Novel compounds for host directed antiviral strategy

Abstract

The present invention concerns novel synthetic compounds for use as antiviral drugs and / or for the treatment of cancer. The compounds of the invention are RED-SMU 1 disruptors and are capable of reducing viral reproduction, notably influenza A infections. The compounds of the invention were designed as functional analogues of compound LSP61 which is an inhibitor of RED-SMU 1 (which stands for its antiviral activity) and an inhibitor of the tyrosine kinase FGFR3 (which stands for its anti-cancer potential). In a preferred embodiment, the new compounds are favorite antiviral agents of increased selectivity for inhibiting RED-SMU1. In other embodiments, compounds of formula I are favorite anti-cancer agents.

Description

[0001] DESCRIPTION

[0002] Title: NOVEL COMPOUNDS FOR HOST DIRECTED ANTIVIRAL STRATEGY

[0003] TECHNICAL FIELD

[0004] The present invention concerns novel synthetic compounds for use as antiviral drugs and for the treatment of cancer. The compounds of the invention are RED-SMU 1 disruptors and are capable of reducing viral reproduction, notably influenza A infections.

[0005] STATE OF THE ART

[0006] Influenza A viruses (lAVs) are a leading cause of illness and death worldwide, causing recurring annual epidemics, frequent outbreaks, and occasional pandemics. The drugs currently approved for influenza treatment target viral components such as the M2 ion channel, the neuraminidase, and the polymerase. However, they have all led to the emergence of drug-resistant variants. M2 inhibitors are no longer recommended due to the natural resistance of currently circulating human H3N2 and H1 N1 pdm09 viruses. While the resistance to neuraminidase inhibitors (NAIs) in currently circulating human lAVs remains low (around 0.5%), there have been instances of large clusters of H1N1pmdO9 viruses developing resistance to oseltamivir, the most widely used NAI. Favipiravir, also known as T- 705, is undergoing phase III trials in America and Europe and has been approved in Japan for treating pandemic influenza virus infections. In October 2018, the FDA approved Xofluza, a selective inhibitor of the polymerase PA subunit, for the treatment of acute uncomplicated influenza. However, there has been recent evidence of viral adaptation to favipiravir treatment in cell culture, and the emergence of PA variants with a mutation conferring resistance to Xofluza was observed in 9.7% of treated patients in the Phase III trial.

[0007] Given this context, there is an urgent need for innovative antiviral medications. There are two main approaches to hinder viral replication and develop new therapeutic strategies. One is to directly target viral proteins of the pathogen, and the other is to target host proteins that are crucial for the viral life cycle and / or pathogenesis. Known as host-directed therapy, (HDT). The latter approach is more likely to address the issue of drug-resistant viruses emerging

[0008] Recently, there has been a growing interest and a rapid expansion in the concept of HDTs. Indeed, preclinical studies suggest that these therapies could offer clinical safety advantages while providing broad-spectrum efficacy and reducing antiviral resistance.

[0009] Currently, there are various host-directed therapies for both bacterial and viral diseases in clinical trials, each with different mechanisms of action. Antivirals currently undergoing advanced clinical trials encompass monoclonal antibodies directed against the viral hemagglutinin (HA) or matrix protein, a specialized inhibitor targeting the polymerase PB2 subunit, along with two compounds focusing on host cell factors: nitaxozanide, which disrupts the trafficking and maturation of the viral HA, and DAS181, which enzymatically eliminates the membrane receptors necessary for IAV attachment to target cells. The ongoing progress in identifying host factors crucial to the IAV life cycle lays the groundwork for the development of alternative host-directed antiviral medications. In alignment with this approach, we have scrutinized the structure of a vital human splicing factor, RED-SMU1 , essential for the IAV life cycle, and explored its potential as a target for IAV therapy.

[0010] Infectious IAV particles contain eight ribonucleoprotein complexes (vRNPs), corresponding to a set of eight distinct viral genomic RNA (vRNA) segments encapsidated with nucleoproteins (NP) and associated with the heterotrimeric viral RNA-dependent RNA polymerase (FluPol) consisting of the PB1, PB2 and PA subunits (Krammer F, et al. (2018) Influenza. Nat Rev Dis Primers 4:3.). The viral genome has a limited size (about 13.5 kb), but lAVs have evolved a variety of strategies to expand their coding capacity. Viral mRNAs are synthesized by the FluPol in the nucleus of infected cells. Although most of these are intronless, the M, NS and PB2 segments produce both unspliced mRNAs (M1, NS1, PB2) and spliced mRNAs (M2, NS2, PB2-S1). FluPol recruits a complex formed by the human splicing factors RED (78.9 kDa) and SMU1 (57.5 kDa) by direct binding to RED (Fournier G, et al. (2014) PLoS Pathog 10:e1004164). The complex RED-SMU1 regulates the splicing of viral NS1 mRNA into the mRNA encoding the multifunctional and essential NS2 / NEP protein. In cells depleted for RED or SMU1, the production of infectious influenza virions showed a 100-fold reduction. The RED-SMU 1 complex has therefore been identified as a new host target for inhibiting viral replication in a HDT approach.

[0011] European patent application EP3 722 295 A1 gives an example of a host directed anti-viral therapy strategy which targets the RED-SMU 1 complex. In particular, novel synthetic pyrido[2,3-d] pyrimidine and oxadiazole compounds were identified as RED-SMU 1 disruptors / destabilizers capable of inhibiting viral infections. Such compounds were identified by virtual and functional structure based drug screening. In order to do so, the researchers initially conducted a subdomain analysis of the human RED and SMU1 proteins using cellbased interaction assays. Then they identified compounds that target an a-helix-groove interface essential for RED-SMU 1 interaction, and then synthetized such compounds. Lastly, they showcased the potential of these compounds in destabilizing RED-SMU 1 for the purpose of inhibiting viral infections, including those caused by IAV. LSP61 was found to be one of the favorite compounds. Its binding mode was deduced from the XRay structure of LLC641 (a structural analog of LSP61) in complex with SMU1 which shows a binding surface identical to that of the natural partner RED, therefore probing its ability to disrupt the formation of the RED-SMU1 complex.

[0012] With the same approach and in continuation of such research work, the present patent application aims to propose novel compounds for inhibiting and destabilizing the RED-SMU1 complex.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention concerns novel synthetic compounds for use as antiviral drugs and / or for the treatment of cancer. The compounds of the invention are RED-SMU 1 disruptors and are capable of reducing viral reproduction, notably influenza A infections.

[0015] In particular, the invention concerns a compound according to formula I

[0016] Wherein : the Het-Het nucleus represents a bicyclic heteroaryl group which contains one, two or three nitrogen atoms, advantageously one or two nitrogen atom(s), in particular two nitrogen atoms;

[0017] Ar represents a C6-Ci0aryl group substituted by a group R1or by a group R1and a group R2wherein R1and R2represent independently of each other a C C2alkoxy group, a halogen atom, a C C6alkyl group substituted by an halogen atom, a -GN group, a -NO2group or a -O-(CH2)n-R3group or a -NH-C=O-R6group;

[0018] In which R3represents a guanidyl group, a -N(R4)(R5) group, a C3-C6heterocycloalkyl group or a C3-C10heteroaryl group, the heteroatom of the heterocycloalkyl group being optionally substituted by a N-protecting group, such as t- butyloxycarbonyl (BOC), when the heteroatom is a nitrogen atom;

[0019] In which R4and R5represent independently of each other a hydrogen atom or a C C4alkyl group; wherein n is an integer selected from 1 , 2 or 3; in which R6represents a C2-C6alkenyl group optionally substituted by a N(R7)(R8) group;

[0020] In which R7and R8represent independently of each other a hydrogen atom or a C1-C4 alkyl group, advantageously a methyl group;

[0021] Y represents a C C6alkyl group which can be substituted by one or several group(s) selected from a C3-C10 aryl group, a C3-C10 cycloalkyl group, a C3-C6heterocycloalkyl group, a C2-C6alkynyl group, a C2-C6alkenyl group, a C C2alkoxy group, a -CN group, a -CF3group, an halogen atom, a -SO3H group, a -PO3H group and a -NO2group, wherein the C3-C10aryl group is optionally substituted by a -NH-C=O-R9group; in which R9represents a C2-C6alkenyl group optionally substituted by a N(R10)(R11) group;

[0022] In which R10and R11represent independently of each other a hydrogen atom or a C1-C4 alkyl group, advantageously a methyl group;

[0023] L represents a linker selected from a -NH-CO- group, a -NH-CO-NH- group, a -NH-CS-NH- group and a -NH-SO2- group

[0024] X represents a C3-C10cycloalkyl group, a C C6alkyl group, a C6-C10aryl group, a C3-C10heterocycloalkyl group or a C3-C10heteroaryl group, and when the Het-Het nucleus contains 3 nitrogen atoms, Ar represents the 2-methoxy-phenyl group in which the phenyl group is optionally substituted by the -O- (CH2)n-R3group as defined above or Ar represents the 3,5-bis(trifluoromethyl)phenyl group or LX represents a group NH-C=O-CH2-t-Bu.

[0025] For the purpose of the present invention, the term “Cx-Cyalkyl group” is intended to mean any straight or branched alkyl group containing from x to y carbon atoms. In particular a C C6alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, t-butyl (t-Bu), n-pentyl, neopentyl (CH2-t-Bu), n-hexyl and the like. Advantageously it is a n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl or neopentyl group, more advantageously a n-propyl, t-butyl, n-pentyl or neopentyl group.

[0026] For the purpose of the present invention, the term “Cx-Cyaryl group” is intended to mean one or more aromatic rings having x to y carbon atoms, which may be joined or fused. In particular, the C3-C10aryl or C6-C10aryl group may be phenyl or naphthyl groups, more advantageously a phenyl group.

[0027] For the purpose of the present invention, the term “Cx-Cycycloalkyl group” is intended to mean one or more saturated rings having x to y carbon atoms which may be joined or fused. In particular, the C3-C10 cycloalkyl groups may be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentyl, norbornyl, adamantyl group. Advantageously it is a cyclopropyl, cyclohexyl or adamantyl group.

[0028] For the purpose of the present invention, the term “Cx-Cyheterocycloalkyl group” is intended to mean one or more saturated rings having x to y carbon atoms and containing one or several heteroatoms (in particular one or two), advantageously selected among N, O and S atoms, in particular an N atom, which may be joined or fused. In particular, the C3-C10or C3- C6heterocycloalkyl group may be a pyrrolidinyl, a tetrahydrofuryl, a piperidinyl, a piperazinyl, an imidazolidinyl, a pyrazolidinyl, a tetrahydropyranyl, a tetrahydrotiophenyl, a 1 ,4 dioxanyl, a thiomorpholinyl, a 1 ,3 dioxolanyl, a decahydroisoquinolinyl, an azaadamantanyl group. Advantageously it is a piperidinyl group.

[0029] For the purpose of the present invention, the term “Cx-Cyalkenyl group” is intended to mean straight or branched chain alkenyl group containing from x to y carbon atoms including, but not limited to, ethenyl (-C=CH2), propenyl, butenyl, pentenyl, hexenyl and the like. Advantageously it is an ethenyl group.

[0030] For the purpose of the present invention, the term “Cx-Cyalkynyl group” is intended to mean straight or branched chain alkynyl group containing from x to y carbon atoms including, but not limited to, ethynyl (—C=CH ), propynyl, butynyl, pentynyl, hexynyl and the like. Advantageously it is an ethynyl group.

[0031] For the purpose of the present invention, the term “Cx-Cyalkoxy group” is intended to mean any straight or branched chain alkoxy group having x to y carbon atom. In particular, the C C2alkoxy group may be a methoxy or ethoxy group. More particularly it is a methoxy group (- O-Me).

[0032] For the purpose of the present invention, the term “halogen atom” is intended to mean any halogen atom, advantageously selected among Cl, Br, I and F, more advantageously among Cl and F, in particular it is F.

[0033] For the purpose of the present invention, the term “Cx-Cyheteroaryl group” is intended to mean one or more aromatic rings having x to y carbon atoms and containing one or several heteroatoms (in particular one or two), advantageously selected among N, O and S atoms, in particular an N atom, which may be joined or fused. In particular, the C3-C10heteroaryl group may be an imidazolyl, a pyrazolyl, a pyrrolyl, a furanyl, a thiophenyl, an oxazolyl, a pyridinyl, a pyridazinyl, a pyrimidinyl, a pyrazinyl, a pyranyl, a thiopyranyl, an oxazinyl, a thiazinyl, a benzimidazolyl, an indazolyl, a benzofuranyl, a quinolinyl or a quinazolinyl group, more advantageously it is an imidazolyl group.

[0034] For the purpose of the present invention, the term “N-protecting group” as used in the present invention refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)). N-protecting groups comprise carbamates, amides, N-alkyl derivatives, amino acetal derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives and N- heteroatom derivatives. In particular, N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), acetyl and the like, advantageously it is t-butyloxycarbonyl (BOC).

[0035] Advantageously, the compound according to the present invention has the following formula II: in which Z-i, Z2and Z3represent independently of each other a nitrogen atom or a CH group on the condition that at least one of Z-i, Z2and Z3, in particular Z2, represent a nitrogen atom and Ar, L, X and Y are as defined above. More advantageously, at least one of Z-i, Z2and Z3, in particular Z-i, represent a CH group.

[0036] Still more advantageous two of Z-i, Z2and Z3, in particular Z2and Z3, represent a nitrogen atom.

[0037] In an advantageous manner in formula I, the Het-Het nucleus represents one of the following formulae:

[0038] More advantageously the Het-Het nucleus represents a bicyclic heteroaryl group which contains one or two nitrogen atoms, in particular two nitrogen atoms, notably according to one of the following formulae:

[0039] IA IB IC

[0040] Most preferably, the Het-Het nucleus denotes a bicyclic heteroaryl containing two nitrogen atoms, in particular according to formula IA.

[0041] Therefore advantageously in formula II, Z-i represents a CH group and Z2and Z3represent a N atom. In this case the compound according to the present invention has the following formula III: in which Ar, L, X and Y are as defined above.

[0042] In another advantageous embodiment in formula II, Z3represents a CH group and Zi and Z2represent a N atom. In this case the compound according to the present invention has the following formula IV: in which Ar, L, X and Y are as defined above. In another advantageous embodiment in formula II, Z2represents a N atom and Z-i and Z3represent a CH group. In this case the compound according to the present invention has the following formula V: in which Ar, L, X and Y are as defined above.

[0043] In another advantageous embodiment in formula II, Z-i, Z2and Z3represent a N atom. In this case the compound according to the present invention has the following formula VI: in which Ar, L, X and Y are as defined above.

[0044] In one embodiment Ar represents a phenyl group. Advantageously the R1and R2groups are not in para position. More advantageously the R1and R2groups are in ortho or meta position, in particular the R1group is in ortho position or meta position and the R2group, if any, is in meta position. More advantageously the R1and R2groups are not on adjacent carbon atoms on the phenyl ring. In particular Ar represents one of the following substituted phenyl group of formulae:

[0045] In one embodiment R1and R2represent independently of each other a CrC2alkoxy group, advantageously a methoxy group, a C C6alkyl group substituted by an halogen atom, advantageously a -CF3group, a -O-(CH2)n-R3group in which n and R3are as defined above, in particular a -O-(CH2)3-R3group or a -O-(CH2)2-R3group in which R3is as defined above, or a -NH-C=O-R6group in which R6is as defined above.

[0046] More advantageously R1represents a C1-C2alkoxy group, advantageously a methoxy group or a C C6alkyl group substituted by a halogen atom, advantageously a -CF3group. In particular R1represents a CrC2alkoxy group, advantageously a methoxy group. In one embodiment R3represents a guanidyl group, a -NH2group, a C5heterocycloalkyl group, in particular a piperidinyl group, or a C3heteroaryl group, in particular an imidazolyl group, the C5heterocycloalkyl group being optionally substituted by a N-protecting group such as a BOC group when the heteroatom is a nitrogen atom, in particular a piperidinyl group in which the nitrogen atom is substituted by a N-protecting group such as a BOC group. Advantageously R3represents a guanidyl group, a -NH2group, a piperidinyl group, a piperidinyl group in which the nitrogen atom is substituted by a BOC group or an imidazolyl group. More advantageously R3represents an imidazolyl group.

[0047] In one embodiment R6represents a C2-C6alkenyl group substituted by a N(R7)(R8) group, advantageously a C3alkenyl group substituted by a N(R7)(R8) group such as N(CH3)2, more advantageously a -CH=CH-CH2-N(R7)(R8) group, still more advantageously a -CH=CH-CH2- N(CH3)2group.

[0048] In one embodiment R1and R2represent independently of each other a -O-Me group, a -CF3group, a -CH=CH-CH2-N(CH3)2group, a -O-(CH2)n-R3group wherein R3represent a guanidyl group, a -NH2group, a piperidinyl group, a piperidinyl group in which the nitrogen atom is substituted by a BOC group or an imidazolyl group and n is an integer selected from 1 , 2 and 3,.

[0049] In one embodiment R1and R2represent both a CrC2alkoxy group, advantageously a methoxy group.

[0050] In one embodiment R1and R2represent both a C C6alkyl group substituted by an halogen atom, advantageously a -CF3group.

[0051] In one embodiment R2represents a CrC2alkoxy group, advantageously a methoxy group, a -O-(CH2)n-R3group in which n and R3are as defined above, in particular a -O-(CH2)3-R3group in which R3is as defined above, or a -NH-C=O-R6group in which R6is as defined above.

[0052] In an advantageous embodiment, Ar represents a 2-methoxy-phenyl, a 3, 6-dimethoxyphenyl or a 1-(3-(5-(3-(1 H-imidazol-1-yl)propoxy)-2-methoxyphenyl.

[0053] In one embodiment Y represents a C C6alkyl group which can be substituted by one or several group(s), advantageously one group, selected from a C3-C10aryl group, advantageously a phenyl group, a C3-C cycloalkyl group, advantageously a cyclohexyl group, a C2-C6alkynyl group, advantageously an ethynyl group, a CrC2alkoxy group, advantageously a methoxy group, or a -CF3group, the C3-C10aryl group being optionally substituted by a -NH-C=O-R9group in which R9is as defined above, advantageously a phenyl group substituted by a -NH-C=O-R9group in which R9is as defined above. Advantageously Y represents a C C6alkyl group, in particular a n-pentyl group or a n-propyl group, which can be substituted by a group selected from a -O-Me group, a -CF3group, a — C==CH group, a cyclohexyl group, a phenyl group and a phenyl group substituted by a - NH-C=O-R9group in which R9is as defined above.

[0054] In one embodiment R9represents a C2-C6alkenyl group substituted by a N(R10)(R11) group, advantageously a C3alkenyl group substituted by a N(R10)(R11) group such as N(CH3)2, more advantageously a -CH=CH-CH2-N(R10)(R11) group, still more advantageously a -CH=CH- CH2-N(CH3)2group.

[0055] In an advantageous embodiment Y represents a group -(CH2)mR12in which m represent an integer selected from 1 to 5, in particular from 3 and 4, and R12represents a -CH3group, a C3-Cw aryl group, a C3-C10cycloalkyl group, a C3-C6heterocycloalkyl group, a C2-C6alkynyl group, a C2-C6alkenyl group, a C C2alkoxy group, a -CN group, a -CF3group, an halogen atom, a -SO3H group, a -PO3H group and a -NO2group, the C3-C10aryl group being optionally substituted by a -NH-C=O-R9group in which R9is as defined above. Advantageously R12represents a -CH3group, a C3-C10aryl group, advantageously a phenyl group, a C3-C10cycloalkyl group, advantageously a cyclohexyl group, a C2-C6alkynyl group, advantageously an ethynyl group, a C C2alkoxy group, advantageously a methoxy group or a -CF3group or a C3-C10aryl group substituted by a -NH-C=O-R9group in which R9is as defined above, advantageously a phenyl group substituted by a -NH-C=O-R9group in which R9is as defined above. More advantageously R12represents a -CH3group, a -O-Me group, a -CF3group, a—C=CH group, a cyclohexyl group, a phenyl group or a phenyl group substituted by a -CH=CH-CH2-N(CH3)2group.

[0056] In another advantageous embodiment Y represents a C2-C4alkyl group substituted by one group selected from a C3-C10aryl group, advantageously a phenyl group, a C3-C10cycloalkyl group, advantageously a cyclohexyl group a -CF3group or a C3-C10aryl group substituted by a -NH-C=O-R9group in which R9is as defined above, advantageously a phenyl group substituted by a -NH-C=O-R9group in which R9is as defined above. Advantageously Y represents a C3alkyl group substituted by a group selected from a -CF3group, a cyclohexyl group and a phenyl group.

[0057] In one embodiment L represents a linker selected from a -NH-CO- group and a -NH-CO-NH- group.

[0058] In one embodiment X represents a C3-C10cycloalkyl group, in particular a cyclopropyl group, an adamantyl group or a cyclohexyl group, more particularly an adamantyl group, a Ci-C6alkyl group, in particular a -CH2-t-Bu group or -t-Bu group, or a C6-C10aryl group, in particular a phenyl group or a naphthyl group, more particularly a phenyl group. Advantageously X represents a -CH2-t-Bu group, a -t-Bu group, a cyclopropyl group, an adamantyl group, a cyclohexyl group, a phenyl group or a naphthyl group, more advantageously a -CH2-t-Bu group, a -t-Bu group, an adamantyl group or a phenyl group.

[0059] In an advantageous embodiment X represents a C3-C10cycloalkyl group, in particular an adamantyl group or a C C6alkyl group, in particular a -CH2-t-Bu group or -t-Bu group. Advantageously X represents a -CH2-t-Bu group, a -t-Bu group or an adamantyl group.

[0060] In one embodiment, the compound according to the present invention has at least one the following characteristics:

[0061] - Y represents a C5alkyl group, a CrC4alkyl group substituted by a O-Me group, a CF3group, — C==CH group or a -C=CH2group, a cyclohexyl group, a cyclopropyl group, a phenyl group or a phenyl group substituted by a -NH-C=O-R9group in which R9is as defined above;

[0062] X represents a C4-C5alkyl group, a C3-C10cycloalkyl group, a C6-C10aryl group; a C3- C6heterocycloalkyl group, or a C3-C10heteroaryl, and more preferably, X represents a -CH2-t-Bu group, a -t-Bu group, a cyclopropyl group, an adamantyl group, a cyclohexyl group, a phenyl group or a naphthyl group; the Het-Het nucleus in formula I represents a bicyclic heteroaryl containing one or two nitrogen atoms according to one of the formulae IA IB or the compounds has the formula III, IV or V as defined above and wherein:

[0063] Ar represents a substituted phenyl group in which the substituents R1and / or R2are selected from -O-Me, -CF3, -CH=CH-CH2-N(CH3)2, -O-(CH2)n-R3wherein R3represents a guanidyl group, a -NH2group, piperidinyl group or an imidazolyl group and n is an integer selected from 1 , 2 and 3.

[0064] In a preferred embodiment, the substituents in formula I, II, III, IV, V or VI are selected from at least one or all of the following options: - X represents a -CH2-tBu group, a t-Bu group, or an adamantyl group;

[0065] - Y represents a C3alkyl group substituted by a -CF3group, a cyclohexyl group or a phenyl group; and / or

[0066] - Ar represents a 2-methoxy-phenyl group, a 2,4-dimethoxy phenyl group, or a group. For example, the compound of formulae I, II, III, IV, V and VI presents one of the following structures:

[0067]

[0068] In a preferred embodiment, in particular for treating cancer, the compound of formula I, II or IV has the following structure:

[0069] 51

[0070] The present invention also concerns compounds of formula I, II, III, IV, V or VI, its enantiomers and pharmaceutical acceptable salts for: use as a medicament and / or use in the prevention and / or treatment of a viral infection, and wherein such viral infection is preferably an infection by a virus chosen from influenza viruses, human immunodeficiency viruses and human papillomaviruses, preferably chosen from Influenza virus A, Influenza virus B, Influenza virus C, Influenza virus D, HIV-1, HIV-2, HPV16, HPV18, HPV6 and HPV11, and more preferably wherein the viral infection is Influenza virus A; and / or for use for treating and / or preventing cancer.

[0071] In the sense of the present invention, the term “pharmaceutically acceptable” is intended to mean all that is useful in the preparation of a pharmaceutical composition, that is generally safe and non-toxic and that is no biologically or else non desirable and that is acceptable for veterinary and human pharmaceutical use.

[0072] In the sense of the present invention, the term “pharmaceutically acceptable salt” of a compound is intended to mean the salts which are pharmaceutically acceptable, as defined above, and which have the desired pharmacologic activity of the parent compound. Such salts include:

[0073] (1) acid addition salts formed with inorganic acids such as hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like or formed with organic acids such as ascorbic acid, benzoic acid, aspartic acid, oxalic acid, benzene sulphonic acid, tartaric acid, diatriazoic acid, glutamic acid, lactic acid, maleic acid, succinic acid, fumaric acid, citric acid, edetic acid, malic acid mandelic acid methanesulfonic acid, mucic acid, pantothenic acid, para-toluenesulfonic acid, acetic acid, gluconic acid, ethanesulfonic acid, propionic acid, salicylic acid and the like; or

[0074] (2) salts formed when an acid proton present in the parent compound is either replaced by a metallic ion, for example alkali metal ion, alkaline-earth metal ion or aluminum ion; or is coordinated with an 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.

[0075] It should be understood that all references to pharmaceutically acceptable salt include solvates and polymorphs of the same acid addition salts.

[0076] The invention also concerns a composition comprising a compound of formula I, II, III, IV, V or VI, its enantiomers or pharmaceutical acceptable salts, as well as mixtures thereof, at least one excipient. Such composition may also include an antiviral agent such as baloxivir marboxil, amantadine, moroxydine, oseltamivir, peramivir, rimantadine, uminfenovir, zanamivir, abacavir, ampligen, amprenavir, atazanavir, cidofovir, elvitegravir, emtricitabine, nirmaltrevir, ritonativ and mixtures thereof.

[0077] Such composition is for example a pharmaceutical composition, and the invention concerns the use of such composition as a medicament, and wherein that medicament is preferably an antiviral medicament or an anticancer, antitumoral and / or cytotoxic medicament.

[0078] Finally, the invention concerns the use of a compound of formula I, II, III, IV, V or VI as an in vitro inhibitor of RED-SMU1 complex and / or FGFR3.

[0079] FIGURES Figure 1 : Rationale for the modulation of biological activities a) Molecular docking of LSP61 in FGFR3. Positioning in the binding pocket (on the left) and key interactions (on the right) ; b) Molecular docking of LSP61 in SMU1. Positioning in the interaction surface (on the left) and key interactions (on the right).

[0080] Figure 2: Working hypotheses to disconnect FGFR3 and RedSMU activities in order to enhance selectivity of new LSP61 analogues, and the four series of molecules thereof.

[0081] Figure 3: Validation of working hypotheses in figure 2, and examples of a new first generation of analogues of LSP61 and their IC50 for inhibition of FGFR3.

[0082] Figure 4: Examples of series IV analogues modified on the exocyclic amine with different substituents interacting with the small hydrophobic pocket in SMU1.

[0083] Figure 5: Examples of series IV analogues modified on the exocyclic amide with different substituents interacting with the hydrophobic pocket in SMU1.

[0084] Figure 6: Examples of series IV analogues modified on the exocyclic aromatic ring with different substituents with possible ionic interactions with E83 in SMU1.

[0085] Figure 7: Viral replication essay at 40 pM. A549 cells infected with WSN-Nanoluc and in the presence of all the new analogues.

[0086] Figure 8: Cell viability assay for evaluating toxicity of all inhibitors at 5pM.

[0087] Figure 9: Viral replication essay at 5 pM. A549 cells infected with WSN-Nanoluc and in the presence of analogues of figure 3.

[0088] Figure 10: Viral replication essay at 5 pM. A549 cells infected with WSN-Nanoluc and in the presence of analogues of figure 4.

[0089] Figure 11: Viral replication essay at 5 pM . A549 cells infected with WSN-Nanoluc and in the presence of analogues of figure 5.

[0090] Figure 12: Viral replication essay at 5 pM. A549 cells infected with WSN-Nanoluc and in the presence of analogues of figure 6.

[0091] Figure 13: 2d representation of RED-SMU1 disruption in rapport with the IAV replication.

[0092] Figure 14: Synthetic strategies toward titled compounds

[0093] DETAILED DESCRIPTION

[0094] The aim of the present invention is to propose novel compounds which are RED SMU 1 disruptors for host directed therapies. The compounds of the invention are able to inhibit viral replication and are particularly useful for treating influenza A virus.

[0095] In particular, the invention concern compounds of formula (I) here bellow:

[0096] In which : the Het-Het nucleus represents a bicyclic heteroaryl group which contains one, two or three nitrogen atoms; Ar represents a C6-Cw aryl group substituted by a group R1or by a group R1and a group R2wherein R1and R2represent independently of each other a C C2alkoxy group, a halogen atom, a C C6alkyl group substituted by an halogen atom, a -CN group, a -NO2group or a -O-(CH2)n-R3group or a -NH-C=O-R6group;

[0097] In which R3represents a guanidyl group, a -N(R4)(R5) group, a C3-C6heterocycloalkyl group or a C3-C10heteroaryl group, the heteroatom of the heterocycloalkyl group being optionally substituted by a N-protecting group, such as t-butyloxycarbonyl (BOC), when the heteroatom is a nitrogen atom;

[0098] In which R4and R5represent independently of each other a hydrogen atom or a C C4alkyl group; wherein n is an integer selected from 1 , 2 or 3, advantageously from 2 or 3; in which R6represents a C2-C6alkenyl group optionally substituted by a N(R7)(R8) group;

[0099] In which R7and R8represent independently of each other a hydrogen atom or a CrC4alkyl group, advantageously a methyl group;

[0100] Y represents a C C6alkyl group which can be substituted by one or several group(s) selected from a C3-C10aryl group, a C3-C10cycloalkyl group, a C3-C6heterocycloalkyl group, a C2-C6alkynyl group, a C2-C6alkenyl group, a C C2alkoxy group, a -CN group, a -CF3group, an halogen atom, a -SO3H group, a -PO3H group and a -NO2group, wherein the C3-C10aryl group is optionally substituted by a -NH-C=O-R9group; in which R9represents a C2-C6alkenyl group optionally substituted by a N(R10)(R11) group;

[0101] In which R10and R11represent independently of each other a hydrogen atom or a C C4alkyl group, advantageously a methyl group;

[0102] L represents a linker selected from a -NH-CO- group, a -NH-CO-NH- group, a -NH- CS-NH- group and a -NH-SO2- group

[0103] X represents a C3-C10cycloalkyl group, a C C6alkyl group, a C6-C10aryl group, a C3- C10heterocycloalkyl group or a C3-C10heteroaryl group, and when the Het-Het nucleus contains 3 nitrogen atoms, Ar represents the 2-methoxy- phenyl group in which the phenyl group is optionally substituted by the -O-(CH2)n-R3group as defined above or Ar represents the 3,5-bis(trifluoromethyl)phenyl group or LX represents a group NH-C=O-CH2-t-Bu.

[0104] More precisely, such Het-Het nucleus represents one of the following formulae:

[0105] The compounds of the invention were conceived as functional analogues of compound LSP61 disclosed in EP 3 722 295 A. Compound LSP61 (also referenced as ALG61) was originally synthetized as a precursor of a new functional analogue of agent PD173074, which is an anticancer agent from Pfizer and an inhibitor of the tyrosine kinase FGFR3.

[0106] Both PD173074 and LSP641 were discovered to be also disruptors of RED / SMU 1. The functional analogues of LSP641 (ALG 61) are therefore new potential antiviral agents acting as inhibitors of RED-SMU1 complex, and / or as anticancer agents acting as inhibitors of FGFR3. The new RED-SMU 1 disruptors of the invention were designed based on the molecular determinants that are involved in the binding to FGFR3 on the one hand, and to SMU1 on the other hand.

[0107] FGFRs stands for Fibroblast Growth Factor Receptors and are a group of tyrosine kinase receptors found on cell membranes. They play a vital role in various significant biological processes such as cell growth, division, specialization, viability, tissue regeneration, and more. Irregularities in the signaling pathways regulated by FGFRs are associated with various types of cancers. This is why a number of small molecule inhibitors have been created to target these kinases. Such inhibitors include PD173074 which has shown high potency and selectivity to inhibit FGFR3 in nanomolar concentration.

[0108] As it has already being introduced, RED-SMU 1 complex is a vital human splicing factor, essential for the I AV life cycle, and that is recruited by Influenza A virus for regulating the splicing of his own mRNA. For reference, LSP61 (ALG61) inhibits FGFR3 at 0.01 pM and RED-SMU 1 at 15 pM. RED-SMU 1 complex has also been related to other viral infections such as HIV and HPV, however its overall general role in therapeutics is still to be elucidated.

[0109] In order to propose new functional analogues of LSP61 , the key interactions of this compound with FGFR3 and RED-SMU1 were carefully evaluated in silico. Figure 1 a) shows the molecular docking of LSP61 in FGFR3, and Fig. 1 b) shows the molecular docking of LSP61 in SMU1. Comparison of the key interactions highlighted rationale possibilities to modulate biological activities.

[0110] As illustrated in Fig. 2, after careful evaluation of all basic interactions with RED-SMU 1 and FGFR3, the inventors proposed two working hypotheses in order to disconnect FGFR3 and RedSMU activities. This would lead to the development of four new series of functional analogues of LSP61 with enhanced selectivity. First series focuses on modifying substituents of LSP61 while keeping the same scaffold (which corresponds to Formula ID or VI as defined above), and series II, III, and IV focus on modifying the scaffold of LSP61 (which respectively corresponds to formulae IC, IB and IA or V, IV and III as defined above). The analogues from series II (which corresponds to formula IC or V as defined above) have a quinoline central nucleus, and series III and IV ((which respectively corresponds to formulae IB and I A or IV and III as defined above) have respectively a quinazoline and a naphthyridine nucleus center. Hence, the scaffold of series I to IV corresponds respectively to the Het-Het nucleus of formula ID, IC, IA, and ID of formula I or to the compounds of formula VI, V, IV and III as defined above.

[0111] Fig. 3 shows examples of the first new generation of analogues in the present study, and their IC50(pM) against FGFR3, as the validation of the working hypotheses. The IC50of the anticancer reference PD173074 is also shown for comparison. Results show that series III analogues are potent inhibitors of FGFR3 and are therefore preferred potential anticancer agents. In particular, the quinazoline 51 showed the same sub-nanomolar range as the reference inhibitor PD173074. On the other hand, compounds from series I bearing selected substituents (such as 21, 22 and 25) and IV (as 86 for example) showed a decreased ability to bind FGFR3, and are preferred candidates as antiviral agents. Indeed, such compounds will bind preferably SMU 1 resulting in an increased selectivity.

[0112] In the next stage of the research, the antiviral activity was studied with regards to the effect of substituents in order to design new analogues with higher selectivity and / or antiviral activity. Focus was first made on substituents fitting in hydrophobic pockets (corresponding to substituents Y and X in formulae I, II, III, IV, V and VI) and with possible ionic interactions with E83 (corresponding to the Ar substituent in formula I, II, III, IV, V and VI). Figures 4 to 6 provide specific examples of such analogues which were studied with the naphthyridine scaffold, and wherein the Het-Het nucleus is denoted by formula IA of formula I or of compounds of formula III as defined above. It is to be noticed that even though the effect of such substituents was studied within the naphthyridine scaffold, the substituent effect shall be considered valid for all scaffolds (according to scaffold hopping strategy).

[0113] The antiviral activity of the compounds of the invention was then evaluated. The test for the evaluation of the inhibition of the IAV replication relies on the use of A549 cells (which are lung carcinoma epithelial cells) infected with a replication-competent Influenza reporter virus named WSN-Nanoluc, which in addition of the viral proteins, express a luciferase, therefore emitting bioluminescence. The compounds of the invention were first tested at a concentration of 40 pM and the results are presented in fig. 7. The results are very positive and all the tested compounds exhibit antiviral activity against influenza A virus in a better or similar way than the original molecule LSP61. Noteworthy, these compounds are also nontoxic (figure 8). For almost all the tested compounds, the percentages of bioluminescence after incubations are below 20, meaning that the viral replication is inhibited for more than 80% compared to the DMSO control.

[0114] In light of the above, all of the new analogues are potential new antiviral agents. However, at the 40 pM tested concentration, it is difficult to distinguish which are the best candidates and the effect of the substituents and scaffold. Hence, the analogues were also tested at a concentration 5 pM by triplicate twice. Figure 9 shows the results of each test for the antiviral activity at 5 pM of the first synthetized new analogues (illustrated in figure 3). As it can be observed, while all the analogues exhibit antiviral activity at 40 pM, at 5pM only the quinazoline derivative 51 maintained an antiviral activity comparable with the one of ALG61. Since quinazoline 51 is also a very active inhibitor of FGFR3, this compound is a preferred anticancer agent.

[0115] However, it is also to be noticed from this experiment that compound 21 exhibits the best antiviral activity within the series I scaffold, while also exhibiting an increased selectivity to RED-SMU 1 when compared to ALG61 (LSP61). Therefore, pyridopyrimidine 21 can be considered a superior antiviral agent when compared to ALG61 , as it will have increase selectivity for RED-SMU1. Indeed, compound 21 showed the highest IC50to FGFR3(see fig.3) in the present study. Compound 21 presents also the same pyridopyrimidine scaffold as ALG61(LSP61), as well as the same substituents with the exception of 2-methoxy-phenyl (corresponding to the Ar substituent in formula I, II and VI). Hence the increased selectivity of compound 21 (with regards of ALG 61) is the effect of substituent 2-methoxy-phenyl.

[0116] Fig. 10 shows the antiviral activity measured at 5 pM concentration for the naphthyridine series modified with different substituents fitting the small hydrophobic pocket in SMU1 , and corresponding to substituent Y in formula I, II and III. The tested compounds are illustrated in figure 4, and they are all active at 40 pM. However, at the 5 pM concentration, only some compounds exhibit significant antiviral activity. From these results, it is possible to conclude that the best substituents for an antiviral agent of increased inhibition of RED-SMU 1 are those of compounds 94b, 94c, and 94d. Thus, preferred substituents for Y in formula I are C2-C4alkyl, preferably C3alkyl, and wherein such alkyl is substituted by a CF3, cyclohexyl or phenyl.

[0117] Fig. 11 shows the antiviral activity measured at 5 pM concentration for the naphthyridine series IV modified with different substituents fitting the second hydrophobic pocket in SMU1 and corresponding to substituents L and X in formulae I, II and III. The tested compounds are illustrated in figure 5 and the antiviral results show that the preferred substituents for increased antiviral activity are those of compounds 90a and 90e. Hence, preferred substituents for X in formulae I, II and III are -CH2-t-Butyl, -t-Butyl, and adamantyl, and wherein L is -NHCO. However, it is reasonable to expect that the effect of substituent X will be preserved when L is NH-CO-NH, NH-CS-NH, NH-SO2based on molecular affinity and size of the linker L.

[0118] In a similar way, Fig. 12 shows the antiviral activity measured at 5 pM concentration for the naphthyridine series IV modified with different substituents fitting the long hydrophobic groove in SMU1, and corresponding to substituent Ar in formula I, II and III. Fig. 6 illustrates the compounds that were tested and who appear once again less active than at a 40 pM concentration. However, the results allow us to conclude that the preferred substituents for new antiviral agents are those of compounds 131 and 123a and 123b. Hence, preferred substituents for Ar in formula I, II and III are 2-methoxy-phenyl, 3, 6-dimethoxyphenyl and 1- (3-(5-(3-(1 H-imidazol-1-yl)propoxy)-2-methoxyphenyl.

[0119] Further tests were done in order to confirm the results of figures 10 to 12, in which some of the compounds exhibit a great variability in antiviral activity depending on the experiment. In particular, the results of antiviral activity were correlated with the ability in cellulo of the compounds to selectively disrupt RED-SMU1 , and which is of course the mechanism of action of the exhibited anti-viral activity.

[0120] Fig. 13 shows the 2d representation of RED-SMU 1 in cellulo disruption in rapport with the IAV replication. The in cellulo evaluation of the ability of the inhibitors to selectively disrupt RED-SMU 1 interaction relies on the use of the split-gaussia luciferase. The percentages of the reduction of RED-SMU1 interaction are normalized using JUN-FOS interaction as control. In fact, JUN-FOS are, like Red and SMU1 , two interacting proteins located in the nucleus of the cells and, moreover, the measure of their interaction with the split-Gaussia luciferase system is well established and frequently used. The results are reported in a bidimensional graphic with the % of RED-SMU 1 interaction in rapport with the % of the IAV viral replication. This allows to confirm the correlation between the measured antiviral activity and the target inhibition. Furthermore, it enables the identification with only one graph of best RED-SMU1 disruptors and of the best antiviral agents. The compounds positioned in the lower left corner are the best candidates for anti-viral agents acting as RED-SMU 1 disruptors. The results confirm that compounds 21, 51 , 94b, 94c, 94d, 90a, 90e, 131 , 123a and 123b are indeed the best antiviral agents and disruptors of RED-SMU1. Excluding compound 51, all of such compounds have increased selectivity for RED-SMU1 and can therefore be considered superior antiviral agents when compared to the original inhibitor LSP61 (ALG61).

[0121] Toxicity tests were also carried out to evaluate the toxicity of the synthetized compounds of the invention at the 5 pM concentration. The results (fig. 8) show that the compounds are not toxic and they do not affect cell viability.

[0122] In light of the above, the compounds of formula I, II, III, IV, V and VI are proposed for use as antiviral and / or anticancer agents.

[0123] Antiviral use

[0124] According to a first embodiment, the compounds of formula (I), II, III, IV, V or VI as defined above, their enantiomers and / or their pharmaceutically acceptable salts may be used for preventing and / or treating a viral infection.

[0125] By "preventing", it is meant for the purpose of the present invention avoiding the viral infection to occur. By "treatment" it is meant for the purpose of the present invention the curative treatment of viral infection. A curative treatment is defined as a treatment that completely treats (cure) or partially treats a viral infection. The "subject" refers to any subject and typically designates a patient afflicted by a viral infection, in particular an animal including a human being, more particularly a human being.

[0126] By "viral infection", it is meant for the purpose of the present invention an infection of a subject by a virus. Said virus is typically a virus which hijacks the host splicing machinery, and thus benefits from the function of the RED-SMU1 complex. The virus may be any virus which replicates in the nucleus of infected cells and produces intron-containing viral mRNAs. In such a case the compound of the present invention typically has a direct mode of action, because it alters the viral mRNA splicing.

[0127] Alternatively, typically, the compound of the present invention has an indirect mode of action, and is able to alter a cellular mRNA splicing, which encodes for a protein which plays a role in the viral replication cycle, and the virus may be any type of virus.

[0128] The virus may be chosen from influenza viruses, human immunodeficiency viruses (HIV) and human papillomaviruses (HPV).

[0129] Influenza virus may be chosen from Influenza virus A, Influenza virus B, Influenza virus C and Influenza virus D.

[0130] HIV may be chosen from HIV-1 and HIV-2, preferably it is HIV-1. It has to be noted that RED and SMU1 were identified as hits in two high-throughput screens looking for cellular factors involved in HIV-1 life cycle.

[0131] HPV may be notably chosen from HPV16, HPV18, HPV6 and HPV11 , preferably is HPV18. Indeed, the SMU1 factor was found to be associated to the E6 protein of HPV18.

[0132] Preferably, the viral infection is an influenza virus infection, more preferably an Influenza virus A infection.

[0133] Anticancer use

[0134] According to a second embodiment, the compounds of formula I, II, III, IV, V, or VI, their enantiomers and / or their pharmaceutically acceptable salts may be used for preventing and / or treating cancer.

[0135] By "treatment" it is meant for the purpose of the present invention the curative treatment of cancer. A curative treatment is defined as a treatment that completely treats (cure) or partially treats cancer (i.e. induces tumor growth stabilization, retardation or regression). The "subject" refers to any subject and typically designates a patient afflicted by cancer, in particular an animal including a human being, more particularly a human being.

[0136] By "cancer" it is meant for the purpose of the present invention any type of cancer. The cancer is for example selected from a colon cancer, a colorectal cancer, a melanoma, a breast cancer, a thyroid cancer, a prostate cancer, an ovarian cancer, a lung cancer, a pancreatic cancer, a glioma, a cervical cancer, an endometrial cancer, a head and neck cancer, a liver cancer, a renal cancer, a skin cancer, a stomach cancer, a testis cancer, an urothelial cancer or an adrenocortical carcinoma, but also non solid cancers such as lymphoma.

[0137] The cancer can be a metastatic cancer or not. In any case, the subject is preferably a vertebrate, more preferably a mammal, even more preferably a human being. The compound of formula I, II, III, IV, V, or VI of the invention is preferably administered at a therapeutically effective amount or dose. As used herein, "a therapeutically effective amount or dose" refers to an amount of the compound of the invention which prevents, removes, slows down the disease, or reduces or delays one or several symptoms or disorders caused by or associated with said disease in the subject, preferably a human being. The effective amount, and more generally the dosage regimen, of the compound of the invention and pharmaceutical compositions thereof may be determined and adapted by the one skilled in the art. An effective dose can be determined by the use of conventional techniques and by observing results obtained under analogous circumstances. The therapeutically effective dose of the compound of the invention will vary depending on the disease to be treated or prevented, its gravity, the route of administration, any co-therapy involved, the patient's age, weight, general medical condition, medical history, etc.

[0138] Typically, the amount of the compound to be administered to a patient may range from about 0.01 to 500 mg / kg of body weight for a human patient. In a particular embodiment, the pharmaceutical composition according to the invention comprises 0.01 mg / kg to 300 mg / kg of the compound of the invention, preferably from 0.01 mg / kg to 3 mg / kg, for instance from 25 to 300 mg / kg.

[0139] In a particular aspect, the compounds of the invention can be administered to the subject by parenteral route, topical route, oral route or intravenous injection. The compound or the composition of the invention may be administered to the subject daily (for example 1, 2, 3, 4, 5, 6 or 7 times a day) during several consecutive days, for example during 2 to 10 consecutive days, preferably from 3 to 6 consecutive days. Said treatment may be repeated during 1 , 2, 3, 4, 5, 6 or 7 weeks, or every two or three weeks or every two or three months. Alternatively, several treatment cycles can be performed, optionally with a break period between two treatment cycles, for instance of 1, 2, 3, 4 or 5 weeks. The compound of the invention can for example be administered as a single dose once a week, once every two weeks, or once a month. The treatment may be repeated one or several times per year.

[0140] Doses are administered at appropriate intervals which can be determined by the skilled person. The amount chosen will depend on multiple factors, including the route of administration, duration of administration, time of administration, the elimination rate of the compound, or of the various products used in combination with said compound, the age, weight and physical condition of the patient and his / her medical history, and any other information known in medicine.

[0141] The administration route can be oral, topical or parenteral, typically rectal, sublingual, intranasal, intraocular, intra-peritoneal (IP), intra-venous (IV), intra-arterial (IA), intramuscular (IM), intra-cerebellar, intrathecal, intratumoral and / or intradermal. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition is preferably administered by injection or by intravenous infusion of suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.

[0142] The compound of formula I, II, III, IV, V, or VI, its enantiomers or its pharmaceutically acceptable salts, may be present in a composition comprising a pharmaceutically acceptable carrier.

[0143] The carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof (the patient) and non-toxic and as defined above. The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as gels, oils, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets, capsules, powders, suppositories, etc. that contain solid vehicles in a way known in the art, possibly through dosage forms or devices providing sustained and / or delayed release. For this type of formulation, an agent such as cellulose, lipids, carbonates or starches are used advantageously.

[0144] Agents or vehicles that can be used in the formulations (liquid and / or injectable and / or solid) are excipients or inert vehicles, i.e. pharmaceutically inactive and non-toxic vehicles. Mention may be made, for example, of saline, physiological, isotonic and / or buffered solutions, compatible with pharmaceutical use and known to those skilled in the art. The compositions may contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc.

[0145] Particular examples are methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, cyclodextrins, polysorbate 80, mannitol, gelatin, lactose, liposomes, vegetable oils or animal, acacia, etc. Preferably, vegetable oils are used.

[0146] Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.

[0147] Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and non-toxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances.

[0148] When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. The tablets may be coated with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and they continuously release a predetermined amount of active principle.

[0149] A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard capsules.

[0150] A preparation in the form of a syrup or an elixir may contain the active ingredient together with a sweetener, an antiseptic, and also a taste enhancer and a suitable coloring agent.

[0151] The water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents or wetting agents, or suspending agents, and with flavor correctors or sweeteners.

[0152] For rectal administration, suppositories are used which are prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols.

[0153] For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents are used.

[0154] The active principle may also be formulated in the form of microcapsules, optionally with one or more carrier additives. Materials and Methods

[0155] 1. In silico-screeninq

[0156] 1.1 Molecular docking of ALG61 / FGFR3

[0157] The docking studies were carried out with The Biovia Discovery Studio software (DS 2016). A 3D model of FGFR3 was obtained by structural homology from the FGFR1 / XOJ complex (PDB code 5A4C) using the Modeler 9.15 program (Room, A. et al.; J. Comp. Chem., 1983, 4, 187-217). The water molecules present in the crystallographic structure of FGFR1 (PDB code 5A4C) were removed and then the protein was prepared using the default parameters of the DS Protein Preparation protocol. The position of hydrogen atoms was minimized with CHARMm (Wu, G. S.; J. Comput. Chem. 2003, 24, 1549-1562). The ligands were prepared at pH 7.4 ± 1.0 using the DS Prepare Ligand module and then minimized using the Smart Minimizer module. A maximum of 50 random conformations per ligand was generated using DS's generate conformation protocol and the Random Search algorithm. The docking experiments were conducted using the CDOCKER program and then flexible (Koska, J.; C. M. J. Chem. Inf. Model. 2008, 48 (10), 1965-1973.). The binding domain to the active site was defined by a sphere of 11 A on the XOJ ligand. 10 docking poses were generated for each conformer after a post-docking minimization with CHARMm. Pose selection was based on the CDocker interaction Energy function and then ligand-protein interactions were visually analyzed using DS's Receptor-Ligand interactions module. The docking protocol was validated by re-docking the PD183074 and XOJ ligands in the active site of the FGFR3 model.

[0158] 1.2 Molecular docking of ALG61 / SMU1

[0159] The docking studies were carried out with the Biovia Discovery Studio software (DS 2020). A 3D model of SMU1 was obtained from the complex described in the article Asraf et al. (PDB code 6Q8J),170 using the Modeler 9.15 program. The water molecules present in the crystallographic structure were removed and then the protein was prepared using the default parameters of the DS Protein Preparation protocol. The position of hydrogen atoms was minimized with CHARMm (Wu, G. S. et al Comput. Chem. 2003, 24, 1549-1562). The ligands were prepared at pH 7.4 ± 1.0 using the DS Prepare Ligand module and then minimized using the Smart Minimizer module. A maximum of 50 random conformations per ligand was generated using DS's generate conformation protocol as well as the Random Search and BEST algorithms. The docking experiments were conducted using the CDOCKER program. The binding domain to the active site was defined by a sphere of 10 A on the XS4 ligand. Ten docking poses were generated for each conformer after a post-docking minimization with CHARMm. The selection of poses was based on the CDocker interaction Energy function. The pre-selected ligands were then redocked by releasing the residues located 5A from the ligand. The selected complexes were then minimized, solved (water box of 10A) and balanced over 1ns with the protocols solvation and NAMD (Phillips, J. C. et al.; J. Comput. Chem. 2005, 26 (16), 1781-1802). Finally, ligand-protein interactions were visually analyzed using the Receptor-Ligand interactions module of DS. The docking protocol has been validated by re-docking XS4 ligands in the active site of the SMU1 model.

[0160] 2. Antiviral activity

[0161] The A549 cells were infected with the WSN-Nanoluc and incubated with the potential disruptors at concentrations of 40 and 5 pM, using DMSO as negative control and Baloxavir Marboxyl as positive control. After 24 h of incubation, the luciferase activity, which indicates the level of the viral replication, is measured and is reported as percentages relative to the DMSO-treated controls. The data shown below are the mean ± SD of one (for the antiviral activity at 40 pM) or two (for the antiviral activity at 5 pM) independent experiments in triplicate. The results of the test at 40 pM of disruptor is reported in Figure 7. As can be observed, very positively, for almost all the tested compounds, the percentages of bioluminescence after incubations are below 20, meaning that the viral replication is inhibited for more than 80% compared to the DMSO control.

[0162] 3. Toxicity

[0163] The test for the evaluation of the toxicity of the synthesized inhibitors relies on a cell viability assay performed with A549 cells incubated with the inhibitors. The A549 cells are incubated for 24 h with the inhibitors at a 5 pM concentration, using DMSO as negative control. After the incubation, the ATP levels, which reflect the number of viable cells, were measured using the CellTiter-Glo Kit (Promega) and are reported as percentages relative to DMSO (Figure 13).

[0164] 4. Synthesis

[0165] The compounds were prepared following specific optimized procedures. According to the general synthetic pathways depicted in figure 14, pyridopyrimidines ID and VI can be synthesized from 4-Amino-2-(methylthio)-5-pyrimidinecarboxaldehyde, quinolines IC and V from 4-Bromo-3-nitroaniline, quinazolines IB and IV from 2-Cyano-5-nitroaniline and naphthyridines IA and III from 2,6-Diamino-3-bromo-pyridine. Several synthetic pathways can lead to the general structures IC and V. The most versatile relies on the introduction of the aryl moiety first, followed by the annulation with malonic esters or acid in order to get the bicycle core structure. Finally, chlorination, reduction, acylation (general procedure VIII) or SNAr (general procedure VII) can be performed in various ways depending on the substituents that need to be introduced. Except where specified, all the compounds are described according to this systematical numbering:

[0166] Z Z2and Z3= CH or N

[0167] General procedure for mCPBA oxidation (I) To a solution of the thioether (1 equiv.) in CHCI3(0.16 M) at 0 °C, mCPBA (3.0 equiv.) was added portion wise during 20 min. The mixture was stirred at 0 °C for 2 h before adding DCM (20 mL-mmol-1), Na2SO4(12 equiv.) and Ca(OH)2(4 equiv.). The stirring was prolonged for 30 more min at 0 °C. The resulting suspension was filtered and the filtrate was concentrated under vacuum. The crude product was purified as specified.

[0168] General procedure for SNAr with pent -4-yn-1 -amine hydrochloride (II) To a suspension of the sulphone (1 equiv.) in anhydrous 1,4-dioxane (0.11 M), pent-4-yn-1-amine hydrochloride (2 equiv.) and DI PEA (4 equiv.) were added. The resulting mixture was stirred at 50 °C for 20 h before being concentrated under vacuum. The residue was dissolved in DCM, washed with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified as specified. General procedure for the CuAAC reaction (III) To a solution of the alkyne (1.5 equiv.) in DMSO (0.13 M), a solution of the compound 6 (1 equiv.) in DMSO (0.13 M), L-ascorbic acid (0.3 equiv.) and CuSO4(0.2 equiv.) were added. The resulting mixture was stirred at 60 °C overnight before being diluted in EtOAc, washed with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified as specified.

[0169] General procedure for the pyrido[2,3-c(]pyrimidine condensation (IV) To a suspension of 4-amino-2-(methylsulfanyl)pyrimidine-5-carbaldehyde (1 equiv.) in anhydrous DMF (0.4 M) at 0 °C, NaH 60% in mineral oil (1.1 equiv.) was added. The mixture was stirred at 0 °C for 30 min before adding the substituted phenylacetonitrile (1.1 equiv.). The stirring was prolonged for 5 h more at 0 °C, then 18 h at room temperature. The reaction was cooled at 0 °C and quenched with ice cold saturated NH4CI aqueous solution. The resulting suspension was filtered and the precipitate was purified as specified.

[0170] General procedure for the Suzuki coupling (V) To a solution of the halide (1 equiv.), the appropriate boronic acid (1.1 equiv.) and an aqueous solution of NaHCO3(2 equiv. in 2.5 mL I mmol) in dioxane (5 mL / mmol) in a sealed tube, Pd(PPh3)4(0.01 or 0.1 equiv., as specified) was added after three cycles of vacuum / Ar to ensure a perfect inert atmosphere. The resulting mixture was stirred at 90 °C overnight before being concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified as specified.

[0171] General procedure for the urea synthesis (VI) To a solution of the amine (1 equiv.) in anhydrous THF (0.13 M) in a sealed tube at 0 °C, f-Butyl isocyanate (1.1 equiv.) was added dropwise. The resulting mixture was stirred at 75 °C for 18 h before being concentrated under vacuum. The crude product was purified as specified.

[0172] General procedure for the optimized SNAr (VII) In a sealed tube, a solution of the halide (1 equiv.) in the appropriate amine (0.3 M) was stirred at 100 °C for 18 h. The resulting mixture was concentrated under vacuum and the crude product was purified as specified.

[0173] General procedure for the amides synthesis (VIII) To a solution of the amine (1 equiv.) in anhydrous pyridine (0.17 M) in a sealed tube under inert atmosphere at 0 °C, the appropriate acyl chloride (1.05 equiv.), DMAP (1 equiv.), and DIPEA (3 equiv.) were added. The resulting mixture was stirred at 110 °C for 24-72 h, before being concentrated under vacuum. The crude product was purified by as specified.

[0174] General procedure for the O-Alkylation (IX) To a solution of the 3-bromo-4-methoxyphenol 115 (1 equiv.) in anhydrous acetone or DMF (0.4 M) in a sealed tube under inert atmosphere, K2CO3(2 equiv.) and the halide (1.2 equiv.) were added. The resulting mixture was stirred at 80 °C for 6-18 h, before being concentrated under vacuum. The residue was dissolved in EtOAc, washed with a saturated Na2CO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified as specified.

[0175] General procedure for the synthesis of boronates (X) To a solution of the halide (1 equiv.), KOAc (3 equiv.) and bis(pinacolato)diboron (1.5 equiv.) in anhydrous dioxane (0.07 M) in a sealed tube, PdCI2(dppf) (0.1 equiv.) was added after three cycles of vacuum / Ar to ensure a perfect inert atmosphere. The resulting mixture was stirred at 100 °C overnight before being diluted with EtOAc. The resulting suspension was filtered through a Celite pad and the filtrate was concentrated under vacuum. The crude product was purified as specified. Synthesis Methods

[0176] 1-(tert-butyl)-3-(6-(3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-c / ]pyrimidin-7- yl)urea (2)

[0177] This compound (2) was prepared according to the method described in the article of Le Corre et al. (Le Corre, L.; Girard, A.-L.; Aubertin, J.; Radvanyi, F.; Benoist-Lasselin, C.; Jonquoy, A.; Mugniery, E.; Legeai-Mallet, L.; Busca, P.; Le Merrer, Y. Org. Biomol. Chem. 2010, 8 (9), 2164.).

[0178] Formula: C21H25N5O5S Mass: 459.52 g-mol1

[0179] 1-tert-Butyl-3-(6-(3,5-dimethoxyphenyl)-2-(prop-2-ynylamino)-Pyrido[2,3-c(]pyrimidin-7- yl) urea (3)

[0180] To a suspension of the compound 2 (350 mg, 0.76 mmol, 1 equiv.) in anhydrous 1 ,4-dioxane (1.7 mL), propargylamine (0.12 mL, 1.90 mmol, 2.5 equiv.) was added. The resulting mixture was stirred at 50 °C for 20 h, before being concentrated under vacuum. The residue was purified by flash chromatography (DCM / MeOH, 97:3) to afford the compound 3 as a beige solid (212 mg, 0.49 mmol, 64% yield).

[0181] Formula: C23H26N6O3Mass: 434.21 g-mol1

[0182] 1-tert-Butyl-3-(6-(3,5-dimethoxyphenyl)-2-(but-3-ynylamino)-pyrido[2,3-c ]pyrimidin-7- yl)urea (4)

[0183] To a suspension of the compound 2 (517 mg, 1.13 mmol, 1 equiv.) in anhydrous 1 ,4-dioxane (13 mL), but-3-yn-1 -amine hydrochloride (119 mg, 1.13 mmol, 1 equiv.) and DIPEA (0.37 mL, 2.26 mmol, 2 equiv.) were added. The resulting mixture was stirred at 70 °C for 24 h, before being concentrated under vacuum. The residue was dissolved in DOM, washed with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified a first time by flash chromatography (DCM / MeOH, 99:1) and a second time by PLC (DCM / MeOH, 95:5) to afford the compound 4 as a white solid (150 mg, 0.33 mmol, 30% yield).

[0184] Formula: C^H^NsOs Mass: 448.22 g-mol1

[0185] 1-tert-Butyl-3-(6-(3,5-dimethoxyphenyl)-2-(pent-4-ynylamino)-pyrido[2,3-c ]pyrimidin-7- yl)urea (ALG61)

[0186] According to the general procedure II, ALG61 was synthesized from the compound 2 (300 mg, 0.65 mmol, 1 equiv.) and obtained as a white solid (210 mg, 0.45 mmol, 70% yield) after purification by flash chromatography (DCM / MeOH, 98:2).

[0187] Formula: C25H30N6O3Mass: 462.24 g-mol1

[0188] 5-azidofluoresceine (6)

[0189] To a solution of 5-aminofluorescein 5 (180 mg, 0.52 mmol, 1 equiv.) in AcOH / H2O 2:1 (12 mL) at 0 °C, NaNO2 (53 mg, 0.78 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 0 °C for 15 min, before adding NaN3 (67 mg, 1.04 mmol, 2 equiv.) portionwise. The stirring was prolonged at 0 °C for 1 h. The resulting suspension was filtered. The precipitate was washed with a 2M HCI aqueous solution, then with H2O and it was dried under vacuum to afford the compound 6 as an orange solid (159 mg, 0.43 mmol, 82% yield).

[0190] Formula: C2oH11N3OsMass: 373.32 g-mol1

[0191] 6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-c(]pyrimidin-7-amine (14)

[0192] According to the general procedure IV, the pyrido[2,3-d]pyrimidine 14 was synthesized from the reaction of amino-2-(methylsulfonyl)pyrimidine-5-carbaldehyde 10 (277 mg, 1.64 mmol, 1 equiv.) with 3,5-dimethoxyphenylacetonitrile and obtained as a white solid (488 mg, 1.49 mmol, 91% yield) after washing once with ice cold water and finally three times with Et2O.

[0193] Formula: C16H16N4O2S Mass: 328.39 g-mol1

[0194] 6-(2-methoxyphenyl)-2-(methylthio)pyrido[2,3-c(]pyrimidin-7-amine (15)

[0195] According to the general procedure IV, the pyrido[2,3-d]pyrimidine 15 was synthesized from the reaction of the compound 10 (500 mg, 2.96 mmol, 1 equiv.) with 2- methoxyphenylacetonitrile and obtained as a white solid (327 mg, 1.09 mmol, 37% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 2:3).

[0196] Formula: C15H14N4OS Mass: 298.36 g-mol1

[0197] 6-(3,5-bis(trifluoromethyl)phenyl)-2-(methylthio)pyrido[2,3-c(]pyrimidin-7-amine (16)

[0198] According to the general procedure IV, the pyrido[2,3-d]pyrimidine 16 was synthesized from the reaction of the compound 10 (500 mg, 2.96 mmol, 1 equiv.) with 3,5- bis(trifluoromethyl)phenylacetonitrile and obtained as a yellow solid (796 mg, 1.97 mmol, 67% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 4:1).

[0199] Formula: C16H10F6N4S Mass: 404.33 g-mol1

[0200] 1-(tert-butyl)-3-(6-(2-methoxyphenyl)-2-(methylthio)pyrido[2,3-c(]pyrimidin-7-yl)urea

[0201] (17)

[0202] To a solution of the compound 15 (325 mg, 1.09 mmol, 1 equiv.) in anhydrous DMF (3 mL) at 0 °C, NaH 60% in mineral oil (49 mg, 1.23 mmol, 1.1 equiv.) was added. The mixture was stirred at 0 °C for 30 min before adding the f-Butyl isocyanate (122 mg, 0.14 mL, 1.23 mmol, 1.1 equiv.). The stirring was prolonged for 5 more h at 0 °C, then 18 h at room temperature. The reaction was cooled at 0 °C and quenched with 0.5 mL of ice cold 6M HCI aqueous solution, before adding ice cold H2O. The resulting suspension was filtered and the precipitate was washed once with ice cold water, three times with Et2O and it was finally dried under vacuum to afford the compound 17 as a white solid (429 mg, 1.08 mmol, 99% yield).

[0203] Formula: C20H23N5O2S Mass: 397.50 g-mol1

[0204] 1-(6-(3,5-bis(trifluoromethyl)phenyl)-2-(methylthio)pyrido[2,3-c(]pyrimidin-7-yl)-3-(tert- butyl)urea (18)

[0205] To a solution of the compound 16 (580 mg, 1.43 mmol, 1 equiv.) in anhydrous DMF (5 mL) under inert atmosphere at 0 °C, NaH 60% in mineral oil (65 mg, 1.62 mmol, 1.1 equiv.) was added. The mixture was stirred at 0 °C for 30 min before adding the f-Butyl isocyanate (160 mg, 0.19 mL, 1.62 mmol, 1.1 equiv.). The stirring was prolonged for 5 more h at 0 °C, then 18 h at room temperature. The reaction was cooled at 0 °C and quenched with 0.5 mL of ice cold 6M HCI aqueous solution, before adding ice cold H2O. The resulting suspension was filtered and the precipitate was washed once with ice cold water, three times with Et2O and it was finally purified by flash chromatography (Cyclohexane / EtOAc, 1 :1) to afford the compound 18 as a yellow amorphous solid (722 mg, 1.43 mmol, 100% yield).

[0206] Formula: C21H19F6N5OS Mass: 503.48 g-mol1

[0207] 1-(tert-butyl)-3-(6-(2-methoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-c]pyrimidin-7-yl)urea

[0208] (19)

[0209] According to the general procedure I, the sulphone 19 was synthesized from the compound 17 (429 mg, 1.08 mmol, 1 equiv.) and obtained as a white solid (350 mg, 0.81 mmol, 75% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 1:1).

[0210] Formula: C2oH23N504S Mass: 429.50 g-mol’1

[0211] 1-(6-(3,5-bis(trifluoromethyl)phenyl)-2-(methylsulfonyl)pyrido[2,3-c(]pyrimidin-7-yl)-3- (tert-butyl)urea (20)

[0212] According to the general procedure I, the sulphone 20 was synthesized from the compound 18 (100 mg, 0.20 mmol, 1 equiv.) and obtained as a white solid (70 mg, 0.14 mmol, 70% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 3:2).

[0213] Formula: C2iH19F6N5O3S Mass: 535.47 g-mol’1

[0214] 1-(tert-butyl)-3-(6-(2-methoxyphenyl)-2-(pent-4-yn-1-ylamino)pyrido[2,3-c(]pyrimidin-7- yl)urea (21)

[0215] According to the general procedure II, the final pyrido[2,3-d]pyrimidine 21 was synthesized from the compound 19 (350 mg, 0.81 mmol, 1 equiv.) and obtained as a white solid (172 mg, 0.40 mmol, 49% yield) after purification by flash chromatography (Cyclohexane / EtOAc 3:2). Another fraction of 21 in a mixture 1 :0.4 with the starting compound 19 (112 mg, estimated from NMR: 0.26 mmol, 32%) was collected.

[0216] Formula: C24H28N6O2 Mass: 432.52 g-mol’1

[0217] 1-(6-(3,5-bis(trifluoromethyl)phenyl)-2-(methylsulfonyl)pyrido[2,3-c(]pyrimidin-7-yl)-3- (tert-butyl)urea (22)

[0218] According to the general procedure II, the final pyrido[2,3-d]pyrimidine 22 was synthesized from the compound 20 (360 mg, 0.67 mmol, 1 equiv.) and obtained as a white solid (230 mg, 0.43 mmol, 64% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 3:2). A fraction of the compound 22, for the characterization and the biological evaluations, was further purified

[0219] Formula: C25H24F6N6O Mass: 538.50 g-mol’1

[0220] A / -(6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-c(]pyrimidin-7-yl)-3,3- dimethylbutanamide (23)

[0221] To a suspension of the compound 14 (488 mg, 1.49 mmol, 1 equiv.) in anhydrous 1,4- dioxane (4 mL) under inert atmosphere, f-Butylacetyl chloride (0.26 mL, 1.86 mmol, 1.2 equiv.) was added dropwise. The resulting mixture was stirred at reflux temperature for 1 h, before being concentrated under vacuum. The residue was dissolved in DCM and washed with cold 5% NaOH aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1 :1) to afford the compound 23 as a yellow solid (287 mg, 0.67 mmol, 45% yield).

[0222] Formula: C22H26N4O3S Mass: 426.54 g-mol1

[0223] A / -(6-(3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-c]pyrimidin-7-yl)-3,3- dimethylbutanamide (24)

[0224] According to the general procedure I, the sulphone 24 was synthesized from the compound 23 (432 mg, 1.01 mmol, 1 equiv.) and obtained as a white amorphous solid (110 mg, 0.24 mmol, 24% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 1:1).

[0225] Formula: C22H26N4O5S Mass: 458.53 g-mol1

[0226] A / -(6-(3,5-dimethoxyphenyl)-2-(pent-4-yn-1-ylamino)pyrido[2,3-c(]pyrimidin-7-yl)-3,3- dimethylbutanamide (25)

[0227] According to the general procedure II, the final pyrido[2,3-d]pyrimidine 25 was synthesized from the compound 24 (100 mg, 0.22 mmol, 1 equiv.) and obtained as a white solid (75 mg, 0.16 mmol, 75% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 1 :1).

[0228] Formula: C26H31N5O3 Mass: 461.24 g-mol1

[0229] 4-(3,5-dimethoxyphenyl)-3-nitroaniline (27)

[0230] According to the general procedure V, the compound 27 was synthesized from the reaction of 4-bromo-3-nitroaniline (400 mg, 1.84 mmol, 1 equiv.) with 3,5-dimethoxyphenylboronic acid (1.5 equiv.) in the presence of 0.1 equiv. of Pd(PPh3)4. It was obtained as a brown solid (480 mg, 1.75 mmol, 95% yield) after purification by flash chromatography (cyclohexane / EtOAc, 7:3).

[0231] Formula: C14H14N2O4Mass: 274.21 g-mol1 4-(3,5-dimethoxyphenyl)-3-nitrophenylacetamide (29)

[0232] To a solution of the compound 27 (117 mg, 0.43 mmol, 1 equiv.) in DPE (0.2 mL) in a MW tube, malonic acid (49 mg, 0.47 mmol, 1.1 equiv.) was added. The resulting mixture was irradiated at 200 °C (150 Watt) for 20 min, before being concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1 :1) to afford the compound 29 as a brown solid (36 mg, 0.12 mmol, 27% yield).

[0233] Formula: C14H14N2O4Mass: 242.03 g-mol1ethyl 3-((4-bromo-3-nitrophenyl)amino)-3-oxopropanoate (31) and 4-Br-3- nitroacetamide (32)

[0234] A solution of 4-bromo-3-nitroaniline (200 mg, 0.92 mmol, 1 equiv.) in diethylmalonate (0.3 mL) in a MW tube was irradiated at 200 °C (150 Watt) for 15 min, before being concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1:1) to afford the compound 32 as a brown oil (143 mg, 0.43 mmol, 47%) and the compound 31 as a brown solid (80 mg, 0.31 mmol, 34% yield).

[0235] Formula: CnHnBrN^s Mass: 331.12 g-mol1

[0236] 32

[0237] Formula: C8H7BrN2O3Mass: 259.06 g-mol1ethyl 3-((3-amino-4-bromophenyl)amino)-3-oxopropanoate (33)

[0238] To a solution of the compound 31 (210 mg, 0.63 mmol, 1 equiv.) in EtOAc (1.2 mL), SnCI2-2H2O (572 mg, 2.53 mmol, 4 equiv.) was added. The resulting mixture was stirred at r.t. for 18 h, before being neutralized with a saturated NaHCO3aqueous solution and filtered. The filtrate was further diluted in EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 2:1) to afford the compound 33 as colorless oil (143 mg, 0.48 mmol, 75% yield).

[0239] Formula: C11H13BrN2O3Mass: 301.14 g-mol1

[0240] 4-(3,5-dimethoxyphenyl)-1 ,3-diaminobenzene (34)

[0241] To a solution of the compound 27 (200 mg, 0.73 mmol, 1 equiv.) in EtOH (0.5 mL) and H2O (0.5 mL), Fe (36 mg, 0.37 mmol, 0.5 equiv.) and 37% HCI aqueous solution (0.03 mL, 3.65 mmol, 5 equiv.) were added. The resulting mixture was stirred at 110 °C for 5 h, before being neutralized with 1M NaOH aqueous solution. The suspension was diluted in DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 7:3) to afford the compound 34 as an amorphous white solid (110 mg, 0.45 mmol, 62% yield).

[0242] Formula: C14H16N2O2Mass: 244.29 g-mol1

[0243] 4,6-dibromobenzene-1,3-diamine (37)

[0244] To a solution of 1 ,3-benzenediamine (0.90 g, 8.32 mmol, 1 equiv.) in anhydrous acetonitrile (41 mL), NH4OAC (0.06 g, 0.83 mmol, 0.1 equiv.) was added, followed by N- bromosuccinimide (2.96 g, 16.64 mmol, 2 equiv.) portion wise. The resulting mixture was stirred at 30 °C for 15 min, before being concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 7:3) to afford the compound 37 as a white solid (1.23 g, 4.62 mmol, 56% yield).

[0245] Formula: C6H6Br2N2Mass: 265.94 g-mol1

[0246] 2-Bromo-4-(3,5-dimethoxyphenyl)-1,3-diaminobenzene (38)

[0247] According to the general procedure V, the compound 38 was synthesized from the reaction of the compound 37 (444 mg, 1.67 mmol, 1 equiv.) with 3,5-dimethoxyphenylboronic acid (1.0 equiv.) in the presence of 0.1 equiv. of Pd(PPh3)4. It was obtained as a white solid (210 mg, 0.65 mmol, 39% yield) after purification by flash chromatography (cyclohexane / EtOAc, 4:1).

[0248] Formula: C14H1sBrN2O2Mass: 323.19 g-mol1

[0249] N,N'-(4,6-dibromo-1,3-phenylene)bis(2,2,2-trifluoroacetamide) (40)

[0250] To a solution of the compound 37 (0.89 g, 3.33 mmol, 1 equiv.) in anhydrous THF (4 mL) at 0 °C, trifluoroacetic anhydride (1.50 mL, 10.82 mmol, 3.3 equiv.) was added dropwise. The resulting mixture was stirred at r.t. for 18 h, before being quenched with H2O. The solution was diluted in Et2O, washed three times with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the compound 40 as a white solid (1.50 g, 3.28 mmol, 98% yield).

[0251] Formula: C10H15Br2F6N2O2Mass: 457.95 g-mol1

[0252] N,N'-(4-bromo-6-vinyl-1,3-phenylene)bis(2,2,2-trifluoroacetamide) (41)

[0253] To a solution of the compound 40 (312 mg, 0.68 mmol, 1 equiv.) in anhydrous 1 ,4-dioxane (5 mL) in a sealed tube under inert atmosphere, tributyl(vinyl)tin (216 mg, 0.20 mL, 0.68 mmol, 1 equiv.) and Pd(PPh3)4(8 mg, 0.01 mmol, 0.01 equiv.) were added. The resulting mixture was stirred at 125 °C for 4 h. The reaction was quenched with an aqueous solution of KF 10% and stirred at room temperature for 1 h before filtering. The filtrate was concentrated under vacuum. The residue was dissolved in EtOAc, washed once with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc 95:5, with 20% of fine silica in the stationary phase) to afford the compound 41 as a brown solid (120 mg, 0.30 mmol, 43% yield).

[0254] Formula: C12H7BrF6N2O2Mass: 405.09 g-mol1

[0255] 2-amino-5-bromo-4-nitrobenzonitrile (43)

[0256] To a solution of 2-amino-4-nitrobenzonitrile (1.5 g, 9.19 mmol, 1 equiv.) in anhydrous acetonitrile (45 mL), NH4OAc (71 mg, 0.92 mmol, 0.1 equiv.) was added, followed by N- bromosuccinimide (172 g, 9.65 mmol, 1.05 equiv.) portion wise. The resulting mixture was stirred at 30 °C for 15 min, before being concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (gradient of cyclohexane / EtOAc from 9:1 to 7:3) to afford the compound 43 as a yellow solid (1.86 g, 7.68 mmol, 84% yield).

[0257] Formula: C7H4BrN3O2Mass: 242.03 g.mol’1

[0258] 4-amino-3',5'-dimethoxy-6-nitro-[1 ,1 '-biphenyl]-3-carbonitrile (45)

[0259] According to the general procedure V, the compound 45 was synthesized from the reaction of the halide 43 (1.05 g, 4.32 mmol, 1 equiv.) with 3,5-dimethoxyphenylboronic acid, in the presence of 0.1 equiv. of Pd(PPh3)4. It was obtained as a yellow solid (1.16 g, 3.88 mmol, 90% yield) after purification by flash chromatography (cyclohexane / EtOAc, 4:1).

[0260] Formula: C15H13N3O4Mass: 299.29 g-mol1

[0261] 2,4-dichloro-6-(3,5-dimethoxyphenyl)-7-nitroquinazoline (46)

[0262] To a suspension of the compound 45 (0.76 g, 2.54 mmol, 1 equiv.) in anhydrous acetonitrile

[0263] (14 mL) in a sealed tube, triphosgene (1.13 g, 3.81 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 130 °C overnight, before being cooled to 0 °C and quenched with ice cold H2O, added dropwise. The resulting suspension was stirred at 0 °C for 30 min, before being diluted EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (cyclohexane / EtOAc, 9:1) to afford the 2,4-dichloroquinazoline derivative 46 as a yellow solid (0.39 g, 1.02 mmol, 40% yield).

[0264] Formula: C16H11CI2N3O4Mass: 380.18 g-mol1

[0265] 2,4-dichloro-6-(3,5-dimethoxyphenyl)quinazolin-7-amine (48) To a solution of the compound 46 (75 mg, 0.20 mmol, 1 equiv.) in EtOAc (0.6 mL), SnCI22H2O (178 mg, 0.79 mmol, 4 equiv.) was added. The resulting mixture was stirred at room temperature overnight, before being neutralized with a saturated NaHCO3aqueous solution and filtered. The filtrate was diluted with EtOAc (15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (cyclohexane / EtOAc, 4:1) to afford the compound 48 as a white amorphous solid (41 mg, 0.12 mmol, 59% yield).

[0266] Formula: C16H13CI2N3O2Mass: 350.20 g-mol’1

[0267] 2-chloro-6-(3,5-dimethoxyphenyl)-7-nitroquinazoline (49)

[0268] To a solution of the compound 46 (0.92 g, 2.42 mmol, 1 equiv.) in a mixture of THF (116 mL) and H2O (29 mL), PPh3(1.90 g, 7.27 mmol, 3 equiv.) was added. The resulting mixture was stirred at room temperature for 24 h, before being concentrated under vacuum. The residue was dissolved in EtOAc, washed with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (cyclohexane / EtOAc, 7:3) to afford the compound 49 as a yellow solid (0.97 g, 2.81 mmol, 61% yield).

[0269] Formula: C16H12CIN3O4Mass: 345.74 g-mol’1

[0270] 2-chloro-6-(3,5-dimethoxyphenyl)quinazolin-7-amine (P.47) and 2-chloro-6-(3,5- dimethoxyphenyl)-3,4-dihydroquinazolin-7-amine (54)

[0271] To a solution of the compound 49 (100 mg, 0.29 mmol, 1 equiv.) in a mixture of anhydrous THF (3 mL) and anhydrous MeOH (3 mL) under inert atmosphere at 0 °C, Sml20.1 M in THF (17.5 mL, 1.74 mmol, 6 equiv.) was added dropwise. The mixture was stirred at room temperature for 1.5 h, before adding Sml20.1 M in THF (12 mL, 1.16 mmol, 4 equiv.). The stirring was prolonged for 1 more h at room temperature. The resulting solution was diluted in EtOAc, washed three times with H2O, then with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 7:3) to afford the compound 47 as a yellow oil (24 mg, 0.08 mmol, 26% yield) and the compound 54 as a yellow oil (47 mg, 0.15 mmol, 51% yield).

[0272] 47

[0273] Formula: C16H14CIN3O2Mass: 315.76 g-mol’1

[0274] 54

[0275] Formula: C16H16CIN3O2Mass: 317.77 g-mol’1 A / -(2-chloro-6-(3,5-dimethoxyphenyl)quinazolin-7-yl)hydroxylamine (53)

[0276] Identified as side product during the synthesis of the compound 47, in a mixture 1 :1 with the compound 47.

[0277] Formula: C16H14CIN3O3Mass: 331.76 g.mol’1

[0278] 6-(3,5-dimethoxyphenyl)-7-nitro-A / -(pent-4-yn-1-yl)quinazolin-2-amine (50)

[0279] To a suspension of the compound 49 (268 mg, 0.78 mmol, 1 equiv.) in absolute EtOH (4 mL) in a sealed tube under inert atmosphere, DIPEA (0.26 mL, 1.55 mmol, 2 equiv.) and pent-4- yn-1-amine hydrochloride (93 mg, 0.78 mmol, 1 equiv.) were added. The resulting mixture was stirred at 150 °C overnight, before being concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 7:3) to afford the compound 50 as a yellow solid (302 mg, 0.77 mmol, 99% yield).

[0280] Formula: C21H20N4O4Mass: 392.42 g-mol1

[0281] 6-(3,5-dimethoxyphenyl)-7-(hydroxyamino)- / V-(pent-4-yn-1-yl)quinazolin-2-amine (57)

[0282] To a solution of the compound 50 (225 mg, 0.62 mmol, 1 equiv.) in EtOAc (1 mL), SnCI2-2H2O (678 mg, 3.01 mmol, 4 equiv.) was added. The resulting mixture was stirred at room temperature for 5 h, before being neutralized with a saturated NaHCO3aqueous solution and filtered. The precipitate was washed three times with hot EtOAc and the filtrate was collected. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the compound 57 as an amorphous white solid (225 mg, 0.62 mmol, 83% yield).

[0283] Formula: C21H22N4O3Mass: 378.43 g-mol1

[0284] 6-(3,5-dimethoxyphenyl)-N2-(pent-4-yn-1-yl)quinazoline-2,7-diamine (56)

[0285] To a solution of the compound 49 (180 mg, 0.46 mmol, 1 equiv.) in EtOAc (1.4 mL), SnCI2-2H2O (414 mg, 1.83 mmol, 4 equiv.) was added. The resulting mixture was stirred at 65 °C for 24 h, before being neutralized with a saturated NaHCO3aqueous solution and filtered. The filtrate was diluted in EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1:1) to afford the compound 56 as an amorphous beige solid (98 mg, 0.27 mmol, 59% yield).

[0286] Formula: C21H22N4O2Mass: 362.43 g-mol1 1-(7-amino-6-(3,5-dimethoxyphenyl)quinazolin-2-yl)-3-(tert-butyl)-1-(pent-4-yn-1-yl)urea

[0287] (58)

[0288] To a solution of the compound 56 (46 mg, 0.13 mmol, 1 equiv.) in anhydrous THF (0.5 mL) in a sealed tube, f-Butyl isocyanate (14 mg, 0.017 mL, 0.14 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at 75 °C for 48 h., before being concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1:1) to afford the compound 58 as a yellow oil (37 mg, 0.08 mmol, 63% yield).

[0289] Formula: C26H31N5O3Mass: 461.57 g-mol1tert-butyl (6-(3,5-dimethoxyphenyl)-2-(pent-4-yn-1-ylamino)quinazolin-7-yl)carbamate (59) and A / -(7-amino-6-(3,5-dimethoxyphenyl)quinazolin-2-yl)-A / -(pent-4-yn-1-yl)-1H- imidazole-1 -carboxamide (61)

[0290] To a solution of the compound 56 (19 mg, 0.05 mmol, 1 equiv.) in anhydrous THF (0.4 mL) at 0 °C, DCI (34 mg, 0.20 mmol, 4 equiv.) was added. The resulting mixture was stirred at room temperature for 5 h, before adding f-BuOH (155 mg, 0.5 mL, 2.10 mmol, 40 equiv.) dropwise at 0 °C. The stirring was prolonged for 24 more h at 75 °C. The solution was concentrated under vacuum. The residue was dissolved in DCM, washed with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 4:1) to afford the compound 59 as a colorless oil (4 mg, 0.01 mmol, 16% yield) and the undesired product 61 as a white solid (6 mg, 0.01 mmol, 25%).

[0291] Formula: C28H27N8O3Mass: 523.58 g-mol1

[0292] 1-(tert-butyl)-3-(6-(3,5-dimethoxyphenyl)-2-(pent-4-yn-1-ylamino)quinazolin-7-yl)urea

[0293] (51)

[0294] To a solution of the compound 56 (39 mg, 0.11 mmol, 1 equiv.) in anhydrous THF (0.8 mL) in a sealed tube, GDI (70 mg, 0.43 mmol, 1.1 equiv.) was added. The mixture was stirred at 75 °C overnight, before adding f-Butyl amine (315 mg, 0.46 mL, 4.30 mmol, 40 equiv.) dropwise at 0 °C. The stirring was prolonged for 24 more h at 75 °C. The solution was concentrated under vacuum. The residue was dissolved in DCM, washed with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1:1) to afford the compound 51 as a yellow oil (5 mg, 0.01 mmol, 10% yield) and the compound 58 (24 mg, 0.07 mmol, 10% yield).

[0295] Formula: C26H31N5O3Mass: 461.57 g-mol’1

[0296] 4-amino-2'-methoxy-6-nitro-[1 ,1 '-biphenyl]-3-carbonitrile (62)

[0297] According to the general procedure V, the compound 62 was synthesized from the reaction of the halide 43 (1.00 g, 4.13 mmol, 1 equiv.) with 3,5-dimethoxyphenylboronic acid, in the presence of 0.1 equiv. of Pd(PPh3)4. It was obtained as a yellow solid (0.75 g, 2.79 mmol, 67% yield) after purification by flash chromatography (cyclohexane / EtOAc, 7:3).

[0298] Formula: C15H13N3O3Mass: 269.26 g-mol’1

[0299] 2,4-dichloro-6-(2-methoxyphenyl)-7-nitroquinazoline (63)

[0300] According to the procedure for the compound 46, the 2,4-dichloroquinazoline derivative 63 was synthesized from the compound 62 (592 mg, 2.20 mmol, 1 equiv.) and obtained as a yellow solid (600 mg, 1.71 mmol, 78% yield) after purification by flash chromatography (cyclohexane / EtOAc, 95:5).

[0301] Formula: C15H9CI2N3O3Mass: 349.16 g-mol’1

[0302] 2-chloro-6-(2-methoxyphenyl)-7-nitroquinazoline (64) and 2-chloro-4-hydroxy-6-(2- methoxyphenyl)-7-nitroquinazoline (annex)

[0303] To a solution of the compound 63 (48 mg, 0.14 mmol, 1 equiv.) in a mixture of THF (3 mL) and H2O (1 mL), polymer-supported triphenylphosphine (140 mg, 3 mmol / g, 3 equiv.) was added. The resulting mixture was stirred at room temperature for 24 h, before being filtered through a Celite pad. The filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (cyclohexane / EtOAc, 1:1) to afford the compound 64 as a yellow solid (22 mg, 0.07 mmol, 51% yield) and the compound 132 as a yellow solid (22 mg, 0.07 mmol, 49% yield).

[0304] 64

[0305] Formula: C15H10CIN3O3Mass: 315.71 g-mol’1

[0306] 132

[0307] Formula: C15H10CIN3O4 Mass: 331.71 g-mol’1

[0308] 6-(2-methoxyphenyl)-7-nitro- / V-(pent-4-yn-1-yl)quinazolin-2-amine (65) According to the procedure for the compound 50, the compound 65 was synthesized from the 2-chloroquinazoline derivative 64 (50 mg, 0.16 mmol, 1 equiv.) and obtained as a yellow solid (56 mg, 0.15 mmol, 98% yield) after purification by flash chromatography (cyclohexane / EtOAc, 4:1).

[0309] Formula: C20H18N4O3Mass: 362.39 g-mol1

[0310] 6-(3,5-dimethoxyphenyl)-N2-(pent-4-yn-1-yl)quinazoline-2,7-diamine (66)

[0311] According to the procedure for the compound 56, the compound 66 was synthesized from the nitro derivative 65 (63 mg, 0.17 mmol, 1 equiv.) and obtained as an amorphous yellow solid (46 mg, 0.14 mmol, 80% yield) after purification by flash chromatography (cyclohexane / EtOAc, 1:4).

[0312] Formula: C20H20N4O Mass: 332.41 g-mol1

[0313] 3-(3,5-dimethoxyphenyl)pyridine-2,6-diamine (72)

[0314] According to the general procedure V, the compound 72 was synthesized from the reaction of 3-bromopyridine-2,6-diamine (400 mg, 2.13 mmol, 1 equiv.) with 3,5- dimethoxyphenylboronic acid, in the presence of 0.1 equiv. of Pd(PPh3)4. The crude product was diluted in EtOAc and an aqueous solution of HCI 1N was added. After extraction, the aqueous phase was neutralized with a saturated NaHCO3aqueous solution and washed three times with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the compound 72 as a white solid (384 mg, 1.57 mmol, 74% yield).

[0315] Formula: C13H15N3O2Mass: 245.28 g-mol-1

[0316] N,N-dibutylformamide dimethylacetal (75)

[0317] Under a perfect inert atmosphere, a solution of N,N-dibutylformamide (3 mL, 16.40 mmol, 1 equiv.) and dimethylsulphate (1.6 mL, 17.06 mmol, 1.05 equiv.) was stirred at 100 °C for 4 h, before adding a freshly prepared solution of Na (0.48 g, 20.87 mmol, 1.3 equiv.) in ice-cold anhydrous MeOH (9 mL). The stirring was prolonged for 1 more h at room temperature. The resulting suspension was concentrated under vacuum. The residue was suspended in Et2O and filtered. The filtrate was concentrated under vacuum. The crude residue was distilled with a Kugelrohr apparatus under vacuum at 40 °C to afford the compound 75 as a colorless oil in a mixture with N,N-dibutylformamide, which was used as such for the next step.

[0318] Formula: C11H2SNO2Mass: 203.32 g-mol-1

[0319] 7-amino-1 ,2-dihydro-1 ,8-naphthyridin-2-one (69) To a mixture of 2,6-diaminopyridine (1.23 g, 11.27 mmol, 1 equiv.) and malic acid (1.66 g, 12.40 mmol, 1.1 equiv.), grinded together and cooled to 0 °C, concentrated H2SO4(5 mL) was added dropwise. The resulting mixture was stirred at 110 °C for 3 h, before being quenched with ice-cold H2O and basified with concentrated NH4OH until pH= 8. The resulting suspension was filtered. The precipitate was washed with H2O, with Et2O and dried under vacuum to afford the compound 69 as a beige solid (1.80 g, 11.16 mmol, 99% yield).

[0320] Formula: C8H7N3O Mass: 161.16 g-mol’1

[0321] 7-amino-3,6-diiodo-1,8-naphthyridin-2(1H)-one (76)

[0322] To a suspension of the compound 69 (1.00 g, 6.21 mmol, 1 equiv.) in anhydrous DMF (10 mL), NIS (4.19 g, 18.61 mmol, 3 equiv.) was added. The resulting mixture was stirred at 80 °C for 24 h, before being cooled to r.t. and filtered. The filtrate was washed three times with H2O to afford the compound 76 as a beige solid (2.05 g, 4.96 mmol, 80% yield).

[0323] Formula: C8H5I2N3O Mass: 412.96 g-mol’1

[0324] 2-(N,N-Dibutylaminomethylidene)amino-3,6-diiodo-7-hydroxy-1,8-naphthyridine (77)

[0325] To a suspension of the amine 76 (771 mg, 1.87 mmol, 1 equiv.) in anhydrous DMF (4 mL), the compound 75 (643 mg, 1.96 mmol, 1.05 equiv.) was added. The resulting mixture was stirred at room temperature overnight, before being concentrated under vacuum. The residue was suspended in EtOAc and filtered. The filtrate was concentrated under vacuum to afford the compound 77 as a yellow solid (520 mg, 0.94 mmol, 51 % yield).

[0326] Formula: C17H22I2N4O Mass: 552.20 g-mol’1

[0327] 2-(N,N-Dibutylaminomethylidene)amino-7-hydroxy-3-iodo-1,8-naphthyridine (78)

[0328] To a suspension of the compound 77 (1.18 g, 2.14 mmol, 1 equiv.) in anhydrous DMF (21 mL) in a sealed tube, Bu3SnH (0.75 g, 2.56 mmol, 1.2 equiv.) and Pd(PPh3)4(0.49 g, 0.43 mmol, 0.2 equiv.) were added. The resulting mixture was stirred at 60 °C for 3 h, before being concentrated under vacuum. The crude product was purified by flash chromatography (DCM / MeOH, 99:1) to afford the compound 78 as a yellow solid (0.69 g, 1.62 mmol, 76% yield).

[0329] Formula: C17H23IN4O Mass: 426.30 g-mol’1

[0330] 2-(N,N-Dibutylaminomethylidene)amino-3-(3,5-dimethoxy)phenyl-7-hydroxy -1,8- naphthyridine (79)

[0331] According to the general procedure V, the compound 79 was synthesized from the reaction of the halide 78 (1.29 g, 3.02 mmol, 1 equiv.) with 3,5-dimethoxyphenylboronic acid (1.5 equiv.) in the presence of only 0.01 equiv. of Pd(PPh3)4. It was obtained as a white solid (1.02 g, 2.34 mmol, 77% yield), after purification by flash chromatography (Cyclohexane / EtOAc, 1:1).

[0332] Formula: C25H32N4O3 Mass: 436.56 g-mol’1

[0333] 7-amino-6-(3,5-dimethoxyphenyl)-1 ,8-naphthyridin-2(1 H)-one (80)

[0334] • Before the development of the tandem reaction, starting from the compound 79 A solution of the compound 79 (898 mg, 2.06 mmol, 1 equiv.) in a 7 N methanolic ammonia (1.5 mL) in a sealed tube was stirred at 80 °C for 15 h, before being concentrated under vacuum. The residue was suspended in cyclohexane. The resulting suspension was filtered to afford the compound 80 as a yellow solid (605 mg, 2.03 mmol, 99% yield).

[0335] • Through the tandem reduction and coupling, starting from the compound 76

[0336] To a suspension of the compound 76 (893 mg, 2.16 mmol, 1 equiv.) in anhydrous NMP (27 mL) in a sealed tube, Bu3SnH (944 mg, 3.20 mmol, 1.5 equiv.) and Pd(PPh3)4(499 mg, 0.43 mmol, 0.2 equiv.) were added. The mixture was stirred at 65 °C for 24 h, before adding 3,5- dimethoxyphenylboronic acid (472 mg, 2.60 mmol, 1.2 equiv.) and an aqueous solution of K2CO3(598 mg, 4.33 mmol, 2 equiv. in 13 mL). The stirring was prolonged for 24 more h at 90 °C. The resulting solution was concentrated under vacuum. The crude product was purified by flash chromatography (gradient from DCM to DCM / MeOH 100% to 99:1) and then recrystallized in DCM to afford the compound 80 as a yellow solid (294 mg, 0.99 mmol, 46% yield) and traces of the compound 87.

[0337] Formula: C16H15N3O3Mass: 297.31 g-mol’1

[0338] Formula: C24H23N3O5Mass: 433.46 g-mol’1

[0339] 7-chloro-3-(3,5-dimethoxyphenyl)-1 ,8-naphthyridin-2-amine (81 )

[0340] A solution of the compound 80 (685 mg, 2.30 mmol, 1 equiv.) in phenylphosphonic dichloride (10 mL) in a sealed tube was stirred at 100 °C for 18 h. The resulting solution was poured in ice-cold H2O, stirred for 30 more min at 0 °C, neutralized with a 1 M NaOH aqueous solution and diluted in EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1 :1) to afford the compound 81 as a yellow solid (461 mg, 1.46 mmol, 63% yield).

[0341] Formula: C16H14CIN3O2Mass: 315.76 g-mol’1 6-(3,5-dimethoxyphenyl)-N2-(pent-4-yn-1-yl)-1,8-naphthyridine-2,7-diamine (82)

[0342] To a suspension of the compound 81 (56 mg, 0.18 mmol, 1 equiv.) in absolute EtOH (1 mL), DIPEA (0.17 mL, 1.06 mmol, 6 equiv.) and pent-4-yn-1 -amine hydrochloride (64 mg, 0.53 mmol, 3 equiv.) were added. The resulting mixture was irradiated with microwave at 150 °C for 1 h (from 25 to 150 °C in 40 s, pressure 10 barr), before being was concentrated under vacuum. The crude product was purified by flash chromatography (gradient from DCM / MeOH 99:1 to 98:2) to afford the compound 82 as a colorless oil (10 mg, 0.03 mmol,

[0343] 16% yield) and the starting compound 81 (45 mg, 0.14 mmol, 80% yield).

[0344] Formula: C21H22N4O2Mass: 362.43 g-mol’1pent-4-yn-1 -amine hydrochloride hydrate (84)

[0345] To a suspension of 1-phthalimido-4-pentyne (150 mg, 0.70 mmol, 1 equiv.) in absolute EtOH (1.4 mL) at 0 °C, a IM hydrazine monohydrate solution in EtOH (0.70 mL, 0.70 mmol, 1 equiv.) was added dropwise. The resulting mixture was stirred at 70 °C for 2 h, before being filtered. The filtrate was concentrated under vacuum to afford the compound 84 as a white solid (58 mg, 0.70 mmol, 100% yield). HCIH2°(84)

[0346] Formula: C21H22N4O2 Mass: 362.43 g-mol’1

[0347] 1-(tert-butyl)-3-(3-(3,5-dimethoxyphenyl)-7-(pent-4-yn-1-ylamino)-1,8-naphthyridin-2- yl)urea (86)

[0348] According to the general procedure VI, the compound 86 was synthesized from the amine 82 (20 mg, 0.06 mmol, 1 equiv.) and obtained as a yellow film (22 mg, 0.05 mmol, 86% yield) after purification by flash chromatography (gradient from Cyclohexane / EtOAc 7:3 to 3:7).

[0349] Formula: C26H31N5O3 Mass: 461.57 g.mol’1

[0350] 6-(3,5-dimethoxyphenyl)-N2-pentyl-1,8-naphthyridine-2,7-diamine (88)

[0351] According to the general procedure VII, the compound 88 was synthesized from the reaction of the compound 81 (39 mg, 0.12 mmol, 1 equiv.) with amylamine and was obtained as a yellow film (46 mg, 0.12 mmol, 100% yield) after purification by flash chromatography

[0352] (DCM / MeOH, 95:5).

[0353] Formula: C21H26N4O2 Mass: 366.47 g-mol’1

[0354] 1-(tert-butyl)-3-(3-(3,5-dimethoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2-yl)urea

[0355] (89)

[0356] According to the general procedure VII, the compound 89 was synthesized from the compound 88 (30 mg, 0.08 mmol, 1 equiv.) and obtained as a yellow film (28 mg, 0.06 mmol, 73% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 7:3).

[0357] Formula: C26H35N5O3 Mass: 465.60 g-mol-1

[0358] A / -(3-(3,5-dimethoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2-yl)-3,3- dimethylbutanamide (90a)

[0359] To a solution of the compound 88 (30 mg, 0.8 mmol, 1 equiv.) in anhydrous pyridine (0.3 mL) in a sealed tube at 0 °C, f-Butylacetyl chloride (0.014 mL, 0.10 mmol, 1.25 equiv.) was added dropwise. The resulting mixture was stirred at 110 °C for 18 h, before being concentrated under vacuum. The crude product was purified by flash chromatography (a first time with DCM / MeOH 98:2 and a second time with DCM / MeOH 99:1) to afford the final amide 90a as a yellow film (21 mg, 0.04 mmol, 55% yield).

[0360] Formula: C27H36N4O3 Mass: 464.61 g-mol-1

[0361] A / -(3-(3,5-dimethoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2- yl)cyclohexanecarboxamide (90b)

[0362] According to the general procedure VIII, the final amide 90b was synthesized from the reaction, for 24 h, of the compound 88 (20 mg, 0.06 mmol, 1 equiv.) with cyclohexanecarbonyl chloride. It was obtained as a yellow film (6 mg, 0.01 mmol, 23% yield) after purification by flash chromatography (cyclohexane / EtOAc, 7:3), along with the substrate 88 (10 mg, 0.03 mmol, 50% yield).

[0363] Formula: C28H36N4O3Mass: 476.62 g-mol-1

[0364] A / -(3-(3,5-dimethoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2-yl)benzamide (90c)

[0365] According to the general procedure VIII, the final amide 90c was synthesized from the reaction, for 9 days, of the compound 88 (50 mg, 0.14 mmol, 1 equiv.) with benzoyl chloride. It was obtained as a yellow oil (30 mg, 0.06 mmol, 47% yield) after purification by flash chromatography

[0366] Formula: C28H30N4O3Mass: 470.57 g-mol-1

[0367] A / -(3-(3,5-dimethoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2- yl)cyclopropanecarboxamide (90d)

[0368] According to the general procedure VIII, the final amide 90d was synthesized from the reaction, for 72 h, of the compound 88 (70 mg, 0.19 mmol, 1 equiv.) with cyclopropanecarbonyl chloride. It was obtained as a yellow solid (58 mg, 0.13 mmol, 70% yield) after purification by flash chromatography (cyclohexane / EtOAc, 9:1), along with the substrate 88 (19 mg, 0.05 mmol, 27% yield).

[0369] Formula: C25H30N4O3 Mass: 434.23 g-mol’1

[0370] (3r,5r,7r)-A / -(3-(3,5-dimethoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2- yl)adamantane-1 -carboxamide (90e)

[0371] According to the general procedure VIII, the final amide 90e was synthesized from the reaction, for 18 h, of the compound 88 (53 mg, 0.14 mmol, 1 equiv.) with 1- adamantanecarbonyl chloride. It was obtained as a yellow solid (70 mg, 0.13 mmol, 92% yield) after purification by flash chromatography (cyclohexane / EtOAc, 3:2).

[0372] Formula: C32H40N4O3 Mass: 528.70 g-mol’1

[0373] A / -(3-(3,5-dimethoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2-yl)-1 -naphthamide (90f)

[0374] According to the general procedure VIII, the final amide 90f was synthesized from the reaction, for 24 h, of the compound 88 (50 mg, 0.14 mmol, 1 equiv.) with 1 -naphthoyl chloride. It was obtained as a yellow oil (5 mg, 0.01 mmol, 7% yield) after purification by flash chromatography (a first time with DCM / MeOH 97:3 and a second time with cyclohexane / EtOAc 3:7, using 20% of fine silica in the stationary phase), along with the substrate 88 (45 mg, 0.12 mmol, 90% yield).

[0375] Formula: C32H32N4O3 Mass: 520.63 g-mol’1

[0376] 1-(tert-butyl)-3-(7-chloro-3-(3,5-dimethoxyphenyl)-1,8-naphthyridin-2-yl)urea (91)

[0377] According to the general procedure VI, the compound 91 was synthesized from the amine 81

[0378] (220 mg, 0.70 mmol, 1 equiv.) and obtained as a yellow solid (251 mg, 0.61 mmol, 87% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 7:3).

[0379] Formula: C21H23CIN4O3 Mass: 414.89 g-mol’1

[0380] 1-(3-(3,5-dimethoxyphenyl)-7-((4,4,4-trifluorobutyl)amino)-1,8-naphthyridin-2-yl)-3-

[0381] (4,4,4-trifluorobutyljurea (92a) According to the general procedure VII, the compound 92a was synthesized from the reaction of the compound 91 (40 mg, 0.10 mmol, 1 equiv.) with 4,4,4-trifluorobutan-1-amine and obtained as a yellow film (47 mg, 0.08 mmol, 87% yield) after purification by flash chromatography

[0382] Formula: C2sH27F6NsO3 Mass: 559.51 g-mol-1

[0383] 1-(3-(3,5-dimethoxyphenyl)-7-((3-methoxypropyl)amino)-1,8-naphthyridin-2-yl)-3-(3- methoxypropyl)urea (92b)

[0384] According to the general procedure VII, the compound 92b was synthesized from the reaction of the compound 91 (40 mg, 0.10 mmol, 1 equiv.) with 3-methoxypropylamine and obtained as a yellow film (24 mg, 0.05 mmol, 51% yield) after purification by flash chromatography (a first time with DCM / MeOH 98:2 and a second time with DCM / MeOH 99.5:0.5, using 20% of fine silica in the stationary phase).

[0385] Formula: C2sH33NsOsMass: 483.57 g-mol-1

[0386] 6-(3,5-dimethoxyphenyl)-N2-(3-methoxypropyl)-1,8-naphthyridine-2,7-diamine (93a)

[0387] According to the general procedure VII, the amine 93a was synthesized from the reaction of the compound 77 (48 mg, 0.15 mmol, 1 equiv.) with 3-methoxypropylamine. The residue was dissolved in DCM, washed once with a 1M HCI aqueous solution, then three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (DCM / MeOH 98:2) to afford the amine 93a as a yellow film (55 mg, 0.15 mmol, 98% yield).

[0388] Formula: C20H24N4O3 Mass: 268.18 g-mol-1

[0389] 6-(3,5-dimethoxyphenyl)-N2-(4,4,4-trifluorobutyl)-1,8-naphthyridine-2,7-diamine (93b)

[0390] According to the general procedure VII, the amine 93b was synthesized from the reaction of the compound 77 (47 mg, 0.15 mmol, 1 equiv.) with 4,4,4-trifluorobutan-1-amine. The residue was dissolved in DCM, washed once with a 1 M HCI aqueous solution, then three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (a first time with EtOAc / MeOH 99:1 and a second time with EtOAc 100%) to afford the amine 93b as a yellow film (35 mg, 0.09 mmol, 59% yield).

[0391] Formula: C2OH2IF3N402 Mass: 406.41 g-mol’1

[0392] N2-(3-cyclohexylpropyl)-6-(3,5-dimethoxyphenyl)-1,8-naphthyridine-2,7-diamine (93c)

[0393] According to the general procedure VII, the amine 93c was synthesized from the reaction of the compound 77 (39 mg, 0.12 mmol, 1 equiv.) with 4-cyclohexyl-1-propanamine. The residue was dissolved in DCM, washed once with a IM HCI aqueous solution, then three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (EtOAc / MeOH, 99:1) to afford the amine 93c as a yellow film (43 mg, 0.10 mmol, 83% yield).

[0394] Formula: C2SH32N4O2 Mass: 420.56 g-mol’1

[0395] 6-(3,5-dimethoxyphenyl)-N2-(3-phenylpropyl)-1,8-naphthyridine-2,7-diamine (93d)

[0396] According to the general procedure VII, the amine 93d was synthesized from the reaction of the compound 77 (50 mg, 0.16 mmol, 1 equiv.) with 3-phenyl-1 -propylamine. The residue was dissolved in DCM, washed once with a 1M HCI aqueous solution, then three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (DCM / MeOH, 98:2) to afford the amine 93d as a yellow film (55 mg, 0.13 mmol, 84% yield).

[0397] Formula: C25H26N4O2 Mass: 414.51 g-mol’1

[0398] 6-(3,5-dimethoxyphenyl)-N2-(3-methoxypropyl)-1,8-naphthyridine-2,7-diamine (94a)

[0399] According to the general procedure VI, the final naphthyridine 94a was synthesized from the compound 93a (55 mg, 0.15 mmol, 1 equiv.) and obtained as a colorless oil (56 mg, 0.12 mmol, 80% yield) after purification by flash chromatography (gradient from cyclohexane / EtOAc 4: 1 to 1:1).

[0400] Formula: C2SH33NSO4Mass: 467.57 g-mol’1

[0401] 1-(tert-butyl)-3-(3-(3,5-dimethoxyphenyl)-7-((4,4,4-trifluorobutyl)amino)-1,8- naphthyridin-2-yl)urea (94b) According to the general procedure VI, the final naphthyridine 94b was synthesized from the compound 93b (30 mg, 0.07 mmol, 1 equiv.) and obtained as a yellow oil (20 mg, 0.04 mmol, 54% yield) after purification by flash chromatography (a first time with cyclohexane / EtOAc 1 :1 and a second time

[0402] Formula: C25H30F3N5O3 Mass: 505.54 g-mol’1

[0403] 1-(tert-butyl)-3-(7-((3-cyclohexylpropyl)amino)-3-(3,5-dimethoxyphenyl)-1,8- naphthyridin-2-yl)urea (94c)

[0404] According to the general procedure VI, the final naphthyridine 94c was synthesized from the compound 93c (35 mg, 0.08 mmol, 1 equiv.) and obtained as a yellow film (25 mg, 0.05 mmol, 60% yield) after purification by flash chromatography (gradient from cyclohexane / EtOAc 4:1 to 7:3).

[0405] Formula: C3oH4oNs03 Mass: 519.69 g-mol’1

[0406] 1-(tert-butyl)-3-(3-(3,5-dimethoxyphenyl)-7-((3-phenylpropyl)amino)-1,8-naphthyridin-2- yl)urea (94d)

[0407] According to the general procedure VI, the final naphthyridine 94d was synthesized from the compound 93d (45 mg, 0.11 mmol, 1 equiv.) and obtained as a yellow film (44 mg, 0.09 mmol, 79% yield) after purification by flash chromatography (Cyclohexane / EtOAc, 7:3).

[0408] Formula: C30H35N5O3 Mass: 513.64 g-mol’1

[0409] 7-chloro-1 ,8-naphthyridin-2-amine (96)

[0410] A solution of the compound 69 (950 mg, 5.90 mmol, 1 equiv.) in phenylphosphonic dichloride (19 mL) in a sealed tube was stirred at 100 °C for 18 h, before being poured in ice-cold H2O. The stirring was prolonged for 30 more min. The resulting suspension was neutralized with a 1 M NaOH aqueous solution and diluted in EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (DCM / MeOH 9:1) to afford the compound 96 as a beige solid (920 mg, 5.12 mmol, 87% yield). J cr N N NH2(96)

[0411] Formula: C8H6CIN3Mass: 179.61 g-mol’1

[0412] N2-pentyl-1 ,8-naphthyridine-2,7-diamine (97)

[0413] According to the general procedure VII, the compound 97 was synthesized from the reaction of the compound 96 (0.92 g, 5.13 mmol, 1 equiv.) with amylamine and obtained as an orange solid (1.13 g, 4.89 mmol, 95% yield) after purification by flash chromatography (DCM / MeOH, 95:5).

[0414] Formula: C13H18N4Mass: 230.32 g-mol’1

[0415] 3,3-dimethyl-A / -(7-(pentylamino)-1,8-naphthyridin-2-yl)butanamide (98)

[0416] According to the general procedure VIII, the amide 98 was synthesized from the reaction, for 18 h, of the compound 97 (550 mg, 2.39 mmol, 1 equiv.) with the acyl chloride and with only 0.1 equiv of DMAP. It was obtained as a yellow solid (640 mg, 1.95 mmol, 82% yield) after purification by flash chromatography (cyclohexane / EtOAc, 4:1).

[0417] Formula: C19H28N4O Mass: 328.46 g-mol’1

[0418] 3,3-dimethyl- / V-(7-(pentylamino)-1,8-naphthyridin-2-yl)butanamide (100)

[0419] To a suspension of the compound 98 (55 mg, 0.17 mmol, 1 equiv.) in a mixture of acetonitrile (0.9 mL) and H2O (0.1 mL), NaBr (69 mg, 0.67 mmol, 4 equiv.) and Oxone (25 mg, 0.17 mmol, 1 equiv.) were added. The mixture was stirred at room temperature for 24 h, before adding Oxone (25 mg, 0.17 mmol, 1 equiv.). The stirring was prolonged for 24 more h at r.t. The resulting solution was concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (cyclohexane / EtOAc, 9:1) to afford the compound 100 as a yellow oil (55 mg, 0.14 mmol, 81% yield).

[0420] Formula: C19H27BrN4O Mass: 406.36 g-mol’1

[0421] A / -(3,6-dibromo-7-(pentylamino)-1,8-naphthyridin-2-yl)-3,3-dimethylbutanamide (101)

[0422] To a suspension of the compound 98 (120 mg, 0.37 mmol, 1 equiv.) in anhydrous toluene (1.5 mL), NBS (136 mg, 0.77 mmol, 2 equiv.), APTS (31 mg, 0.18 mmol, 0.5 equiv.), and Pd(PPh3)4(4 mg, 0.19 mmol, 0.05 equiv.) were added. The mixture was stirred at room temperature for 24 h, before adding again NBS (136 mg, 0.77 mmol, 2 equiv.). The stirring was prolonged for 48 more h at r.t. and the resulting solution was concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (cyclohexane / EtOAc, 4:1) to afford the compound 101 as an orange oil (105 mg, 0.22 mmol, 59% yield).

[0423] Formula: C19H26Br2N4O Mass: 486.25 g-mol’1 A / -(7-chloro-1,8-naphthyridin-2-yl)acetamide (102)

[0424] To a suspension of the compound 96 (110 mg, 0.61 mmol, 1 equiv.) in anhydrous DCM (1 mL) at 0 °C, acetic anhydride (0.086 mL, 0.92 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 60 °C for 18 h, before being concentrated under vacuum. The residue was dissolved in DCM, washed three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the compound 102 as a white solid (134 mg, 0.61 mmol, 99% yield).

[0425] Formula: C10H8CIN3O Mass: 221.64 g-mol’1

[0426] 7-azido-1,8-naphthyridin-2-amine (104)

[0427] To a suspension of the compound 96 (100 mg, 0.56 mmol, 1 equiv.) in anhydrous DMF (1.3 mL), NaN3(72 mg, 1.12 mmol, 2 equiv.) was added. The resulting mixture was stirred at 100 °C for 24 h, before being filtered. The filtrate was concentrated under vacuum. The solid residue was suspended in H2O and filtered. The precipitate was washed three times with Et2O to afford the compound 104 as a red solid (87 mg, 0.47 mmol, 84% yield).

[0428] Formula: C8H6N6Mass: 186.18 g-mol’1

[0429] 2-azido-3-bromo-7-chloro-1,8-naphthyridine (105)

[0430] To a suspension of the compound 104 (70 mg, 0.38 mmol, 1 equiv.) in a mixture of acetonitrile (0.25 mL) and H2O (1.75 mL), NaBr (38 mg, 0.38 mmol, 1 equiv.) and Oxone (114 mg, 0.75 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 1 h, adding Oxone (29 mg, 0.19 mmol, 0.5 equiv.). The stirring was prolonged for 1 h more. The mixture was concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with H2O and finally with Et2O to afford the compound 105 and the compounds 104 / 106 / 107 in a mixture 1 :0.2:0.1:0.2. As these compounds are insoluble in the common solvents, their separation by column chromatography was not possible. This mixture containing a majority of 105 (86 mg, 66% pure, estimated from NMR: 0.22 mmol, 57% yield) that was used as such for the next step.

[0431] Formula: C8H5BrN6Mass: 265.07 g.mol’1

[0432] 7-azido-6-bromo-N-pentyl-1,8-naphthyridin-2-amine (P.108) and 7-azido-3-bromo-N- pentyl-1,8-naphthyridin-2-amine (109)

[0433] To a mixture of the compounds 104 / 105 / 106 / 107 (119 mg, 0.42 average mmol, 1 equiv.) suspended in anhydrous DMF (0.7 mL) in a sealed tube at - 46 °C, NaH 60% in mineral oil (18 mg, 0.44 mmol, 1.05 equiv.) was added. The mixture was stirred at - 46 °C for 1 h, before adding 1-Bromopentane (60 mg, 0.050 mL, 0.40 mmol, 0.95 equiv.). The stirring was prolonged for 18 more h slowly passing from - 46 °C to r.t. and then for 24 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was dissolved in EtOAc, washed once with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (gradient from cyclohexane / EtOAc 9:1 to 1:1) to afford the compound 108 and the compound 109 in a mixture 1 :0.3. As these compounds have exactly the same Rf, their separation by column chromatography failed to get pure 108. This mixture containing a majority of 108 (52 mg, 71% pure, estimated from H-NMR: 0.11 mmol, 59% yield) was used as such for the next step.

[0434] Formula: C13H15BrN6Mass: 335.21 g.mol’1

[0435] 7-azido-6-bromo-N,N-dipentyl-1,8-naphthyridin-2-amine (110)

[0436] To a suspension of the compound 105 (56 mg, 0.21 mmol, 1 equiv.) in anhydrous DMF (0.7 mL) in a sealed tube at 0 °C, NaH 60% in mineral oil (9 mg, 0.22 mmol, 1.05 equiv.) was added. The mixture was stirred at 0 °C for 1 h, before adding 1 -bromopentane (64 mg, 0.053 mL, 0.42 mmol, 2 equiv.). The stirring was prolonged for 18 h more at 80 °C. The resulting solution was concentrated under vacuum. The residue was dissolved in EtOAc, washed once with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (cyclohexane / EtOAc, 7:3) to afford the compound 110 as a yellow oil (71 mg, 0.18 mmol, 83% yield).

[0437] Formula: C18H27BrN4Mass: 405.34 g-mol-1

[0438] 6-bromo-N2-pentyl-1,8-naphthyridine-2,7-diamine (111)

[0439] To a solution of the compound 108 (342 mg, in a mixture 1 :0.3 with 109, estimated from H- NMR: 0.72 mmol, 1 equiv.) in a mixture of anhydrous THF (18 mL) and H2O, PPh3(787 mg, 3 mmol, 4 equiv.) was added. The mixture was stirred at 90 °C for 72 h, before being concentrated under vacuum. The residue was dissolved in anhydrous THF and a 1 M HCI aqueous solution (3 mL, 3 mmol, 4 equiv.) was added. The resulting suspension was stirred at room temperature for 30 min and at 80 °C for 2 h, before being concentrated under vacuum. The residue was dissolved in EtOAc, washed three times with H2O and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (a first time with cyclohexane / EtOAc 1 :1 and a second time with DCM / MeOH 98.5:1.5, using 20% of fine silica in the stationary phase) to afford the compound 111 as a yellow oil (192 mg, 0.62 mmol, 86% yield).

[0440] Formula: C13H17BrN4Mass: 309.21 g-mol’1

[0441] 1-(3-bromo-7-(pentylamino)-1,8-naphthyridin-2-yl)-3-(tert-butyl)urea (112)

[0442] According to the general procedure VI, the urea 112 was synthesized from the compound 111 (18 mg, 0.06 mmol, 1 equiv.) and obtained as a yellow solid (24 mg, 0.06 mmol, 100% yield) after purification by flash chromatography (cyclohexane / EtOAc, 7:3).

[0443] Formula: C18H26BrN5O Mass: 408.34 g-mol’1tert -butyl 2-(2-bromoethyl)piperidine-1 -carboxylate (114)

[0444] To a solution of f-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate (103 mg, 0.45 mmol, 1 equiv.) in anhydrous DCM (1.4 mL), PPh3(130 mg, 0.49 mmol, 1.1 equiv.) and a solution of tetrabromomethane (164 mg, 0.49 mmol, 1.1 equiv.) in anhydrous DCM (0.4 mL) were added. The resulting mixture was stirred at room temperature for 2 h, before being concentrated under vacuum. The crude product was purified by flash chromatography (gradient from cyclohexane 100% to cyclohexane / EtOAc 9:1) to afford the compound 114 as a colorless oil (123 mg, 0.42 mmol, 94% yield).

[0445] Formula: C12H22BrNO2Mass: 291.22 g-mol’1tert-butyl 2-(2-(3-bromo-4-methoxyphenoxy)ethyl)piperidine-1 -carboxylate (116)

[0446] According to the general procedure IX, the compound 116 was synthesized from the reaction of 3-bromo-4-methoxyphenol (35 mg, 0.17 mmol, 1 equiv.) with the compound 114 in anhydrous DMF and obtained as a colorless oil (32 mg, 0.08 mmol, 45% yield) after purification by flash chromatography (DCM 100%).

[0447] Formula: C19H28BrNO4Mass: 414.34 g-mol’1

[0448] 2-(3-(3-bromo-4-methoxyphenoxy)propyl)isoindoline-1, 3-dione (117)

[0449] According to the general procedure IX, the compound 117 was synthesized from the reaction of 3-bromo-4-methoxyphenol (100 mg, 0.49 mmol, 1 equiv.) with / V-(3- bromopropyl)phthalimide in anhydrous DMF and obtained as a white solid (158 mg, 0.40 mmol, 82% yield) after purification by flash chromatography (DCM 100%).

[0450] Formula: C18H16BrNO4Mass: 389.03 g-mol’1

[0451] 2-bromo-4-(3-chloropropoxy)-1 -methoxybenzene (118)

[0452] According to the general procedure IX, the compound 118 was synthesized from the reaction of 3-bromo-4-methoxyphenol (326 mg, 1.61 mmol, 1 equiv.) with 1-bromo-1 -chloropropane in anhydrous acetone and obtained as a colorless oil (417 mg, 1.49 mmol, 93% yield) after purification by flash chromatography (cyclohexane / EtOAc, 4:1).

[0453] Formula: C10H12BrCIO2Mass: 279.56 g-mol’1

[0454] 1-(3-(3-bromo-4-methoxyphenoxy)propyl)-1H-imidazole (119)

[0455] To a solution of the compound 118 (81 mg, 0.29 mmol, 1 equiv.) in anhydrous acetonitrile (1.2 mL) in a sealed tube, imidazole (59 mg, 0.87 mmol, 3 equiv.), DIPEA (0.07 mL, 0.43 mmol, 1.5 equiv.), and Nal (48 mg, 0.32 mmol, 1.1 equiv.) were added. The resulting mixture was stirred at 110°C for 48 h, before being concentrated under vacuum. The residue was dissolved in EtOAc, washed once with a saturated Na2CO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (DCM / MeOH, 95:5) to afford the compound 119 as a colorless oil (64 mg, 0.21 mmol, 71% yield).

[0456] Formula: C13H15BrN2O2Mass: 311.18 g-mol’1tert-butyl2-(2-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)ethyl)piperidine-1 -carboxylate (120)

[0457] According to the general procedure X, the compound 120 was synthesized from the halide 116 (18mg, 0.04 mmol, 1 equiv.) and obtained after purification by flash chromatography (gradient from cyclohexane / EtOAc 4:1 to 7:3) in a mixture 1 :0.3:0.3 with bis(pinacolato)diboron and pinacol. This mixture, containing a majority of 120 (15 mg, estimated from NMR: 0.03 mmol, 75% yield) was used as such for the next step.

[0458] Formula: C25H40BNO6Mass: 461.41 g-mol’1

[0459] 2-(3-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)propyl)isoindoline-1 ,3-dione (121 )

[0460] According to the general procedure X, the compound 121 was synthesized from the halide 117 (95 mg, 0.24 mmol, 1 equiv.). The crude product was purified by flash chromatography (DCM / MeOH, 95:5), dissolved in anhydrous THF (0.5 mL) and stirred at room temperature overnight, after adding pinacol (35 mg, 0.29 mmol, 1.2 equiv.) and Na2SO4(104 mg, 0.73 mmol, 3 equiv.). The resulting mixture was filtered, concentrated in vacuo and purified by flash chromatography (Cyclohexane / EtOAc, 7:3) to afford the compound 121 as a colorless oil (92 mg, 0.19 mmol, 77% yield).

[0461] Formula: C24H28BNO6Mass: 437.30 g-mol’1 1 -(3-(4-methoxy-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)propyl)-1 H- imidazole (122)

[0462] According to the general procedure X, the compound 122 was synthesized from the halide 119 (60 mg, 0.19 mmol, 1 equiv.). The crude product was purified by flash chromatography (DCM / MeOH, 95:5), dissolved in anhydrous THF (0.5 mL) and stirred at room temperature overnight, after adding pinacol (34 mg, 0.29 mmol, 1.2 equiv.) and Na2SO4(103 mg, 0.73 mmol, 3 equiv.). The resulting suspension was filtered and concentrated in vacuum to afford a mixture 1:0.7 of the compound 122 and pinacol. This mixture, containing a majority of 1 2 (53 mg, 58% pure; estimated from NMR: 0.12 mmol, 62% yield) was used as such for the next step.

[0463] Formula: C19H27BN2O4Mass: 358.25 g-mol-1

[0464] 1-(tert-butyl)-3-(3-(2,5-dimethoxyphenyl)-7-(pent-4-yn-1-ylamino)-1,8-naphthyridin-2- yl)urea (1 3a)

[0465] According to the general procedure V, the final naphthyridine 1 3a was synthesized from the reaction of the compound 112 (36 mg, 0.09 mmol, 1 equiv.) with 2,5-dimethoxyphenylboronic acid, in the presence of 0.01 equiv. of Pd(PPh3)4. It was obtained as a colorless oil (33 mg, 0.07 mmol, 80% yield) after purification by flash chromatography (cyclohexane / EtOAc, 7:3).

[0466] Formula: C26H35N5O3Mass: 465.60 g-mol-1

[0467] 1 -(3-(5-(3-( 1 H-imidazol-1 -yl)propoxy)-2-methoxyphenyl)-7-(pentylamino)-1 ,8- naphthyridin-2-yl)-3-(tert-butyl)urea (123b)

[0468] According to the general procedure V, the final naphthyridine 1 3b was synthesized from the reaction of the compound 112 (40 mg, 0.10 mmol, 1 equiv.) with the boronate 122, in the presence of 0.01 equiv. of Pd(PPh3)4. It was obtained as a colorless oil (41 mg, 0.07 mmol, 74% yield) after purification by flash chromatography (a first time with DCM / MeOH 96:4 and a second time with a gradient from EtOAc / MeOH 100:0 to 96:4).

[0469] Formula: C31H41N7O3Mass: 559.72 g-mol-1tert-butyl 2-(2-(3-(2-(3-(tert-butyl)ureido)-7-(pentylamino)-1,8-naphthyridin-3-yl)-4- methoxyphenoxy)ethyl)piperidine-1 -carboxylate (123c)

[0470] According to the general procedure V, the naphthyridine 123c was synthesized from the reaction of the compound 112 (27 mg, 0.07 mmol, 1 equiv.) with the boronate 120 in the presence of 0.01 equiv. of Pd(PPh3)4. It was obtained as a yellow oil (32 mg, 0.05 mmol, 72% yield) after purification by flash chromatography (gradient from cyclohexane / EtOAc 4:1 to 7:3).

[0471] Formula: C37HS4N6OSMass: 662.41 g-mol’1

[0472] 1-(tert-butyl)-3-(3-(2-methoxy-5-(2-(piperidin-2-yl)ethoxy)phenyl)-7-(pentylamino)-1,8- naphthyridin-2-yl)urea (124)

[0473] To a solution of the compound 123c (30 mg, 0.05 mmol, 1 equiv.) in anhydrous DCM (0.3 mL) at 0 °C, TFA (0.067 mL, 0.90 mmol, 20 equiv.) was added dropwise. The resulting mixture was stirred at room temperature for 2 h, before being diluted with EtOAc and neutralized with NaOH 1 M. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (gradient from DCM / MeOH / NEt3from 95:5:1 to 90:10:1) to afford the final naphthyridine 124 as a yellow oil (25 mg, 0.04 mmol, 98% yield).

[0474] Formula: C32H46N6O3Mass: 562.76 g-mol’1

[0475] 3-(3-(2-(3-(tert-butyl)ureido)-7-(pentylamino)-1,8-naphthyridin-3-yl)-4- methoxyphenoxy)propan-1-aminium formate (126)

[0476] According to the general procedure V, the final naphthyridine 126 was synthesized from the reaction of the compound 112 (64 mg, 0.16 mmol, 1 equiv.) with the boronate 121 in the presence of 0.01 equiv. of Pd(PPh3)4. The crude product was purified by flash chromatography (gradient from DCM / MeOH 97:3 to 90:10) to afford the intermediate 125 as a yellow oil (83 mg, 0.13 mmol, 81% yield). To a solution of the intermediate 125 in f-Butanol (1 mL), ethylenediamine (0.056 mL, 0.83 mmol, 7 equiv.) was added. The resulting mixture was stirred at 100 °C for 24 h, before being concentrated under vacuum. The residue was purified by flash chromatography (a first time with a gradient from DCM / MeOH 9:1 to 4:1 and a second time using basic alumina as stationary phase with DCM / MeOH 95:5) to afford the final naphthyridine 126 as a yellow oil (34 mg, 89% pure as calculated by HPLC-HRMS, 0.70 mmol, 56% yield). A fraction of the compound 126, for the characterization and the biological evaluations was further purified by HPLC, as specified in general information. The rest has been used as such in the next step.

[0477] Formula: C29H42N6O5Mass: 554.69 g-mol’1

[0478] 1-(3-(3-(2-(3-(tert-butyl)ureido)-7-(pentylamino)-1,8-naphthyridin-3-yl)-4- methoxyphenoxy)propyl) guanidinium formate (127)

[0479] To a solution of the compound 126 (19 mg, 0.03 mmol, 1 equiv.) in anhydrous DMF (0.5 mL) in a sealed tube, 1 H-pyrazole-1-carboxamidine hydrochloride (5 mg, 0.04 mmol, 1.1 equiv.) and DIPEA (0.005 mL, 0.04 mmol, 1.1 equiv.) were added. The resulting mixture was stirred at 60 °C for 24 h, before being concentrated under vacuum. The crude product was purified by flash chromatography (a first time with basic alumina as stationary phase, gradient from DCM / MeOH / NEt395:5:1 to 90:10:1 , and a second time with C18 stationary phase, gradient from acetonitrile 100% to aqueous 0.1 % HCOOH 100%) to afford the final naphthyridine 127 as a colorless oil (9 mg, 0.02 mmol, 51% yield).

[0480] NH

[0481] Formula: C30H44N8OsMass: 596.73 g-mol-1

[0482] 7-chloro-3-(2-methoxyphenyl)-1,8-naphthyridin-2-amine (129)

[0483] To a suspension of the compound 76 (500 mg, 1.21 mmol, 1 equiv.) in anhydrous NMP (15 mL) in a sealed tube under inert atmosphere, Bu3SnH (529 mg, 1.81 mmol, 1.5 equiv.) and Pd(PPh3)4(280 mg, 0.24 mmol, 0.2 equiv.) were added. The mixture was stirred at 65 °C for 24 h, before adding 2-dimethoxyphenylboronic acid (221 mg, 1.45 mmol, 1.2 equiv.) and an aqueous solution of K2CO3(335 mg, 2.42 mmol, 2 equiv. in 8 mL). The stirring was prolonged for 24 more h at 90 °C. The mixture was concentrated under vacuum. The crude product was purified by flash chromatography (gradient from DCM to DCM / MeOH 100% to 99:1) and then recrystallized in DCM to afford the compound 128 as a yellow solid (169 mg, 0.39 mmol, 100% pure, 32% yield). A solution of the compound 128 (60 mg, 0.22 mmol, 1 equiv.) in phenylphosphonic dichloride (1 mL) in a sealed tube under inert atmosphere was stirred at 100 °C for 18 h, before being quenched in ice-cold H2O and stirred 30 more min. The resulting suspension was neutralized with aqueous NaOH 1 M and diluted in EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Cyclohexane / EtOAc, 1 :1) to afford the 2-chloronaphthyridine derivative 129 as a yellow solid (32 mg, 0.11 mmol, 50% yield).

[0484] Formula: C15H12CIN3O Mass: 285.73 g-mol-1

[0485] 6-(2-methoxyphenyl)-N2-pentyl-1 ,8-naphthyridine-2,7-diamine (130)

[0486] According to the general procedure VII, the compound 130 was synthesized from the reaction of the compound 129 (29 mg, 0.10 mmol, 1 equiv.) with amylamine. The residue was dissolved in DCM, washed once with a 1 N HCI aqueous solution, then three times with a saturated NaHCO3aqueous solution and finally with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (gradient from DCM / MeOH 99:1 to 95:5) to afford the compound 130 as a yellow film (31 mg, 0.09 mmol, 91% yield).

[0487] Formula: C20H24N4O Mass: 336.44 g-mol-1

[0488] 1-(tert-butyl)-3-(3-(2-methoxyphenyl)-7-(pentylamino)-1,8-naphthyridin-2-yl)urea (131)

[0489] According to the general procedure VI, the final naphthyridine 131 was synthesized from the compound 130 (25 mg, 0.07 mmol, 1 equiv.) and obtained as a yellow film (26 mg, 0.06 mmol, 80% yield) after purification by flash chromatography (cyclohexane / EtOAc, 7:3).

[0490] Formula: C25H33N5O2Mass: 435.57 g-mol’1

[0491] Process of preparation of the compound of formula 132: The following process has been carried out :

[0492] Process of preparation of the compound of formula 133: The following process has been carried out :

[0493] Process of preparation of the compound of formula 134: The following process has been carried out :

Claims

CLAIMS1 . A compound according to formula IIn which : the Het-Het nucleus represents a bicyclic heteroaryl group which contains one, two or three nitrogen atoms;Ar represents a C6-C10aryl group substituted by a group R1or by a group R1and a group R2wherein R1and R2represent independently of each other a C C2alkoxy group, a halogen atom, a CrC6alkyl group substituted by an halogen atom, a -CN group, a -NO2group or a -O-(CH2)n-R3group or a -NH-C=O-R6group;In which R3represents a guanidyl group, a -N(R4)(R5) group, a C3-C6heterocycloalkyl group or a C3-C10heteroaryl group, the heteroatom of the heterocycloalkyl group being optionally substituted by a N-protecting group when the heteroatom is a nitrogen atom;In which R4and R5represent independently of each other a hydrogen atom or a C C4alkyl group; wherein n is an integer selected from 1 , 2 or 3, advantageously from 2 or 3; in which R6represents a C2-C6alkenyl group optionally substituted by a N(R7)(R8) group;In which R7and R8represent independently of each other a hydrogen atom or a C1-C4 alkyl group;Y represents a CrC6alkyl group which can be substituted by one or several group(s) selected from a C3-C aryl group, a C3-C cycloalkyl group, a C3-C6heterocycloalkyl group, a C2-C6alkynyl group, a C2-C6alkenyl group, a C C2alkoxy group, a -CN group, a -CF3group, an halogen atom, a -SO3H group, a -PO3H group and a -NO2group, wherein the C3-C10aryl group is optionally substituted by a -NH-C=O-R9group in which R9represents a C2-C6alkenyl group optionally substituted by a N(R10)(R11) groupIn which R10and R11represent independently of each other a hydrogen atom or a C1-C4 alkyl group, advantageously a methyl group;L represents a linker selected from a -NH-CO- group, a -NH-CO-NH- group, a -NH-CS-NH- group and a -NH-SO2- groupX represents a C3-C10cycloalkyl group, a CrC6alkyl group, a C6-C10aryl group, a C3-C10heterocycloalkyl group or a C3-C10heteroaryl group, and when the Het-Het nucleus contains 3 nitrogen atoms, Ar represents the 2- methoxy-phenyl group in which the phenyl group is optionally substituted by the -O- (CH2)n-R3group as defined above or Ar represents the 3,5-bis(trifluoromethyl)phenyl group or LX represents a group NH-C=O-CH2-t-Bu.

2. A compound according to claim 1 , characterized in that it has the following formula II:In which Z-i, Z2and Z3represent independently of each other a nitrogen atom or a CH group on the condition that at least one of Z-i , Z2and Z3represent a nitrogen atom and Ar, L, X and Y are as defined in claim 1 .

3. A compound according to claim 2, characterized in that at least one of Z-i, Z2and Z3represent a CH group.

4. A compound according to any one of claims 1 to 3, characterized in that it has the following formula III:In which Ar, L, X and Y are as defined in claim 1.

5. A compound according to any of the preceding claims, characterized in that Y represents a C C6alkyl group which can be substituted by a group selected from a -O-Me group, a -CF3group, a — C=CH group, a cyclohexyl group and a phenyl group.

6. A compound according to any of the preceding claims, characterized in that X represents a C C6alkyl group, a C3-C10cycloalkyl group or a C6-C10aryl group.

7. A compound according to claim 6, characterized in that X represents a -CH2-t-Bu group, a -t-Bu group, a cyclopropyl group, an adamantyl group, a cyclohexyl group, a phenyl group or a naphthyl group.

8. A compound according to any of the preceding claims, characterized in that R1and R2represent independently of each other a -O-Me group, a -CF3group, -O- (CH2)n-R3group wherein R3represent a guanidyl group, a -NH2group, a piperidinyl group, or an imidazolyl group and n is an integer selected from 1 , 2 and 3.

9. A compound according to any of the preceding claims, characterized in that L represents a linker selected from a -NH-CO- group and a -NH-CO-NH- group.

10. A compound according to any of the preceding claims, characterized in that the substituents in formula I, II or III are selected from at least one or all of the following options:- X represents a -CH2-tBu group, a t-Bu group, or an adamantyl group;- Y represents a C3alkyl group substituted by a -CF3group, a cyclohexyl group or a phenyl group; and / or- Ar represents a 2-methoxy-phenyl group, a 2,4-dimethoxy phenyl group, or agroup.

11. A compound according to claim 1 , characterized in it has one of the following formulae:

12. A compound according to claim 1 characterized in that it has the following13. A compound according to any one of claims 1 to 12, its enantiomers and pharmaceutical acceptable salts thereof or a pharmaceutical composition comprising it for its use as a medicament.

14. A compound according to any one of claims 1 to 12, its enantiomers and pharmaceutical acceptable salts or a pharmaceutical composition comprising it for its use in the prevention and / or treatment of a viral infection, and wherein suchviral infection is preferably an infection by a virus chosen from influenza viruses, human immunodeficiency viruses and human papillomaviruses, preferably chosen from Influenza virus A, Influenza virus B, Influenza virus C, Influenza virus D, HIV- 1 , HIV-2, HPV16, HPV18, HPV6 and HPVH.

15. A compound or a pharmaceutical composition comprising it for its use according to claim 14, characterized in that the viral infection is Influenza virus A.

16. A compound according to any one of claims 1 to 12, its enantiomers and pharmaceutical acceptable salts or a pharmaceutical composition comprising it for its use for treating and / or preventing cancer.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, its enantiomers or pharmaceutical acceptable salts, as well as mixtures thereof and at least one pharmaceutically acceptable excipient.

18. A composition according to claim 17, characterized in that the composition further comprises another antiviral agent such as baloxivir marboxil, amantadine, moroxydine, oseltamivir, peramivir, rimantadine, uminfenovir, zanamivir, abacavir, ampligen, amprenavir, atazanavir, cidofovir, elvitegravir, emtricitabine, nirmaltrevir, ritonativ and mixtures thereof.

19. A composition according to any one of claims 17 or 18 for use as a medicament, preferably an antiviral medicament or an anticancer, antitumoral and / or cytotoxic medicament.

20. Use of a compound according any of claims 1 to 12 as an in vitro inhibitor of RED- SMU1 complex and / or FGFR3.

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