiment, Y represents an aryl, heteroaryl or L-(CH 2 )pW, L representing -CH 2 NH or -NHC(O)NH-, in particular -CH 2 NH, p being an integer from 0 to 2, and W being chosen from: a phenyl group optionally substituted by a hydroxyl group, or a C1-C6 alkyl group, preferably a hydroxyl, and a 5-10 member heteroaryl group comprising 1 to 2 heteroatoms independently selected from N, O and S, especially N, preferably selected from the group consisting of: pyrrole, imidazole, thiophene, pyridine, pyrimidine, benzofuran, benzodioxole, indole and benzimidazole,

[0061] Preferably, when Y represents L-(CH 2 )pW, L representing -CH 2 NH or -NHC(O)NH-, in particular -CH 2 NH, p being an integer from 0 to 2, W is chosen from: a phenyl group optionally substituted by a hydroxyl group, or a C1-C6 alkyl group, preferably a hydroxyl, and a pyrrole, imidazole, 3-oxo-2,3-dihydro-1H-pyrazole, thiophene, pyridine, 2(1H)-pyridinone, 4(1H)-pyridinone, pyrimidine, pyrimidine-2,4-dione, benzofuran, benzodioxole, indole and benzimidazole, more preferably imidazole.

[0062] In this embodiment, Z preferably represents -CH 2 R 4 or -O(CH 2 ) m R 5 and more preferably -CH 2 R 4 . Preferably, in this embodiment, R 4 and R 5 independently represent a piperazine or morpholine group, optionally substituted by a C 1 -C 6 alkyl or a C(O)O(C 1 -C 6 )-alkyl group. More preferably, Z represents -CH 2 R 4 in which R 4 represents a piperazine group, substituted by a methyl. Furthermore, in this embodiment, X advantageously represents a halogen, in particular fluorine.

[0063] In another advantageous embodiment, Y represents -NHC(O)-W, with W representing a heteroaryl group of 5 to 10 members, comprising from 1 to 2 heteroatoms chosen independently from N, O and S, in particular N, said heteroaryl being optionally substituted by 1 to 4 substituents independently chosen from: an oxo group, a C 1 -C 6 alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, in particular a methyl, and a C 6 -C 10 aryl optionally substituted by a halogen atom (in particular a fluorine) and / or a C 1 -C 6 alkyl, for example a methyl, a fluorophenyl (preferably 4-fluorophenyl) or a methylfluorophenyl (for example 4-fluoro-2-methylphenyl).

[0064] Preferably, in this embodiment, the heteroaryl group is selected from the group consisting of: pyrazole, pyrrole, imidazole, thiophene, pyridine, pyrimidine, benzofuran, benzodioxole, indole and benzimidazole, optionally substituted with 1 to 4 substituents independently selected from: an oxo group, a C 1 -C 6 alkyl, in particular a methyl, and a C 6 -C 10 aryl optionally substituted by a C 1 -C 6 alkyl, for example a methyl.

[0065] Even more preferably, in this embodiment, W is a pyrazole, pyrrole, imidazole, 3-oxo-2,3-dihydro-1H-pyrazole, thiophene, pyridine, 2(1H)-pyridinone, 4(1H)-pyridinone, pyrimidine, pyrimidine-2,4-dione, benzofuran, benzodioxole, indole, or benzimidazole, preferably a 2(1H)-pyridinone, optionally substituted by 1 to 4 substituents independently selected from: a C 1 -C 6 alkyl group, in particular a methyl, and a C 6 -C 10 aryl group, in particular a phenyl optionally substituted by a halogen atom, in particular a fluorine.

[0066] In this embodiment, Z preferably represents CH 2 R 4 or O(CH 2 ) m R 5 , more preferably -CH 2 R 4 . Preferably, in this embodiment, R 4 and R 5 independently represent a piperazine or morpholine group, optionally substituted by a C 1 -C 6 alkyl or a C(O)O(C 1 -C 6 )-alkyl group. More preferably, Z represents -CH 2 R 4 in which R 4 represents a piperazine group, substituted by a methyl.

[0067] Preferably, the compound of the invention is chosen from: And more preferably among And Compositions and Therapeutic Applications

[0068] The compounds of the present invention inhibit AXL receptors. Since AXL is involved in many biological processes and is a therapeutically validated target, the compounds of the present invention and their pharmaceutically acceptable salts, or the compositions of the invention as defined below, are useful as a medicament, in particular in the treatment of viral infections whose infectious cycle depends on AXL and associated signaling.

[0069] The present invention relates to compounds of formula (I) as defined above for use in the prevention and / or treatment of viral infections.

[0070] More specifically, the compounds can be used to prepare pharmaceutical compositions comprising, as an active ingredient, at least one compound of formula (I) described above or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable excipient. Thus, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of viral infections. Said excipients are selected according to the desired pharmaceutical form and route of administration from among the usual excipients known to those skilled in the art.

[0071] The pharmaceutical composition according to the invention may further comprise an additional therapeutic agent, typically selected from an antiviral agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, an agent for the treatment of immunodeficiency disorders and an agent for the treatment of pain. In particular, it is an agent useful in a treatment against viral infections.

[0072] The compounds of formula (I) according to the invention or their pharmaceutically acceptable salts, or the pharmaceutical composition according to the invention are particularly useful for the prevention and / or treatment of viral infections due to Flaviviruses (including dengue, Zika, West Nile, Kunjin viruses), Alphaviruses (including Chikungunya, Mayaro, Semliki Forest, Sindbis viruses, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus), Filoviruses (including Ebola virus, Marburg fever virus), arenaviruses (including Lassa fever virus, Junin virus, Amapari virus), picornaviruses (including vesicular stomatitis virus), paramyxoviruses (influenza virus), coronaviruses such as SARS-COV2.

[0073] In a particular embodiment, the invention relates to the compounds of formula (I) as defined above or the pharmaceutical composition as defined above in the prevention and / or treatment of viral infections due to a coronavirus, in particular SARS-Cov2.

[0074] In this embodiment, the compound of formula (I) preferably corresponds to the following compounds: And

[0075] Also described is a kit comprising: a) a first composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient, and b) a second composition comprising an additional therapeutic agent, typically selected from an antiviral agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, an agent for the treatment of immunodeficiency disorders and an agent for the treatment of pain, preferably an agent useful in a treatment against viral infections, as a combination product for separate, concomitant or spread-out use.

[0076] Said kit is useful as a medicament, in particular for the prevention and / or treatment of viral infections, in particular viral infections as defined above.

[0077] The pharmaceutical compositions according to the invention can be administered parenterally, such as intravenously or intradermally, or topically, orally or nasally.

[0078] Parenteral forms include aqueous suspensions, isotonic saline solutions, or sterile injectable solutions that may contain pharmacologically compatible dispersing and / or wetting agents. Oral forms include tablets, soft or hard capsules, powders, granules, oral solutions and suspensions. Nasal forms include aerosols. Topical forms include patches, gels, creams, ointments, lotions, sprays, and eye drops.

[0079] Preferably, the compounds or compositions of the invention are administered orally or parenterally (in particular intravenously).

[0080] The effective dose of a compound of the invention varies depending on numerous parameters such as, for example, the route of administration chosen, weight, age, sex, the stage of the pathology to be treated and the sensitivity of the individual to be treated.

[0081] The treatment of the pathologies indicated above comprises the administration, to a patient in need thereof, of an effective dose of a compound of formula (I) according to the invention, or one of its pharmaceutically acceptable salts or of a composition according to the invention, preferably by parenteral route (in particular intravenous) or oral route. Process for the preparation of the compounds of the invention

[0082] Also described are the methods of preparing the compounds described above, in particular from 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine.

[0083] One method is represented in Diagram 1. where X and Z are as defined previously and Y represents a hydrogen atom, CHO, CN, CH2OH, CO2H, NH2, or a phenyl group.

[0084] The method then includes at least the following steps: a) tosylation of 5-bromo-3-iodo-1 H-pyrrolo[2,3-b]pyridine (II), for example with toluene-4-sulfonyl chloride in the presence of a base such as sodium hydride, to obtain intermediate (III), b) Suzuki-Miyaura type coupling reaction in the presence of a palladium catalyst such as palladium dichloro[1,1'-Bis(diphenylphosphino)ferrocene] (Pd(dppf)Cl 2 ), with the intermediate of formula (IV) in which U represents a boronic acid or its pinacole ester, to obtain the compound of formula (V), c) Suzuki-Miyaura type coupling reaction in the presence of a palladium catalyst such as palladium dichloro[1,1'-Bis(diphenylphosphino)ferrocene] (Pd(dppf)Cl 2 ), with the intermediate of formula (VI) in which U' represents a boronic acid or its pinacole ester, to obtain the intermediate of formula (VII), and d) hydrolysis of the tosyl group by a base, preferably sodium hydroxide or cesium carbonate, to obtain a compound of formula (I).

[0085] The synthesis of the amino intermediate compounds (VIII) (i.e. the compounds of formula (I) for which X and Z are as defined above and Y represents a group (CH 2 ) n NH 2 where n is equal to 1 is shown in Scheme 2. where X and Z are as defined previously.

[0086] In this embodiment, the method for preparing the amine intermediates of formula (VIII) may comprise at least the steps of: e) condensation of hydroxylamine with a compound of formula (I) in which Y is CHO to form the oxime of formula (IX), f) reduction of the oxime (IX), in particular in the presence of zinc under ultrasound to obtain the methylamine intermediate of formula (VIII)

[0087] The skilled person will naturally apply all other well-described and known synthetic techniques to synthesize these types of compounds.

[0088] The compounds of formula (I) in which Y represents a group L-(CH 2 ) p -W with L representing an amide group -NHC(O)- or -CH 2 NHC(O)-, are for example obtained by a synthetic method from the amino-7-azaindoles derivatives shown in Scheme 3: where W, X, Z and p are as defined previously and n equals 0 or 1.

[0089] The method of Scheme 3 comprises at least one peptide coupling reaction step between an acid of formula W-(CH 2 ) p -C(O)OH and the amino intermediate of formula (VIII) as defined previously, in particular in the presence of at least one activating agent such as 2-(7-aza-)hexafluorophosphate 1H -benzotriazol-1-yl)- N,N,N' , N'- tetramethyluronium (HATU) and a base such as diisopropylethylamine (DIEA).

[0090] The person skilled in the art will naturally apply all other well-known synthetic techniques to obtain these types of amide compounds.

[0091] The compounds of formula (I) in which Y represents a group L-(CH 2 ) p -W with L representing a group -CONH-, are for example obtained by a synthetic method from the 7-azaindole carboxylic derivatives of formula (X) shown in Scheme 4 according to two methods among others: where W, Z and p are as defined previously.

[0092] Advantageously, the methods of Scheme 4 comprise at least one peptide coupling reaction step between an acid of formula (X) and an amine of formula W-(CH 2 ) p -NH 2 , either by coupling or by generation in situ acyl chlorides by prior action of thionyl chloride.

[0093] The urea compounds of the present invention, i.e. the compounds of formula (I) in which Y represents a group L-(CH 2 ) p -W with L representing a urea group -NHCONH-, are for example prepared according to the method shown in Scheme 5: where W, X and Z are as defined previously.

[0094] Advantageously, the methods of Scheme 5 comprise at least one reaction of a compound of formula (VIII) in which n is equal to 0, with an isocyanate of formula W-NCO, W being as defined above. Said isocyanates are either commercially available or obtained according to synthetic methods known to those skilled in the art. In addition, those skilled in the art will naturally apply all other well-known synthetic techniques to obtain these types of urea compounds.

[0095] According to another embodiment, concerning the method of synthesis of the secondary amine compounds of the present invention, i.e. the compounds of formula (I) in which Y represents a group L-(CH 2 ) p -W with L representing a group -CH 2 NH-, two methods among others are represented in Scheme 6: where W, X, Z and p are as defined previously.

[0096] Advantageously, the methods of Scheme 6 include at least one reductive amination step between either a compound of formula (VIII) in which n is equal to 1, with aldehydes of formula W-CHO, or between the 7-azaindoles aldehydes of formula (XI) and an amine of formula W(CH 2 ) p -NH 2 .

[0097] Aldehydes of formula W-CHO and amines of formula W(CH 2 ) p -NH 2 are notably available commercially, or easily obtained by means of preparation processes known to those skilled in the art.

[0098] The person skilled in the art will naturally apply all other well-known synthetic techniques to obtain these types of amide compounds.

[0099] Another embodiment relates to the method of synthesis of secondary amine derivatives of formula (XII) obtained by deprotection of the compound of formula (XIII) according to the following Scheme 7: where X and Y are as defined previously.

[0100] Advantageously, the method comprises at least one step of hydrolysis of the carbamate compound of formula (XIII) in an acidic medium to form the desired secondary amine of formula (XII).

[0101] The skilled person will naturally apply all other well-known synthetic techniques to deprotect the expected secondary amine. DESCRIPTION OF FIGURES

[0102] Figure 1 : Inhibition of Axl phosphorylation in cellulo by compounds 1, 2 and 3 compared to R428 / Bemcentinib. A549 cells were preincubated for 1 h with 2.5 µM of Axl-targeting compound. They were then stimulated for 5 min with 1 mM pervanadate. Evaluation of the inhibition of phosphorylation of residue Y779 of the intracytoplasmic domain of Axl kinase was done by immunoblotting using the R&D Systems antibody (AF2228) and measurement of signal intensity by densitometry (Image J) (P-Axl / Axl ratio). Figure 2Determination of the IC50 values ​​of compounds 1, 2, and 3 against the inhibition of Axl kinase and FLT3 kinase. Ten concentrations of the compound were prepared by serial dilutions. The compounds were screened in 1% final DMSO. The kinases were diluted to a two-fold concentrated concentration in kinase buffer. All ATP solutions were diluted to a four-fold working concentration (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA). Each compound was incubated at 10 concentrations ranging from 100 nM to 0.00495 nM to calculate the IC50. The IC50 values ​​are shown: a) results for compound 1; b) results for compound 2; c) results for compound 3. Figure 3 :Anti-ZIKV activity of compounds 1, 2, 3, 10, and 11 compared to R428 / Bemcentinib. Cells were pre-incubated for 1 hour with the compounds at the indicated concentrations and then infected with the viral strain (MOI = 0.1). Cells were maintained in culture for 24 hours in the presence of the compound. Residual viral replication was quantified by qRT-PCR of the viral genomic RNA. Values ​​are expressed as the percentage of infection detected in the control condition obtained by incubating cells in the diluent DMSO (0). The Axl inhibitor R428 / Bemcentinib was evaluated in parallel.The values ​​are triplicate means + standard deviation: a) results for compounds 1, 2, 3, 10 and R428 at a concentration of 2.5 µM; b) results for compounds 1, 2 and R428 at concentrations of 0.15, 0.31, 0.62, 1.25, 2.5 and 5 µM; c) results for compound 10 at concentrations of 0.1, 0.2, 0.4, 0.5, 1 and 2.5 µM and compound 11 at concentrations of 0.001, 0.1, 0.4, 0.5, and 1 µM; d) logarithmic dose-response modeling obtained for compounds 1 (left) and 10 (right). The results obtained with R428 are presented in parallel. Figure 4 :Anti-DENV activity of compounds 10, 11 and 14. Cells were preincubated for 1 hour with the compounds at the indicated concentrations (0.01, 0.1, 0.5, 1 and 2.5 µM), then infected with the viral strain DENV2 (MOI = 0.1). Cells were maintained in culture for 3 days in the presence of the compound. Residual viral replication, measured by quantification of intracellular viral RNA by RT-PCR, values ​​are expressed as a percentage of the infection detected in the control condition obtained by incubation of cells in the presence of the dilution solvent DMSO (0). Values ​​are means of triplicates + standard deviation. Figure 5Anti-KUNV activity of compound 10. Cells were pre-incubated for 1 hour with the compounds at the indicated concentrations (0.001, 0.1, 0.5, 1, and 2.5 µM) and then infected with the viral strain (MOI = 0.1). Cells were maintained in culture for 24 hours in the presence of the compound. Residual viral replication was measured by quantifying luciferase activity in the cell lysate and is expressed as a percentage of the infection detected in the control condition obtained by incubating cells in the diluent DMSO (0). Values ​​are triplicate means + standard deviation. Figure 6 :Anti-CHIKV activity of compound 10. Cells were preincubated for 1 hour with the compounds at the indicated concentrations (0.001, 0.1, 0.25, 0.5, 1 and 1.5 µM), then infected with the viral strain LR-OPY-1 (MOI = 0.1). Cells were maintained in culture for 24 hours in the presence of the compound. Residual viral replication, measured by quantification of luciferase activity in the cell lysate, is expressed as a percentage of the infection detected in the control condition obtained by incubating cells in the presence of DMSO (0). Values ​​are means of triplicates + standard deviation. Figure 7 :Anti-SARS-CoV2 activity of compounds 1, 2, 3, 10 and 14 determined in the VeroE6 cell line. Cells were preincubated for 1 hour with the compounds at a concentration of 1.25 µM, then infected with the viral strain BetaCoV / France / IDF0371 / 2020 (MOI = 0.01). Cells were maintained in culture for 24 hours in the presence of the compound. Residual viral replication is measured by quantification of viral RNA in cell culture by qRT-PCR. The control condition is obtained by incubation of cells in the presence of the dilution solvent DMSO (0). Values ​​are means of triplicates + standard deviation. Figure 8: Anti-SARS-CoV2 activity of compounds 1, 2, 3, 10 and 14 determined in A549-ACE2 cells. The cells were preincubated for 1 hour with the compounds at a concentration of 1.25 µM, then infected with the viral strain BetaCoV / France / IDF0371 / 2020 (MOI = 0.01). The cells were maintained in culture for 24 hours in the presence of the compound. Residual viral replication is measured by quantification of viral RNA in the cell culture by qRT-PCR. The control condition is obtained by incubation of cells in the presence of the dilution solvent DMSO (0). The Axl inhibitor R428 / Bemcentininb is evaluated in parallel. Values ​​are means of triplicates + standard deviation. Figure 9: Calculation of the specific activities of compounds 1, 2 and 3 on SARS-CoV2. A549-ACE2 cells were incubated with increasing concentrations of compounds for 1 hour, then infected with the viral strain BetaCoV / France / IDF0371 / 2020 (MOI = 0.01). The cells were maintained in culture for 24 hours in the presence of the compound. Residual viral replication is measured by quantification of viral RNA in the cell culture by qRT-PCR. The control condition is obtained by incubation of cells in the presence of DMSO. Values ​​are means of triplicates + standard deviation. IC50 are calculated using Prism software (GraphPad). Figure 10: Anti-SARS-CoV2 activity of compound 1 determined in a human primary bronchial epithelium model. The cells were preincubated for 1 hour with the compounds used at a concentration of 1.25 µM, added to the basal compartment of the culture (MucilAir ™ < , Epithelix). The cells are then infected with the viral strain BetaCoV / France / IDF0371 / 2020 added to the apical compartment (MOI = 0.1). After 2 hours, the inoculum is removed and the cells are maintained in culture for 24 hours in the presence of the compound. Residual viral replication is measured by quantification of viral RNA in the cell culture by qRT-PCR. The control condition is obtained by incubation of cells in the presence of the dilution solvent DMSO (0). NI indicates the condition corresponding to uninfected cells. Individual values ​​as well as means and standard deviations are indicated. Figure 11: Mechanism of inhibition of infection of A549-ACE2 cells by compound 1. A549-ACE2 (a) or veroE6 (b) cells were infected with SARS-CoV2 (strain BetaCoV / France / IDF0371 / 2020) (MOI = 0.01). Compound 1 (1.25 µM) was added to the cell culture either 1h before viral challenge and maintained throughout the experiment (Scheme 1, SARS-CoV2 condition); 1h before viral challenge and only during the first 4 hours of infection (Scheme 2, Pre-Tt condition); from the 4th hour following exposure to SARS-CoV2 (Scheme 3, Post-Tt condition). Cell infection was determined by intracellular detection of the Spike protein by FACS using specific antibodies (anti-Spike SARS-CoV2; clone 1A9, Gene Tex). Individual values ​​as well as means and standard deviations are indicated and compared to the control condition carried out from cells maintained in the presence of DMSO dilution solvent (0). EXAMPLES

[0103] The invention will be better understood upon reading the following examples, which are given for illustrative purposes only and should not be interpreted as limiting the scope of the present invention. Example 1 : Synthesis Material

[0104] The syntheses and analyses were carried out under the following conditions.

[0105] Nuclear Magnetic Resonance 1< H and 13< C: Device : Bruker Avance 400 (400 MHz); Bruker Avance 300 (300 MHz) Terms of Use : Room temperature, chemical shifts expressed in parts per million (ppm), signal multiplicity indicated by lowercase letters (singlet s, doublet d, triplet t, quadruplet q, multiplet m), dimethyl sulfoxide d 6, methanol d 4, chloroform d 1 as deuterated solvents.

[0106] High Pressure Liquid Chromatography (HPLC): Device : Agilent Technology 1260 Infinity Terms of Use:Zorbax SB-C18 or Eclipse Plus column (2.1 x 50 mm), 1.8 µm; temperature: 30°C, flow rate: 0.5 mL / min for methods X and Y and 0.4 mL / min for method Z, elution gradient Water (A) / Acetonitrile (B) / 0.1% Formic Acid (Time (min) / % B): Method X: 0 / 10, 0.3 / 10, 5.7 / 100, 6.0 / 100; Method Y: 0 / 10, 1 / 50, 6 / 100, 8 / 100; Method Z: 0 / 10, 11 / 100, 15 / 100

[0107] Mass Spectrometry (MS): Device: Agilent Technologies 6120 Quadrupole Terms of Use : ElectroSpray (ESI) in positive and / or negative mode.

[0108] Weighings: Device : Denver Instrument TP214 (accuracy 0.1 mg) Terms of Use : Weighings carried out to the nearest milligram.

[0109] Reactions under pressure: Device : Parr 300 mL Autoclave. Terms of Use : Hydrogenation under 20 bars of hydrogen.

[0110] Reaction under microwave irradiation: Device : CEM Discover SP ®< Terms of Use: 200 Watts power, Medium stirring speed

[0111] In the following, the following abbreviations are used: eq equivalent DMF N,N-dimethylformamide YOUR Room temperature DMSO dimethyl sulfoxide General synthesis of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridine intermediates (1) 1st step, synthesis of 5-bromo-3-iodo-1-(toluene-4-sulfonyl)-1 H -pyrrolo[2,3-b]pyridine (III)

[0112] 3 g of 5-bromo-3-iodo-1 H -pyrrolo[2,3-b]pyridine(II) are diluted in 60 mL of anhydrous THF under argon and cooled in an ice bath. 558 mg (1.5 eq) of sodium hydride (60%) are added slowly, and the mixture is stirred at 0°C for 20 minutes. Then, tosyl chloride (2.11 g, 1.2 eq) is added, and the mixture is stirred at room temperature for 5 hours. The solvent is evaporated. The resulting residue is suspended in a minimal amount of petroleum ethers and filtered. The precipitate is washed twice with 2 M sodium hydroxide solution and then dried under vacuum overnight.

[0113] NMR 1< H (400 MHz, DMSO-d6) δ (ppm) 8.52 (d, J = 1.9, 1H), 8.22 (s, 1H), 8.01 (m, 3H), 7.44 (d, J = 8.2, 2H), 2.51 (s, 3H).

[0114] Yield: 97%; HPLC: 99%; MS [M+1]: 476.9-478.9 2nd step, general synthesis of 3-5-bis-aryl-1 H -pyrrolo[2,3-b]pyridines (I) (in which Y = CHO, NH2 or a phenyl substituted by a phenyl)

[0115] 5-bromo-3-iodo-1-(toluene-4-sulfonyl)-1 H-pyrrolo[2,3-b]pyridine (III) (100 mg), the first boronic acid to be coupled (IV) (1 eq) and potassium carbonate (3 eq) are suspended in a 3 / 1 dioxane / water mixture (3 mL), and the mixture is degassed under Argon for 20 minutes. Pd(dppf)Cl 2 (2%) is added and the mixture is stirred at 80°C under microwave irradiation for 1 to 3 times 20 minutes until the starting reagent is completely consumed. The reaction medium is washed with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The solvents are evaporated, the residue is taken up in ethyl acetate, washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered and evaporated to dryness, then purified on a silica column. The compound is then dissolved in a dioxane / water mixture (3 / 1.4 mL), in the presence of the second boronic acid or its pinacol(VI) ester (1.2 eq) and potassium carbonate (3 eq). The medium is degassed again under Argon for 20 minutes, Pd(dppf)Cl2 (0.025 eq) is then added and the mixture is stirred at 120°C for 45 minutes under microwave irradiation. 500 µL of 1M sodium hydroxide (3 eq) is then added to the reaction medium and stirred at 100°C for 45 minutes under microwave irradiation. The reaction medium is then washed with a saturated aqueous NaHCO3 solution, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and evaporated to dryness, then purified on a normal phase silica column (dichloromethane / methanol-ammonia). 4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzaldehyde Reagents: First 2-Fluoro-5-formylbenzeneboronic acid then 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine Yield: 95%; HPLC: 97%; MS [M+1]: 429.2 3-{5-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenylamine Reagents: First 3-Aminophenylboronic acid then 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine Yield: 66%; HPLC: 98%; MS [M+1]: 398.3 3-Biphenyl-3-yl-5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine (Example 16) Reagents: First 3-Biphenylboronic acid then 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine NMR 1< H (400 MHz, DMSO-d6) δ (ppm) 12.06 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.83 - 7.79 (m, 1H), 7.79 - 7.75 (m, 2H), 7.67 - 7.62 (m, 2H), 7.56 (d, J = 4.9 Hz, 2H), 7.52 - 7.36 (m, 4H), 7.30 (d, J = 7.5 Hz, 1H), 3.55 (s, 2H), 2.48 - 2.20 (m, 7H), 2.13 (s, 3H). Yield: 37%; HPLC: 99%; MS [M+1]: 459.3 Synthesis of amines Method 1: Synthesis of 4-Fluoro-3-{5-[3-(4-methylpiperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenylamine

[0116] Step 1: Synthesis of 5-Bromo-3-(2-fluoro-5-nitro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0117] 5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-pyrrolo[2,3-b]pyridine (460 mg), 2-(2-Fluoro-5-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and potassium carbonate (3 eq) are suspended in a dioxane / water mixture (9 / 1, 20 mL), and degassed under Argon for 20 minutes. Pd(dppf)Cl 2 (18 mg, 0.025 eq) is added and the mixture is stirred for 2 to 4 times 20 minutes at 50°C under microwave irradiation until total consumption of the reagent measured by LC / MS. The solvents are evaporated, the residue is taken up in ethyl acetate, washed with a saturated aqueous solution of NaHCO3, dried over anhydrous Na2SO4, filtered and evaporated to dry, then purified on a normal phase silica column (petroleum ether / dichloromethane).

[0118] Yield: 66%; HPLC: 90%; MS [M+1]: 490.0-492.0 Step 2: Synthesis of 3-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-fluoro-phenylamine

[0119] 5-Bromo-3-(2-fluoro-5-nitro-phenyl)-1-(toluene-4-sulfonyl)-1 H-pyrrolo[2,3-b]pyridine (100 mg) is suspended in 3 mL of ethyl acetate with 232 mg of tin chloride dihydrate (5 eq) and stirred at reflux for 4 hours. The reaction medium is taken up in ethyl acetate and washed with a saturated aqueous solution of NaHCO3. The precipitate is filtered and rinsed with water, then with ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phases are dried over anhydrous Na2SO4, filtered and evaporated to dryness, then purified on a normal phase silica column (petroleum ether / ethyl acetate).

[0120] Yield: 76%; HPLC: 97%; MS [M+1]: 460.0-462.0 Step 3: Synthesis of 4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H- pyrrolo[2,3-b]pyridin-3-yl}-phenylamine

[0121] 3-[5-Bromo-1-(toluene-4-sulfonyl)-1 H1-pyrrolo[2,3-b]pyridin-3-yl]-4-fluorophenylamine (475 mg), 1-methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (1.2 eq), and potassium carbonate (3 eq) are suspended in a dioxane / water mixture (9:1, 20 mL) and degassed under argon for 20 minutes. Pd(dppf)Cl₂ (19 mg, 0.025 eq) is then added, and the mixture is stirred at 120°C for 45 minutes under microwave irradiation. 3 mL of 1 M sodium hydroxide solution is then added to the reaction mixture and stirred at 100°C for 45 minutes under microwave irradiation. The reaction medium is then washed with a saturated aqueous solution of NaHCO3, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and evaporated to dry, then purified over normal phase silica column (dichloromethane / ammoniacal methanol).

[0122] Yield: 91%; HPLC: 98%; MS [M+1]: 416.3 Synthesis of various non-commercial carboxylic acids:

[0123] 1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (HPLC: 97%; MS [M+1]: 243.1) was obtained according to the described procedure [Traore et al. European Journal of Medicinal Chemistry (2013), 70, 789-801].

[0124] 1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (HPLC: 97%; MS [M+1]: 248.2) was obtained according to the procedure described [Flynn et al. Organic Process Research & Development (2014), 18(4), 501-510]. 1-(4-Fluorophenyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (HPLC: 100%; MS [M+1]: 248.2) was obtained as a by-product during the synthesis of 1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid described above.

[0125] General synthesis of amide compounds from amino-7-azaindole compounds and carboxylic acids.

[0126] The carboxylic acid (1 eq) is dissolved in anhydrous DMF and placed in a dried Schlenck flask under an argon atmosphere. N,N'-Dicyclohexylcarbodiimide (1 eq) and then the amino-7-azaindole derivative (1 eq) are added. The mixture is then stirred at 70°C overnight. The solvent is evaporated. The resulting residue is dissolved in ethyl acetate, washed twice with a saturated aqueous solution of NaHCO3, once with a saturated aqueous solution of sodium chloride, dried over anhydrous Na2SO4, filtered through cotton, evaporated to dryness, and purified on a reversed-phase silica column (water / acetonitrile) with 1% trifluoroacetic acid to give the desired amide derivative. 2-Hydroxy-N-(3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenyl)-nicotinamide (Example 9) Reagents: 3-{5-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenylamine and 2-Hydroxy-nicotinic acid NMR 1< H (400 MHz, DMSO-d6) δ (ppm) 13.00 - 12.55 (m, 1H), 12.27 (s, 1H), 12.04 (d, J = 2.2, 1H), 8.59 (d, J = 2.1, 1H), 8.54 - 8.48 (m, 2H), 8.36 - 8.30 (m, 1H), 7.95 (d, J = 2.6, 1H), 7.83 (dd, J = 2.2, 6.2, 1H), 7.72 - 7.63 (m, 2H), 7.57 - 7.41 (m, 4H), 7.35 - 7.28 (m, 1H), 6.59 (dd, J = 6.3, 7.2, 1H), 3.57 (s, 2H), 2.49 - 2.20 (m, 8H), 2.15 (s, 3H). Yield: 48%; HPLC: 99%; MS [M+1]: 519.3 1-(4-Fluoro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenyl)-amide (Example 8) Reagents: 3-{5-[3-(4-Methylpiperazin-1-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenylamine and 1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid. 1H NMR (600 MHz, D2O) δ (ppm) 8.63 (m, 1H), 8.44 (s, 1H), 7.89 (d, J = 7.0, 1H), 7.71–7.58 (m, 3H), 7.44 (d, J = 7.4, 1H), 7.22–7.08 (m, 6H), 7.08–7.01 (m, 2H), 7.00– 6.92 (m, 1H), 6.35 (d, J = 7.5, 1H), 4.22 (s, 2H), 3.89 - 3.31 (m, 8H), 2.92 (s, 3H), 1.94 (s, 3H). Yield: 67%; HPLC: 99%; MS [M+1]: 627.3 1-(4-Fluoro-phenyl)-4-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenyl)-amide (Example 10) Reagents: 3-{5-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenylamine and 1-(4-Fluoro-phenyl)-4-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid NMR 1< H (400 MHz, DMSO-d6) δ (ppm) 12.02 (d, J = 2.5, 1H), 10.63 (s, 1H), 8.56 (d, J = 1.9, 1H), 8.50 (d, J = 1.9, 1H), 8.24 - 8.19 (m, 1H), 7.90 (d, J = 2.5, 1H), 7.71 (d, J = 7.0, 1H), 7.66 - 7.61 (m, 2H), 7.61 - 7.55 (m, 1H), 7.52 - 7.34 (m, 7H), 7.30 (d, J = 7.6, 1H), 6.36 (d, J = 7.0, 1H), 3.53 (s, 2H), 2.47 - 2.16 (m, 11H), 2.12 (s, 3H). Yield: 54%; HPLC: 97%; MS [M+1]: 627.3 1-(4-Fluoro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (4-fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenyl)-amide (Example 11) Reagents: 4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenylamine and 1-(4-Fluoro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid RMN 1< H (400 MHz, DMSO-d6) δ (ppm) 12.16 (d, J = 2.2, 1H), 11.95 (s, 1H), 8.60 (d, J = 2.0, 1H), 8.52 (d, J = 7.5, 1H), 8.40 - 8.37 (m, 1H), 8.35 (dd, J = 2.6, 7.0, 1H), 7.89 - 7.85 (m, 1H), 7.70 - 7.61 (m, 2H), 7.54 - 7.40 (m, 6H), 7.35 - 7.26 (m, 2H), 6.70 (d, J = 7.9, 1H), 3.56 (s, 2H), 2.47 - 2.21 (m, 8H), 2.13 (s, 3H), 2.07 (s, 3H). Rendement : 63% ; HPLC : 99% ; MS [M+1] : 645.3 General summary of ureas

[0127]

[0128] The amine derivative (1 eq), phenyl isocyanate (1.05 eq) and triethylamine (2 eq) are dissolved in anhydrous THF and stirred, under argon, at room temperature overnight. The reaction medium is quenched with a saturated solution of NaHCO3. The aqueous phase is extracted with ethyl acetate and dried over sodium sulfate. The organic phases are combined, evaporated to dryness, and purified on a normal phase silica column (dichloromethane / methanol-ammonia) to give the desired urea derivative. 1-(3-{5-[3-(4-Méthyl-pipérazin-1-ylméthyl)-phényl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phényl)-3-phényl-urée (Exemple 14) Réactifs : 3-{5-[3-(4-Méthyl-pipérazin-1-ylméthyl)-phényl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phénylamine et Isocyanate de phényle RMN 1< H (400 MHz, DMSO-d6) δ (ppm) 12.01 (d, J = 2.0, 1H), 8.76 (bs, 1H), 8.70 (bs, 1H), 8.57 (d, J = 2.0, 1H), 8.52 (d, J = 1.9, 1H), 8.04 - 8.00 (m, 1H), 7.89 (d, J = 2.6, 1H), 7.72 - 7.62 (m, 2H), 7.53 - 7.42 (m, 3H), 7.41 - 7.24 (m, 6H), 7.01 - 6.94 (m, 1H), 3.55 (s, 2H), 2.47 - 2.19 (m, 8H), 2.12 (s, 3H). Rendement : 57% ; HPLC : 99% ; MS [M+1] : 517.3 1-(4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenyl)-3-phenyl-urea (Example 3) Reagents: 4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-phenylamine and Phenyl Isocyanate NMR 1< H (400 MHz, DMSO-d6) δ (ppm) 12.15 (d, J = 2.1, 1H), 8.79 (bs, 1H), 8.70 (bs, 1H), 8.61 (d, J = 2.0, 1H), 8.47 - 8.42 (m, 1H), 8.06 (dd, J = 2.5, 6.9, 1H), 7.84 (t, J = 2.2, 1H), 7.72 - 7.66 (m, 1H), 7.66 - 7.63 (m, 1H), 7.52 - 7.41 (m, 3H), 7.35 - 7.21 (m, 5H), 7.01 - 6.95 (m, 1H), 3.54 (s, 2H), 2.47 - 2.17 (m, 8H), 2.12 (s, 3H). Yield: 46%; HPLC: 97%; MS [M+1]: 535.3 Synthesis of amine compounds from formyl-azaindoles

[0129]

[0130] The aldehyde derivative (1 eq) and the amine derivative (1 eq) are dissolved in a methanol / acetic acid mixture (9 / 1). The mixture is stirred for 3 hours at room temperature, then sodium cyanoborohydride (2 eq) is added and the medium is stirred at room temperature overnight. The solvent is evaporated, the residue is taken up in ethyl acetate, washed twice with saturated aqueous NaHCO3 solution, once with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered through cotton and evaporated to dryness. The residue obtained is purified on a silica column with a gradient of 100% dichloromethane to 90 / 10 dichloromethane / methanol-ammoniacal. Benzyl-(4-fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzyl)-amine (Example 2) Reagents: 4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzaldehyde and Benzylamine RMN 1< H (400 MHz, DMSO-d6) δ (ppm) 12.13 (bs, 1H), 8.57 (d, J = 2.1, 1H), 8.24 (t, J = 1.9, 1H), 7.84 - 7.80 (m, 1H), 7.77 - 7.72 (m, 1H), 7.62 - 7.56 (m, 2H), 7.42 (t, J = 7.6, 1H), 7.36 - 7.15 (m, 8H), 3.74 (s, 2H), 3.72 (s, 2H), 3.51 (s, 2H), 2.47-2.15 (m, 8H), 2.13 (s, 3H). Rendement : 25% ; HPLC : 94% ; MS [M+1] : 520.3 (4-Fluoro-3-{5-[3-(4-méthyl-pipérazin-1-ylméthyl)-phényl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzyl)-(1H-imidazol-2-ylméthyl)-amine (Exemple 7) Réactifs : 4-Fluoro-3-{5-[3-(4-méthyl-pipérazin-1-ylméthyl)-phényl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzaldéhyde et (1H-Imidazol-2-yl)-méthylamine RMN 1< H (400 MHz, DMSO-d6) δ (ppm) 12.13 (s, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.77 - 7.70 (m, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.29 (dd, J = 11.3, 4.7 Hz, 3H), 6.87 (s, 2H), 3.73 (d, J = 9.6 Hz, 4H), 3.52 (s, 2H), 2.47-2.20 (m, 8H), 2.14 (s, 3H). Rendement : 46% ; HPLC : 99% ; MS [M+1] : 510.3 4-[2-(4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzylamino)-ethyl]-phenol (Example 1) Reagents: 4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzaldehyde and 4-(2-Amino-ethyl)-phenol NMR 1< H (400 MHz, DMSO-d6) δ (ppm) 12.23 - 12.01 (m, 1H), 9.08 (bs, 1H), 8.57 (d, J = 1.9, 1H), 8.27 - 8.19 (m, 1H), 7.85 - 7.78 (m, 1H), 7.76 - 7.69 (m, 1H), 7.61 (s, 2H), 7.42 (t, J = 7.6, 1H), 7.33 - 7.20 (m, 3H), 6.95 (d, J = 8.3, 2H), 6.61 (d, J = 8.3, 2H),, 3.76 (s, 2H), 3.52 (s, 2H), 2.74 - 2.65 (m, 2H), 2.65 - 2.58 (m, 2H), 2.45 - 2.19 (m, 8H), 2.13 (s, 3H).. Yield: 25%; HPLC: 98%; MS [M+1]: 550.3 Deprotection of amino derivatives.

[0131]

[0132] The protected amine derivative (1 eq) is dissolved in dioxane and concentrated hydrochloric acid (4 eq). The mixture is stirred for 2 hours at room temperature. The solvent is evaporated, the residue is taken up in an ethyl acetate / water mixture. The aqueous phase is neutralized by adding powdered NaHCO 3. The precipitate is filtered, then washed with water and dried. Example 2. BIOLOGICAL TESTS A- Selectivity of the compounds of the invention with respect to the AxL kinase

[0133] The compounds of the invention were evaluated for their Axl kinase inhibitory activity, selectively. 1- Inhibition of Axl kinase phosphorylation in cellulo

[0134] A549 cells were preincubated for 1 h with 2.5 µM of compound 1, 2 or 3. They were then stimulated for 5 min with 1 mM pervanadate, a compound known to activate Axl kinase by phosphorylation.

[0135] Inhibition of phosphorylation of residue Y779 of the intracytoplasmic domain of Axl is visualized by immunoblotting using the R&D Systems antibody (AF2228).

[0136] The results are illustrated in Figure 1 They show a much lower or even no activation of the Y779 residue of AxL in the presence of compounds 1, 2 and 3 compared to the control (DMSO). 2- Selective inhibition of Axl kinase

[0137] The inhibitory activity of the compounds on a panel of kinases including AXL and FLT3 was evaluated by Thermo Fisher Scientific using Z'-LYTE ®< and ADAPTA ®< Select Screen technologies.

[0138] The fluorescence-based biochemical assay uses coupled enzymes and is based on the difference in sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage. The peptide substrate is labeled with two fluorophores—one at each end—enabling fluorescence resonance transfer (FRET).

[0139] Compounds 1, 2 and 3 are tested in wells at the final concentration of 100 nM in 1% DMSO.

[0140] The results are presented in the following table:

[0141] Percentage of kinase inhibition by the compounds of the invention. Columns from left to right: the kinases tested - compound 1- compound 2- compound 3.

[0142] The results show that each of the compounds of the invention shows excellent activity (95%, 95% and 94% inhibition) on Axl kinase when, with respect to other kinases, the results are disparate from one compound to another.

[0143] To calculate the IC 50 values ​​for inhibition of Axl and FLT3 by the compounds of the invention, 10 concentrations of each compound 1, 2 and 3 were prepared by serial dilutions of one-third from the starting concentration. Axl or FLT3 kinases were diluted to a 2X concentration in kinase buffer. All ATP solutions were diluted to a 4X working concentration (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA).

[0144] Each compound is incubated at 10 concentrations ranging from 100 nM to 0.00495 nM to calculate the IC 50 .

[0145] The results are illustrated in figure 2 and summarized in the table below Compound IC 50 Axl IC 50 FLT3 1 5.36 nM 2.5 nM 2 2.36 nM 2.33 nM 3 6.3 nM 48.2 nM

[0146] Compounds 1, 2 and 3 show excellent activity against both Axl and FLT3 kinases. Compound 3 even shows selectivity for Axl over FLT3, with Axl playing a critical role in FLT3 activation. B- Antiviral evaluation

[0147] The compounds of the invention were evaluated for their antiviral activity in vitro, by testing the inhibitory effect of the molecules on the replication of complete infectious viruses. The chosen cell systems (HeLa, A549, A549-ACE2 cells) are relevant for the envisaged infectious models and have been validated for the expression of the Axl molecule in flow cytometry. Infectious models used:

[0148] Virus Model Strain Cells ZIKV mCherry Reporter BeH-8 HeLa DENV Luciferase reporter DENV2 HeLa WNV Luciferase reporter Kunjin (KUNV) HeLa CHIKV Luciferase reporter LROPY-1 HeLa SARS-CoV-2 Viral isolate BetaCoV / France / IDF0371 / 202 A549-ACE2, VeroE6, primary bronchial epithelium 1- Antiviral activity against the Zika virus

[0149] The assays are performed by pre-incubating 2.5 × 10⁴ HeLa cell line (cervical carcinoma; ATCC# CCL-2) cultured in 96-well plates with increasing concentrations of compounds for 1 h at 37°C. The cells are cultured in a 5% CO₂ atmosphere in Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum and 1% penicillin / streptomycin. The cells are then exposed to the ZIKV BeH8 strain (MOI = 0.1) for 1 h in the presence of the compound.

[0150] The viral inoculum is then removed and the cells are maintained in the presence of inhibitors for 24 h. Cell infection is determined by quantification of viral RNA detected by qRT-PCR using the Luna Universal One-Step RT-PCR kit and the primers 5'-CCGCTGCCCAACACAAG and 5'-CCACTAACGTTCTTTTGCAGACAT using the Luna Universal One-Step RT-PCR kit. The values ​​(DCT) are normalized to the quantification of GAPDH mRNA. The values ​​represented are the means of triplicates + standard deviation.

[0151] Control conditions were achieved by incubating the cells in the presence of DMSO, the solvent used for solubilization of the tested compounds. The volumes of DMSO used under these conditions correspond to the volumes provided by the compounds under the test conditions.

[0152] A parallel treatment, under the same experimental conditions, was carried out with R428 / Bemcentinib, Axl inhibitors in clinical trial phase developed by the company Bergenbio.

[0153] The results obtained with compounds 1, 2, 3, 10 and 11 are illustrated in Figure 3 The IC50 values ​​of compounds 1, 10 and R428 / Bemcetinib were determined using Graphpad Prism software.

[0154] Under these experimental conditions, compounds 1, 2, 3, 10 and 11 used at a concentration greater than or equal to 150 nM prevent infection of HeLa cells by the ZIKV BeH-8 strain. The in vitro efficacy of these compounds is at least equivalent to that of R428 / Bemcentinib described in the literature for its efficacy against the ZIKV virus at concentrations of 1 to 3 µM. 2- Antiviral activity against the Dengue virus

[0155] The assays are performed by preincubating 4×10 4< HeLa cells (human cervical adenocarcinoma; ATCC# CCL-2) grown in 96-well plates with increasing concentrations of compounds for 1 h. The cells are grown in a 5% CO2 atmosphere in Dulbecco's modified Eagle's medium (DMEM) comprising 10% calf serum and 1% Penicilin / streptomycin. The cells are then exposed to the DENV subtype 2 strain (DENV2) expressing a nanoluciferase gene upstream of the capsid protein coding sequence, in the presence of the compounds, for 1 h. The viral inoculum is then removed and the cells are maintained in the presence of the inhibitors for 3 days.

[0156] Cells were lysed using Passive Lysis Buffer reagent (Promega). Viral infection was detected by quantifying nanoluciferase activity in the cell lysate in the presence of Genofax A reagent (Yelen) using an Infinite F200PRO fluorometer (Tecan). Values ​​were normalized to the total protein content of the cell lysate, determined using the BCA Protein Assay kit (Pierce) by measuring absorbance at 562 nm. Values ​​shown are triplicate means plus standard deviation. Control conditions were identical to those described previously.

[0157] The results obtained with compounds 10, 11 and 14 are illustrated in Figure 4 .

[0158] Under these experimental conditions, compounds 10, 11 and 14 used at a concentration greater than or equal to 500 nM prevent infection of HeLa cells by the DENV2 subtype. 3- Antiviral activity against WNV virus Kunjin strain

[0159] The assays are performed by preincubating 4×10 4< HeLa cell line (ATCC# CCL-2) cultured in 96-well plates with increasing concentrations of compounds for 1 h. The cells are cultured in a 5% CO2 atmosphere in Dulbecco's modified Eagle's medium (DMEM) comprising 10% calf serum and 1% Penicillin / streptomycin. The cells are then exposed to WNV virus, Kunjin strain expressing a nanoluciferase gene upstream of the sequence coding for the capsid protein, in the presence of the compounds, for 1 h. The viral inoculum is then removed and the cells are maintained in the presence of the inhibitors for 24 h.

[0160] Cells were lysed using Passive Lysis Buffer reagent (Promega). Viral infection was detected by quantifying nanoluciferase activity in the cell lysate in the presence of Genofax A reagent (Yelen) using an Infinite F200PRO fluorometer (Tecan). Values ​​were normalized to the total protein content of the cell lysate, determined using the BCA Protein Assay kit (Pierce) by measuring absorbance at 562 nm. Values ​​shown are triplicate means plus standard deviation. Control conditions were identical to those described previously.

[0161] The results obtained for compound 10 are illustrated in Figure 5 .

[0162] Under these experimental conditions, compound 10 used at a concentration greater than or equal to 500 nM prevents infection of HeLa cells by WNV strain Kunjin. 4- Antiviral activity against Chikungunya virus

[0163] The assays are performed by preincubating 4×10 4< HeLa cells (ATCC# CCL-2) grown in 96-well plates with increasing concentrations of compounds for 1 h. The cells are grown in a 5% CO2 atmosphere in Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum and 1% penicillin / streptomycin. The cells are then exposed to the CHIKV virus, strain LR-OPY1, expressing either a luciferase gene or a GFP coding sequence upstream of the nsP3 protein coding sequence. The cells are incubated for 1 h in the presence of the compounds.

[0164] The viral inoculum is then removed and the cells are maintained in the presence of inhibitors for 24 h. Viral infection is measured after cell lysis using the Passive lysis Buffer reagent (Promega), either by direct quantification of GFP fluorescence or by quantification of luciferase activity in the cell lysate carried out in the presence of the Genofax A reagent (Yelen) and using an Infinite F200PRO fluorimeter (Tecan). The values ​​are normalized to the amount of total protein contained in the cell lysate and determined using the BCA Protein Assay kit (Pierce) by measuring the absorbance at 562 nm. In both protocols, the values ​​are normalized to the amount of total protein contained in the cell lysate and determined using the BCA Protein Assay kit (Pierce). The values ​​represented are the means of triplicates + standard deviation.The control conditions are identical to those described previously.

[0165] The results obtained for compound 10 are illustrated in Figure 6 .

[0166] Under these experimental conditions, compound 10 used at a concentration greater than or equal to 100 nM prevents infection of HeLa cells by the Chikungunya virus.

[0167] For each of the infectious models tested, the IC 50 of the active compounds were determined using Graphpad Prism software. Compound Virus CHIKV KUNV DENV ZIKV 1 198 Nm 2 25 nM 10 572 nM 836 nM 626 nM 397 nM 11 > 1 µM < 100 nM 14 > 1 µM > 1 µM R428 / Bemcentinib (reference) 239 nM ND 488 nM 285 nM

[0168] These evaluations indicate that several compounds have an EC 50 lower than 1µM. 5- Antiviral activity against SARS-CoV2 coronavirus

[0169] The inhibitory activity of the compounds of the invention on SARS-CoV2 infection was evaluated in vitro by infection of three lines relevant for the study of this pathogen: the green monkey line VeroE6 (immortalized kidney epithelium, ATCC#CRL-1586), the A549-ACE2 line produced by transfection of the ACE2 receptor in the A549 line (pulmonary epithelial carcinoma; ATCC# CCL-185), commercial primary bronchial epithelium cells (Mucilair Epithélix). a- Evaluation of antiviral activities in VeroE6 and A549-ACE2 cells

[0170] Infection tests are performed by preincubating 4×10 4< VeroE6 or A549-ACE2 cells cultured in 96-well plates with the indicated concentrations of compounds for 1 hour. The cells are cultured in a 5% CO2 atmosphere in Dulbecco's modified Eagle's medium (DMEM) comprising 2% calf serum and 1% penicillin / streptomycin. The cells were then exposed to the SARS-CoV2 virus, strain BetaCoV / France / IDF0371 / 2020 (MOI = 0.01) for 2 hours in the presence of the compounds before removal of the inoculum, washing and re-culturing the cells in the presence of the compounds. 24 hours after the viral challenge, the infection is quantified by amplification of viral RNA by qRT-PCR using the Luna Universal One-Step RT-PCR kit. (DCT) values ​​are normalized to GAPDH mRNA. Values ​​shown are triplicate means + standard deviation.Control conditions were achieved by incubating the cells in the presence of DMSO, the solvent used for solubilization of the tested compounds. The volumes of DMSO used under these conditions correspond to the volumes provided by the compounds under the test conditions.

[0171] A parallel treatment, under the same experimental conditions, was carried out with R428 / Bemcentinib, Axl inhibitors in clinical trial phase developed by the company Bergenbio.

[0172] The results obtained for compounds 1, 2, 3, 10 and 14 are illustrated in Figures 7 (VeroE6 line) and 8 (A549-ACE2 line).

[0173] Under these experimental conditions, compounds 1, 2, 3, 10 and 14 prevent infection of VeroE6 and A549-ACE2 cells by the SARS-CoV2 virus.

[0174] The IC 50 of compounds 1, 2 and 3 were determined on VeroE6 and A549-ACE2 cells using Graphpad Prism software.

[0175] The results obtained are illustrated in Figure 9 and in the following table: IC 50 Compound 1 2 3 A549-ACE2 19 nM 57 nM 38 nM Vero E6 77 nM 289 nM ND

[0176] Compounds 1, 2, 3, 10 and 14 exhibit anti-SARS-CoV2 activity in vitro. b- Evaluation of antiviral activities in primary human bronchial epithelium model

[0177] Primary bronchial epithelial infection tests were performed using the MucilAir™ Human airway epithelial cells (Epithelix) model cultured in appropriate medium (HAE medium, Epithelix). Compounds are added to the basal compartment of the culture and preincubated for 1 hour at 37°C. Viral inoculum (MOI = 0.01) is then added to the apical compartment at the same time as the compounds. After 2 hours at 37°C, the viral inoculum is removed, replaced with medium containing the test compound and the culture is maintained at 37°C for 24 hours. Cell infection is determined by quantification of viral RNA detected by qRT-PCR using the Luna Universal One-Step RT-PCR kit. The values ​​(DCT) are normalized to GAPDH mRNA.

[0178] The results obtained for compound 1 are illustrated in Figure 10 .

[0179] These evaluations indicate that compound 1 inhibits SARS-CoV2 infection of the primary bronchial epithelium.7- Preventive and curative activity of compound #1 against SARS-CoV2 coronavirus The inhibitory activity of compound 1 on SARS-CoV2 infection was evaluated in vitro in the context of preventive (Pre-Tt) or curative (Post-Tt) treatment of the A549-ACE2 line produced by transfection of the ACE2 receptor in the A549 line (lung epithelial carcinoma; ATCC# CCL-185) a), and the green monkey line VeroE6 (immortalized kidney epithelium, ATCC#CRL-1586).

[0180] Infection tests are performed on 4×10 4< cells cultured in 96-well plates, in a 5% CO2 atmosphere in Dulbecco's modified Eagle's medium (DMEM) comprising 2% calf serum and 1% penicillin / streptomycin. The cells are exposed to the SARS-CoV2 virus, strain BetaCoV / France / IDF0371 / 2020 (MOI = 0.01). The compounds are added to the cells either 1h before infection and maintained for 24h; or added to the cells 1h before infection and washed off 4h after viral challenge; or added to the cells 4h after exposure to the virus and maintained for 24h (Post-Tt). Residual infection is quantified by amplification of viral RNA by qRT-PCR using the Luna Universal One-Step RT-PCR kit. (DCT) values ​​are normalized to GAPDH mRNA.

[0181] Control conditions were achieved by incubating cells in the presence of DMSO (SARS-CoV-2), the solvent used to solubilize the tested compounds. The volumes of DMSO used in these conditions correspond to the volumes provided by the compounds in the test conditions.

[0182] The results obtained are illustrated in Figure 11 .

[0183] These evaluations indicate that the preventive use of the compounds inhibits SARS-CoV2 infection in human A549-ACE2 cells and monkey VeroE6 cells. Administration of the compounds after viral challenge reduces viral multiplication in A549-ACE2 cells, but not in the VeroE6 cell line, which is characterized by a defect in the production of type I interferons.

[0184] In conclusion, the active compounds on the different infectious models tested are as follows: Compound Virus CHIKV MAYV KUNV DENV ZIKV SARS-CoV-2 1 ND ND ACTIVE ND ACTIVE ACTIVE 2 ND ND ACTIVE ND ACTIVE ACTIVE 3 ND ND ND ND ND ACTIVE 10 ACTIVE ACTIVE ACTIVE ACTIVE ACTIVE ACTIVE 11 ND ND ND ACTIVE ACTIVE ND 14 ND ND ACTIVE ACTIVE ND ND

Claims

1. A compound of formula (I): in which X represents a hydrogen atom or a halogen atom, Y is selected from a hydrogen atom, a -CN, -CH2OH, -CH=NOH, -CO2H group, an aryl optionally mono- or polysubstituted, a heteroaryl optionally mono- or polysubstituted, and -L-(CH2)p-W, - L represents -C(O)NH-, -CH2NH-, -NHC(O)-, -CH2N=CH-, -CH=N-, - NHC(O)NH- or -CH2NHC(O)-, - p is an integer from 0 to 2, - when L represents -CH2NH-, -NHC(O)-, -CH2N=CH-, -CH=N-, -NHC(O)NH- or -CH2NHC(O)-, W is selected from: • a hydrogen atom, • a C1-C6 alkyl, preferably a methyl, • a C6-C10 aryl, optionally mono- or polysubstituted, advantageously by 1 to 3 groups independently selected from a halogen atom, a hydroxyl, a C1-C6 alkyl, or a C1-C6 alkoxyl, and • a 5- to 10-membered heteroaryl containing from 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl optionally being mono- or polysubstituted, advantageously it is optionally substituted with 1 to 4 groups independently selected from ∘ a halogen atom, ∘ a hydroxyl, ∘ an oxo group, ∘ a C1-C6 alkoxyl, ∘ a C1-C6 alkyl, wherein 1 or several hydrogen atoms is optionally replaced with a fluorine atom, and o a C6-C10 aryl, optionally substituted with a halogen atom and / or a C1-C6 alkyl; - when L represents -C(O)NH-, W is selected from: • an optionally mono- or polysubstituted phenyl, advantageously it is optionally substituted with a halogen atom, a hydroxyl group, a C1-C6 alkyl, or a C1-C6 alkoxyl group, and • a 5- to 10-membered heteroaryl comprising from 1 to 2 heteroatoms independently selected from N, O and S, said heteroaryl optionally being mono- or polysubstituted, advantageously it is optionally substituted with 1 to 4 substituents independently selected from ∘ a halogen atom, ∘ a hydroxyl, ∘ an oxo group, ∘ a C1-C6 alkoxyl group, ∘ a C1-C6 alkyl, wherein 1 or several hydrogen atoms is optionally replaced with a fluorine atom, and ∘ a C6-C10 aryl, optionally substituted with a halogen atom and / or a C1-C6 alkyl; - Z represents -CH2Q or -O(CH2)mT, - Q represents -OH, -SO2R1, -NR2R3, or -R4 - R1 represents a C1-C6 alkyl, - R2 and R3 each independently represent a C1-C6 alkyl, and - R4 represents a 5-7 membered heterocycloalkyl, comprising 1 to 2 heteroatoms independently selected from N, O and S, said heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from a C1-C6 alkyl, a C1-C6 C(O)-alkyl and a C1-C6 C(O)O-alkyl, - m is equal to 1 or 2, - T is -O(CH2)nCH3 or -R5 • n is 0 or 1 • R5 is a 5-7 membered heterocycloalkyl, comprising 1 to 2 heteroatoms independently selected from N, O and S, said heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from a C1-C6 alkyl, a C1-C6 C(O)-alkyl and a C1-C6 C(O)O-alkyl; or a pharmaceutically acceptable salt thereof or a mixture thereof, for use in the prevention and / or treatment of viral infections.

2. The compound for its use according to claim 1, of formula (Id): wherein X, Y and Z are as defined in claim 1.

3. The compound for its use according to claim 1 or 2, characterized in that Z represents -CH2R4 wherein R4 represents a piperazine group, optionally substituted with a C1-C6, alkyl, in particular a methyl.

4. The compound for its use according to any one of claims 1 to 3, characterized in that X represents a halogen, in particular fluorine.

5. The compound for its use according to any one of claims 1 to 4, characterized in that Y represents an aryl, a heteroaryl or L-(CH2)p-W, L representing -CH2NH or -NHC(O)NH-, p being an integer from 0 to 2, and W being selected from: - a phenyl optionally substituted with a hydroxyl group, or a C1-C6 alkyl group, and - a 5- to 10-membered heteroaryl comprising from 1 to 2 heteroatoms independently selected from N, O or S.

6. The compound for its use according to claim 5, characterized in that Y represents L-(CH2)p-W, L representing -CH2NH or -NHC(O)NH-, p being an integer from 0 to 2, and W being selected from: - a phenyl optionally substituted with a hydroxyl group, and - an imidazole.

7. The compound for its use according to any one of claims 1 to 4, characterized in that Y represents -NHC(O)-W, with W representing a 5- to 10-membered heteroaryl group, comprising from 1 to 2 heteroatoms independently selected from N, O or S, said heteroaryl being optionally substituted with 1 to 4 substituents independently selected from: - an oxo group, - a C1-C6 alkyl group, wherein 1 or several hydrogen atoms is optionally replaced with a fluorine atom, and - a C6-C10 aryl group, optionally substituted with a halogen atom and / or a C1-C6 alkyl group.

8. The compound for its use according to claim 7, characterized in that W is 2(1H)- pyridinone, optionally substituted with 1 to 4 substituents independently selected from: - a methyl, and - a phenyl optionally substituted with a fluorine atom.

9. A compound for its use according to claim 1, selected from: and preferably from and 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient for use in the prevention and / or treatment of viral infections.

11. The pharmaceutical composition for its use according to claim 10, further comprising an additional therapeutic agent, chosen from an antiviral agent, an antiinflammatory agent, an immunomodulatory or immunosuppressive agent, an agent for the treatment of immunodeficiency disorders and an agent for pain treatment.

12. A compound for its use according to any one of the claims 1 to 9 or composition for its use according to claim 10 or 11, wherein the viral infections are due to Flaviviruses, such as dengue virus, Zika virus, West Nile virus, Kunjin virus, Alphaviruses, such as Chikungunya virus, Mayaro virus, Semliki Forest virus, Sindbis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Filoviruses such as Ebola virus, Marburg fever virus, arenaviruses such as Lassa fever virus, Junin virus, Amapari virus, picornaviruses such as vesicular stomatitis virus, paramyxoviruses such as influenza virus or coronaviruses such as SARS-COV2.