Phenyl / pyridinyl-N-phenyl / pyridinyl derivatives for the treatment of RNA virus infections

Abstract

The present invention relates to any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof: wherein Y 1 represents an aryl group, X 2 represents an -O-group, an -NH-group, an -S-group, a -CO-NH-group, a -NH-CO-NH-group, a -NH-CO-group, a -CH(OH)-group, a -CH(COOH)NH-group, a -CH(COOCH3)NH-group, a -C(OH)(CH2OH)-, an (AA) group, i.e. (AA), a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or more heteroatoms, a -SO2-group or a -SO2-NH-group, and Y 2 Represents hydrogen atom, hydroxyl group, (C1-C4) alkoxy group, ‑CHC(OH)2, COOR f , where R f represents a hydrogen atom or a (C1-C4)alkyl group, a morpholinyl group, a dihydropyranyl group, a (BB) group, i.e. (BB), a (CC) group, i.e. (CC), ‑PO(OR f )(OR' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group, an oxetanyl group, a -Si(CH3)3 group, a -NHCOO-(C1-C4) alkyl group or a -CR 1 R 2 R 3 The present invention further relates to pharmaceutical compositions containing them and to synthetic methods for preparing them.

Description

[0001] The present invention relates to compounds useful for preventing and / or treating RNA viral infections, and most preferably RNA viral infections caused by RNA viruses belonging to Group IV or V of the Baltimore classification.

[0002] The present invention further relates to novel compounds, particularly useful for the prevention and / or treatment of RNA viral infections, and most preferably RNA viral infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification.

[0003] It further relates to pharmaceutical compositions containing said novel compounds and to chemical synthesis processes for obtaining them.

[0004] background

[0005] Viruses are one of the leading causes of disease worldwide. Viruses are generally defined as small, inanimate infectious agents that replicate only within living cells, as they do not possess a fully autonomous replication mechanism. Although they vary in shape and size, they generally consist of virus particles (called "virions") made of a protein coat comprising at least one nucleic acid molecule and optionally one or more proteins or nucleoproteins depending on the virus type.

[0006] Because viruses do not have completely autonomous replication mechanisms, they must rely on the mechanisms and metabolism of the infected cell or host to replicate and produce multiple copies of themselves.

[0007] Although their replication cycles vary widely among species, it is generally accepted that the viral life cycle consists of six basic steps: attachment, entry, uncoating, replication, assembly, and release.

[0008] Depending on the nature of the virus being targeted, therapeutic molecules have been designed that may interfere with one or more of those mechanisms.

[0009] Among them, the replication step involves not only the proliferation of the viral genome, but also the synthesis of viral messenger RNA, the synthesis of viral proteins, and the regulation of the host's transcription or translation machinery. However, it is also obvious that the type of genome (single-stranded, double-stranded, RNA, DNA...) is a significant feature of this replication step. For example, most DNA viruses assemble in the nucleus, while most RNA viruses develop only in the cytoplasm. Moreover, there is increasing evidence that single-stranded RNA viruses (such as influenza) use host RNA splicing and maturation mechanisms.

[0010] Therefore, and taking into account the involvement of a given type of genome in the replication steps, the Baltimore virus classification was developed. This classification divides viruses into families (or "groups") based on their genome type. As in 2018, the current virus classification includes seven different groups:

[0011] - Group I: double-stranded DNA viruses (dsDNA);

[0012] - Group II: single-stranded DNA viruses (ssDNA);

[0013] - Group III: double-stranded RNA viruses (dsRNA);

[0014] - Group IV: (+) strand or sense RNA viruses ((+)ssRNA);

[0015] - Group V: (-)sense or negative sense RNA viruses ((-)ssRNA);

[0016] - Group VI: single-stranded RNA viruses with a DNA intermediate (ssRNA-RT);

[0017] - Group VII: double-stranded DNA viruses with an RNA intermediate (dsDNA-RT).

[0018] According to this classification, strictly speaking, viruses belonging to Group VI are not RNA viruses. For the same reason, strictly speaking, viruses belonging to Group VII are not DNA viruses. A well-studied example of a virus family belonging to Group VI is the Retroviridae (retroviruses), which includes HIV. A well-studied example of a virus family belonging to Group VII is the Hepadnaviridae, which includes the Hepatitis B virus (HBV).

[0019] As representatives of viruses belonging to group IV, one can cite the Picornaviruses (a family of viruses that includes well-known viruses such as hepatitis A virus, enterovirus, rhinovirus, poliovirus and foot-and-mouth disease virus), SARS virus, hepatitis C virus, yellow fever virus and rubella virus. The Togaviridae family also belongs to group IV, and one of its known genus is alphavirus, which covers Chikungunya virus. The Flaviridae family is also a family belonging to group IV, which covers the well-known virus transmitted by mosquitoes, namely dengue virus.

[0020] Representatives of viruses belonging to Group V include the Filoviridae family, which includes Ebola virus, the Paramyxoviridae family, which includes respiratory syncytial virus (RSV), the Rhabdoviridae family, and the Orthomyxoviridae family, which includes influenza virus A, influenza virus B, and influenza virus C.

[0021] A group included within the Viridae family of particular interest within the framework of the present invention is that which encompasses RNA viruses, in particular single-stranded RNA viruses, and more specifically RNA viruses belonging to Groups IV and V of the Baltimore classification.

[0022] There are few cures for diseases caused by RNA virus infections, especially single-stranded RNA viruses, and more specifically RNA virus infections belonging to groups IV and V of the Baltimore classification. Treatment focuses on alleviating symptoms. Therefore, there remains a need to identify new antiviral drugs to treat RNA virus infections, such as those from groups IV and V, especially small chemical molecules.

[0023] definition

[0024] The term "patient" as used herein refers to an animal, such as a valuable animal for breeding, companionship or preservation purposes, or preferably a human or human child, that suffers from, or has a potential to suffer from, one or more of the diseases and disorders described herein.

[0025] Specifically, as used in this application, the term "patient" refers to a mammal such as a rodent, a cat, a dog, a primate or a human, preferably the subject is a human, and also extends to birds.

[0026] The identification of those patients who need treatment for the diseases and conditions described herein is well within the ability and knowledge of those skilled in the art. By using clinical trials, physical examinations, medical / family history or biological and diagnostic tests, a veterinarian or physician in the art can readily identify those patients who need such treatment.

[0027] In the context of the present invention, the term "treat" as used herein refers to reversing, alleviating, preventing a disease caused by an RNA virus infection, and more particularly an RNA virus infection from group IV or V, or one or more symptoms of such a disease, or inhibiting its progression.

[0028] As used herein, an "effective amount" means an amount of a compound of the invention that is effective to prevent, reduce, eliminate, treat or control the symptoms of the diseases and disorders described herein, i.e., RNA virus infections, and more particularly RNA virus infections from Group IV or V. The term "control" is intended to mean all processes in which the progression of the diseases and disorders described herein may be slowed, interrupted, prevented or stopped, but does not necessarily indicate complete elimination of all disease and disorder symptoms, and is intended to include prophylactic treatment.

[0029] The term "effective amount" includes a "prophylactically effective amount" as well as a "therapeutically effective amount".

[0030] As used herein, the term "prevent" refers to reducing the risk of occurrence of a given phenomenon, or slowing down the onset of a given phenomenon, which in the present invention is a disease caused by an RNA virus infection, and more particularly an RNA virus infection from group IV or V.

[0031] As used herein, "prevent" also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0032] The term "prophylactically effective amount" refers to a concentration of a compound of the invention that, when administered prior to infection (i.e., before, during and / or shortly after the exposure phase to RNA viruses, and in particular RNA viruses from groups IV or V), effectively inhibits, prevents, reduces the likelihood of disease caused by RNA viruses, and more particularly RNA viruses from groups IV or V of the Baltimore classification, or prevents RNA virus infection, and in particular RNA virus infection from groups IV or V, or prevents the delayed onset of disease caused by RNA viruses, and more particularly RNA viruses from groups IV or V.

[0033] Likewise, the term "therapeutically effective amount" refers to a concentration of a compound that is effective in treating an RNA viral infection, such as when administered after an infection has already occurred, resulting in a reduction in RNA viral infection upon detection.

[0034] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, excipients, compositions or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problematic complications, commensurate with a reasonable benefit / risk ratio.

[0035] As used herein, "viral infection or related condition" refers to an infection with a condition associated with a virus, more particularly a virus having an RNA genome, and particularly an RNA virus belonging to group IV or V according to the Baltimore classification. Viruses can be further divided into different families, orders and genera.

[0036] For reference, the content of the "Baltimore classification" reported herein further refers to the virus taxonomy listed in the database of the 2017 International Committee of Taxonomy of Viruses (ICTV) published online at http: / / ictvonline.org / virusTaxonomy.asp on March 12, 2018. The taxonomy is incorporated herein in its entirety.

[0037] The present invention particularly contemplates alphaviruses, which belong to group IV RNA viruses and the Togaviridae family, which can be defined as positive-sense single-stranded RNA viruses or (+)ssRNA viruses. According to the 2017 taxonomy of viruses, their order is "unspecified". The Togaviridae family includes the genus Alphavirus and Rubivirus.

[0038] Examples of alphaviruses contemplated by the present invention include: Barmah Forest virus, Chikungunya virus, Mayaro virus, O'nyong'nyong virus, Ross River virus, Semliko Forest virus, Una virus, Eastern equine encephalitis virus, Tonat virus, Venezuelan equine encephalitis virus, and Western equine encephalitis virus.

[0039] Most preferably, according to the present invention, the alphavirus infection or alphavirus-associated disorder is a Chikungunya virus infection or a Chikungunya virus-associated disorder.

[0040] More specifically, Chikungunya virus (CHIKV) is an RNA virus belonging to the genus Alphavirus, which in turn belongs to the family Togaviridae, i.e., group IV from the Baltimore classification. Chikungunya is a mosquito-borne viral disease that was first described in an outbreak in southern Tanzania in 1952. CHIKV is an enveloped, positive-sense, single-stranded RNA virus with a genome of approximately 12 kb nucleotide length. The genome of CHIKV is organized as follows: 5'-cap-nsP1-nsP2-nsP3-nsP4-(joining region)-C-E3-E2-6k-E1-poly(A)-3', wherein the first four proteins (nsP1-4) are nonstructural proteins, and the structural proteins are capsid (C) and envelope proteins (E). There is no obvious serotype difference between CHIKV isolated from Africa, Asia, and the Indian Ocean islands. Phylogenetic analysis based on E1 gene sequences can divide CHIKV into three genotypes (lineages): Asian, East / Central / South Africa (ECSA) and West Africa. The Asian genotype differs from the ECSA and West African genotypes at the nucleotide level of -5% and -15%, respectively. The African genotype (ECSA relative to West Africa) has a -15% difference. The amino acid identity between the three genotypes varies between 95.2-99.8%.

[0041] Chikungunya virus may cause outbreaks associated with severe morbidity.

[0042] Chikungunya is a viral disease transmitted to humans by infected mosquitoes. Both Ae. aegypti and Ae. albopictus have been implicated in major outbreaks of chikungunya. Ae. aegypti is restricted to tropical and subtropical areas, while Ae. albopictus also occurs in temperate and even cold temperature regions. In recent decades, Ae. albopictus has spread from Asia to areas of Africa, Europe, and the Americas.

[0043] After infection with the chikungunya virus, the average incubation period is 2-4 days, after which symptoms of the disease appear. Among these symptoms, fever and severe joint pain can be listed. Other symptoms include myalgia, headache, nausea, back pain, fatigue, myalgia and rash. Severe clinical manifestations of chikungunya infection may also occur, for example, hemorrhagic fever, conjunctivitis, photophobia, hepatitis, stomatitis. Neurological manifestations such as encephalitis, febrile convulsions, meningeal syndrome and acute encephalopathy have also been reported.

[0044] Joint pain is often debilitating and can last for varying lengths of time.

[0045] The proximity of mosquito breeding sites to human habitation is a significant risk factor for buckling.

[0046] The distribution of Chikungunya virus occurs mainly in Africa, India and Southeast Asia. In recent decades, the mosquito vector of Chikungunya has spread to Europe and America. Disease transmission was first reported in 2007 during a local outbreak in northeastern Italy. Outbreaks have since been recorded in France and Croatia.

[0047] Dengue viruses with multiple serotypes are also contemplated by the present invention and belong to group IV RNA viruses and the Flaviviridae family, which can be defined as positive-sense single-stranded RNA or (+)ss RNA viruses. More specifically, dengue virus is a (+)ssRNA virus belonging to group IV of the Baltimore classification. It is part of the genus Flavivirus, which belongs to the family Flaviviridae. Other viruses belonging to the family Flaviviridae are hepatitis C virus and yellow fever virus.

[0048] The present invention also specifically contemplates viruses of the order Mononegavirales. The order Mononegavirales includes viruses belonging to group V of the Baltimore classification. As of 2018, this order primarily includes the following viral families: Bornaviridae, Mymonaviridae, Filoviridae, Nyamiviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, and Sunviridae.

[0049] Human respiratory syncytial virus (HRSV) is a syncytial virus that causes respiratory tract infections. It is the main cause of lower respiratory tract infections and hospital visits during infancy and childhood. HRSV virus is particularly contemplated by the present invention and belongs to group V of RNA viruses. More specifically, RSV virus is a (-)ssRNA virus belonging to group V of the Baltimore classification. It is a pneumovirus, which is part of the Paramyxoviridae family, which belongs to the order Monomyxovirales. Among other viruses of the order Monomyxovirales, those viruses that are particularly contemplated by the present invention include: measles virus, mumps virus, Nipah virus, rabies virus and human parainfluenza virus (which includes HPIV-1, HPIV-2, HPIV-3 and HPIV-4). It is worth noting that according to the taxonomy of the order Monomyxovirinae updated in 2016, the subfamily Paramyxovirinae is routinely merged into the Paramyxovirinae family.

[0050] Virus genera that are specifically considered within the Paramyxoviridae family include: Aquaparamyxovirus, Avulavirus, Ferlavirus, Henipavirus, Morbillivirus, Respirovirus, and Rubulavirus.

[0051] The present invention also specifically contemplates viruses of the family Orthomyxoviridae. According to the 2017 Virus Taxonomy, the family Orthomyxoviridae belongs to the order "unspecified". Viral genera specifically contemplated within the family Orthomyxoviridae include: Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus, Gammainfluenzavirus, Isavirus, Quaranjavirus, and Thogotovirus.

[0052] Influenzavirus A, Influenzavirus B, Influenzavirus C are particularly contemplated by the present invention and belong to group V RNA viruses and the Orthomyxoviridae family, which can be defined as negative sense single stranded RNA or (-)ss RNA viruses. Isavirus and Togotovirus also belong to the order Orthomyxovirales. DETAILED DESCRIPTION OF THE INVENTION

[0054] The inventors have surprisingly found that aryl-N-aryl compounds have a broad spectrum of activity against RNA viruses, and more particularly single-stranded RNA viruses belonging to Group IV or V of the Baltimore classification. Groups IV and V include (+)ssRNA viruses and (-)ssRNA viruses, respectively; which also means positive-sense single-stranded RNA viruses and negative-sense single-stranded RNA viruses.

[0055] For reference, we considered the content of the “Baltimore Classification” based on the classification and nomenclature of viruses as described in the Tenth Report on Virus Taxonomy in 2017.

[0056] This document discloses any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular Chikungunya virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders

[0057]

[0058] in:

[0059] Ring and The rings independently refer to a phenylene or pyridinylene group,

[0060] Among them Relative to the -NH- group is The meta or para position on the ring, especially in the meta position,

[0061] X 1 represents an alkenylene group, in particular a vinylene group, a -NH-CO- group, a -CO-NH- group, a -CR a R b O-group,

[0062] Y 1 represents an aryl group selected from a 2-pyridyl group or a pyrimidinyl group, wherein one of the nitrogen atoms of the pyrimidinyl group is in the position relative to X 1 The adjacent position of

[0063] or alternatively X 1 -Y 1 A group (A) representing the formula

[0064]

[0065] X 2 represents a -CO-NH- group, a -NH-CO-NH- group, a -OCH2- group, a -NH-CO- group or a -SO2-NH- group,

[0066] n is 0, 1, 2, or 3,

[0067] m and m' are independently 0, 1 or 2,

[0068] Y 2 Represents a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group. It should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by oxygen atoms,

[0069] R and R' independently represent a halogen atom, a (C1-C4) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C5) alkoxy group, -SO2-NR a R b Group, -SO3H group, -OH group, -O-SO2-OR c The group or -OP(=O)-(OR c )(OR d ) group,

[0070] R a , R b , R c and R d independently represent a hydrogen atom or a (C1-C4) alkyl group,

[0071] The prerequisite is that when X 1 Yes-CR a R b When the group is O-, Y 1 It may further be a 3-pyridyl group, a 4-pyridyl group or a phenyl group, which may be optionally substituted by one or two substituents selected from the following: a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SO2-NR a R b Group, -SO3H group, -OH group, -O-SO2-OR c The group or -OP(=O)-(OR c )(OR d ) group.

[0072] according to First aspect The present invention relates to any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof,

[0073]

[0074] in

[0075] Y 1 , R, R', R a , R b 、m、m'、 ring, Ring, X 2 , n and Y 2 As defined above for formula (I).

[0076] Still according to the first aspect The present invention further relates to any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof, wherein the group Relative to the -NH- group is The meta or para position on the ring and preferably the meta position,

[0077] m is 0, n is 0, 1, 2 or 3,

[0078] Y 1 represents a pyridyl or phenyl group, which is optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a (C1-C4) alkyl group and a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, -SO2-NR a R b Group, -SO3H group, -OH group, -O-SO2-OR c The group or -OP(=O)-(OR c )(OR d ) group,

[0079] Y 2 Represents a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom or a (C1-C2) alkyl group, it should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C6) cycloalkyl group, which is optionally substituted by one or two halogen atoms, and the (C3-C6) cycloalkyl group is optionally substituted by one or two halogen atoms in the R 1 and / or R 2 is interrupted by an oxygen atom.

[0080] according to Second aspect The present invention relates to compounds of formula (Ie) as defined above for use in the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular Chikungunya virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders.

[0081] according to The third aspect The present invention relates to any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof

[0082]

[0083] in

[0084] Ring and The rings independently refer to a phenylene or pyridinylene group,

[0085] Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group or a pyrimidinyl group, the aryl group being optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SO2-NR a R b Group, -SO3H group, -OH group, -O-SO2-OR c The group or -OP(=O)-(OR c )(OR d ) group,

[0086] X 2 represent

[0087] -O-group,

[0088] -NH- groups,

[0089] -S-group,

[0090] -CO-NH- groups,

[0091] -NH-CO-NH- groups,

[0092] -NH-CO- group,

[0093] -CH(OH)- group,

[0094] -CH(COOH)NH- group,

[0095] -CH(COOCH3)NH- group,

[0096] -C(OH)(CH2OH)-,

[0097] Group,

[0098] A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or more heteroatoms such as triazole, tetrazole or Oxadiazole,

[0099] -SO2- group,

[0100] or

[0101] -SO2-NH- group,

[0102] n is 0, 1, 2, or 3,

[0103] m and m' are independently 0, 1 or 2,

[0104] Y 2 represent

[0105] Hydrogen atoms,

[0106] Hydroxyl groups,

[0107] (C1-C4) alkoxy group,

[0108] -CHC(OH)2,

[0109] COOR f , where R f represents a hydrogen atom or a (C1-C4) alkyl group,

[0110] Morpholinyl group,

[0111] dihydropyranyl group, Group,

[0112] Group,

[0113] -PO(OR f )(OR' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group,

[0114] Oxetanyl group,

[0115] -Si(CH3)3 group,

[0116] -NHCOO-(C1-C4)alkyl group,

[0117] or

[0118] -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group. It should be understood that R 1 , R 2and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by oxygen atoms,

[0119] or alternatively X 2 -Y 2 Representative group-CONR c R d , where R c and R d Together with the nitrogen atom, it forms a heterocyclic group, which is optionally substituted by a hydroxyl group or a (C1-C4)alkyl group,

[0120] R and R' independently represent

[0121] (C1-C4)alkyl group,

[0122] -S-(C1-C4)alkyl group,

[0123] (C3-C6) cycloalkyl group,

[0124] Halogen atoms, such as fluorine atoms,

[0125] trifluoromethyl group,

[0126] -SO2(C1-C4)alkyl group,

[0127] (C3-C6)cycloalkenyl group,

[0128] (C1-C5) alkoxy group,

[0129] -SO2-NR a R b Group,

[0130] -SO3H or SO2-CH3 groups,

[0131] -OH group,

[0132] -CONHR g , where R g represents a hydrogen atom or a (C1-C4) alkyl group,

[0133] -O-SO2-OR c Group,

[0134] an azetidinyl group,

[0135] A morpholinyl group, or

[0136] Cyano group,

[0137] R" represents a hydrogen atom, a (C1-C4)alkyl group optionally substituted by a -COOH group.

[0138] according to The fourth aspect , The present invention relates to compounds of formula (Ie) as defined above for use as medicaments.

[0139] according to Fifth Aspect The present invention relates to compounds of formula (Ie) as defined above for use in the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular Chikungunya virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders.

[0140] The above compounds (I) and (Ie) are particularly suitable for treating or preventing viral infections or related disorders, especially RNA virus infections or related disorders caused by RNA viruses belonging to group IV or V of the Baltimore classification, and most preferably Chikungunya virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders.

[0141] The above compounds are even more particularly suitable for the treatment or prevention of Chikungunya virus infection, dengue virus infection or RSV virus infection or virus-related disorders, most particularly RSV virus infection.

[0142] Other aspects of the invention will be described herein after the use of the novel compounds, such as those of formula (Ie), as medicaments, pharmaceutical compositions and methods of synthesis.

[0143] According to a specific embodiment, a subject of this document describes any one of the compounds of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular Chikungunya virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders, wherein the alkenylene group is an (E)-alkenylene group,

[0144] m and m' are independently 0 or 1,

[0145] Y 2 Representative-CR 1 R 2 R 3 Group, where R 1 , R 2 and R3 independently represent a hydrogen atom, a fluorine atom or a (C1-C2) alkyl group. It should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C6) cycloalkyl group, which is optionally substituted by one or two halogen atoms, and the (C3-C6) cycloalkyl group is optionally substituted by one or two halogen atoms in the R 1 and / or R 2 is interrupted by oxygen atoms,

[0146] R and R' independently represent a halogen atom, a (C1-C2) alkyl group, a (C3-C6) cycloalkyl group or a (C1-C2) alkoxy group.

[0147] According to another embodiment, this document describes any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of RNA viral infections caused by RNA viruses belonging to group IV or V of the Baltimore classification

[0148]

[0149] in:

[0150] Ring and The rings independently refer to a phenylene or pyridinylene group,

[0151] Among them Relative to the -NH- group is The meta or para position on the ring,

[0152] X 1 represents an alkenylene group, a -NH-CO- group, a -CO-NH- group, a -CR a R b O-group,

[0153] Y 1 represents an aryl group selected from a 2-pyridyl group or a pyrimidinyl group, wherein one of the nitrogen atoms of the pyrimidinyl group is in the position relative to X 1 The adjacent position of

[0154] or alternatively X 1 -Y 1 A group (A) representing the formula

[0155]

[0156] X 2represents a -CO-NH- group, a -NH-CO-NH- group, a -OCH2- group, a -NH-CO- group or a -SO2-NH- group,

[0157] n is 0, 1, 2, or 3,

[0158] m and m' are independently 0, 1 or 2,

[0159] Y 2 Represents a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group. It should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by oxygen atoms,

[0160] R and R' independently represent a halogen atom, a (C1-C4) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C5) alkoxy group, -SO2-NR a R b Group, -SO3H group, -OH group, -O-SO2-OR c The group or -OP(=O)-(OR c )(OR d ) group,

[0161] R a , R b , R c and R d independently represent a hydrogen atom or a (C1-C4) alkyl group,

[0162] The prerequisite is that when X 1 Yes-CR a R b When the group is O-, Y 1It may further be a 3-pyridyl, 4-pyridyl or phenyl group, which is optionally substituted by one or two substituents selected from the following: a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SO2-NR a R b Group, -SO3H group, -OH group, -O-SO2-OR c The group or -OP(=O)-(OR c )(OR d ) group,

[0163] And the prerequisite is that when Y 1 -X 1 When X represents a 2-pyridylvinylene group, 2 represents a -CO-NH- group and Y 2 Representative-CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represents a hydrogen atom or a (C1-C4)alkyl group, and m' is different from 0.

[0164] According to a specific embodiment, the present invention relates to any one of the compounds of formula (Ie) as defined above or a pharmaceutically acceptable salt thereof, wherein

[0165] Ring and The rings all represent a phenylene group, or The ring represents a pyridinylene group and The ring represents a phenylene group.

[0166] In another embodiment, the present invention relates to any one of the compounds of formula (Ie) as defined above or a pharmaceutically acceptable salt thereof, wherein

[0167] m and m' are independently 0 or 1,

[0168] Y 2 Representative-CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C2) alkyl group. It should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2Together with the carbon atoms carrying them, they form a (C3-C6) cycloalkyl group, which is optionally substituted by one or two halogen atoms, and the (C3-C6) cycloalkyl group is optionally substituted by one or two halogen atoms in the R 1 and / or R 2 is interrupted by oxygen atoms,

[0169] R and R' independently represent a halogen atom, a (C1-C2) alkyl group, a (C3-C6) cycloalkyl group or a (C1-C2) alkoxy group.

[0170] In another embodiment, the present invention is directed to any one of the compounds of formula (Ie) or a pharmaceutically acceptable salt thereof, wherein R" is a hydrogen atom.

[0171] In another embodiment, the present invention relates to any one of the compounds of formula (Ie) or a pharmaceutically acceptable salt thereof, wherein

[0172] Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group or a pyrimidinyl group, the aryl group being optionally substituted by one or two substituents selected from the following: a halogen atom, a (C1-C4)alkyl group, a cyano group, a (C1-C5)alkoxy group, a trifluoromethyl group, a trifluoromethoxy group.

[0173] In another embodiment, the present invention relates to any one of the compounds of formula (Ie) or a pharmaceutically acceptable salt thereof, wherein X 2 represent

[0174] -O-group,

[0175] -NH- groups,

[0176] -S-group,

[0177] -CO-NH- groups,

[0178] -NH-CO-NH- groups,

[0179] -NH-CO- group,

[0180] A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms such as a triazole, a tetrazole or Oxadiazole,

[0181] -SO2- group,

[0182] or

[0183] -SO2-NH- group.

[0184] In another embodiment, the present invention relates to any one of the compounds of formula (Ie) or a pharmaceutically acceptable salt thereof, wherein Y 2 represent

[0185] Hydrogen atoms,

[0186] Hydroxyl,

[0187] -PO(OR f )(R' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group,

[0188] or

[0189] -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group. It should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by an oxygen atom.

[0190] In another embodiment, the present invention relates to any one of the compounds of formula (Ie) or a pharmaceutically acceptable salt thereof, wherein R and R' independently represent

[0191] (C1-C4)alkyl group,

[0192] (C3-C6) cycloalkyl group,

[0193] Halogen atoms, such as fluorine atoms,

[0194] a trifluoromethyl group, or

[0195] -SO3H or SO2-CH3 group.

[0196] In another embodiment, the present invention relates to any one of the compounds of formula (Ie) or a pharmaceutically acceptable salt thereof, wherein Ring and The rings all represent phenylene groups,

[0197] R" is a hydrogen atom,

[0198] Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group or a pyrimidinyl group, the aryl group being optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group,

[0199] X 2 represent

[0200] -O-group,

[0201] -CO-NH- groups,

[0202] -NH-CO-NH- groups,

[0203] -NH-CO- group,

[0204] A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms such as a triazole, a tetrazole or Oxadiazole,

[0205] or

[0206] -SO2-NH- group,

[0207] Y 2 represent

[0208] Hydrogen atoms,

[0209] Hydroxyl groups,

[0210] -PO(OR f )(R' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group,

[0211] or

[0212] -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group. It should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R2 Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by oxygen atoms,

[0213] and

[0214] R and R' independently represent

[0215] (C1-C4)alkyl group,

[0216] (C3-C6) cycloalkyl group,

[0217] Halogen atoms, such as fluorine atoms,

[0218] trifluoromethyl group,

[0219] -SO3H or SO2-CH3 group, or

[0220] Morpholinyl group.

[0221] In another embodiment, the present invention relates to any one of the compounds of formula (Ie) or a pharmaceutically acceptable salt thereof, wherein Ring and The rings all represent phenylene groups,

[0222] R" is a hydrogen atom,

[0223] Y 1 represents a phenyl group or a pyridyl group,

[0224] X 2 represent

[0225] -O-group,

[0226] -CO-NH- groups,

[0227] -NH-CO- group,

[0228] or

[0229] A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms such as a triazole, a tetrazole or Oxadiazole,

[0230] Y 2 represent

[0231] -PO(OR f )(R' f ) group, wherein R fand R' f independently represent a hydrogen atom or a (C1-C4) alkyl group,

[0232] or

[0233] -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group. It should be understood that R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8)cycloalkyl group,

[0234] and

[0235] R and R' independently represent

[0236] (C1-C4)alkyl group,

[0237] (C3-C6)cycloalkyl group, or

[0238] Morpholinyl group.

[0239] About R, R', R", m, m', ring, Ring, X 1 , X 2 ,n,Y 1 , Y 2 , R a and R b Any arbitrary combination of the embodiments defined above with one another actually forms part of the present invention.

[0240] According to a preferred embodiment of the present invention, the compound of formula (Ie) is selected from:

[0241] -(36) N-(2-cyclopentylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0242] -(37)N-isopentyl-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0243] -(38) N-(2-cyclohexylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0244] -(39)N-(2-cyclopentylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0245] -(40)N-(2-cyclopentylethyl)-3-((3-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0246] -(41) N-(2-cyclopentylethyl)-3-((6-(pyridin-2-ylmethoxy)pyridin-3-yl)amino)benzamide

[0247] -(42) N-(2-cyclopentylethyl)-6-((4-(pyridin-2-ylmethoxy)phenyl)amino)picolinamide

[0248] -(43)N-(2-cyclopentylethyl)-3-((3-methoxy-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0249] -(44) N-(2-cyclopentylethyl)-3-((5-(pyridin-2-ylmethoxy)pyridin-2-yl)amino)benzamide

[0250] -(45)N-(2-cyclopropylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0251] -(46) N-(2-cyclobutylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0252] -(47) N-(2-cyclohexylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0253] -(48)N-(2-cyclobutylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0254] -(49)N-(2-cyclopropylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0255] -(50)N-(2-cyclopentylethyl)-3-((4-((2-fluorobenzyl)oxy)phenyl)amino)benzamide

[0256] -(51) 3-((4-((2-cyanobenzyl)oxy)phenyl)amino)-N-(2-cyclopentylethyl)benzamide

[0257] -(52) 3-((4-(Benzyloxy)phenyl)amino)-N-(2-cyclopentylethyl)benzamide

[0258] -(53)N-(2-cyclopentylethyl)-3-((3-hydroxy-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0259] -(54)N-isopentyl-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0260] -(55)N-(2-cyclopentylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide

[0261] -(56) N-(2-cyclohexylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide

[0262] -(57) 3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-isopentylbenzamide

[0263] -(58)N-(2-cyclopentylethyl)-3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0264] -(59)N-(2-cyclopropylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide

[0265] -(60)N-(2-cyclopentylethyl)-3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0266] -(61)3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-isopentylbenzamide

[0267] -(62) N-(Cyclopentylmethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0268] -(63) N-((3-methyloxetan-3-yl)methyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0269] -(64) N-(Pentan-2-yl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0270] -(65)3-((4-(pyridin-2-ylmethoxy)phenyl)amino)-N-(3,3,3-trifluoropropyl)benzamide

[0271] -(66) N-(2-cyclopentylethyl)-3-((2-methyl-4-(1-(pyridin-2-yl)ethoxy)phenyl)amino)benzamide

[0272] -(67)N-isopentyl-3-((2-methyl-4-(1-(pyridin-2-yl)ethoxy)phenyl)amino)benzamide

[0273] -(68)1-Isopentyl-3-(3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)phenyl)urea

[0274] -(69) 3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-(oxetan-3-yl)benzamide

[0275] -(70)N-(2-(3,3-difluorocyclobutyl)ethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0276] -(71) N-cyclopentyl-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0277] -(72) 3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-(4-methylpentyl)benzamide

[0278] -(73)3-(3-cyclopentylpropoxy)-N-(4-(pyridin-2-ylmethoxy)phenyl)aniline

[0279] -(74)3-((2-methylpentyl)oxy)-N-(4-(pyridin-2-ylmethoxy)phenyl)aniline

[0280] -(75)N-(2-(cyclohexyl)ethyl)-3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0281] -(76) N-(2-(cyclohexyl)ethyl)-3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0282] -(77)N-(1-methylbutyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0283] -(78)N-(1-methylbutyl)-3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0284] -(79) N-(2-(cyclohexyl)ethyl)-3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide

[0285] -(80)(3-(cyclohexyl)propionamide), N-[3-([2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl]amino)phenyl]

[0286] -(81)N-(3-methylbutyl)-4-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0287] -(82)N-(2-(cyclopentyl)ethyl)-3-((2-cyclopropyl-4-(phenylmethoxy)phenyl)amino)benzamide

[0288] -(83)3-(3-cyclohexylpropoxy)-N-(2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)aniline

[0289] -(84)3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide

[0290] -(85)N-(2-cyclohexylethyl)-3-((2-cyclopropyl-4-(pyridin-3-ylmethoxy)phenyl)amino)benzamide

[0291] -(86) N-(2-cyclohexylethyl)-6-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)picolinamide

[0292] -(87)3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide

[0293] -(88)N-(2-cyclohexylethyl)-5-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)nicotinamide

[0294] -(89)N-(2-cyclopentylethyl)-3-((2-cyclopropyl-4-(pyridin-4-ylmethoxy)phenyl)amino)benzamide

[0295] -(90)N-(2-cyclohexylethyl)-2-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)isonicotinamide

[0296] -(91)N-(3-{[4-(Benzyloxy)-2-tert-butylphenyl]amino}phenyl)-3-cyclohexylpropionamide

[0297] -(92) N-(3-{[4-(Benzyloxy)-2-(cyclopent-1-en-1-yl)phenyl]amino}phenyl)-3-cyclohexylpropionamide

[0298] -(93)N-(3-{[4-(Benzyloxy)-2-cyclopentylphenyl]amino}phenyl)-3-cyclohexylpropionamide

[0299] -(94) N-(3-{[4-(Benzyloxy)-2-(methylsulfanyl)phenyl]amino}phenyl)-3-cyclohexylpropionamide

[0300] -(95)N1-[4-(Benzyloxy)-2-cyclopropylphenyl]-N3-(3-cyclohexylpropyl)benzene-1,3-diamine

[0301] -(96)1-(2-cyclohexylethyl)-3-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenyl]urea

[0302] -(97)1-(3-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-4-cyclohexylbutan-1-ol

[0303] -(98) N-(3-{[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]amino}phenyl)-3-cyclohexylpropionamide

[0304] -(99)3-cyclohexyl-N-[3-({4-[(4-fluorophenyl)methoxy]-2-(trifluoromethyl)phenyl}amino)phenyl]propionamide

[0305] -(100)N-{3-[4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline

[0306] -(101)2-{[4-(Benzyloxy)-2-tert-butylphenyl]amino}-N-(2-cyclohexylethyl)benzamide

[0307] -(102) 1-cyano-N-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenyl]cyclopropane-1-carboxamide

[0308] -(103)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-N-(3-cyclohexylpropyl)benzamide

[0309] -(104)3-{[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]amino}-N-(2-cyclopentylethyl)benzamide

[0310] -(105)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)-2-methylphenyl]-2-cyclopropylaniline

[0311] -(106)2-Cyclopropyl-N-{3-[(4-methylpentyl)oxy]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0312] -(107)N-(3-{[4-(Benzyloxy)-2-methylsulfonylphenyl]amino}phenyl)-3-cyclohexylpropionamide

[0313] -(108)N'1-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenyl]cyclopropane-1,1-dicarboxamide

[0314] -(109)[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenoxy]phosphonic acid

[0315] -(110)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-N-(cyclohexylmethyl)benzamide

[0316] -(111)N-(2-cyclohexylethyl)-3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}(methyl)amino)benzamide

[0317] -(112)2-Cyclopropyl-N-{3-[4-(3-methylbutyl)-1H-1,2,3-triazol-1-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0318] -(113)N-(cyclopentylmethyl)-2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)benzamide

[0319] -(114)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-(morpholin-4-yl)aniline

[0320] -(115)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-N-(2-cyclohexylethyl)benzamide

[0321] -(116)N-(5-{[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]amino}-2-fluorophenyl)-3-cyclohexylpropionamide

[0322] -(117) N-(2-cyclohexylethyl)-4-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)pyridine-2-carboxamide

[0323] -(118)N-{3-[1-(3-cyclohexylpropyl)-1H-1,2,3,4-tetrazolyl-5-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline

[0324] -(119)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-(propan-2-yl)aniline

[0325] -(120)2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-N-(3,3,3-trifluoropropyl)benzamide

[0326] -(121)3-cyclohexyl-N-[2-fluoro-5-({4-[(4-fluorophenyl)methoxy]-2-methylphenyl}amino)phenyl]propionamide

[0327] -(122)4-(Benzyloxy)-N-[2-(3-cyclohexylpropanesulfonyl)phenyl]-2-cyclopropylaniline

[0328] -(123)2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-N-(3-methylbutyl)benzamide

[0329] -(124)3-{[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]amino}-N-(2-cyclohexylethyl)benzene-1-sulfonamide

[0330] -(125)3-cyclohexyl-N-[2-fluoro-5-({4-[(4-fluorophenyl)methoxy]-2-(trifluoromethyl)phenyl}amino)phenyl]propanamide

[0331] -(126)2-Cyclopropyl-N-{3-[1-(4-methylpentyl)-1H-1,2,3,4-tetrazolyl-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0332] -(127)2-cyclopropyl-N-{3-[5-(3-methylbutyl)-1,2,4- oxadiazol-3-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0333] -(128)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-6-cyano-N-(propan-2-yl)benzamide

[0334] -(129)N-{3-[5-(2-cyclohexylethyl)-1,2,4- oxadiazol-3-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline

[0335] -(130)N-{3-[5-(2-cyclohexylethyl)-1,3,4- oxadiazol-2-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline

[0336] -(131)2-(azetidin-1-yl)-4-(benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]aniline

[0337] -(132)N-(3-{[4-(Benzyloxy)-2-methylphenyl]amino}phenyl)-3-cyclohexylpropionamide

[0338] -(133)[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenoxy]phosphonic acid

[0339] -(134) tert-butyl 4-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)benzoyl]piperazine-1-carboxylate

[0340] -(135)2-(3-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-2-[(2-cyclohexylethyl)amino]acetic acid

[0341] -(136) N-(1-cyanocyclopropyl)-2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)benzamide

[0342] -(137)N-(3-cyclobutyloxyphenyl)-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline

[0343] -(138) methyl 2-(3-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-2-[(2-cyclohexylethyl)amino]acetate

[0344] -(139)2-{[4-(Benzyloxy)-2-methylphenyl]amino}-N-(2-cyclohexylethyl)benzamide

[0345] -(140)3-cyclohexyl-N-[3-({4-[(4-fluorophenyl)methoxy]-2-methylphenyl}amino)phenyl]propionamide

[0346] -(141)2-Cyclopropyl-4-[(pyridin-2-yl)methoxy]-N-{3-[(trimethylsilyl)oxy]phenyl}aniline

[0347] -(142)4-(Benzyloxy)-N-[3-(3-cyclohexylpropanesulfonyl)phenyl]-2-cyclopropylaniline

[0348] -(143)N-(2-cyclohexylethyl)-2-[(2-cyclopropyl-4-{[4-(trifluoromethoxy)phenyl]methoxy}phenyl)amino]pyridine-4-carboxamide

[0349] -(144) tert-butyl N-[2-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)ethyl]carbamate

[0350] -(145)2-Cyclopropyl-N-{3-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0351] -(146)N-(5-{[4-(Benzyloxy)-2-methylphenyl]amino}-2-fluorophenyl)-3-cyclohexylpropionamide

[0352] -(147)2-Cyclopropyl-N-{3-[2-(2-methylpropyl)-2H-1,2,3,4-tetrazolyl-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0353] -(148) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyridazin-3-yl)methoxy]aniline

[0354] -(149)4-(Benzyloxy)-N-{3-[(3-cyclohexylpropyl)sulfanyl]phenyl}-2-cyclopropylaniline

[0355] -(150)N-(3-{[4-(Benzyloxy)-2-fluorophenyl]amino}phenyl)-3-cyclohexylpropionamide

[0356] -(151)2-Cyclopropyl-N-[3-(oxetan-3-yloxy)phenyl]-4-[(pyridin-2-yl)methoxy]aniline

[0357] -(152)N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrimidin-2-yl)methoxy]aniline

[0358] -(153)3-cyclohexyl-N-{3-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]methoxy}phenyl)amino]phenyl}propanamide

[0359] -(154)4-(Benzyloxy)-N-[2-(3-cyclohexylpropoxy)phenyl]-2-cyclopropylaniline

[0360] -(155)2-(3-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-4-cyclohexylbutane-1,2-diol

[0361] -(156) N-[3-(3-cyclohexylpropoxy)phenyl]-2-cyclopropyl-N-methyl-4-[(pyridin-2-yl)methoxy]aniline

[0362] -(157) 3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenyl diethyl phosphate

[0363] -(158)N-(2-cyclohexylethyl)-3-[(2-cyclopropyl-4-{[4-(trifluoromethoxy)phenyl]methoxy}phenyl)amino]benzene-1-sulfonamide

[0364] -(159) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrimidin-4-yl)methoxy]aniline

[0365] -(161)2-Cyclopropyl-N-{3-[2-(3-methylbut-2-en-1-yl)-2H-1,2,3,4-tetrazolyl-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0366] -(160) 3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenyl diethyl phosphate

[0367] -(162)2-Cyclopropyl-N-{3-[2-(2-methoxyethyl)-2H-1,2,3,4-tetrazolyl-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0368] -(163)2-Cyclopropyl-N-{3-[1-(cyclopropylmethyl)-1H-1,2,3,4-tetrazolyl-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline

[0369] -(164)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-( 4-Alkyl)aniline

[0370] -(165)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-(3,6-dihydro-2H-pyran-4-yl)aniline

[0371] -(166)5-(3-cyclohexylpropoxy)-N-{2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}pyridin-3-amine

[0372] -(167)4-(Benzyloxy)-N-{2-[(3-cyclohexylpropyl)sulfanyl]phenyl}-2-cyclopropylaniline

[0373] -(168)5-{[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]amino}-2-fluorobenzamide

[0374] -(169)3-cyclohexyl-N-{3-[(2-cyclopropyl-4-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)amino]phenyl}propionamide

[0375] -(170)3-cyclohexyl-N-[3-({2-cyclopropyl-4-[(4-methoxyphenyl)methoxy]phenyl}amino)phenyl]propionamide

[0376] -(171)2-(3-{[4-(Benzyloxy)-2-methylphenyl]amino}phenoxy)ethan-1-ol

[0377] -(172)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]aniline

[0378] -(173) 5-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy) valeric acid ethyl ester

[0379] -(174)4-(Benzyloxy)-N-[3-(2-methoxyethoxy)phenyl]-2-methylaniline

[0380] -(175)4-(Benzyloxy)-N-[3-(cyclopentylmethoxy)phenyl]-2-methylaniline

[0381] -(176) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrimidin-5-yl)methoxy]aniline

[0382] -(177)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-methylaniline

[0383] -(178)3-{1-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenyl]-1H-1,2,3-triazol-4-yl}propan-1-ol

[0384] -(179)2-cyclopropyl-N-[3-(1,3- oxazol-5-yl)phenyl]-4-[(pyridin-2-yl)methoxy]aniline

[0385] -(180)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-6-methyl-N-(propan-2-yl)benzamide

[0386] -(181)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-N-(propan-2-yl)-6-(trifluoromethyl)benzamide

[0387] -(182)[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenoxy](methoxy)phosphinic acid

[0388] -(183)5-(Benzyloxy)-2-{[3-(3-cyclohexylpropoxy)phenyl]amino}benzonitrile

[0389] -(184)2-{[4-(Benzyloxy)phenyl]amino}-N-(2-cyclohexylethyl)benzamide

[0390] -(185)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)-4-methylphenyl]-2-cyclopropylaniline

[0391] -(186)4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)-5-methylphenyl]-2-cyclopropylaniline

[0392] -(187)4-(Benzyloxy)-N-[5-(3-cyclohexylpropoxy)-2-methylphenyl]-2-cyclopropylaniline

[0393] -(188)4-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-2-(3-cyclohexylpropoxy)benzamide

[0394] -(189)3-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-5-(3-cyclohexylpropoxy)benzamide

[0395] -(190)N-(2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-3-cyclohexylpropionamide

[0396] -(191)3-{[4-(Benzyloxy)-2-methylphenyl][3-(3-cyclohexylpropoxy)phenyl]amino}propanoic acid

[0397] -(192)2-(3-{[4-(Benzyloxy)-2-methylphenyl]amino}phenoxy)acetic acid

[0398] -(193)5-(3-{[4-(Benzyloxy)-2-methylphenyl]amino}phenoxy)pentanoic acid

[0399] -(194) methyl 2-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)acetate

[0400] -(195)4-(Benzyloxy)-2-methyl-N-[3-(trifluoromethoxy)phenyl]aniline

[0401] -(196)4-(Benzyloxy)-2-methyl-N-{3-[( 4-Alkyl)methoxy]phenyl}aniline

[0402] -(197)4-(3-cyclohexylpropoxy)-N-{2-methyl-4-[(pyridin-3-yl)methoxy]phenyl}pyridin-2-amine

[0403] -(198)6-(3-cyclohexylpropoxy)-N-{2-methyl-4-[(pyridin-3-yl)methoxy]phenyl}pyridin-2-amine

[0404] -(199)N-[4-(Benzyloxy)-2-methylphenyl]-4-(3-cyclohexylpropoxy)pyridin-2-amine

[0405] -(200)N-[4-(Benzyloxy)-2-methylphenyl]-6-(3-cyclohexylpropoxy)pyridin-2-amine

[0406] -(201)N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrazin-2-yl)methoxy]aniline

[0407] -(202)N-(5-{[4-(Benzyloxy)-2-fluorophenyl]amino}-2-fluorophenyl)-3-cyclohexylpropionamide

[0408] -(203)N-[3-(morpholin-4-yl)propyl]-3-({4-[(pyridin-2-yl)methoxy]phenyl}amino)benzamide

[0409] -(204)2-Cyclopropyl-4-[(pyridin-2-yl)methoxy]-N-[3-(1H-1,2,3,4-tetrazolyl-5-yl)phenyl]aniline

[0410] -(205)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-6-cyclopropyl-N-(propan-2-yl)benzamide

[0411] -(206)2-{[4-(Benzyloxy)-2-cyclopropylphenyl]amino}-6-chloro-N-(propan-2-yl)benzamide

[0412] and pharmaceutically acceptable salts thereof.

[0413] The present invention extends to compounds (36) to (206) and their pharmaceutically acceptable salts, such as hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, trifluoromethylsulfonate, maleate, methanesulfonate, formate, acetate and fumarate.

[0414] According to another aspectOne subject of the present invention relates to any one of compounds (36) to (206) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0415] According to another aspect A subject of the present invention relates to any one of the compounds of formula (Ie) as defined above or their pharmaceutically acceptable salts, and any one of compounds (36) to (206) or their pharmaceutically acceptable salts for use as a medicament for preventing, inhibiting or treating RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification.

[0416] Any of compounds (38), (40), (43), (45), (46), (48), (49), (61), (62), (64), (35), (68), (82), (98), (119), (121), (132), (140), (150), (151), (156), (169), (175), (176) and (192) or pharmaceutically acceptable salts thereof may be particularly useful for preventing, inhibiting or treating dengue infection.

[0417] Any of compounds (36), (38), (39), (45), (46), (47), (54), (57), (60), (61), (64), (68), (70), (71), (72), (75)-(80), (82)-(86), (88)-(142), (147)-(156), (164)-(166) and (179) or pharmaceutically acceptable salts thereof may be particularly useful for preventing, inhibiting or treating RSV infection.

[0418] Any of compounds (36)-(41), (43), (45)-(52), (53), (54), (57), (58), (60)-(62), (64), (68), (70), (71) and (73) or pharmaceutically acceptable salts thereof may be particularly useful for preventing, inhibiting or treating flexor infection.

[0419] The compounds of the present invention may exist in the form of a free base or an addition salt with a pharmaceutically acceptable acid.

[0420] “Pharmaceutically acceptable salts thereof” means salts formed from acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed from organic acids (such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and poly-galacturonic acid).

[0421] Suitable physiologically acceptable acid addition salts of compounds of formula (Ie) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, trifluoromethylsulfonate, maleate, methanesulfonate, formate, acetate and fumarate.

[0422] The compound of formula (Ie) and any one of compounds (36) to (206) or any one of their pharmaceutically acceptable salts may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0423] The compounds of formula (Ie) may also exist in tautomeric forms and are part of the present invention.

[0424] The terms "hydrate" and "solvate" simply mean that the compound (Ie) according to the invention can be in the form of a hydrate or a solvate, i.e. combined or bound with one or more water or solvent molecules. This is merely a chemical feature of such compounds, which can be applied to all organic compounds of this type.

[0425] In the context of the present invention, the terms:

[0426] - "halogen" is understood to mean chlorine, fluorine, bromine or iodine and in particular means chlorine, fluorine or bromine,

[0427] - As used in this article, “(C1-C x )alkyl" respectively means C1-C x Normal, secondary or tertiary saturated hydrocarbons, such as (C1-C6) alkyl. Examples are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,

[0428] - "Alkenylene" refers to a divalent (C1-C x )alkyl groups, and more specifically vinylene groups, also known as vinylene or 1,2-ethylenediyl,

[0429] - As used herein, "(C3-C6)cycloalkyl" means a cyclic saturated hydrocarbon. Examples are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0430] - As used herein, "(C3-C6)cycloalkenyl" means a cyclic non-aromatic hydrocarbon containing at least one unsaturated bond. Examples are, but are not limited to, cyclopentenyl and cyclohexenyl,

[0431] - As used in this article, “(C1-C x ")alkoxy" means an O-(C1-Cx)alkyl moiety, wherein alkyl is as defined above, for example (C1-C6)alkoxy. Examples are, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy, pentoxy,

[0432] - "Aryl" as used herein means a monocyclic aromatic group containing 6 carbon atoms and containing 0-2 heteroatoms (such as nitrogen, oxygen or sulfur, and especially nitrogen). As examples of aryl groups, phenyl, pyridine, pyrimidine, pyridazine, pyrazine, etc. can be mentioned, but are not limited to them. Within the framework of the present invention, the aryl is advantageously phenyl, pyridazine, pyrazine, pyridine, such as 2-pyridine or 3-pyridine and pyrimidine. The aryl is even more advantageously phenyl and pyridine,

[0433] - As used herein, a "divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms" refers to a divalent ring consisting of an aromatic ring containing 5 chains and 1, 2, 3 or 4 heteroatoms selected from nitrogen and oxygen atoms. In one embodiment, it contains at least 1 heteroatom, and preferably at least one nitrogen atom. In another embodiment, it contains at least 2 heteroatoms, and for example at least one nitrogen atom. According to another embodiment, it contains 2, 3 or 4 nitrogen atoms, preferably 3 nitrogen atoms. According to yet another embodiment, it contains one nitrogen atom and one oxygen atom, or two nitrogen atoms and one oxygen atom. Examples are, but are not limited to, divalent triazoles such as 1,2,3- or 1,2,4-triazole, Oxadiazoles such as 1,2,4- Oxadiazole or 1,2,3- Oxadiazole, and divalent oxadiazoles such as oxadiazole and imidazole.

[0434] The compounds of formula (Ie) may contain one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof (including racemic mixtures) are encompassed within the scope of the present invention.

[0435] The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequence described below represents a general method that can be used to prepare the compounds of the present invention and is not intended to be limiting in scope or applicability.

[0436] Compounds of general formula (I) and (Ie) can be prepared according to Scheme 1 below.

[0437]

[0438] Solution 1

[0439] The synthesis is based on a coupling reaction starting from a halogenated aromatic compound of formula (III) wherein R, R', m, m', ring, Ring, X 1 , X 2 ,n,Y 1 , Y 2 As defined above, and X is a chlorine atom, an iodine atom or a bromine atom.

[0440] According to one embodiment, when the group Relative to the -NH- group is When the moiety is in the meta or para position on the ring, protocol (A1) can be advantageously used.

[0441] According to route (A1), the compound of formula (III) can be placed in a protic solvent such as tert-butyl alcohol. Then, in the presence of an inorganic base such as Cs2CO3 or K2CO3, for example, still at a molar ratio in the range of 1-5 relative to the compound of formula (III), a diphosphine such as Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethyl In the presence of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) or rac-BINAP, in particular in an amount ranging from 2 mol% to 15 mol% relative to the total amount of the compound of formula (III), and in the presence of an organometallic catalyst such as Pd(OAc)2, Pd2dba3 or BrettPhos Pd G3 in an amount ranging from 2 mol% to 25 mol% relative to the total amount of the compound of formula (III), the compound of formula (II) is added, for example in a molar ratio ranging from 1 to 1.5 relative to the compound of formula (III). The reaction mixture may then be heated at a temperature ranging from 80 to 130° C., for example at 90° C., and stirred under an inert gas and, for example, argon, for a time ranging from 15 to 25 hours, for example 20 hours. The reaction mixture may be concentrated under reduced pressure, and the residue may be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give compounds of formula (I) and (Ie).

[0442] According to one embodiment, when the group Relative to the -NH- group is When the moiety is located at an ortho position on the ring, protocol (A2) can be advantageously used.

[0443] According to procedure (A2), the compound of formula (II) can be placed in a polar aprotic solvent such as dimethyl sulfoxide. The compound of formula (III) can then be added in the presence of an inorganic base such as Cs2CO3 or K2CO3, for example still in a molar ratio in the range of 1-5 relative to the compound of formula (II), in the presence of a ligand such as L-proline, especially in an amount in the range of 2mol% to 25mol% relative to the total amount of the compound of formula (II), and in the presence of an organometallic catalyst such as CuI in an amount in the range of 2mol% to 25mol% relative to the total amount of the compound of formula (II), for example in a molar ratio in the range of 1-1.5 relative to the compound of formula (II). The reaction mixture can then be heated at a temperature in the range of 80-130°C, for example at 90°C, and stirred for a time in the range of 15-25 hours, for example 20 hours, under an inert gas and, for example, argon. The reaction mixture can be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give compounds of formula (I) and (Ie).

[0444] The starting compounds of formula (II), (III) are available or can be prepared according to methods known to those skilled in the art.

[0445] Therefore, this document further describes a synthetic process for preparing the novel compounds of formula (I) and (Ie) as defined above, which comprises at least the following steps: reacting a compound of formula (II) in the presence of an inorganic base and a diphosphine and in the presence of an organometallic catalyst

[0446]

[0447] Coupling with a compound of formula (III)

[0448]

[0449] Where X 1 , Y 1 , R, R', m, m', ring, Ring, X 2 , Y 2 As defined above, and X is a chlorine atom, an iodine atom or a bromine atom,

[0450] To obtain the compound of formula (I) or (Ie).

[0451] The compounds of the general formula (Ie) according to the present invention can be prepared according to the following Scheme 1'.

[0452]

[0453] For (Ie), when R”≠H Scheme 1'

[0454] The synthesis is based on a coupling reaction starting from a halogenated aromatic compound of formula (IIIe) with a compound of formula (IIe), wherein R, R', R", m, m', ring, Ring, X 1 , X 2 ,n,Y 1 , Y 2 , R a and R b As defined above, and X is a chlorine atom, an iodine atom or a bromine atom.

[0455] More specifically, the present invention relates to a synthetic method for preparing a compound of formula (Ie) as defined above, which comprises at least the following steps: reacting a compound of formula (IIe) in the presence of an inorganic base and a ligand and in the presence of an organic metal catalyst

[0456]

[0457] Coupling with a compound of formula (IIIe)

[0458]

[0459] Where X 1 , Y 1 , R, R', m, m', ring, Ring, X 2 , Y 2 , R a and R b As defined above, X is a chlorine atom, an iodine atom or a bromine atom, and Y 1 is a phenyl group, a pyridine group, a pyrazine group, a pyridazine group or a pyrimidine group,

[0460] To obtain the compound of formula (Ie).

[0461] In order to obtain (Ie) when R"≠H, an additional step (K) can be implemented, wherein the compound can be placed in an anhydrous polar solvent such as anhydrous N,N-dimethylformamide in the presence of NaH in a molar ratio in the range of 2-5 (for example 3), and the reaction mixture can be stirred at room temperature for a time in the range of 10 minutes to 50 minutes, for example 30 minutes. The halide derivative R"-X can then be added, and the resulting reaction mixture can be stirred at a temperature in the range of 70-110°C, for example at 90°C, for a time in the range of 2 hours to 10 hours, for example 5 hours. After cooling to room temperature, the reaction mixture can be concentrated under reduced pressure, and the resulting residue can be diluted with an organic solvent such as ethyl acetate. The organic phase can then be washed with a saturated brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to obtain a compound of formula (Ie), wherein R"≠H.

[0462] More specifically, when used to prepare a compound of formula (Ie) (wherein R a =R b =H), the compound of formula (IIe) can be prepared according to the following scheme 6. a or R b In the case of ≠H, a route starting from a 4-nitrophenol derivative and a suitable alcohol derivative and using classical Mitsunobu conditions can produce such compounds, and for example compounds 66 and 67 as defined in Table I below.

[0463] Preparation of (IIe) for (Ie)

[0464]

[0465] Solution 6

[0466] The intermediate compounds of formula (IIe) and (IVe) can be used to prepare the compounds of formula (Ie) according to the present invention.

[0467] According to route (I), the 4-nitrophenol derivative can be placed in a polar solvent such as N,N-dimethylformamide. Then, in the presence of an inorganic base such as Cs2CO3 or K2CO3, for example, still in a molar ratio in the range of 1-5 relative to the 4-nitrophenol derivative, a 2-(bromomethyl)aryl derivative can be added, for example, in a molar ratio in the range of 1-2 relative to the 4-nitrophenol derivative. The reaction mixture can then be heated at a temperature in the range of 50-150°C, for example, at 90°C, and stirred under an inert gas and, for example, argon for a time in the range of 15-30 hours, for example, 24 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be distributed between an organic solvent such as dichloromethane and water. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a compound of formula (IVe).

[0468] According to route (C), the compound of formula (IVe) and tin (II) chloride dihydrate can be placed in a protic solvent such as ethanol in a ratio in the range of 3-8 equivalents. The reaction mixture can then be heated at a temperature in the range of 40-80°C, for example at 60°C, and stirred for a time in the range of 15-25 hours, for example 20 hours. The mixture can be poured into a 1N NaOH aqueous solution and extracted with an organic solvent such as ethyl acetate. The organic phase can then be washed with water and a saturated brine aqueous solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a compound of formula (IIe).

[0469] More specifically, when used to prepare a compound of formula (Ie) (wherein R a =R b =H and one of the R' groups (ie R c When ') is different from H and Me), the compound of formula (IIe) can be prepared according to the following Scheme 7.

[0470] For the preparation of (IIe) from (Ie), when R c '≠Me and R c '≠H

[0471]

[0472] Solution 7

[0473] The intermediate compounds of formula (IIe), (IVe) and (Ve) can be used to prepare the compounds of formula (Ie) according to the present invention.

[0474] According to route (I), the 4-nitrophenol derivative can be placed in a polar solvent such as N,N-dimethylformamide. Then, in the presence of an inorganic base such as Cs2CO3 or K2CO3, for example, still in a molar ratio in the range of 1-5 relative to the 4-nitrophenol derivative, a 2-(bromomethyl)aryl derivative can be added, for example, in a molar ratio in the range of 1-2 relative to the 4-nitrophenol derivative. The reaction mixture can then be heated at a temperature in the range of 50-150°C, for example, at 90°C, and stirred under an inert gas and, for example, argon for a time in the range of 15-30 hours, for example, 24 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be distributed between an organic solvent such as dichloromethane and water. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a compound of formula (Ve).

[0475] According to route (J), the compound of formula (Ve) and an organic metal catalyst such as Pd(dppf)Cl2.CH2Cl2 can be placed in a non-polar solvent such as 1,4-dichlorobenzene in an amount ranging from 2 mol% to 20 mol% relative to the amount of the compound of formula (Ve). Then, in the presence of an inorganic base such as K3PO4 or K2CO3, for example, still in a molar ratio in the range of 2-5 relative to the compound of formula (Ve), a boric acid R is added. c '-B(OH)2, for example in a molar ratio in the range of 1-5 relative to the compound of formula (Ve). The reaction mixture can then be heated at a temperature in the range of 50-150°C, for example at 100°C, and stirred under an inert gas and, for example, argon, for a time in the range of 10-70 hours, for example 20 hours. The reaction mixture can be concentrated under reduced pressure to obtain a compound of formula (IVe).

[0476] According to route (C), the compound of formula (IVe) and tin (II) chloride dihydrate can be placed in a protic solvent such as ethanol in a ratio in the range of 3-8 equivalents. The reaction mixture can then be heated at a temperature in the range of 40-80°C, for example at 60°C, and stirred for a time in the range of 15-25 hours, for example 20 hours. The mixture can be poured into a 1N NaOH aqueous solution and extracted with an organic solvent such as ethyl acetate. The organic phase can then be washed with water and a saturated brine aqueous solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a compound of formula (IIe).

[0477] The chemical structures and spectral data of some compounds of formula (Ie) of the present invention are illustrated in Tables I and II below, respectively.

[0478] Table I

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504] Table II

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560] The following examples are provided by way of illustration and in no way limit the scope of the present invention.

[0561] The following examples illustrate in detail the preparation of some compounds according to the invention. The structures of the products obtained have been confirmed by NMR spectroscopy. Example

[0562] Example 1 :Compound (39) in Table 1

[0563] According to route (I), 4-nitro-5-methylphenol (3.06 g, 20 mmol, 1 eq.) was placed in N,N-dimethylformamide (15 mL) together with K2CO3 (8.3 g, 60 mmol, 3 eq.). After adding 2-(bromomethyl)pyridine hydrobromide (5.06 g, 20 mmol, 1 eq.), the reaction mixture was heated at 90 °C and stirred under an argon inert atmosphere for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between dichloromethane and water. After decantation, the organic phase was washed with a saturated aqueous brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 92%).

[0564] 1 H NMR (300MHz, CDCl3) δ8.65-8.60(m,1H),8.07(d,J=9.8Hz,1H),7.75(td,J=7.7,1.7H z, 1H), 7.48 (d, J = 7.7Hz, 1H), 7.27 (t, J = 6.2Hz, 1H), 6.90-6.87 (m, 2H), 2.62 (s, 3H).

[0565] According to route (C), 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 18.4 mmol, 1 eq.) and tin(II) chloride dihydrate (20.8 g, 92 mmol, 5 eq.) were placed in EtOH (184 mL). The reaction mixture was heated at 60 °C and stirred under an argon inert atmosphere for 14 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N NaOH aqueous solution and then with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-methyl-4-(pyridin-2-ylmethoxy)aniline (2.0 g, 51%).

[0566] 1 H NMR (300MHz, CDCl3) δ8.58(d,J=4.3Hz,1H),7.70(td,J=7.7,1.7Hz,1H),7.52(d,J=7.7Hz,1H),7.20(dd,J=6.9,5.5Hz ,1H),6.76(d,J=2.7Hz,1H),6.69(dd,J=8.5,2.7Hz,1H),6.60(d,J=8.5Hz,1H),5.13(s,2H),3.37(s,2H),2.15(s,3H).

[0567] 2-Cyclopentylethane-1-amine hydrochloride (1.3 g, 8.7 mmol, 1.1 equivalents) was placed in a 3N NaOH aqueous solution (5.9 mL), and dichloromethane (1.5 mL) was added to the solution. The reaction mixture was cooled to 0 ° C with an ice bath, and a solution of 3-bromobenzoyl chloride (1.0 mL, 7.9 mmol, 1.0 equivalents) in dichloromethane (2.4 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an argon inert atmosphere. After decantation, the organic phase was washed with a saturated brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to obtain 3-bromo-N-(2-cyclopentylethyl)benzamide (1.8 g, 77%).

[0568] 1 H NMR (300MHz, CDCl3) δ7.89(t,J=1.7Hz,1H),7.67(d,J=7.9Hz,1H),7.65-7.58(m,1H),7.31(t,J=7.9Hz, 1H), 6.07 (s, 1H), 3.46 (dt, J = 7.4, 5.9Hz, 2H), 1.88-1.79 (m, 3H), 1.67-1.47 (m, 6H), 1.18-1.13 (m, 2H).

[0569] According to route (A), a reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (830 mg, 2.8 mmol, 1 eq.), 2-methyl-4-(pyridin-2-ylmethoxy)aniline (600 mg, 2.8 mmol, 1 eq.), Pd2(dba)3 (258 mg, 282 μmol, 10 mol%), XPhos (266 mg, 559 μmol, 20 mol%) and K2CO3 (1.55 g, 11.2 mmol, 4 eq.) in t-BuOH (11.2 mL) was heated at 90 °C and stirred under an argon inert atmosphere for 88 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with saturated aqueous brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford fractions which, after trituration with diethyl ether, yielded N-(2-cyclopentylethyl)-3-{[2-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}benzamide (39) (734 mg, 61%).

[0570] 1 H NMR(300MHz,d6-DMSO)δ8.59(d,J=4.3Hz,1H),8.26(t,J=5.5Hz,1H),7.85(td,J=7.7,1.6Hz ,1H),7.54(d,J=7.7Hz,1H),7.47(s,1H),7.35(dd,J=6.9,5.5Hz,1H),7.20-7.05(m,4H),6. 97(d,J=2.7Hz,1H),6.85(dd,J=8.6,2.7Hz,1H),6.75(d,J=7.7Hz,1H),5.16(s,2H),3.21(d d,J=13.4,6.5Hz,2H),2.14(s,3H),1.82-1.70(m,2H),1.64-1.39(m,6H),1.12-1.07(m,3H).

[0571] 13 C NMR(75MHz,d6-DMSO)δ165.1,155.5,153.2,147.6,145.4,135.5,134.4,132.7,132.3,127.3,1 23.6,121.5,120.1,115.6,114.6,114.2,111.3,111.2,68.9,37.1,35.9,34.0,30.7,23.2,16.6

[0572] [M+H] + =430.3

[0573] Example 2 :Compound (50) in Table 1

[0574] According to route (I), 4-nitrophenol (1.4 g, 10 mmol, 1 eq.) was placed in N,N-dimethylformamide (7.7 mL) together with K2CO3 (4.2 g, 30 mmol, 3 eq.). After adding 2-fluorobenzyl bromide (1.2 mL, 10 mmol, 1 eq.), the reaction mixture was heated at 90 °C and stirred under an argon inert atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. After decantation, the organic phase was washed with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 1-fluoro-2-(4-nitrophenoxymethyl)benzene (2.0 g, 81%).

[0575] 1 H NMR (300MHz, CDCl3) δ8.22(d,J=9.3Hz,2H),7.47(t,J=7.5Hz,1H),7.37(dd,J=13.6,5. 8Hz, 1H), 7.19 (t, J = 7.5Hz, 1H), 7.16-7.10 (m, 1H), 7.05 (d, J = 9.3Hz, 2H), 5.23 (s, 2H).

[0576] According to route (C), 1-[(2-fluorophenyl)methoxy]-4-nitrobenzene (1.0 g, 4.0 mmol, 1 eq.) and tin(II) chloride dihydrate (4.6 g, 20 mmol, 5 eq.) were placed in EtOH (40 mL). The reaction mixture was heated at 60 °C and stirred under an argon inert atmosphere for 14 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N NaOH aqueous solution and then with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-[(2-fluorophenyl)methoxy]aniline (836 mg, 95%).

[0577] 1 H NMR(300MHz, CDCl3)δ7.50(td,J=7.5,1.0Hz,1H),7.33-7.27(m,1H),7.14(td,J=7.5,1.0Hz,1 H),7.10-7.03(m,1H),6.82(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),5.06(s,2H),3.43(s,2H).

[0578] 2-Cyclopentylethane-1-amine hydrochloride (3.0 g, 19.1 mmol, 1.1 equivalents) was placed in a 3N NaOH aqueous solution (13 mL), and dichloromethane (3.2 mL) was added to the solution. The reaction mixture was cooled to 0 ° C with an ice bath, and a solution of 3-bromobenzoyl chloride (2.3 mL, 17.4 mmol, 1 equivalent) in dichloromethane (5.5 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an argon inert atmosphere. After decantation, the organic phase was washed with a saturated brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to obtain 3-bromo-N-(2-cyclopentylethyl)benzamide (4.6 g, 89%).

[0579] 1 H NMR (300MHz, CDCl3) δ7.89(t,J=1.7Hz,1H),7.67(d,J=7.9Hz,1H),7.62(d,J=7.9Hz,1H),7.30(t,J=7.9H z,1H),6.07(s,1H),3.46(dd,J=7.4,5.9Hz,2H),1.90-1.76(m,3H),1.67-1.52(m,6H),1.20-1.09(m,2H).

[0580] According to route (A), a reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (296 mg, 1 mmol, 1 eq), 4-[(2-fluorophenyl)methoxy]aniline (217 mg, 1 mmol, 1 eq), Pd2(dba)3 (92 mg, 100 μmol, 10 mol%), XPhos (95 mg, 200 μmol, 20 mol%) and K2CO3 (553 mg, 4 mmol, 4 eq) in t-BuOH (4 mL) was heated at 90 °C and stirred under an argon inert atmosphere for 14 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford fractions which, after trituration with diethyl ether, yielded N-(2-cyclopentylethyl)-3-({4-[(2-fluorophenyl)methoxy]phenyl}amino)benzamide (50) (168 mg, 39%).

[0581] 1H NMR(300MHz,d6-DMSO)δ8.31(t,J=5.6Hz,1H),8.05(s,1H),7.57(td,J=7.4,1 .5Hz,1H),7.47-7.36(m,2H),7.30-7.19(m,3H),7.15(d,J=7.7Hz,1H),7.07(d ,J=9.0Hz,2H),7.05-7.0(m,1H),6.98(d,J=9.0Hz,2H),5.10(s,2H),3.23(dd ,J=13.8,6.3Hz,2H),1.86-1.72(m,3H),1.62-1.45(m,6H),1.11-1.04(m,2H).

[0582] 13 C NMR(75MHz,d6-DMSO)δ164.6,160.2,156.9,151.1,143.3,134.4,134.2,128.9,128.8,128.4,127.1,122.7 ,122.7,122.4,122.2,118.7,117.4,115.3,114.9,113.8,113.4,111.8,78.0,62.0,35.6,33.7,30.4,22.9

[0583] Example 3 :Compound (60) in Table 1

[0584] According to route (I), 3-bromo-4-nitrophenol (1.7 g, 7.9 mmol, 1 eq.) was placed in N,N-dimethylformamide (6 mL) together with K2CO3 (3.3 g, 23.7 mmol, 3 eq.). After adding 2-(bromomethyl)pyridine hydrobromide (2.0 g, 7.9 mmol, 1 eq.), the reaction mixture was heated at 90 °C and stirred under an argon inert atmosphere for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between dichloromethane and water. After decantation, the organic phase was washed with a saturated aqueous brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-(3-bromo-4-nitrophenoxymethyl)pyridine (2.4 g, 98%).

[0585] 1H NMR (300MHz, CDCl3) δ8.63(d,J=4.8Hz,1H),7.97(d,J=9.1Hz,1H),7.76(td,J=7.7,1.7Hz,1H),7.47 (d,J=7.7Hz,1H),7.35(d,J=2.7Hz,1H),7.32-7.27(m,1H),7.01(dd,J=9.1,2.7Hz,1H),5.27(s,2H).

[0586] According to route (J), 2-(3-bromo-4-nitrophenoxymethyl)pyridine (2.4 g, 7.8 mmol, 1 eq.) and Pd(dppf)Cl2.CH2Cl2 (634 mg, 0.78 mmol, 0.1 eq.) were placed in 1,4-dihydro- oxane (28 mL). After adding K3PO4 (6.6 g, 31 mmol, 4 eq.) and cyclopropylboronic acid (2.0 g, 23.3 mmol, 3 eq.), the reaction mixture was heated at 100°C and stirred for 20 hours under an argon inert atmosphere. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give 2-(3-cyclopropyl-4-nitrophenoxymethyl)pyridine (1.5 g, 71%).

[0587] 1 H NMR (300MHz, CDCl3) δ8.62(d,J=4.2Hz,1H),7.94(d,J=9.0Hz,1H),7.74(td,J=7.7,1.7Hz,1H),7.47(d,J=7.7Hz,1H),7.30-7.22(m,2H), 6.84(dd,J=9.0,2.7Hz,1H), 6.72(d,J=2.7Hz,1H), 5.24(s,2H), 2.54(tt,J=8.5,5.5Hz,1H), 1.06(q,J=4.8Hz,2H), 0.67(q,J=4.8Hz,2H).

[0588] According to route (C), 2-(3-cyclopropyl-4-nitrophenoxymethyl)pyridine (1.5 g, 5.6 mmol, 1 eq.) and tin(II) chloride dihydrate (6.3 g, 28 mmol, 5 eq.) were placed in EtOH (56 mL). The reaction mixture was heated at 60 °C and stirred under an argon inert atmosphere for 64 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N NaOH aqueous solution and then with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-cyclopropyl-4-(pyridin-2-ylmethoxy)aniline (1.1 g, 82%).

[0589] 1 H NMR (300MHz, CDCl3) δ8.58(d,J=4.2Hz,1H),7.70(td,J=7.7,1.7Hz,1H),7.52(d,J=7.7Hz,1H),7.20(dd,J=6.9,5.4Hz,1H),6.73(t,J=2.7Hz ,1H),6.69(d,J=2.7Hz,1H),6.61(d,J=8.3Hz,1H),5.12(s,2H),3.71(s,2H),1.74-1.65(m,1H),0.90(q,J=4.1Hz,2H),0.58(q,J=4.1Hz,2H).

[0590] 2-Cyclopentylethane-1-amine hydrochloride (1.3 g, 8.7 mmol, 1.1 equivalents) was placed in a 3N NaOH aqueous solution (5.9 mL), and dichloromethane (1.5 mL) was added to the solution. The reaction mixture was cooled to 0 ° C with an ice bath, and a solution of 3-bromobenzoyl chloride (1.0 mL, 7.9 mmol, 1.0 equivalents) in dichloromethane (2.4 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an argon inert atmosphere. After decantation, the organic phase was washed with a saturated brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to obtain 3-bromo-N-(2-cyclopentylethyl)benzamide (1.8 g, 77%).

[0591] 1 H NMR (300MHz, CDCl3) δ7.89(t,J=1.7Hz,1H),7.67(d,J=7.9Hz,1H),7.65-7.58(m,1H),7.31(t,J=7.9Hz, 1H), 6.07 (s, 1H), 3.46 (dt, J = 7.4, 5.9Hz, 2H), 1.88-1.79 (m, 3H), 1.67-1.47 (m, 6H), 1.18-1.13 (m, 2H).

[0592] According to route (A), a reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (148 mg, 0.5 mmol, 1 eq.), 2-cyclopropyl-4-(pyridin-2-ylmethoxy)aniline (120 mg, 0.5 mmol, 1 eq.), Pd2(dba)3 (46 mg, 50 μmol, 10 mol%), XPhos (48 mg, 100 μmol, 20 mol%) and K2CO3 (277 mg, 2.0 mmol, 4 eq.) in t-BuOH (2 mL) was heated at 90 °C and stirred under an argon inert atmosphere for 14 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel to give N-(2-cyclopentylethyl)-3-{[2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl]amino}benzamide (60) (190 mg, 83%).

[0593] 1 H NMR (300MHz, CDCl3) δ8.61(d,J=4.2Hz,1H),7.73(td,J=7.7,1.7Hz,1H),7.54(d,J=7.7Hz,1H),7.26 -7.19(m,3H),7.16(d,J=8.6Hz,1H),7.08(d,J=7.7Hz,1H),6.95(dd,J=7.7,1.7Hz,1H),6.78(dd,J=8 .6,2.9Hz,1H),6.68(d,J=2.9Hz,1H),6.03(s,1H),5.71(s,1H),5.18(s,2H),3.43(dd,J=9.8,4.7Hz ,2H),1.90-1.78(m,5H),1.66-1.51(m,4H),1.17-1.09(m,3H),0.94-0.87(m,2H),0.67-0.59(m,2H).

[0594] 13 C NMR (75MHz, CDCl3) δ165.4,155.1,152.7,146.9,143.9,135.4,134.5,133.8,132.2,127.0,120. 9,120.3,119.0,115.3,114.4,111.8,111.2,110.0,68.6,37.2,35.6,33.6,30.4,22.8,9.3,4.9

[0595] [M+H] + =456.4

[0596] Example 4 :Compound (68) in Table 1

[0597] According to route (I), 4-nitro-5-methylphenol (3.06 g, 20 mmol, 1 eq.) was placed in N,N-dimethylformamide (15 mL) together with K2CO3 (8.3 g, 60 mmol, 3 eq.). After adding 2-(bromomethyl)pyridine hydrobromide (5.06 g, 20 mmol, 1 eq.), the reaction mixture was heated at 90 °C and stirred under an argon inert atmosphere for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between dichloromethane and water. After decantation, the organic phase was washed with a saturated aqueous brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 92%).

[0598] 1 H NMR (300MHz, CDCl3) δ8.65-8.60(m,1H),8.07(d,J=9.8Hz,1H),7.75(td,J=7.7,1. 7Hz, 1H), 7.48 (d, J = 7.7Hz, 1H), 7.30-7.24 (m, 1H), 6.90-6.87 (m, 2H), 2.62 (s, 3H).

[0599] According to route (C), 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 18.4 mmol, 1 eq.) and tin(II) chloride dihydrate (20.8 g, 92 mmol, 5 eq.) were placed in EtOH (184 mL). The reaction mixture was heated at 60 °C and stirred under an argon inert atmosphere for 14 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N NaOH aqueous solution and then with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-methyl-4-(pyridin-2-ylmethoxy)aniline (2.0 g, 51%).

[0600] 1 H NMR (300MHz, CDCl3) δ8.58(d,J=4.3Hz,1H),7.70(td,J=7.7,1.7Hz,1H),7.52(d,J=7.7Hz,1H),7.23-7.17(m,1H) ,6.76(d,J=2.7Hz,1H),6.69(dd,J=8.5,2.7Hz,1H),6.60(d,J=8.5Hz,1H),5.13(s,2H),3.37(s,2H),2.15(s,3H).

[0601] 3-Bromophenyl isocyanate (624 μL, 5.0 mmol, 1.0 equivalent) and triethylamine (695 μL, 5.0 mmol, 1.0 equivalent) were placed in dichloromethane (5 mL), and a solution of 3-methylbutyl-1-amine (580 μL, 5.0 mmol, 1.0 equivalent) in dichloromethane (2 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 16 hours under an argon inert atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic phase was washed with 1N HCl aqueous solution, then with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain 1-(3-bromophenyl)-3-(3-methylbutyl)urea (1.06 g, 74%).

[0602] 1 H NMR (300MHz, CDCl3) δ7.54(s,1H),7.49(t,J=1.9Hz,1H),7.18(dt,J=7.2,1.9Hz,1H),7.13-7.03(m,2H),5.5 6(t,J=5.3Hz,1H),3.20(dt,J=7.5,5.8Hz,2H),1.60-1.54(m,1H),1.36-1.30(m,2H),0.86(d,J=6.6Hz,6H).

[0603] According to route (A), a reaction mixture of 1-(3-bromophenyl)-3-(3-methylbutyl)urea (285 mg, 1.0 mmol, 1 eq), 2-methyl-4-(pyridin-2-ylmethoxy)aniline (214 mg, 1.0 mmol, 1 eq), Pd2(dba)3 (92 mg, 100 μmol, 10 mol%), XPhos (95 mg, 200 μmol, 20 mol%) and K2CO3 (553 mg, 4.0 mmol, 4 eq) in t-BuOH (4 mL) was heated at 90 °C and stirred under an argon inert atmosphere for 24 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with saturated brine solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford fractions which, after trituration with diethyl ether, yielded 1-isopentyl-3-(3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)phenyl)urea (68) (76 mg, 18%).

[0604] 1H NMR(300MHz,d6-DMSO)δ8.59(d,J=4.5Hz,1H),8.15(s,1H),7.85(td,J=7.9,1.5Hz,1H),7.54(d,J=7.9Hz ,1H),7.39-7.31(m,1H),7.18(s,1H),7.06(d,J=8.6Hz,1H),6.96-6.90(m,2H),6.82(dd,J=8.6,2.8Hz,1H ),6.73(s,1H),6.67(d,J=7.9Hz,1H),6.21(d,J=7.9Hz,1H),5.92(t,J=5.4Hz,1H),5.14(s,2H),3.06(dd ,J=13.3,6.7Hz,2H),2.14(s,3H),1.57(td,J=13.3,6.7Hz,1H),1.33-1.25(m,2H),0.88(d,J=6.7Hz,6H).

[0605] [M+H] + =419.4

[0606] Example 5 :Compound (73) in Table 1

[0607] According to route (I), 4-nitrophenol (2.75 g, 19.8 mmol, 1 eq.) was placed in N,N-dimethylformamide (15 mL) together with K2CO3 (8.2 g, 59.3 mmol, 3 eq.). After adding 2-(bromomethyl)pyridine hydrobromide (5.0 g, 19.8 mmol, 1 eq.), the reaction mixture was heated at 90 °C and stirred under an argon inert atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained residue was partitioned between ethyl acetate and water. After decantation, the organic phase was washed with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel to give 2-(4-nitrophenoxymethyl)pyridine (3.1 g, 68%).

[0608] 1 H NMR(300MHz, CDCl3)δ8.63(d,J=4.8Hz,1H),8.25-8.16(m,2H),7.75(td,J=7.7,1. 7Hz, 1H), 7.48 (d, J = 7.7Hz, 1H), 7.31-7.26 (m, 1H), 7.11-7.03 (m, 2H), 5.30 (s, 2H).

[0609] According to route (C), 2-(4-nitrophenoxymethyl)pyridine (2.0 g, 8.7 mmol, 1 eq.) and tin(II) chloride dihydrate (9.8 g, 43 mmol, 5 eq.) were placed in EtOH (87 mL). The reaction mixture was heated at 60 °C and stirred under an argon inert atmosphere for 14 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic phase was washed with 1 N NaOH aqueous solution and then with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-(pyridin-2-ylmethoxy)aniline (1.1 g, 63%).

[0610] 1 H NMR (300MHz, CDCl3) δ8.58(d,J=4.3Hz,1H),7.70(td,J=7.7,1.7Hz,1H),7.52(d,J=7.7Hz,1 H),7.20(dd,J=7.2,5.2Hz,1H),6.85-6.79(m,2H),6.67-6.61(m,2H),5.13(s,2H),3.43(br s,2H).

[0611] Cyclopentanepropanol (2.0 g, 15.6 mmol, 1 eq.) and triethylamine (2.8 mL, 20.1 mmol, 1.3 eq.) were placed in dichloromethane (9.1 mL). The solution was cooled to 0 ° C with an ice bath, and a solution of 4-toluenesulfonyl chloride (2.6 g, 13.6 mmol, 0.9 eq.) in dichloromethane (4.6 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 24 hours under an argon inert atmosphere. The organic phase was washed with 1N HCl aqueous solution and then with saturated NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain 4-methylbenzene-1-sulfonic acid 3-cyclopentylpropyl ester (3.2 g, 83%).

[0612] 1 H NMR (300MHz, CDCl3) δ7.79 (d, J = 8.1Hz, 2H), 7.34 (d, J = 8.1Hz, 2H), 4.02 (t, J = 6. 6Hz,1H),2.45(s,2H),1.75-1.43(m,11H),1.34-1.23(m,2H),1.05-0.95(m,2H).

[0613] 3-Bromophenol (613 mg, 3.5 mmol, 1 eq.) was placed in N,N-dimethylformamide (25 mL) along with Cs2CO3 (3.5 g, 10.7 mmol, 3 eq.). After adding 4-methylbenzene-1-sulfonic acid 3-cyclopentylpropyl ester (1.0 g, 3.5 mmol, 1 eq.), the reaction mixture was heated at 90 °C and stirred under an argon inert atmosphere for 14 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. After decantation, the organic phase was washed with saturated aqueous NH4Cl solution and then with saturated aqueous brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 1-bromo-3-(3-cyclopentylpropoxy)benzene (716 mg, 71%).

[0614] 1 H NMR (300MHz, CDCl3) δ7.14-7.10(m,1H),7.07-7.03(m,2H),6.82(ddd,J=8.1,2.3,1.2H z, 1H), 3.92 (t, J = 6.6Hz, 2H), 1.86-1.70 (m, 6H), 1.69-1.40 (m, 7H), 1.18-1.03 (m, 2H).

[0615] According to route (A), a reaction mixture of 1-bromo-3-(3-cyclopentylpropoxy)benzene (282 mg, 1.0 mmol, 1 eq.), 4-(pyridin-2-ylmethoxy)aniline (200 mg, 1.0 mmol, 1 eq.), Pd2(dba)3 (92 mg, 100 μmol, 10 mol%), XPhos (95 mg, 200 μmol, 20 mol%) and K2CO3 (553 mg, 4.0 mmol, 4 eq.) in t-BuOH (4 mL) was heated at 90 °C and stirred under an argon inert atmosphere for 64 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with saturated brine aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel to give 3-(3-cyclopentylpropoxy)-N-(4-(pyridin-2-ylmethoxy)phenyl)aniline (73) (94 mg, 23%).

[0616] 1H NMR (300MHz, CDCl3) δ8.59(d,J=5.2Hz,1H),7.71(td,J=7.7,1.7Hz,1H),7.53(d,J=7.7Hz,1H),7.21(dd,J=7 .0,5.2Hz,1H),7.12-7.03(m,3H),6.96-6.89(m,2H),6.50-6.44(m,2H),6.38(dd,J=7.7,1.7Hz,1H),5.55(br s,1H),5.18(s,2H),3.88(t,J=6.6Hz,2H),1.82-1.68(m,7H),1.66-1.46(m,5H),1.17-1.04(m,3H).

[0617] Example 6 :Compound (93) in Table 1

[0618] According to procedure (A1), the reaction mixture of N-(3-bromophenyl)-3-cyclohexylpropionamide (113 mg, 0.423 mmol, 1.2 eq), 4-(benzyloxy)-2-(cyclopent-1-en-1-yl)aniline (100 mg, 0.351 mmol, 1.0 eq), BrettPhos Pd G3 (6.4 mg, 7.0 μmol, 2 mol%) and Cs2CO3 (171 mg, 0.526 mmol, 1.5 eq) in anhydrous DMF (1.3 mL) was degassed with argon and heated at 80°C under an inert atmosphere for 75 min. The reaction mixture was then cooled to room temperature, filtered through a pad of celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate, and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel to give N-(3-{[4-(benzyloxy)-2-(cyclopent-1-en-1-yl)phenyl]amino}phenyl)-3-cyclohexylpropionamide (131 mg, 76%).

[0619] 1 H NMR (400MHz, d6-DMSO) δ7.52-7.22(m,5H),6.76-6.53(m,3H),6.01(s,1H),4.97(s,2H),4.50(s,2H),2.62(t,J=6.6Hz,2H),1.89(p,J=7.5Hz,2H).

[0620] [M+H] + =495.3

[0621] A 0.025 M solution of N-(3-{[4-(benzyloxy)-2-(cyclopent-1-en-1-yl)phenyl]amino}phenyl)-3-cyclohexylpropionamide (100 mg, 0.202 mmol, 1.0 equiv) in MeOH:THF (1:1) was passed through an H-cube apparatus (cartridge Pd / C 30 mm, 30° C., 2 bar, 1 mL / min). The solvent was then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-(3-{[4-(benzyloxy)-2-cyclopentylphenyl]amino}phenyl)-3-cyclohexylpropionamide (93) (50.0 mg, 50%).

[0622] 1 H NMR (400MHz, d6-DMSO) δ9.55 (s, 1H), 7.55-7.27 (m, 5H), 7.17 (s, 1H), 7.08-6.73 (m, 6H), 6.27 (d, J = 8.9Hz, 1H), 5.08 (s, 2H), 3. 26-3.13(m,1H),2.28-2.15(m,2H),1.89(d,J=6.1Hz,2H),1.79-1.36(m,14H),1.28-1.04(m,4H),0.87(q,J=10.4,8.9Hz,2H).

[0623] [M+H] + =497.3

[0624] Example 7 :Compound (101) in Table 1

[0625] According to route (I), 4-amino-3-tert-butylphenol (100 mg, 0.581 mmol, 1 eq.) was placed in anhydrous N,N-dimethylformamide (2 mL) with Cs2CO3 (227 mg, 0.697 mmol, 1.2 eq.). After adding bromomethylbenzene (75.9 μL, 0.639 mmol, 1 eq.), the reaction mixture was stirred at room temperature for 16 hours under an argon inert atmosphere. The reactants were quenched with 1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a mixture of O and N poly-benzylated products. The residue was dissolved in methanol (15 mL) and hydrogenated using an H-cube apparatus (Pd / C 10%, 1 bar hydrogen pressure, 1 mL / min flow rate). The solvent was then concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel to give 4-(benzyloxy)-2-tert-butylaniline (23.8 mg, 21%).

[0626] 1H NMR (400MHz, d6-DMSO) δ7.42(d,J=6.9Hz,2H),7.37(t,J=7.3Hz,2H),7.31(d,J=7.0Hz,1H),6.72(d ,J=2.7Hz,1H),6.61(d,J=2.7Hz,1H),6.58(d,J=8.5Hz,1H),4.94(s,2H),4.32(s,2H),1.31(s,9H).

[0627] According to procedure (A1), a reaction mixture of methyl 2-bromobenzoate (11.0 μL, 78.3 μmol, 1.0 eq.), 4-(benzyloxy)-2-tert-butylaniline (20.0 mg, 78.3 μmol, 1.0 eq.), Pd(OAc)2 (0.53 mg, 2.3 μmol, 3 mol%), rac-BINAP (0.98 mg, 1.6 μmole, 2 mol%) and K2CO3 (32.5 mg, 235 μmol, 3 eq.) in anhydrous toluene (1.0 mL) was degassed with N2 and heated at 110°C under an inert atmosphere for 75 min. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate, and the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure to give methyl 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}benzoate (50.0 mg, 47% purity, 77%).

[0628] Methyl 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}benzoate (50.0 mg, 47% purity, 60.3 μmol, 1 eq) was placed in methanol (2 mL) and a 2M aqueous NaOH solution (151 μL, 302 μmol, 5 eq) was added. The reaction mixture was heated at 80° C. and stirred for 3 hours. It was then concentrated under reduced pressure and extracted with dichloromethane after adding a 2M aqueous HCl solution (10 eq). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}benzoic acid (28.0 mg, 42% purity, 52%).

[0629] 2-{[4-(Benzyloxy)-2-tert-butylphenyl]amino}benzoic acid (28.0 mg, 42% purity, 74.6 μmol, 1 eq) and 2-cyclohexylethylamine (12.5 μL, 89.5 μmol, 1.2 eq) were placed in anhydrous N,N-dimethylformamide (1.0 mL). HATU (44.3 mg, 112 μmol, 1.5 eq) and DIPEA (39.1 μL, 224 μmol, 3 eq) were added and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}-N-(2-cyclohexylethyl)benzamide (101) (5.1 mg, 14%).

[0630] 1 H NMR (400MHz, d6-DMSO) δ9.47(s,1H),8.40(s,1H),7.61(d,J=6.9Hz,1H),7.48(d,J=7.1Hz,2H),7.41(t,J=7.4Hz,2 H),7.34(t,J=7.2Hz,1H),7.16(t,J=7.7Hz,1H),7.06(d,J=8.6Hz,1H),7.00(d,J=2.8Hz,1H),6.90(dd,J=8.6,2.8 Hz,1H),6.61(t,J=7.4Hz,1H),6.49(d,J=8.4Hz,1H),5.09(s,2H),3.27(d,J=6.8Hz,2H),1.74(d,J=12.2Hz,2H),1 .64(dd,J=20.5,11.1Hz,3H),1.44(q,J=6.9Hz,2H),1.31(s,9H),1.26-1.13(m,4H),0.90(q,J=13.3,12.5Hz,2H).

[0631] [M+H] + =485.3

[0632] Pharmacology data

[0633] Example 8: Chikungunya virus

[0634] The compounds according to the invention have been the subject of pharmacological tests which have demonstrated their relevance as active substances in therapy, in particular for the prevention, inhibition or treatment of Chikungunya virus infections.

[0635] Materials and methods

[0636] Inhibition of Chikungunya virus (CHIKV) production in infected HEK293T cell lines.

[0637] The ability of the compounds to inhibit viral replication was evaluated in an experiment in which infected cells were treated with 1 μM of the compound of formula (Ie). As a positive control for the inhibition of buckling, ribavirin was used. The toxicity of the compounds was evaluated in parallel.

[0638] Cell expansion

[0639] Human embryonic kidney 293T cells (HEK293T, CRL-11268) were maintained in Dulbecco's modified Eagle's medium (DMEM, 31966-021, Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (FBS), penicillin and streptomycin. After removing the medium, the cells were incubated with Ca-free medium. 2+ and Mg 2+ After aspiration of the washing solution, the cells were dissociated with 0.25% trypsin-EDTA solution and incubated in a 37°C incubator for at least 30 s. The concentration of the cell suspension was determined by an automated cell counter (EVE, NanoEntek) and, if necessary, adjusted to 0.33 × 10 cells / mL with DMEM medium supplemented with 10% FBS. 6 cells / mL.

[0640] Preparation of compounds

[0641] 100 μL of the cell suspension was distributed in ViewPlate-96 Black (6005182, PerkinElmer) and a clear 96-well cell culture plate (655180, Greiner bio-one). After incubation for 24 h at 37° C. under 5% CO 2 , compounds were added at appropriate concentrations.

[0642] Screening at 1 μM

[0643] Intermediate dilutions were prepared from stock solutions at 2 mM in DMSO (D8418, Sigma) in 96-well V-bottom microplates:

[0644] Mix 1 μL of 50 mM stock solution in 25 μL DMSO.

[0645] Mix 2 μL of 25 mM stock solution in 25 μL DMSO.

[0646] ·IC 50 Determination of value

[0647] Intermediate dilutions were prepared from stock solutions at 25 mM in DMSO (D8418, Sigma) in 96-well V-bottom microplates:

[0648] Mix 2 μL of 50 mM stock solution in 2 μL DMSO.

[0649] Perform 13 serial dilutions in 2 μL DMSO to reach 0.0015 mM. Perform as shown in Table III below:

[0650] Table III

[0651]

[0652] About IC 50 For screening and determination, 1 μL of each solution was added to 1 mL Masterblock 96 wells (Greiner bio-one, 780261) containing 1 mL DMEM medium. As a positive control, 5 μL of 80 mM ribavirin solution (R9644, Sigma) was added to 1 mL DMEM. On the other hand, DMSO was used as a negative control.

[0653] ·Infect

[0654] Cells were infected with 30 μL of the La Réunion outbreak CHIKV strain (LR2006-OPY1) (CHIK 5'LR) with a GFP modification at the 5' position (Tsetsarkin K, Higgs S, McGee CE, De Lamballerie X, Charrel RN, Vanlandingham DL. Infectious Clones of Chikungunya Virus (La Réunion Isolate- Ref-SKU:001N-EVA249 (PMID: 17187566), available at the following address: https: / / www.european-virus-archive.com / nucleic-acid / chikv-lr-5gfp-infe ctious-clone) for Vector Competence Studies. Vector Borne Zoonotic Dis. 2006; 6(4)). The modified virus was used to infect cells at an MOI of 0.1. The LR2006-OPY1 strain of CHIKV (CHIKV-LR) was obtained from the World Reference Center for Arboviruses at the University of Texas Medical Branch, Galveston, TX. The strain was originally isolated from the serum of a febrile French patient returning from La Réunion Island.

[0655] Cell lysis

[0656] After 22 h at 37° C. under 5% CO 2 , the medium was removed and the cells were washed as described above. 60 μL of RIPA buffer (50 mM Tris-HCl pH 8, 100 mM NaCl, 1 mM MgCl 2 , 1% Triton X-100) was added to the cells and incubated for at least 20 min before reading the fluorescence signal. Pierce 660 nm Protein Assay Reagent (22660, Thermo scientific) was used to normalize the fluorescence signal by protein amount.

[0657] CellTiter AQueous One Solution Cell Proliferation Assay (MTS) (G3581, Promega) was used to examine the toxicity of the compounds. We added 20 μL of MTS solution and read the absorbance at 492 nm after 1 hour.

[0658] result

[0659] - Already done First round of experiments , where the results are expressed as percent inhibition, which is calculated as follows by the following steps:

[0660] 1. Fluorescence intensity (FI) / absorbance 660nm (A660) = A

[0661] This ratio allows to take into account the infection (GFP virus) as a protein amount.

[0662] 2. A' = A - background noise of uninfected plate,

[0663] 3. B = Fluorescence intensity (FI) of infected but untreated plates / absorbance 660 nm (A660),

[0664] 4. C = A' / B, which is then converted to percent infection after treatment relative to untreated samples and subsequently expressed as percent infection. For example, a value of 100 in Table IV below means that after treatment, the signal caused by GFP fluorescence is eliminated, which is associated with the absence of infection.

[0665] 5.C'=100-C

[0666] This value corresponds to the percentage of inhibition.

[0667] Table IV below contains the C' values ​​(calculated as above using the average of 2 experiments) and the corresponding standard deviations for some compounds.

[0668] Some values ​​were initially above 100. In these cases, the values ​​have decreased to 100. This means that some molecules also have an effect on the viability of the cells. In other words, the A value may be lower than the background noise.

[0669] In addition, for each measurement, ribavirin was tested as a control. The values ​​of the percentage inhibition were checked so as to give 100%.

[0670] Table IV

[0671]

[0672]

[0673] - Already done Second round of experiments , giving the result as IC 50 value.

[0674] IC 50 The values ​​are in the range of 0.1 nM to 1 μM, in particular 0.5 to 500 nM, and even more particularly 1-400 nM, for example 1-200 nM. For example, compounds (36)-(41), (53), (54), (57), (58), (60)-(62), (64), (68), (70) and (71) have IC values ​​in the range of 1-400 nM. 50 value.

[0675] in conclusion

[0676] Based on the foregoing results, it can be concluded that compounds of formula (Ie) are suitable chemical compounds for the treatment and / or prevention of RNA virus infections caused by RNA viruses of group IV, more specifically alphavirus infections and most particularly Chikungunya virus infections.

[0677] Example 9: RSV virus

[0678] The compounds according to the invention have been the subject of pharmacological tests which have demonstrated their relevance as active substances in therapy and in particular for the prevention, inhibition or treatment of RSV viral infections.

[0679] Materials and methods

[0680] Protocol for Screening Antiviral Compounds for RSV Inhibition and Cytotoxicity Using the Viral ToxGlo Assay

[0681] HEp-2 cells were maintained in Eagle's Minimum Essential Medium (EMEM) containing Earle's BSS adjusted to contain 2mM L-glutamine, 10% fetal bovine serum, 100U / ml penicillin and 100μg / ml streptomycin. For the purpose of screening assays, they were grown to 90% confluence, treated with trypsin and recovered. Trypsin was neutralized with cell culture medium and the cells were centrifuged at 150x g for 5 minutes, then the supernatant was discarded and the cell pellet was resuspended in assay medium (EMEM containing Earle's BSS, which was adjusted to contain 2mM L-glutamine, 2% fetal bovine serum and 100U / ml penicillin and 100μg / ml streptomycin). For 96-well plates and 384-well plates, 1.5x10 4 The density of cells / well was 4x10 3 Cells were seeded into white clear bottom cell culture plates at a density of 10 cells / well. For the medium / background control column, only assay medium was added. The cell plates were placed in a humidity controlled chamber and incubated overnight at 37°C / 5% CO2. After overnight incubation, cells were examined for confluence and healthy appearance.

[0682] The test article was prepared at 10 times the test concentration of the maximum DMSO concentration of 10% (the final assay concentration was 1% DMSO at most) and added to the cell plate in a volume of 10 μl (for 96-well plates) and 5 μl (for 384-well plates). For the cell control and virus control wells, only the test article solvent was added. For 96 and 384-well plates, virus or assay medium was added to the cytotoxicity test wells and culture medium / cell control wells immediately after the test article at an MOI of 0.5 for 40 or 20 μl. Virus suspension was prepared by melting the RSV A2 frozen stock and diluting it to the required plaque forming unit concentration in assay medium on ice.

[0683] The cell plates were further incubated for 72 h at 37 ° C / 5% CO2 in a humidity controlled room. After the incubation period, cells were observed under a microscope to check for characteristic cytopathic effects in the virus control wells and healthy cells in the cell control wells. After the plates were adjusted to room temperature, 20 / 40 μl Viral ToxGlo (Promega) was added to each well of the 384 / 96 well cell plate. The plates were incubated on a plate shaker at room temperature in the dark for 20 minutes, and then luminescence was measured on a spectrophotometer (Biotek Synergy HTX).

[0684] RSV inhibition was calculated as the percentage of inhibition of cytopathic effect relative to the virus control, and cytotoxicity was calculated as the percentage of cell survival relative to the cell control wells. This allowed calculation of the EC for each test article. 50 Values ​​were used to identify viral inhibition or cytotoxicity dose responses. EC values ​​ranging from 0.001 μM to 2.5 μM were found. 50 values, and more particularly with respect to the EC values ​​of compounds (36), (38), (39), (45), (46), (47), (54), (57), (60), (61), (64), (68), (70), (71), (72), (75)-(80), (82)-(86), (88)-(142), (147)-(156), (164)-(166) and (179). 50 value.

[0685] Table V

[0686]

[0687]

[0688]

[0689]

[0690]

[0691] in conclusion

[0692] Based on the foregoing results, it can be concluded that compounds of formula (Ie) are suitable chemical compounds for the treatment and / or prevention of RNA virus infections caused by RNA viruses of group V, more specifically pneumovirus infections and most particularly RSV virus infections.

[0693] Example 10: Dengue 2 virus

[0694] The compounds according to the invention have been the subject of pharmacological tests which have demonstrated their relevance as active substances in therapy and in particular for the prevention, inhibition or treatment of dengue 2 virus infections.

[0695] Materials and methods

[0696] Protocol for Screening Antiviral Compounds for DENV-2 Inhibition and Cytotoxicity Using the Viral ToxGlo Assay

[0697] A549 cells were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin. For the purpose of screening assays, they were grown to 90% confluence, treated with trypsin and recovered. Trypsin was neutralized with cell culture medium and the cells were centrifuged at 150 x g for 5 minutes, then the supernatant was discarded and the cell pellet was resuspended in assay medium (DMEM supplemented with 2% fetal bovine serum and 100 U / ml penicillin and 100 μg / ml streptomycin). The cells were incubated at 1.0 x 10 4 Cells were plated at a density of 10 cells / well into 96-well white clear bottom cell culture plates. For the medium / background control column, only assay medium was added. The cell plates were placed in a humidity controlled chamber and incubated overnight at 37°C / 5% CO2. After overnight incubation, cells were examined for confluence and healthy appearance.

[0698] Test compounds were prepared at a maximum DMSO concentration of 1% at a final concentration of 10 μM (final assay concentration maximum 0.1% DMSO) and added to the cell plates in a volume of 10 μl. For cell control and virus control wells, only the test substance solvent was added. As a positive inhibition control, 7-deaza-2'-C-methyladenosine was added at 100 μM in 3 wells. For 96-well plates, virus (DENV-2 strain 16681) or assay medium was added at an MOI of 0.5 immediately after the test substance to the cytotoxicity test wells and medium / cell control wells, respectively, in 40 μl (40 for 96well plates). Virus suspensions were prepared by thawing the DENV-2 frozen stock and diluting in assay medium to the desired plaque forming unit concentration.

[0699] The cell plates were further incubated for 5 days at 37°C / 5% CO2 in a humidity controlled room. After the incubation period, cells were observed under a microscope to check for characteristic cytopathic effects in the virus control wells and healthy cells in the cell control wells. After the plates were adjusted to room temperature, 20 μl of Viral ToxGlo (Promega) was added to each well of the 96-well cell plate. The plates were incubated at room temperature for 5 minutes and then luminescence was measured on a spectrophotometer (Envision, PerkinElmer).

[0700] DENV-2 inhibition was calculated as the percentage of inhibition of cytopathic effect relative to virus control, and cytotoxicity was calculated as the percentage of cell survival relative to cell control wells.

[0701] Table VI

[0702]

[0703]

[0704] in conclusion

[0705] Based on the foregoing results, it can be concluded that compounds of formula (Ie) are suitable chemical compounds for the treatment and / or prevention of RNA virus infections caused by RNA viruses of group IV, more specifically Flavivirus infections and most particularly Dengue 2 virus infections.

[0706] The present invention further relates to a pharmaceutical composition comprising at least one novel compound as defined above or any one of its pharmaceutically acceptable salts, or at least any one of compounds (36) to (206) as defined above or any one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

[0707] The pharmaceutical compositions of the invention may contain one or more compounds of the invention in any form described herein.

[0708] Yet another object of the present invention consists of the use of at least one compound of formula (Ie) as defined above, and compounds (36) to (206) as defined above, or one of their pharmaceutically acceptable salts according to the present invention, for the preparation of a medicament for preventing or treating an RNA virus infection in a subject caused by an RNA virus from group IV or group V according to the Baltimore classification, and for example, a Chikungunya infection, a dengue infection, an influenza infection or an RSV infection.

[0709] Therefore, the present invention relates to a compound of formula (Ie) as defined above and one of compounds (36) to (206) or an acceptable salt thereof as a medicament for inhibiting, preventing or treating RNA virus infection, and most preferably RNA virus infection from group IV or V, and for example Chikungunya infection, dengue infection, influenza infection or RSV infection.

[0710] According to certain embodiments, the treatment is continuous or non-continuous.

[0711] "Continuous treatment" refers to long-term treatment that can be achieved with various frequencies of administration, such as once a day, once every 3 days, once a week, or once every 2 weeks or once a month.

[0712] According to one embodiment, any of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof is administered in a specific dose varying between 0.1-1000 mg, in particular between 0.1-10 mg, or for example between 10-200 mg, or for example between 200-1000 mg.

[0713] Another object of the present invention relates to a method for treating and / or preventing RNA viral infection in a subject, and most preferably RNA viral infection caused by a virus belonging to group IV or V of the Baltimore classification, which comprises administering a therapeutically effective amount of a compound of formula (Ie) as defined above, compounds (36) to (206) or one of their acceptable salts.

[0714] In a specific embodiment, the present invention provides the use of a compound of formula (Ie) according to the present invention or a pharmaceutically acceptable salt or a pharmaceutically active derivative thereof or a method according to the present invention, wherein the compound of formula (Ie) is to be administered in combination with an active co-agent, which can be used to treat the RNA virus infection, and most preferably the RNA virus infection from group IV or V, and for example, Chikungunya infection, dengue infection, influenza infection or RSV infection.

[0715] The compounds can be administered by any mode of administration such as intramuscular, intravenous, intranasal or oral routes and the like.

[0716] Where appropriate, the compounds of the present invention can be used as prodrugs (such as esters) of compounds involved in the present invention. "Prodrug" refers to a compound that can be converted into a compound of the present invention in vivo by metabolic means (e.g., by hydrolysis, reduction or oxidation). For example, the ester prodrug of the compound of the present invention can be converted into a parent molecule by hydrolysis in vivo. Suitable esters of the compounds of the present invention are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-di-β-hydroxynaphthoate, gentisate, isethionate, di-toluoyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate and quinate. The example of ester prodrugs is those described by FJLeinweber, Drug Metab.Res., 1987, 18, 379. As used herein, the reference to the compounds of the present invention is also intended to include any prodrug or metabolite form.

[0717] The compositions of the present invention may also include one or more additives such as diluents, excipients, stabilizers and preservatives. Such additives are well known to those skilled in the art and are particularly described in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition" (Editors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0718] The aforementioned excipients are selected according to the dosage form and intended mode of administration.

[0719] The compositions of the present invention can be administered in any manner, including, but not limited to, orally, parenterally, sublingually, transdermally, vaginally, rectally, transmucosally, topically, intranasally, by inhalation, by buccal or intranasal administration, or a combination thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular. The compositions of the present invention can also be administered in the form of an implant, which allows for sustained release of the composition as well as slow controlled intravenous infusion.

[0720] According to another embodiment, the pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (such as by powders, ointments or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection to be treated.

[0721] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injection preparations can also be sterile injection solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Available acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are typically used as solvents or suspension media.

[0722] For example, the compounds of formula (Ie) may be in any pharmaceutical form suitable for enteral or parenteral administration, accompanied by suitable excipients, for example in the form of plain or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories or potable forms such as suspensions, syrups or injectable solutions or suspensions, in a dosage allowing administration of 0.1-1000 mg of active substance per day.

[0723] In a particular embodiment, the compounds of formula (Ie) according to the invention are administered orally.

[0724] The oral route of administration is particularly preferred in the prophylactic or therapeutic aspects of the present invention.

Claims

1. Any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof: in: Ring and The rings all represent phenylene, Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group or a pyrimidinyl group, the aryl group being optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SO2-NR a R b Group, -SO3H group, -OH group, -O-SO2-OR c The group or -OP(=O)-(OR c )(OR d ) group, R a , R b , R c and R d independently represent a hydrogen atom or a (C1-C4) alkyl group, X 2 represent -O-group, -NH- groups, -S-group, -CO-NH- groups, -NH-CO-NH- groups, -NH-CO- group, -CH(OH)- group, -CH(COOH)NH- group, -CH(COOCH3)NH- group, -C(OH)(CH2OH)-, Group, a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, -SO2- group, or -SO2-NH- group, n is 0, 1, 2, or 3, m and m' are independently 0, 1 or 2, Y 2 represent Hydroxyl, (C1-C4) alkoxy group, -CHC(OH)2, COOR f , where R f represents a hydrogen atom or a (C1-C4) alkyl group, Morpholinyl group, dihydropyranyl group, Group, Group, -PO(OR f )(OR' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group, Oxetane, -Si(CH3)3 group, -NHCOO-(C1-C4)alkyl group, or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group, wherein R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by oxygen atoms, R and R' independently represent (C1-C4)alkyl group, -S-(C1-C4)alkyl group, (C3-C6) cycloalkyl group, Halogen atoms, trifluoromethyl group, -SO2(C1-C4)alkyl group, (C3-C6)cycloalkenyl group, (C1-C5) alkoxy group, -SO2-NR a R b Group, -SO3H, -OH group, -CONHR g , where R g represents a hydrogen atom or a (C1-C4) alkyl group, -O-SO2-OR c Group, an azetidinyl group, A morpholinyl group, or Cyano group, R" represents a hydrogen atom, a (C1-C4) alkyl group optionally substituted by a -COOH group, and the compound does not include 2. The compound of formula (Ie) according to claim 1 or any one of its pharmaceutically acceptable salts, wherein R" is a hydrogen atom.

3. Any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof according to claim 1, wherein Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group or a pyrimidinyl group, the aryl group being optionally substituted by one or two substituents selected from the following: a halogen atom, a (C1-C4)alkyl group, a cyano group, a (C1-C5)alkoxy group, a trifluoromethyl group, a trifluoromethoxy group.

4. Any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof according to claim 1, wherein X 2 represent -O-group, -NH- groups, -S-group, -CO-NH- groups, -NH-CO-NH- groups, -NH-CO- group, A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from triazole, tetrazole or Oxadiazole, -SO2- group, or -SO2-NH- group.

5. Any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof according to claim 1, wherein Y 2 represent Hydroxyl, -PO(OR f )(R' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group, or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group, wherein R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by an oxygen atom.

6. Any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof according to claim 1, wherein R and R' independently represent (C1-C4)alkyl group, (C3-C6) cycloalkyl group, Halogen atoms, a trifluoromethyl group, or -SO3H or SO2-CH3 group.

7. Any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof according to claim 1, wherein R" is a hydrogen atom, Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group or a pyrimidinyl group, the aryl group being optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, X 2 represent -O-group, -CO-NH- groups, -NH-CO-NH- groups, -NH-CO- group, A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from triazole, tetrazole or Oxadiazole, or -SO2-NH- group, Y 2 represent Hydroxyl, -PO(OR f )(R' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group, or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group, wherein R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8) cycloalkyl group, which is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups. 1 and / or R 2 is interrupted by oxygen atoms, and R and R' independently represent (C1-C4)alkyl group, (C3-C6) cycloalkyl group, Halogen atoms, trifluoromethyl group, -SO3H or SO2-CH3 group, or Morpholinyl group.

8. The compound of formula (Ie) according to claim 1 or any one of its pharmaceutically acceptable salts, wherein R" is a hydrogen atom, Y 1 represents a phenyl group or a pyridyl group, X 2 represent -O-group, -CO-NH- groups, -NH-CO- group, or A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from triazole, tetrazole or Oxadiazole, Y 2 represent -PO(OR f )(R' f ) group, wherein R f and R' f independently represent a hydrogen atom or a (C1-C4) alkyl group, or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group, wherein R 1 , R 2 and R 3 No more than one of them is a hydrogen atom, or R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8)cycloalkyl group, and R and R' independently represent (C1-C4)alkyl group, (C3-C6)cycloalkyl group, or Morpholinyl group.

9. The compound of formula (Ie) according to claim 1, which is selected from: or any of its pharmaceutically acceptable salts.

10. A compound selected from the group consisting of: or any pharmaceutically acceptable salt thereof.

11. Use of a compound of formula (Ie) according to claim 1, or any of the compounds according to claim 9 or 10, or any of their pharmaceutically acceptable salts, in the preparation of a medicament for treating and / or preventing RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification.

12. The use according to claim 11, wherein the RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification is caused by an RNA virus selected from the group consisting of RSV, chikungunya, influenza and dengue.

13. A pharmaceutical composition comprising at least one compound as defined in claim 1 or any one of its pharmaceutically acceptable salts, or at least any one of the compounds as defined in claim 9 or 10 or any one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient.

14. A synthetic process for preparing a compound of formula (Ie) as defined in claim 1 or any one of its pharmaceutically acceptable salts, or a compound as defined in claim 9 or 10 or any one of its pharmaceutically acceptable salts, comprising at least the following steps: In the presence of an inorganic base and a diphosphine and in the presence of an organic metal catalyst, a compound of formula (IIe) Coupling with a compound of formula (IIIe) where Y 1 , R, R', m, m', n, ring, Ring, X 2 , Y 2 , R a and R b As defined in claim 1, X is a chlorine atom, an iodine atom or a bromine atom, and Y 1 is a phenyl group, a pyridine group, a pyrazine group, a pyridazine group or a pyrimidine group, To obtain any one of the compounds of formula (Ie) as defined in claim 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds as defined in claim 9 or 10 or a pharmaceutically acceptable salt thereof.

15. Use of any one of the compounds of formula (Ie) or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating and / or preventing RNA viral infections caused by RNA viruses belonging to group IV or V of the Baltimore classification: in: The ring represents a pyridinylene group and The ring represents a phenylene group, or The ring represents a phenylene group and The ring represents a pyridinylene group, Y 1 represents an aryl group selected from a phenyl group or a pyridyl group, said aryl group being optionally substituted by a trifluoromethoxy group, R a and R b represents a hydrogen atom, X 2 represent -O-group, -CO-NH- group, or -NH-CO- group, n is 0, 1, 2, or 3, m is 0 and m' is 0 or 1, Y 2 represent -CR 1 R 2 R 3 Group, where R 3 is a hydrogen atom, and R 1 and R 2 Together with the carbon atoms carrying them, they form a (C3-C8)cycloalkyl group, R and R' independently represent (C1-C4)alkyl group, or (C3-C6) cycloalkyl group, "R" represents a hydrogen atom.

16. The use according to claim 15, wherein the RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore classification is caused by an RNA virus selected from the group consisting of RSV, Chikungunya, influenza and dengue.

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