Aryl-N-aryl derivatives for treating RNA virus infections

Abstract

The present invention relates to a compound of formula (Ie) below, or any one of its pharmaceutically acceptable salts: [Formula 1] where Y 1 represents an aryl group, and X 2 -O- group, -NH- group, -S- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, -CH(OH)- group, -CH(COOH)NH- group, -CH(COOCH3)NH- group, -C(OH)(CH2OH)-, [chemical 2] represents a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or __ heteroatoms, such as triazole, tetrazole or oxadiazole, a —SO2— group or a —SO2—NH— group; Y 2 represents a hydrogen atom, a hydroxyl group, a (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; [C3] -PO(OR f )(OR' f ) group, where R f and R' f each independently represents 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 Represents a group. The invention further relates to pharmaceutical compositions containing them and to synthetic processes for their preparation. [Selection diagram] None

Description

[Technical field]

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

[0002] The present invention further relates to certain novel compounds, in particular certain novel compounds useful for preventing and / or treating RNA viral infections, most preferably RNA viral infections caused by RNA viruses belonging to Group IV or Group V of the Baltimore Classification.

[0003] The present invention further relates to pharmaceutical compositions containing the above-mentioned novel compounds, and to chemical synthesis methods for obtaining them. [Background technology]

[0004] Viruses are one of the major causes of disease worldwide. Viruses are generally defined as small, non-living infectious agents that replicate only inside living cells, as they lack a fully autonomous replication mechanism. Although they vary in shape and size, viruses typically consist of a virus particle (known as a "virion") made up of at least one nucleic acid molecule and, optionally, a protein coat containing one or more proteins or nucleoproteins, depending on the type of virus.

[0005] Viruses do not possess a completely autonomous replication mechanism and therefore must necessarily depend on the machinery and metabolism of the infected cell or host to replicate and produce multiple copies of themselves.

[0006] Although viral replication cycles vary widely among species, it is generally accepted that the viral life cycle involves six basic steps: attachment, entry, uncoating, replication, assembly, and release.

[0007] Depending on the nature of the target virus, therapeutic molecules have been designed that can interfere with one or more of these mechanisms.

[0008] Among them, the replication process also includes the multiplication of the viral genome, as well as the synthesis of viral messenger RNA, viral proteins, and the regulation of the host's transcription or translation machinery. However, it is also clear that the type of genome (single-stranded, double-stranded, RNA, DNA, etc.) dramatically characterizes this replication process. For example, most DNA viruses assemble in the nucleus, whereas most RNA viruses unfold exclusively in the cytoplasm. There is also growing evidence that single-stranded RNA viruses, such as influenza, use the host's RNA splicing and maturation machinery.

[0009] Therefore, taking into account the influence of a given type of genome on the replication process, the Baltimore classification of viruses was developed. This classification clusters viruses into families (or "groups") depending on the viral type of the genome. As of 2018, the current virus classification consists of seven different groups: Group I: double-stranded DNA viruses (dsDNA); Group II: single-stranded DNA viruses (ssDNA); Group III: double-stranded RNA viruses (dsRNA); Group IV: (+) strand or sense viruses ((+)ssRNA); Group V: (-)strand or antisense RNA viruses ((-)ssRNA); Group VI: single-stranded RNA viruses with DNA intermediates (ssRNA-RT); Group VII: double-stranded DNA viruses with an RNA intermediate (dsDNA-RT).

[0010] According to that classification, viruses belonging to group VI are not RNA viruses in the strict sense. For the same reason, viruses belonging to group VII are not DNA viruses in the strict sense. One well-studied example of a virus family belonging to group VI is the Retroviridae (retroviruses), which includes HIV. One well-studied example of a virus family belonging to group VII is the Hepadnaviridae, which includes the Hepatitis B virus (HBV).

[0011] Representatives of viruses related to group IV may include Picornaviruses (a virus family that includes well-known viruses such as Hepatitis A virus, enteroviruses, rhinoviruses, poliovirus, and foot-and-mouth virus), SARS virus, Hepatitis C virus, yellow fever virus, and rubella virus. The Togaviridae family also belongs to group IV, and its known genus is the alphavirus, which includes the Chikungunya virus. The Flaviridae family also belongs to group IV, and includes the well-known mosquito-borne virus, namely the Dengue virus.

[0012] Representatives of viruses related to Group V may include the Filoviridae viruses, which include the Ebola virus, the Paramyxoviridae family, which includes the Respiratory Syncytial virus (RSV), the Rhabdoviridae family, and the Orthomyxoviridae family, which includes influenza A virus, influenza B virus, and influenza C virus.

[0013] A group within the virus family that is particularly focused on within the framework of the present invention is the viruses that include the RNA viruses, in particular the single-stranded RNA viruses, and more particularly the RNA viruses that belong to Group IV or Group V of the Baltimore Classification.

[0014] There are few treatments for diseases caused by RNA virus infections, especially single-stranded RNA viruses, more especially RNA virus infections from viruses belonging to groups IV and V of the Baltimore classification. Treatments are focused on alleviating symptoms. Therefore, RNA virus infections, such as RNA virus infections from groups IV and V, are difficult to treat. of Novel antiviral drugs for the treatment of , especially small chemical molecules, There is still a need to identify Summary of the Invention

[0015] definition As used herein, the term "patient" refers to either an animal, such as a valuable animal for purposes of breeding, company or conservation, or, preferably, a human or human child who is suffering from or may be suffering from one or more of the diseases and conditions described herein.

[0016] In particular, as used in this application, the term "patient" refers to a mammal, such as a rodent, cat, dog, primate or human, preferably the subject is a human, and also extends to birds.

[0017] Identifying patients in need of treatment for the diseases and conditions described herein is well within the ability and knowledge of one of ordinary skill in the art, and a veterinarian or physician skilled in the art can readily identify patients in need of such treatment by using clinical tests, physical examinations, medical / family history, or biological and diagnostic tests.

[0018] In the context of the present invention, the term "treat" or "treatment" as used herein means to reverse, alleviate, inhibit the progression of a disease caused by an RNA virus infection, more particularly an RNA virus infection from group IV or V, or one or more symptoms of such a disease, or to prevent said disease or symptoms.

[0019] As used herein, "effective amount" refers to an amount of a compound of the present invention that is effective in preventing, alleviating, eliminating, treating, or controlling the symptoms of the diseases and conditions described herein, i.e., RNA virus infection, more particularly RNA virus infection from Group IV or Group V. The term "control" is intended to refer to any process that may slow, interrupt, hinder, or stop the progression of the diseases and conditions described herein, but does not necessarily indicate the complete elimination of the symptoms of all diseases and conditions, and is intended to encompass prophylactic treatment.

[0020] The term "effective amount" encompasses a "prophylactically effective amount" as well as a "therapeutically effective amount."

[0021] As used herein, the term "prevent" means reducing the risk or delaying the onset of a given phenomenon, i.e., a disease caused by an RNA viral infection, more particularly an RNA viral infection from group IV or V, in this invention.

[0022] As used herein, "prevent" also encompasses "reducing the likelihood of onset" or "reducing the likelihood of re-onset."

[0023] The term "prophylactically effective amount" refers to a concentration of a compound of the present invention that is effective in preventing delayed onset of disease due to an RNA virus, more particularly an RNA virus from Group IV or Group V, when administered prior to infection, i.e., before, during and / or shortly after the period of exposure to an RNA virus, more particularly an RNA virus from Group IV or Group V, in inhibiting, preventing, reducing the likelihood of disease due to an RNA virus, more particularly an RNA virus from Group IV or Group V of the Baltimore Classification, or in preventing an RNA virus infection, more particularly an RNA virus infection from Group IV or Group V.

[0024] Similarly, the term "therapeutically effective amount" refers to a concentration of a compound that is effective in treating an RNA virus infection, e.g., a concentration of a compound that, when administered after infection has occurred, results in a reduction in an RNA virus infection after testing.

[0025] As used herein, the term "pharmacologically acceptable" refers to a compound, substance, excipient, composition, or dosage form that is, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit / risk ratio.

[0026] As used herein, "viral infection or virus-associated condition" refers to infection with a virus, more particularly a condition associated with a virus having an RNA genome, especially an RNA virus belonging to Group IV or Group V according to the Baltimore classification. Viruses can be further classified into different families, orders and genera.

[0027] For reference, the contents of the "Baltimore Classification" reported in this specification further refer to the virus classification set out in the 2017 International Committee of Taxonomy of Viruses (ICTV) database, released online on March 12, 2018, at http: / / ictvonline.org / virusTaxonomy.asp, which is incorporated herein in its entirety.

[0028] Alphaviruses may in particular be considered by the present invention and may be related to group IV RNA viruses and the Togaviridae family, which may be defined as positive-sense single-stranded RNA viruses or (+)ssRNA viruses. According to the 2017 virus classification, their order is "unassigned". The Togaviridae family includes the genera Alphavirus and Rubivirus.

[0029] Examples of alphaviruses contemplated by the present invention include: Barmah Forest virus, Chikungunya virus, Mayaro virus, O'nyong'nyong virus, Ross River virus, Semliki Forest virus, Una virus, Eastern equine encephalitis virus, Tonate virus, Venezuelan equine encephalitis virus, and Western equine encephalitis virus.

[0030] More preferably, the alpha-virus infection or alpha-virus associated state according to the present invention is a chikungunya virus infection or a chikungunya virus associated state.

[0031] More specifically, Chikungunya virus (CHIKV) is an RNA virus belonging to the genus Alphavirus, which belongs to the family Togaviridae, i.e., group IV of the Baltimore classification. Chikungunya fever is a mosquito-borne viral disease that was first reported in 1952 during an outbreak in southern Tanzania. CHIKV is an enveloped, positive-sense, single-stranded RNA virus with a genome of approximately 12 kb nucleotides in length. The genome of CHIKV is organized as follows: 5'-cap-nsPl-nsP2-nsP3-nsP4-(junction region)-C-E3-E2-6k-El-poly(A)-3', in which the first four proteins (nsPl-4) are nonstructural proteins, and the structural proteins are capsid (C) and envelope proteins (E). There are no clear serotype differences between CHIKV isolated from Africa, Asia, and islands in the Indian Ocean. Phylogenetic analysis based on El gene sequences allowed grouping of CHIKV into three genotypes (lineages): Asian, east / central / south African (ECSA), and West African. The Asian genotypes differed from the ECSA and West African genotypes by -5% and -15%, respectively, at the nucleotide level. The African genotypes (ECSA vs. West Africa) diverged by -15%. Amino acid identity across the three genotypes varied from 95.2 to 99.8%.

[0032] Chikungunya virus can cause outbreaks associated with severe morbidity.

[0033] Chikungunya is a viral disease transmitted to humans by infected mosquitoes. Both Aedes aegypti (Ae. Aegypti) and Aedes albopictus (Ae. Albopictus) have been implicated in chikungunya outbreaks. Aedes aegypti is confined to the tropics and subtropics, while Aedes also occurs in temperate and cool temperate regions. In recent decades, Aedes albopictus has spread from Asia and established itself in areas of Africa, Europe, and the Americas.

[0034] After infection with the Chikungunya virus, there is an average incubation period of 2-4 days, followed by symptoms of the disease. Such symptoms may include fever and severe joint pain. Other symptoms include muscle pain, headache, nausea, back pain, fatigue, muscle pain, and rash. Severe clinical symptoms of Chikungunya fever may also occur, such as hemorrhagic fever, conjunctivitis, photophobia, hepatitis, and stomatitis. Neurological symptoms such as encephalitis, febrile convulsions, meningeal syndrome, and acute encephalopathy have also been reported.

[0035] Joint pain is often debilitating and can vary in duration.

[0036] The proximity of mosquito breeding sites to human habitation is a significant risk factor for chikungunya.

[0037] The distribution of the Chikungunya virus occurs mainly in Africa, India and Southeast Asia. In recent decades, the mosquito vector of Chikungunya has spread to Europe and the Americas. In 2007, disease transmission was first reported in a localized outbreak in northeastern Italy. Since then, outbreaks have been recorded in France and Croatia.

[0038] Dengue viruses, which exhibit various serotypes, may also be considered according to the present invention and are related to the group IV RNA viruses and the family Flaviviridae, which can be defined as positive-sense single-stranded RNA or (+)ssRNA 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 related to the family Flaviviridae are hepatitis C virus and yellow fever virus.

[0039] Viruses of the order Mononegavirales are also specifically contemplated by the present invention. The order Mononegavirales includes viruses belonging to group V of the Baltimore classification. As of 2018, this order mainly includes the following virus families: Bornaviridae, Mymonaviridae, Filoviridae, Nyamiviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, and Sunviridae.

[0040] Human respiratory syncytial virus (HRSV) is a syncytial virus that causes respiratory tract infections. It is a major cause of lower respiratory tract infections and hospital visits in infancy and childhood. HRSV virus may be considered in particular by the present invention and is related to group V of RNA viruses. More particularly, RSV virus is a (-)ssRNA virus belonging to group V of the Baltimore classification. It is a pneumovirus that is part of the family Paramyxoviridae, belonging to the order Mononegavirales. Among other viruses of the order Mononegavirales, those that are particularly considered by the present invention include measles virus, mumps virus, Nipah virus, rabies virus, and human parainfluenza virus (including HPIV-1, HPIV-2, HPIV-3, and HPIV). Of note, the subfamily of Paramyxoviridae has traditionally been integrated into the Paramyxoviridae family by reference to the 2016 updated classification of the Mononegavirales.

[0041] Virus genera of particular interest within the Paramyxoviridae family include the genera Aquaparamyxovirus, Avulavirus, Ferravirus, Henipavirus, Morbillivirus, Respirovirus, and Rubulavirus.

[0042] Viruses of the family Orthomyxoviridae are also specifically contemplated by the present invention. The family Orthomyxoviridae belongs to the order "Unassigned" according to the 2017 classification of viruses. Particularly contemplated virus genera in the family Orthomyxoviridae include Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus, Gammainfluenzavirus, Isavirus, Quaranjavirus, and Thogotovirus.

[0043] Influenza virus A, influenza virus B, influenza virus C are particularly considered by the present invention and may relate to the group V RNA viruses and the family Orthomyxoviridae, which may be defined as negative-sense single-stranded RNA or (-)ssRNA viruses. Isavirus and Thogotovirus also belong to the order Orthomyxovirales. [Problem to be solved by the invention]

[0044] The present inventors have surprisingly discovered that aryl-N-aryl compounds have broad spectrum activity against RNA viruses, more particularly single-stranded RNA viruses belonging to Group IV or Group V of the Baltimore Classification, which respectively include (+)ssRNA viruses and (-)ssRNA viruses, which also refer to positive-sense single-stranded RNA viruses and negative-sense single-stranded RNA viruses.

[0045] For reference, the contents of the "Baltimore Classification" have been taken into account in the context of the classification and nomenclature of viruses as described in the 10th Report on Virus Taxonomy, 2017.

[0046] The present specification discloses any one of the compounds of the following formula (I), or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of an RNA virus infection caused by an RNA virus belonging to Group IV or Group V of the Baltimore Classification, in particular a Chikungunya virus infection, a Dengue virus infection, an Influenza virus infection or an RSV virus infection, or a virus-associated condition.

[0047] [ka]

[0048] Where: [ka] [ka] X 1 is an alkenylene group, in particular an ethenylene group, a -NH-CO- group, a -CO-NH- group, a -CR a R b O-group, Y 1 represents an aryl group selected from a 2-pyridyl group or a pyrimidinyl group, in which one of the nitrogen atoms of the pyrimidinyl group is 1 In the ortho position to or alternatively, X 1 -Y 1 represents group (A) of the following formula:

[0049] [ka]

[0050] X 2 represents a -CO-NH- group, a -NH-CO-NH- group, a -OCH2- group, a -NH-CO- group, or a -SO2-NH- group; n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y 2 is a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 represents a group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl group, wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two of a (C1-C4) alkyl group, a halogen atom or a (C1-C4) alkoxy group, and the (C3-C8) cycloalkyl group is optionally substituted by an oxygen atom with respect to the above R 1 and / or R 2 Optionally, interposed on R and R' are independently 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 Group, or -OP(=O)-(OR c )(OR d ) group, R a , R b , R c and R d each independently represents a hydrogen atom or a (C1-C4) alkyl group, However, X 1 -CR a R b When Y is an O-group, 1 further includes a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, -SO2-NR a R b base 、 -SO3H group, -OH group, -O-SO2-ORc Group or -OP(=O)-(OR c )(OR d ) groups.

[0051] First perspective In accordance with the present invention, the present invention relates to a compound of formula (Ie) below, or any one of its pharma- ceutically acceptable salts:

[0052] [ka] Where: [ka]

[0053] In further accordance with the first aspect, the present invention further relates to a compound of formula (Ie) below, or any one of its pharma- ceutically acceptable salts: [ka] m is 0 and n is 0, 1, 2 or 3; Y 1 optionally, a halogen atom, a (C1-C4) alkyl group, 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 Group or -OP(=O)-(OR c )(OR d ) groups, Y 2 is a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 represents a group, where R 1 , R 2 and R 3each independently represents a hydrogen atom or a (C1-C2) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached form a (C3-C6) cycloalkyl group, which may be optionally substituted by one or two halogen atoms, and which may be optionally substituted by an oxygen atom with respect to the above R 1 and / or R 2 It may be interposed above.

[0054] Second perspective Accordingly, the present invention discloses a compound of formula (Ie) as defined above for use in the treatment and / or prevention of an RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore classification, in particular a Chikungunya virus infection, a Dengue virus infection, an Influenza virus infection or an RSV virus infection, or a virus-related condition.

[0055] Third perspective In accordance with the present invention, the present invention relates to a compound of formula (Ie) below, or any one of its pharma- ceutically acceptable salts:

[0056] [ka] Where: [ka] Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, or a pyrimidinyl group, and the aryl group may optionally be a halogen atom, a (C1-C4) alkyl group, 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 cGroup or -OP(=O)-(OR c )(OR d ) groups, X 2 teeth, -O- group, -NH- group, -S- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, -CH(OH)- group, -CH(COOH)NH- group, -CH(COOCH3)NH- group, -C(OH)(CHOH)-, [ka] 1, 2, 3 or 4 divalent 5-membered heteroaromatic rings containing one heteroatom, such as triazole, tetrazole or oxadiazole; -SO2- group, Or, -SO2-NH- group represents n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y 2 teeth, Hydrogen atom, Hydroxyl groups, (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, [ka] [ka] -PO(OR f )(OR'f ) group, where R f and R' f each independently represents a hydrogen atom or a (C1-C4) alkyl group; Oxetanyl group, -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 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl group, which may be optionally substituted by one or two of a (C1-C4) alkyl group, a halogen atom or a (C1-C4) alkoxy group, and which may be optionally substituted by an oxygen atom to form the above R 1 and / or R 2 Optionally, interposed on or alternatively, X 2 -Y 2 -CONR c R d represents a group, where R c and R d forms a heterocyclic group together with the nitrogen atom, which may be optionally substituted by a hydroxy group or a (C1-C4) alkyl group; R and R' are independently (C1-C4) alkyl group, -S-(C1-C4)alkyl group, (C3-C6) cycloalkyl group, Halogen atoms, such as fluorine atoms, Trifluoromethyl group, -SO2(C1-C4)alkyl group, (C3-C6)cycloalkenyl group, (C1-C5)alkoxy group, -SO2-NR a R b basis, -SO3H or SO2-CH3 groups, -OH group, -CONHR g , where R g represents a hydrogen atom or a (C1-C4) alkyl group, -O-SO2-OR c basis, An azetidinyl group, a morpholinyl group, or Cyano group represents R'' represents a hydrogen atom or a (C1-C4) alkyl group optionally substituted with a -COOH group.

[0057] Fourth perspective According to the invention, it relates to a compound of formula (Ie) as defined above, for use as a medicament.

[0058] Fifth perspective According to the present invention relates to compounds of formula (Ie) as defined above for use in the treatment and / or prevention of an RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore classification, in particular a Chikungunya virus infection, a Dengue virus infection, an Influenza virus infection or an RSV virus infection, or a virus-related condition.

[0059] The above-mentioned compounds (I) and (Ie) are particularly suitable for treating or preventing a viral infection or associated condition, in particular an RNA virus infection or associated condition caused by an RNA virus belonging to group IV or group V of the Baltimore classification, more preferably a chikungunya virus infection, a dengue virus infection, an influenza virus infection or an RSV virus infection, or a virus-related condition.

[0060] The above mentioned compounds are even more particularly suitable for treating or preventing a Chikungunya virus infection, a Dengue virus infection or a RSV virus infection or a virus-related condition, most particularly a RSV virus infection.

[0061] Further aspects of the present invention are the uses of the novel compounds of formula (Ie), e.g. as medicaments, pharmaceutical compositions and synthetic processes, as will be described hereinafter.

[0062] According to a particular embodiment, the subject matter of the present patent specification describes a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of an RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification, in particular a chikungunya virus infection, a dengue virus infection, an influenza virus infection or an RSV virus infection, or a virus-related condition, wherein the alkenylene group is an (E)-alkenylene group, m and m' are independently 0 or 1; Y 2 But -CR 1 R 2 R 3 represents a group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C2) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of the groups are not hydrogen atoms, or R 1 and R 2 together with the carbon atom to which they are attached form a (C3-C6) cycloalkyl group, which may be optionally substituted by one or two halogen atoms, and which may be optionally substituted by an oxygen atom with respect to the above R 1 and / or R 2 Optionally, interposed on R and R' independently represent a halogen atom, a (C1-C2) alkyl group, a (C3-C6) cycloalkyl group or a (C1-C2) alkoxy group.

[0063] According to a further embodiment, the present patent specification describes the compounds of formula (I), or any one of its pharma- ceutically acceptable salts, for use in the treatment and / or prevention of an RNA viral infection caused by an RNA virus belonging to group IV or group V of the Baltimore classification.

[0064] [ka]

[0065] Where: [ka] [ka] X 1 represents an alkenylene group, a -NH-CO- group, a -CO-NH- group, a -CR a R b represents an O-group, Y 1 represents an aryl group selected from a 2-pyridyl group or a pyrimidinyl group, in which one of the nitrogen atoms of the pyrimidinyl group is 1 It is in the ortho position to or alternatively, X 1 -Y 1 represents group (A) of the following formula: [ka]

[0066] X 2 represents a -CO-NH- group, a -NH-CO-NH- group, a -OCH2- group, a -NH-CO- group, or a -SO2-NH- group; n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y2 is a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 represents a group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl group, which may be optionally substituted by one or two of a (C1-C4) alkyl group, a halogen atom or a (C1-C4) alkoxy group, and which may be optionally substituted by an oxygen atom to form the above R 1 and / or R 2 Optionally, interposed on R and R' are independently 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 Group or -OP(=O)-(OR c )(OR d ) group, R a , R b , R c and R d each independently represents a hydrogen atom or a (C1-C4) alkyl group, However, X 1 -CR a R b When Y is an O-group, 1 may optionally further include a halogen atom, a (C1-C4) alkyl group, 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 Group or -OP(=O)-(ORc )(OR d ) groups, which may be 3-pyridyl, 4-pyridyl or phenyl groups, optionally substituted by one or two substituents selected from the groups And, however, Y 1 -X 1 represents an ethenylene group, and X 2 represents a -CO-NH- group, and Y 2 -CR 1 R 2 R 3 represents a group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom or a (C1-C4) alkyl group, and m' is different from 0.

[0067] According to a particular embodiment, the present invention relates to a compound of formula (Ie) as defined above, or any one of its pharma- ceutically acceptable salts, wherein [ka]

[0068] In another embodiment, the present invention relates to a compound of formula (Ie) as defined above, or any one of its pharma- ceutically acceptable salts, wherein m and m are independently 0 or 1; Y 2 -CR 1 R 2 R 3 where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C2) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of the groups are not hydrogen atoms, or R 1 and R 2together with the carbon atom to which they are attached form a (C3-C6) cycloalkyl group, which may be optionally substituted by one or two halogen atoms, and which may be optionally substituted by an oxygen atom with respect to the above R 1 and / or R 2 Optionally, interposed on R and R' independently represent a halogen atom, a (C1-C2) alkyl group, a (C3-C6) cycloalkyl group or a (C1-C2) alkoxy group.

[0069] In another embodiment, the present invention relates to a compound of formula (Ie), wherein R″ is a hydrogen atom, or any one of its pharma- ceutically acceptable salts.

[0070] In another embodiment, the present invention relates to a compound of formula (Ie), or any one of its pharma- ceutically acceptable salts, 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, and the aryl group may be optionally substituted by one or two groups selected from a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, and a trifluoromethoxy group.

[0071] In another embodiment, the present invention relates to a compound of formula (Ie), or any one of its pharma- ceutically acceptable salts, wherein: X 2 teeth, -O- group, -NH- group, -S- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, divalent 5-membered heteroaromatic rings containing 1, 2, 3 or 4 heteroatoms, such as triazole, tetrazole or oxadiazole; -SO2- group, Or, -SO2-NH- group Represents.

[0072] In another embodiment, the present invention relates to a compound of formula (Ie), or any one of its pharma- ceutically acceptable salts, wherein: Y 2 teeth, Hydrogen atom, Hydroxyl groups, -PO(OR f )(OR' f ) group, where R f and R' f each independently represents 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 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl group, which may be optionally substituted by one or two of a (C1-C4) alkyl group, a halogen atom or a (C1-C4) alkoxy group, and which may be optionally substituted by an oxygen atom to form the above R 1 and / or R 2 It may be interposed above.

[0073] In another embodiment, the present invention relates to a compound of formula (Ie), or any one of its pharma- ceutically acceptable salts, wherein: R and R' are independently (C1-C4) alkyl group, (C3-C6) cycloalkyl group, Halogen atoms, such as fluorine atoms, a trifluoromethyl group, or -SO3H or SO2-CH3 group Represents.

[0074] In another embodiment, the present invention relates to a compound of formula (Ie), or any one of its pharma- ceutically acceptable salts, wherein: [ka] 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, and the aryl group may be optionally substituted by one or two substituents selected from a halogen atom, a (C1-C4) alkyl group, a cyano group, a (C1-C5) alkoxy group, a trifluoromethyl group, and a trifluoromethoxy group; X 2 but, -O- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, divalent 5-membered heteroaromatic rings containing 1, 2, 3 or 4 heteroatoms, such as triazole, tetrazole or oxadiazole; or -SO2-NH- group, represents Y 2 but, Hydrogen atoms, Hydroxyl groups, -PO(OR f )(R' f ) group, where R f and R' f each independently represents 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 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R2 and R 3 It is understood that two or more of R 1 and R 2 form a (C3-C8) cycloalkyl group together with the carbon atom to which they are attached, the (C3-C8) cycloalkyl group being optionally substituted by one or two of a (C1-C4) alkyl group, a halogen atom or a (C1-C4) alkoxy group, the (C3-C8) cycloalkyl group being optionally substituted by an oxygen atom with respect to the above R 1 and / or R 2 Optionally, interposed on and, R and R' are independently (C1-C4) alkyl group, (C3-C6) cycloalkyl group, Halogen atoms, such as fluorine atoms, Trifluoromethyl group, -SO3H or SO2-CH3 groups, or Morpholinyl group Represents.

[0075] In another embodiment, the present invention relates to a compound of formula (Ie), or any one of its pharma- ceutically acceptable salts, wherein: [ka] R" is a hydrogen atom, Y 1 represents a phenyl group or a pyridyl group; X 2 but, -O- group, -CO-NH- group, -NH-CO-NH- group, Or, divalent 5-membered heteroaromatic rings containing 1, 2, 3 or 4 heteroatoms, such as triazole, tetrazole or oxadiazole; represents Y 2 but, -PO(OR f )(R' f ) group, where Rf and R' f each independently represents 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 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 form together with the carbon atom to which they are attached a (C3-C8) cycloalkyl group; and, R and R' are independently (C1-C4) alkyl group, (C3-C6) cycloalkyl group, or Morpholinyl group Represents.

[0076] [ka]

[0077] According to a preferred embodiment of the invention, the compound of formula (Ie) is selected from: (36) N-(2-cyclopentylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (37) N-Isopentyl 3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (38) N-(2-cyclohexylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (39) N-(2-cyclopentylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (40) N-(2-cyclopentylethyl)-3-((3-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (41) N-(2-cyclopentylethyl)-3-((6-(pyridin-2-ylmethoxy)pyridin-3-yl)amino)benzamide (42) N-(2-cyclopentylethyl)-6-((4-(pyridin-2-ylmethoxy)phenyl)amino)picolinamide (43) N-(2-cyclopentylethyl)-3-((3-methoxy-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (44) N-(2-cyclopentylethyl)-3-((5-(pyridin-2-ylmethoxy)pyridin-2-yl)amino)benzamide (45) N-(2-cyclopropylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (46) N-(2-cyclobutylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (47) N-(2-cyclohexylethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (48) N-(2-cyclobutylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (49) N-(2-cyclopropylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (50) N-(2-cyclopentylethyl)-3-((4-((2-fluorobenzyl)oxy)phenyl)amino)benzamide (51) 3-((4-((2-cyanobenzyl)oxy)phenyl)amino)-N-(2-cyclopentylethyl)benzamide (52) 3-((4-(benzyloxy)phenyl)amino)-N-(2-cyclopentylethyl)benzamide (53) N-(2-cyclopentylethyl)-3-((3-hydroxy-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (54) N-Isopentyl 3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (55) N-(2-cyclopentylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide (56) N-(2-cyclohexylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide (57) 3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-isopentylbenzamide (58) N-(2-cyclopentylethyl)-3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (59) N-(2-cyclopropylethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide (60) N-(2-cyclopentylethyl)-3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (61) 3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-isopentylbenzamide (62) N-(cyclopentylmethyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (63) N-((3-methyloxetan-3-yl)methyl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (64) N-(pentan-2-yl)-3-((4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (65) 3-((4-(pyridin-2-ylmethoxy)phenyl)amino)-N-(3,3,3-trifluoropropyl)benzamide (66) N-(2-cyclopentylethyl)-3-((2-methyl-4-(1-(pyridin-2-yl)ethoxy)phenyl)amino)benzamide (67) N-Isopentyl 3-((2-methyl-4-(1-(pyridin-2-yl)ethoxy)phenyl)amino)benzamide (68) 1-Isopentyl 3-(3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)phenyl)urea (69) 3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-(oxetan-3-yl)benzamide (70) N-(2-(3,3-difluorocyclobutyl)ethyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (71) N-Cyclopentyl-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (72) 3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-N-(4-methylpentyl)benzamide (73) 3-(3-cyclopentylpropoxy)-N-(4-(pyridin-2-ylmethoxy)phenyl)aniline (74) 3-((2-methylpentyl)oxy)-N-(4-(pyridin-2-ylmethoxy)phenyl)aniline (75) N-(2-(cyclohexyl)ethyl)-3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (76) N-(2-(cyclohexyl)ethyl)-3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (77) N-(1-methylbutyl)-3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (78) N-(1-methylbutyl)-3-((2-ethyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (79) N-(2-(cyclohexyl)ethyl)-3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide (80) (3-(cyclohexyl)propanamide), N-[3-([2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl]amino)phenyl] (81) N-(3-methylbutyl)-4-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (82) N-(2-(cyclopentyl)ethyl)-3-((2-cyclopropyl-4-(phenylmethoxy)phenyl)amino)benzamide (83) 3-(3-cyclohexylpropoxy)-N-(2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)aniline (84) 3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzamide (85) N-(2-cyclohexylethyl)-3-((2-cyclopropyl-4-(pyridin-3-ylmethoxy)phenyl)amino)benzamide (86) N-(2-cyclohexylethyl)-6-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)picolinamide (87) 3-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)benzenesulfonamide (88) N-(2-cyclohexylethyl)-5-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)nicotinamide (89) N-(2-cyclopentylethyl)-3-((2-cyclopropyl-4-(pyridin-4-ylmethoxy)phenyl)amino)benzamide (90) N-(2-cyclohexylethyl)-2-((2-cyclopropyl-4-(pyridin-2-ylmethoxy)phenyl)amino)isonicotinamide (91) N-(3-{[4-(benzyloxy)-2-tert-butylphenyl]amino}phenyl)-3-cyclohexylpropanamide (92) N-(3-{[4-(benzyloxy)-2-(cyclopent-1-en-1-yl)phenyl]amino}phenyl)-3-cyclohexylpropanamide (93) N-(3-{[4-(benzyloxy)-2-cyclopentylphenyl]amino}phenyl)-3-cyclohexylpropanamide (94) N-(3-{[4-(benzyloxy)-2-(methylsulfanyl)phenyl]amino}phenyl)-3-cyclohexylpropanamide (95) N1-[4-(benzyloxy)-2-cyclopropylphenyl]-N3-(3-cyclohexylpropyl)benzene-1,3-diamine (96) 1-(2-Cyclohexylethyl)-3-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenyl]urea (97) 1-(3-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-4-cyclohexylbutan-1-ol (98) N-(3-{[4-(benzyloxy)-2-(trifluoromethyl)phenyl]amino}phenyl)-3-cyclohexylpropanamide (99) 3-Cyclohexyl-N-[3-({4-[(4-fluorophenyl)methoxy]-2-(trifluoromethyl)phenyl}amino)phenyl]propanamide (100) N-{3-[4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline (101) 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}-N-(2-cyclohexylethyl)benzamide (102) 1-Cyano-N-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenyl]cyclopropane-1-carboxamide (103) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-N-(3-cyclohexylpropyl)benzamide (104) 3-{[4-(benzyloxy)-2-(trifluoromethyl)phenyl]amino}-N-(2-cyclopentylethyl)benzamide (105) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)-2-methylphenyl]-2-cyclopropylaniline (106) 2-Cyclopropyl-N-{3-[(4-methylpentyl)oxy]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (107) N-(3-{[4-(benzyloxy)-2-methanesulfonylphenyl]amino}phenyl)-3-cyclohexylpropanamide (108) N'1-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenyl]cyclopropane-1,1-dicarboxamide (109) [3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenoxy]phosphorous acid (110) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-N-(cyclohexylmethyl)benzamide (111) N-(2-cyclohexylethyl)-3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}(methyl)amino)benzamide (112) 2-Cyclopropyl-N-{3-[4-(3-methylbutyl)-1H-1,2,3-triazol-1-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (113) N-(cyclopentylmethyl)-2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)benzamide (114) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-(morpholin-4-yl)aniline (115) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-N-(2-cyclohexylethyl)benzamide (116) N-(5-{[4-(benzyloxy)-2-(trifluoromethyl)phenyl]amino}-2-fluorophenyl)-3-cyclohexylpropanamide (117) N-(2-Cyclohexylethyl)-4-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)pyridine-2-carboxamide (118) N-{3-[1-(3-cyclohexylpropyl)-1H-1,2,3,4-tetrazol-5-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline (119) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-(propan-2-yl)aniline (120) 2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-N-(3,3,3- (Trifluoropropyl)benzamide (121) 3-Cyclohexyl-N-[2-fluoro-5-({4-[(4-fluorophenyl)methoxy]-2-methylphenyl}amino)phenyl]propanamide (122) 4-(Benzyloxy)-N-[2-(3-cyclohexylpropanesulfonyl)phenyl]-2-cyclopropylaniline (123) 2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-N-(3-methylbutyl)benzamide (124) 3-{[4-(benzyloxy)-2-(trifluoromethyl)phenyl]amino}-N-(2-cyclohexylethyl)benzene-1-sulfonamide (125) 3-Cyclohexyl-N-[2-fluoro-5-({4-[(4-fluorophenyl)methoxy]-2-(trifluoromethyl)phenyl}amino)phenyl]propanamide (126) 2-Cyclopropyl-N-{3-[1-(4-methylpentyl)-1H-1,2,3,4-tetrazol-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (127) 2-Cyclopropyl-N-{3-[5-(3-methylbutyl)-1,2,4-oxadiazol-3-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (128) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-6-cyano-N-(propan-2-yl)benzamide (129) N-{3-[5-(2-cyclohexylethyl)-1,2,4-oxadiazol-3-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline (130) N-{3-[5-(2-cyclohexylethyl)-1,3,4-oxadiazol-2-yl]phenyl}-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline (131) 2-(Azetidin-1-yl)-4-(benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]aniline (132) N-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenyl)-3-cyclohexylpropanamide (133) [3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenoxy]phosphorous acid (134) tert-Butyl 4-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)benzoyl]piperazine-1-carboxylate (135) 2-(3-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-2-[(2-cyclohexylethyl)amino]acetic acid (136) N-(1-cyanocyclopropyl)-2-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)benzamide (137) N-(3-Cyclobutoxyphenyl)-2-cyclopropyl-4-[(pyridin-2-yl)methoxy]aniline (138) 2-(3-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-2-[(2-cyclohexylethyl)amino]acetic acid methyl ester (139) 2-{[4-(benzyloxy)-2-methylphenyl]amino}-N-(2-cyclohexylethyl)benzamide (140) 3-Cyclohexyl-N-[3-({4-[(4-fluorophenyl)methoxy]-2-methylphenyl}amino)phenyl]propanamide (141) 2-Cyclopropyl-4-[(pyridin-2-yl)methoxy]-N-{3-[(trimethylsilyl)oxy]phenyl}aniline (142) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropanesulfonyl)phenyl]-2-cyclopropylaniline (143) N-(2-cyclohexylethyl)-2-[(2-cyclopropyl-4-{[4-(trifluoromethoxy)phenyl]methoxy}phenyl)amino]pyridine-4-carboxamide (144) tert-Butyl N-[2-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)ethyl]carbamate (145) 2-Cyclopropyl-N-{3-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (146) N-(5-{[4-(benzyloxy)-2-methylphenyl]amino}-2-fluorophenyl)-3-cyclohexylpropanamide (147) 2-Cyclopropyl-N-{3-[2-(2-methylpropyl)-2H-1,2,3,4-tetrazol-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (148) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyridazin-3-yl)methoxy]aniline (149) 4-(Benzyloxy)-N-{3-[(3-cyclohexylpropyl)sulfanyl]phenyl}-2-cyclopropylaniline (150) N-(3-{[4-(benzyloxy)-2-fluorophenyl]amino}phenyl)-3-cyclohexylpropanamide (151) 2-Cyclopropyl-N-[3-(oxetan-3-yloxy)phenyl]-4-[(pyridin-2-yl)methoxy]aniline (152) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrimidin-2-yl)methoxy]aniline (153) 3-Cyclohexyl-N-{3-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]methoxy}phenyl)amino]phenyl}propanamide (154) 4-(Benzyloxy)-N-[2-(3-cyclohexylpropoxy)phenyl]-2-cyclopropylaniline (155) 2-(3-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-4-cyclohexylbutane-1,2-diol (156) N-[3-(3-cyclohexylpropoxy)phenyl]-2-cyclopropyl-N-methyl-4-[(pyridin-2-yl)methoxy]aniline (15 7 ) 3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenyl diethyl phosphate (15 8 ) N-(2-cyclohexylethyl)-3-[(2-cyclopropyl-4-{[4-(trifluoromethoxy)phenyl]methoxy}phenyl)amino]benzene-1-sulfonamide (1 59 ) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrimidin-4-yl)methoxy]aniline (161) 2-Cyclopropyl-N-{3-[2-(3-methylbut-2-en-1-yl)-2H-1,2,3,4-tetrazol-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (1 60 ) 3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)-2-methylphenyl diethyl phosphate (16 2 ) 2-Cyclopropyl-N-{3-[2-(2-methoxyethyl)-2H-1,2,3,4-tetrazol-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (16 3 ) 2-Cyclopropyl-N-{3-[1-(cyclopropylmethyl)-1H-1,2,3,4-tetrazol-5-yl]phenyl}-4-[(pyridin-2-yl)methoxy]aniline (16 4 ) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-(oxan-4-yl)aniline (16 5 ) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-(3,6-dihydro-2H-pyran-4-yl)aniline (16 6 ) 5-(3-cyclohexylpropoxy)-N-{2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}pyridin-3-amine (167) 4-(Benzyloxy)-N-{2-[(3-cyclohexylpropyl)sulfanyl]phenyl}-2-cyclopropylaniline (168) 5-{[4-(benzyloxy)-2-(trifluoromethyl)phenyl]amino}-2-fluorobenzamide (169) 3-Cyclohexyl-N-{3-[(2-cyclopropyl-4-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)amino]phenyl}propanamide (170) 3-Cyclohexyl-N-[3-({2-cyclopropyl-4-[(4-methoxyphenyl)methoxy]phenyl}amino)phenyl]propanamide (171) 2-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)ethan-1-ol (172) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]aniline (173) Ethyl 5-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)valerate (174) 4-(Benzyloxy)-N-[3-(2-methoxyethoxy)phenyl]-2-methylaniline (175) 4-(Benzyloxy)-N-[3-(cyclopentylmethoxy)phenyl]-2-methylaniline (176) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrimidin-5-yl)methoxy]aniline (177) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)phenyl]-2-methylaniline (178) 3-{1-[3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenyl]-1H-1,2,3-triazol-4-yl}propan-1-ol (179) 2-Cyclopropyl-N-[3-(1,3-xazol-5-yl)phenyl]-4-[(pyridin-2-yl)methoxy]aniline (180) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-6-methyl-N-(propan-2-yl)benzamide (181) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-N-(propan-2-yl)-6-(trifluoromethyl)benzamide (182) [3-({2-cyclopropyl-4-[(pyridin-2-yl)methoxy]phenyl}amino)phenoxy](methoxy) Phosphon acid (183) 5-(Benzyloxy)-2-{[3-(3-cyclohexylpropoxy)phenyl]amino}benzonitrile (184) 2-{[4-(benzyloxy)phenyl]amino}-N-(2-cyclohexylethyl)benzamide (185) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)-4-methylphenyl]-2-cyclopropylaniline (186) 4-(Benzyloxy)-N-[3-(3-cyclohexylpropoxy)-5-methylphenyl]-2-cyclopropylaniline (187) 4-(Benzyloxy)-N-[5-(3-cyclohexylpropoxy)-2-methylphenyl]-2-cyclopropylaniline (188) 4-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-2-(3-cyclohexylpropoxy)benzamide (189) 3-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-5-(3-cyclohexylpropoxy)benzamide (190) N-(2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}phenyl)-3-cyclohexylpropanamide (191) 3-{[4-(benzyloxy)-2-methylphenyl][3-(3-cyclohexylpropoxy)phenyl]amino}propanoic acid (192) 2-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)acetic acid (193) 5-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)pentanoic acid (194) 2-(3-{[4-(benzyloxy)-2-methylphenyl]amino}phenoxy)acetate methyl (195) 4-(Benzyloxy)-2-methyl-N-[3-(trifluoromethoxy)phenyl]aniline (196) 4-(Benzyloxy)-2-methyl-N-{3-[(oxan-4-yl)methoxy]phenyl}aniline (197) 4-(3-Cyclohexylpropoxy)-N-{2-methyl-4-[(pyridin-3-yl)methoxy]phenyl}pyridin-2-amine (198) 6-(3-cyclohexylpropoxy)-N-{2-methyl-4-[(pyridin-3-yl)methoxy]phenyl}pyridin-2-amine (199) N-[4-(benzyloxy)-2-methylphenyl]-4-(3-cyclohexylpropoxy)pyridin-2-amine (200) N-[4-(benzyloxy)-2-methylphenyl]-6-(3-cyclohexylpropoxy)pyridin-2-amine (201) N-[3-(3-cyclohexylpropoxy)phenyl]-2-methyl-4-[(pyrazin-2-yl)methoxy]aniline (202) N-(5-{[4-(benzyloxy)-2-fluorophenyl]amino}-2-fluorophenyl)-3-cyclohexylpropanamide (203) N-[3-(morpholin-4-yl)propyl]-3-({4-[(pyridin-2-yl)methoxy]phenyl}amino)benzamide (204) 2-Cyclopropyl-4-[(pyridin-2-yl)methoxy]-N-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]aniline (205) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-6-cyclopropyl-N-(propan-2-yl)benzamide (206) 2-{[4-(benzyloxy)-2-cyclopropylphenyl]amino}-6-chloro-N-(propan-2-yl)benzamide and pharma-ceutically acceptable salts thereof.

[0078] The present invention extends to compounds (36) to (206) and their pharma- ceutically acceptable salts, such as the hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, triflate, maleate, mesylate, formate, acetate and fumarate salts.

[0079] According to another aspect, the subject of the present invention relates to any one of the compounds (36) to (206), or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0080] According to another aspect, a subject of the present invention relates to a compound of formula (Ie) as defined above, or any one of its pharma- ceutically acceptable salts, and to compounds (36) to (206), or any one of their pharma-ceutically acceptable salts, for use as an agent for preventing, inhibiting or treating an RNA viral infection caused by an RNA virus belonging to group IV or group V of the Baltimore classification.

[0081] Any one 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 a pharma- ceutically acceptable salt thereof, may be particularly useful for preventing, inhibiting, or treating a dengue infection.

[0082] Any one 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 a pharma- ceutically acceptable salt thereof, may be particularly useful for preventing, inhibiting, or treating a RSV infection.

[0083] Any one of compounds (36), (41), (43), (45), (52), (53), (54), (57), (58), (60), (62), (64), (68), (70), (71), and (73), or a pharma- ceutically acceptable salt thereof, may be particularly useful for preventing, inhibiting, or treating a chikungunya infection. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0084] The compounds of the present invention may exist in the form of a free base or in the form of an addition salt with a pharma- ceutically acceptable acid.

[0085] "Pharmaceutically acceptable salts thereof" refers to salts formed from acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) as well as salts formed from acid addition salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphlenesulfonic acid, naphlendisulfonic acid, and polygalacturonic acid.

[0086] Suitable physiologically acceptable acid addition salts of the compounds of formula (Ie) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, triflate, maleate, mesylate, formate, acetate and fumarate salts.

[0087] The compound of formula (Ie), and any one of compounds (36) to (206), or any one of their pharma-ceutically acceptable salts, may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0088] The compounds of formula (Ie) may also exist in tautomeric forms and are also part of the present invention.

[0089] The terms "hydrate" and "solvate" simply mean that the compounds (Ie) according to the invention can be in the form of hydrates or solvates, i.e. combined or associated with one or more water or solvent molecules. This is only a chemical property of such compounds, which can be applied to all organic compounds of this type.

[0090] In the context of the present invention: The term "halogen" is understood to mean a chlorine, fluorine, bromine or iodine atom, and in particular denotes a chlorine, fluorine or bromine atom. As used herein, the term "(C1-C x )Alkyl" are C1 to C x "C1-C6" refers to a primary, secondary, or tertiary saturated hydrocarbon, such as (C1-C6) alkyl. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, and pentyl. The term "alkenylene" refers to a divalent (C-C) alkyl group containing a double bond, more particularly a vinylene group (also known as vinylene or 1,2-ethenediyl). x ) alkyl group. As used herein, the term "(C3-C6)cycloalkyl" refers to a cyclic saturated hydrocarbon. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term "(C3-C6)cycloalkenyl" refers to a cyclic non-aromatic hydrocarbon containing at least one unsaturated bond. Examples include, but are not limited to, cyclopentenyl and cyclohexenyl. As used herein, the term "(C1-C x "(C1-Cx)alkoxy" refers to an O-(C1-Cx)alkyl moiety, where alkyl is as defined above, such as (C1-C6)alkoxy. Examples include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy, pentoxy. As used herein, the term "aryl" refers to a monocyclic aromatic group containing 6 carbon atoms and 0-2 heteroatoms, such as nitrogen, oxygen or sulfur atoms, especially nitrogen. Examples of aryl groups may include, but are not limited to, phenyl, pyridine, pyrimidine, pyridazine, pyrazine, etc. In the framework of the present invention, aryl is preferably phenyl, pyridazine, pyrazine, pyridine, such as 2-pyridine or 3-pyridine and pyrimidine. Said aryl is even more preferably phenyl and pyridine. As used herein, the term "divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms" refers to a divalent ring consisting of 5 chains and an aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from nitrogen and oxygen atoms. In one embodiment, it contains at least one heteroatom, preferably at least one nitrogen atom. In another embodiment, it contains at least two heteroatoms, such as at least one nitrogen atom. According to a further embodiment, it contains 2, 3 or 4 nitrogen atoms, preferably 3 nitrogen atoms. According to yet a further embodiment, it contains one nitrogen atom and one oxygen atom, or two nitrogen atoms and one oxygen atom. Examples include, but are not limited to, divalent triazoles, such as 1,2,3- or 1,2,4-triazoles, oxadiazoles, such as 1,2,4-oxadiazoles or 1,2,3-oxadiazoles, and divalent diazoles, diazoles and imidazoles.

[0091] The compounds of formula (Ie) may contain one or more asymmetric carbon atoms. They may therefore exist in enantiomeric or diastereomeric forms. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, are included within the scope of the present invention.

[0092] 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 sequences outlined below represent general methods useful for preparing the compounds of the present invention and are not intended to be limiting in scope or usefulness.

[0093] Compounds of general formula (I) and formula (Ie) can be prepared according to Scheme 1 below.

[0094] [ka]

[0095] The synthesis is based on a coupling reaction starting from a halogenoaromatic compound of formula (III) above, [ka]

[0096] In one embodiment, step (A1) advantageously comprises [ka]

[0097] According to route (A1), a compound of formula (III) may be placed in a protic solvent, such as tert-butanol. The compound of formula (II) may then be added in the presence of an inorganic base, such as Cs2CO3 or K2CO3, for example in a molar ratio of 1 to 1.5 relative to the compound of formula (III), in the presence of a diphosphine, such as Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) or rac-BINAP, for example in a molar ratio of 1 to 5 relative to the compound of formula (III), in particular in an amount of 2 mol % to 15 mol % relative to the total amount of compounds of formula (III) and in the presence of an organometallic catalyst, such as Pd(OAc)2 or Pd2dba3 or BrettPhos Pd G3, in an amount of 2 mol % to 25 mol % relative to the total amount of compounds of formula (III). The reaction mixture can then be heated at a temperature of 80-130°C, for example 90°C, and stirred under an inert gas, for example argon, for 15-25 hours, for example 20 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be diluted with an organic solvent, for example ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give the compounds of formula (I) and formula (Ie).

[0098] In one embodiment, step (A2) advantageously comprises [ka]

[0099] According to procedure (A2), the compound of formula (II) can be placed in a polar aprotic solvent, for example dimethylsulfoxide. Then, the compound of formula (III) can be added in the presence of an inorganic base, for example Cs2CO3 or K2CO3, in a molar ratio of for example 1 to 1.5 relative to the compound of formula (II), in the presence of a ligand, for example L-proline, in a molar ratio of for example 1 to 5 relative to the compound of formula (II), in particular in the presence of an organometallic catalyst, for example CuI, in an amount of 2 mol% to 25 mol% relative to the total amount of the compound of formula (II). The reaction mixture can then be heated at a temperature of 80 to 130°C, for example at 90°C, and stirred under an inert gas, for example argon, for 15 to 25 hours, for example 20 hours. The reaction mixture can be diluted with an organic solvent, for example ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide the compounds of Formula (I) and Formula (Ie).

[0100] Starting compounds of formula (II), formula (III) are available or can be prepared according to methods known to those skilled in the art.

[0101] Accordingly, the present patent specification further provides a synthetic process for preparing the novel compounds of formula (I) and formula (Ie) as defined above, comprising: A compound of formula (II)

[0102] [ka] with a compound of formula (III) [ka] in the presence of an inorganic base and a diphosphine and in the presence of an organometallic catalyst to obtain a novel compound of formula (I) or (Ie), [ka] The above relates to the method.

[0103] The compounds of general formula (Ie) according to the present invention can be prepared according to the following scheme 1'.

[0104] [ka]

[0105] The synthesis is based on a coupling reaction starting from a halogenoaromatic compound of formula (IIIe) above with a compound of formula (IIe), [ka]

[0106] More particularly, the present invention relates to a synthetic process for preparing a compound of formula (Ie) as defined above, comprising the steps of: A compound of formula (IIe)

[0107] [ka] with a compound of formula (IIIe) [ka] in the presence of an inorganic base and a ligand and in the presence of an organometallic catalyst to obtain a compound of formula (Ie), [ka] 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.

[0108] To give (Ie) (where R″≠H), an additional step (K) can be carried out, in which 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 ranging from 2 to 5, such as 3, and the reaction mixture can be stirred at room temperature for 10 to 50 minutes, such as 30 minutes. Then, a halide derivative, R″-X, can be added, and the resulting reaction mixture can be stirred at 70 to 110° C., such as 90° C., for 2 hours to 10 hours, such as 5 hours. Upon 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 aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the compound of formula (Ie) (where R″≠H).

[0109] More particularly, when used to prepare a compound of formula (Ie) (where R″≠H), a compound of formula (IIe) can be prepared according to the following Scheme 6. a or R b In either case ≠H, a route starting from 4-nitrophenol derivatives and the appropriate alcohol derivatives and using classical Mitsunobu conditions can produce such compounds, e.g. compounds 66 and 67 defined in Table I herein below.

[0110] Preparation of (IIe) for (Ie)

[0111] [ka]

[0112] The intermediate compounds of formula (IIe) and formula (IVe) are useful for preparing compounds of formula (Ie) according to the present invention.

[0113] According to route (I), the 4-nitrophenol derivative can be placed in a polar solvent, such as N,N-dimethylformamide. Then, a 2-(bromomethyl)aryl derivative can be added in the presence of an inorganic base, such as Cs2CO3 or K2CO3, in a molar ratio of, for example, 1-2 relative to the 4-nitrophenol derivative, or even in a molar ratio of, for example, 1-5 relative to the 4-nitrophenol derivative. The reaction mixture can then be heated at a temperature of 50-150°C, such as 90°C, and stirred under an inert gas, such as argon, for 15-30 hours, such as 24 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be partitioned 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 give the compound of formula (IVe).

[0114] According to route (C), the compound of formula (IVe) and tin(II) chloride dihydrate in a ratio of 3-8 equivalents can be placed in a protic solvent, such as ethanol. The reaction mixture can then be heated at a temperature of 40-80° C., such as 60° C., and stirred for 15-25 hours, such as 20 hours. The mixture can be poured into a 1N aqueous solution of NaOH and extracted with an organic solvent, such as ethyl acetate. The organic phase can then be washed with water and a saturated aqueous solution of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the compound of formula (IIe).

[0115] More particularly, the formula (Ie) (wherein R a =R b ═H and one R′ group (i.e., R c When M') is used to prepare a compound of formula (IIe) different from H and Me, the compound of formula (IIe) can be prepared according to Scheme 7 below.

[0116] R c '≠Me and R cPreparation of (IIe) for (Ie) when '≠H

[0117] [ka]

[0118] The intermediate compounds of formula (IIe), formula (IVe) and formula (Ve) are useful for preparing the compounds of formula (Ie) according to the present invention.

[0119] According to route (I), the 4-nitrophenol derivative can be placed in a polar solvent, such as N,N-dimethylformamide. Then, a 2-(bromomethyl)aryl derivative can be added in the presence of an inorganic base, such as Cs2CO3 or K2CO3, in a molar ratio of, for example, 1-2 relative to the 4-nitrophenol derivative, or even in a molar ratio of, for example, 1-5 relative to the 4-nitrophenol derivative. The reaction mixture can then be heated at a temperature of 50-150°C, such as 90°C, and stirred under an inert gas, such as argon, for 15-30 hours, such as 24 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be partitioned 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 give the compound of formula (Ve).

[0120] According to route (J), a compound of formula (Ve) and a compound organometallic catalyst, such as Pd(dppf)Cl2.CH2Cl2, in an amount of, for example, 2 mol % to 20 mol % relative to the compound of formula (Ve), can be placed in a non-polar solvent, such as 1,4-dioxane. Then, a boronic acid, R c'-B(OH)2, may be added in the presence of an inorganic base, such as K3PO4 or K2CO3, in a molar ratio of 1 to 5 relative to the compound of formula (Ve), particularly in a molar ratio of 2 to 5 relative to the compound of formula (Ve). The reaction mixture may then be heated at a temperature of 50 to 150°C, for example at 100°C, and stirred under an inert gas, such as argon, for 10 to 70 hours, for example 20 hours. The reaction mixture may be concentrated under reduced pressure to give the compound of formula (IVe).

[0121] According to route (C), the compound of formula (IVe) and tin(II) chloride dihydrate in a ratio of 3-8 equivalents can be placed in a protic solvent, such as ethanol. The reaction mixture can then be heated at a temperature of 40-80° C., such as 60° C., and stirred for 15-25 hours, such as 20 hours. The mixture can be poured into a 1N aqueous solution of NaOH and extracted with an organic solvent, such as ethyl acetate. The organic phase can then be washed with water and a saturated aqueous solution of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the compound of formula (IIe).

[0122] The chemical structures and spectroscopic data of some compounds of formula (Ie) of the present invention are shown in the following Tables I and II, respectively.

[0123] JPEG0007634847000035.jpg129141JPEG0007634847000036.jpg255135JPEG0007634847000037.jpg255135JPEG0007634847000038.jpg255136JPEG0007634847000039.jpg255136JPEG0007634847000040.jpg255133JPEG0007634847000041.jpg255131JPEG0007634847000042.jpg255137JPEG0007634847000043.jpg255143JPEG0007634847000044.jpg255136JPEG0007634847000045.jpg255141JPEG0007634847000046.jpg255143JPEG0007634847000047.jpg255141JPEG0007634847000048.jpg255138JPEG0007634847000049.jpg255135JPEG0007634847000050.jpg255135JPEG0007634847000051.jpg255141JPEG0007634847000052.jpg255133JPEG0007634847000053.jpg255140JPEG0007634847000054.jpg255142JPEG0007634847000055.jpg255140JPEG0007634847000056.jpg255134JPEG0007634847000057.jpg255136JPEG0007634847000058.jpg255143JPEG0007634847000059.jpg238138JPEG0007634847000060.jpg84141

[0124]

Table 2

[0125] The following examples are offered by way of illustration and are not intended to limit the scope of the invention in any way.

[0126] The following examples detail the preparation of some compounds according to the invention. The structures of the products obtained are confirmed by NMR spectroscopy.

[0127] Working Example

[0128] Example 1 Compound (39) in Table I

[0129] According to route (I), 4-nitro-5-methylphenol (3.06 g, 20 mmol, 1 equiv.) was placed in N,N-dimethylformamide (15 mL) with K2CO3 (8.3 g, 60 mmol, 3 equiv.). Upon addition of 2-(bromomethyl)pyridine hydrobromide (5.06 g, 20 mmol, 1 equiv.), the reaction mixture was heated at 90° C. and stirred for 24 h under an inert atmosphere. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between dichloromethane and water. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 92%).

[0130] 1 H NMR(300MHz,CDCl3) δ 8.65~8.60(m,1H),8.07(d,J=9.8Hz,1H),7.75(td,J=7.7,1.7Hz,1H),7.4 8(d,J=7.7Hz,1H),7.27(t,J=6.2Hz,1H),6.90~6.87(m,2H),2.62(s,3H).

[0131] According to route (C), 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 18.4 mmol, 1 equiv.) and tin(II) chloride dihydrate (20.8 g, 92 mmol, 5 equiv.) were placed in EtOH (184 mL). The reaction mixture was heated at 60° C. and stirred for 14 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N aqueous NaOH solution, then with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-methyl-4-(pyridin-2-ylmethoxy)aniline (2.0 g, 51%).

[0132] 1H NMR(300MHz,CDCl3) δ 8.58(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).

[0133] 2-Cyclopentylethan-1-amine hydrochloride (1.3 g, 8.7 mmol, 1.1 equiv.) was placed in 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. using an ice bath and a solution of 3-bromobenzoyl chloride (1.0 mL, 7.9 mmol, 1.0 equiv.) in dichloromethane (2.4 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 h under an inert atmosphere. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 3-bromo-N-(2-cyclopentylethyl)benzamide (1.8 g, 77%).

[0134] 1 H NMR(300MHz,CDCl3) δ 7.89(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).

[0135] According to route (A), a reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (830 mg, 2.8 mmol, 1 equiv.), 2-methyl-4-(pyridin-2-ylmethoxy)aniline (600 mg, 2.8 mmol, 1 equiv.), 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 equiv.) in t-BuOH (11.2 mL) was heated at 90° C. and stirred for 88 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel to give, after trituration in diethyl ether, a fraction which afforded N-(2-cyclopentylethyl)-3-{[2-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}benzamide (39) (734 mg, 61%).

[0136] 1 H NMR(300MHz,d6-DMSO) δ 8.59(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=2.7 Hz,1H),6.85(dd,J=8.6,2.7Hz,1H),6.75(d,J=7.7Hz,1H),5.16(s,2H),3.21(dd,J=1 3.4,6.5Hz,2H),2.14(s,3H),1.82~1.70(m,2H),1.64~1.39(m,6H),1.12~1.07(m,3H).

[0137] 13C NMR(75MHz,d6-DMSO) δ 165.1,155.5,153.2,147.6,145.4,135.5,134.4,132.7,132.3,127.3,123.6,121.5 ,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

[0138] [M+H] + =430.3

[0139] Example 2 Compound (50) in Table I

[0140] According to route (I), 4-nitrophenol (1.4 g, 10 mmol, 1 equiv.) was placed in N,N-dimethylformamide (7.7 mL) with K2CO3 (4.2 g, 30 mmol, 3 equiv.). Upon addition of 2-fluorobenzyl bromide (1.2 mL, 10 mmol, 1 equiv.), the reaction mixture was heated at 90° C. and stirred for 16 h under an inert atmosphere. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 1-fluoro-2-(4-nitrophenoxymethyl)benzene (2.0 g, 81%).

[0141] 1 H NMR(300MHz,CDCl3) δ 8.22(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).

[0142] According to route (C), 1-[(2-fluorophenyl)methoxy]-4-nitrobenzene (1.0 g, 4.0 mmol, 1 equiv.) and tin(II) chloride dihydrate (4.6 g, 20 mmol, 5 equiv.) were placed in EtOH (40 mL). The reaction mixture was heated at 60° C. and stirred for 14 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N aqueous NaOH solution, then with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-[(2-fluorophenyl)methoxy]aniline (836 mg, 95%).

[0143] 1 H NMR(300MHz,CDCl3) δ 7.50(td,J=7.5,1.0Hz,1H),7.33~7.27(m,1H),7.14(td,J=7.5,1.0Hz,1H),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).

[0144] 2-Cyclopentylethan-1-amine hydrochloride (3.0 g, 19.1 mmol, 1.1 equiv.) was placed in 3N NaOH aqueous solution (13 mL) and dichloromethane (3.2 mL) was added to the solution. The reaction mixture was cooled to 0° C. using an ice bath and a solution of 3-bromobenzoyl chloride (2.3 mL, 17.4 mmol, 1 equiv.) in dichloromethane (5.5 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 h under an inert atmosphere. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 3-bromo-N-(2-cyclopentylethyl)benzamide (4.6 g, 89%).

[0145] 1H NMR(300MHz,CDCl3) δ 7.89(t,J=1.7Hz,1H),7.67(d,J=7.9Hz,1H),7.62(d,J=7.9Hz,1H),7.30(t,J=7.9Hz,1H),6.0 7(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).

[0146] According to route (A), a reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (296 mg, 1 mmol, 1 equiv.), 4-[(2-fluorophenyl)methoxy]aniline (217 mg, 1 mmol, 1 equiv.), Pd2(dba)3 (92 mg, 100 μmol, 10 mol%), XPhos (95 mg, 200 μmol, 20 mol%) and K2CO3 (553 mg, 4 mmol, 4 equiv.) in t-BuOH (4 mL) was heated at 90° C. and stirred for 14 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel to give, after trituration in diethyl ether, a fraction which afforded N-(2-cyclopentylethyl)-3-({4-[(2-fluorophenyl)methoxy]phenyl}amino)benzamide (50) (168 mg, 39%).

[0147] 1 H NMR(300MHz,d6-DMSO) δ 8.31(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,2 H),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).

[0148] 13 C NMR(75MHz,d6-DMSO) δ 164.6,160.2,156.9,151.1,143.3,134.4,134.2,128.9,128.8,128.4,127.1,122.7,122.7,12 2.4,122.2,118.7,117.4,115.3,114.9,113.8,113.4,111.8,78.0,62.0,35.6,33.7,30.4,22.9

[0149] Example 3 Compound (60) in Table I

[0150] According to route (I), 3-bromo-4-nitrophenol (1.7 g, 7.9 mmol, 1 equiv.) was placed in N,N-dimethylformamide (6 mL) with K2CO3 (3.3 g, 23.7 mmol, 3 equiv.). Upon addition of 2-(bromomethyl)pyridine hydrobromide (2.0 g, 7.9 mmol, 1 equiv.), the reaction mixture was heated at 90° C. and stirred for 24 h under an inert atmosphere. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between dichloromethane and water. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-(3-bromo-4-nitrophenoxymethyl)pyridine (2.4 g, 98%).

[0151] 1 H NMR(300MHz,CDCl3) δ 8.63(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=7.7H z,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).

[0152] According to route (J), 2-(3-bromo-4-nitrophenoxymethyl)pyridine (2.4 g, 7.8 mmol, 1 equiv.) was placed in 1,4-dioxane (28 mL) with Pd(dppf)Cl2.CH2Cl2 (634 mg, 0.78 mmol, 0.1 equiv.). Upon addition of K3PO4 (6.6 g, 31 mmol, 4 equiv.) and cyclopropylboronic acid (2.0 g, 23.3 mmol, 3 equiv.), the reaction mixture was heated at 100° C. and stirred for 20 h under 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%).

[0153] 1 H NMR(300MHz,CDCl3) δ 8.62(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).

[0154] According to route (C), 2-(3-cyclopropyl-4-nitrophenoxymethyl)pyridine (1.5 g, 5.6 mmol, 1 equiv.) and tin(II) chloride dihydrate (6.3 g, 28 mmol, 5 equiv.) were placed in EtOH (56 mL). The reaction mixture was heated at 60° C. and stirred for 64 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N aqueous NaOH solution, then with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-cyclopropyl-4-(pyridin-2-ylmethoxy)aniline (1.1 g, 82%).

[0155] 1 H NMR(300MHz,CDCl3) δ 8.58(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).

[0156] 2-Cyclopentylethan-1-amine hydrochloride (1.3 g, 8.7 mmol, 1.1 equiv.) was placed in 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. using an ice bath and a solution of 3-bromobenzoyl chloride (1.0 mL, 7.9 mmol, 1.0 equiv.) in dichloromethane (2.4 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 h under an inert atmosphere. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 3-bromo-N-(2-cyclopentylethyl)benzamide (1.8 g, 77%).

[0157] 1 H NMR(300MHz,CDCl3) δ 7.89(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).

[0158] According to route (A), a reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (148 mg, 0.5 mmol, 1 equiv.), 2-cyclopropyl-4-(pyridin-2-ylmethoxy)aniline (120 mg, 0.5 mmol, 1 equiv.), Pd2(dba)3 (46 mg, 50 μmol, 10 mol %), XPhos (48 mg, 100 μmol, 20 mol %) and K2CO3 (277 mg, 2.0 mmol, 4 equiv.) in t-BuOH (2 mL) was heated at 90° C. and stirred for 14 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO, filtered, and concentrated under reduced pressure, and the resulting 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%).

[0159] 1 H NMR(300MHz,CDCl3) δ 8.61(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).

[0160] 13C NMR(75MHz,CDCl3) δ 165.4,155.1,152.7,146.9,143.9,135.4,134.5,133.8,132.2,127.0,120.9,120.3, 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

[0161] [M+H] + =456.4

[0162] Example 4 Compound (68) in Table I

[0163] According to route (I), 4-nitro-5-methylphenol (3.06 g, 20 mmol, 1 equiv.) was placed in N,N-dimethylformamide (15 mL) with K2CO3 (8.3 g, 60 mmol, 3 equiv.). Upon addition of 2-(bromomethyl)pyridine hydrobromide (5.06 g, 20 mmol, 1 equiv.), the reaction mixture was heated at 90° C. and stirred for 24 h under an inert atmosphere. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between dichloromethane and water. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 92%).

[0164] 1 H NMR(300MHz,CDCl3) δ 8.65~8.60(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).

[0165] According to route (C), 2-(3-methyl-4-nitrophenoxymethyl)pyridine (4.5 g, 18.4 mmol, 1 equiv.) and tin(II) chloride dihydrate (20.8 g, 92 mmol, 5 equiv.) were placed in EtOH (184 mL). The reaction mixture was heated at 60° C. and stirred for 14 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1N aqueous NaOH solution, then with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-methyl-4-(pyridin-2-ylmethoxy)aniline (2.0 g, 51%).

[0166] 1 H NMR(300MHz,CDCl3) δ 8.58(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).

[0167] 3-Bromophenyl isocyanate (624 μL, 5.0 mmol, 1.0 equiv.) and triethylamine (695 μL, 5.0 mmol, 1.0 equiv.) were placed in dichloromethane (5 mL) and a solution of 3-methylbutan-1-amine (580 μL, 5.0 mmol, 1.0 equiv.) in dichloromethane (2 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 16 h under an 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 a saturated aqueous solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give 1-(3-bromophenyl)-3-(3-methylbutyl)urea (1.06 g, 74%).

[0168] 1H NMR(300MHz,CDCl3) δ 7.54(s,1H),7.49(t,J=1.9Hz,1H),7.18(dt,J=7.2,1.9Hz,1H),7.13~7.03(m,2H),5.56(t,J=5.3 Hz,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).

[0169] According to route (A), a reaction mixture of 1-(3-bromophenyl)-3-(3-methylbutyl)urea (285 mg, 1.0 mmol, 1 equiv.), 2-methyl-4-(pyridin-2-ylmethoxy)aniline (214 mg, 1.0 mmol, 1 equiv.), Pd2(dba)3 (92 mg, 100 μmol, 10 mol%), XPhos (95 mg, 200 μmol, 20 mol%) and K2CO3 (553 mg, 4.0 mmol, 4 equiv.) in t-BuOH (4 mL) was heated at 90° C. and stirred for 24 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel to give, after trituration in diethyl ether, a fraction which afforded 1-isopentyl 3-(3-((2-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)phenyl)urea (68) (76 mg, 18%).

[0170] 1H NMR(300MHz,d6-DMSO) δ 8.59(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,1 H),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).

[0171] [M+H] + =419.4

[0172] Example 5 Compound (73) in Table I

[0173] According to route (I), 4-nitrophenol (2.75 g, 19.8 mmol, 1 equiv.) was placed in N,N-dimethylformamide (15 mL) with K2CO3 (8.2 g, 59.3 mmol, 3 equiv.). Upon addition of 2-(bromomethyl)pyridine hydrobromide (5.0 g, 19.8 mmol, 1 equiv.), the reaction mixture was heated at 90° C. and stirred for 16 h under inert atmosphere. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give 2-(4-nitrophenoxymethyl)pyridine (3.1 g, 68%).

[0174] 1H NMR(300MHz,CDCl3) δ 8.63(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).

[0175] According to route (C), 2-(4-nitrophenoxymethyl)pyridine (2.0 g, 8.7 mmol, 1 equiv.) and tin(II) chloride dihydrate (9.8 g, 43 mmol, 5 equiv.) were placed in EtOH (87 mL). The reaction mixture was heated at 60° C. and stirred for 14 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with 1N aqueous NaOH solution, then with a saturated aqueous solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give 4-(pyridin-2-ylmethoxy)aniline (1.1 g, 63%).

[0176] 1 H NMR(300MHz,CDCl3) δ 8.58(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 =7.2,5.2Hz,1H),6.85~6.79(m,2H),6.67~6.61(m,2H),5.13(s,2H),3.43(brs,2H).

[0177] Cyclopentanepropanol (2.0 g, 15.6 mmol, 1 equiv.) and triethylamine (2.8 mL, 20.1 mmol, 1.3 equiv.) were placed in dichloromethane (9.1 mL). The solution was cooled to 0° C. using an ice bath, and a solution of 4-toluenesulfonyl chloride (2.6 g, 13.6 mmol, 0.9 equiv.) in dichloromethane (4.6 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 24 h under an inert atmosphere. The organic phase was washed with 1N HCl aqueous solution, then with a saturated aqueous solution of NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give 3-cyclopentylpropyl 4-methylbenzene-1-sulfonate (3.2 g, 83%).

[0178] 1 H NMR(300MHz,CDCl3) δ 7.79(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).

[0179] 3-Bromophenol (613 mg, 3.5 mmol, 1 equiv.) was placed in N,N-dimethylformamide (25 mL) with Cs2CO3 (3.5 g, 10.7 mmol, 3 equiv.). Upon addition of 3-cyclopentylpropyl 4-methylbenzene-1-sulfonate (1.0 g, 3.5 mmol, 1 equiv.), the reaction mixture was heated at 90° C. and stirred for 14 h under inert atmosphere. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the organic phase was washed with a saturated aqueous solution of NH4Cl and then with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 1-bromo-3-(3-cyclopentylpropoxy)benzene (716 mg, 71%).

[0180] 1H NMR(300MHz,CDCl3) δ 7.14~7.10(m,1H),7.07~7.03(m,2H),6.82(ddd,J=8.1,2.3,1.2Hz,1H),3.9 2(t,J=6.6Hz,2H),1.86~1.70(m,6H),1.69~1.40(m,7H),1.18~1.03(m,2H).

[0181] According to route (A), a reaction mixture of 1-bromo-3-(3-cyclopentylpropoxy)benzene (282 mg, 1.0 mmol, 1 equiv.), 4-(pyridin-2-ylmethoxy)aniline (200 mg, 1.0 mmol, 1 equiv.), Pd2(dba)3 (92 mg, 100 μmol, 10 mol%), XPhos (95 mg, 200 μmol, 20 mol%) and K2CO3 (553 mg, 4.0 mmol, 4 equiv.) in t-BuOH (4 mL) was heated at 90° C. and stirred for 64 h under an inert atmosphere. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO, filtered, and concentrated under reduced pressure, and the resulting 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%).

[0182] 1 H NMR(300MHz,CDCl3) δ 8.59(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(brs,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).

[0183] Example 6Compound (93) in Table I

[0184] According to procedure (A1), a reaction mixture of N-(3-bromophenyl)-3-cyclohexylpropanamide (113 mg, 0.423 mmol, 1.2 equiv.), 4-(benzyloxy)-2-(cyclopent-1-en-1-yl)aniline (100 mg, 0.351 mmol, 1.0 equiv.), BrettPhos Pd G3 (6.4 mg, 7.0 μmol, 2 mol %) and Cs2CO3 (171 mg, 0.526 mmol, 1.5 equiv.) in anhydrous DMF (1.3 mL) was degassed with argon and heated at 80° C. for 75 h under an inert atmosphere. The reaction mixture was then cooled to room temperature and 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 MgSO, filtered, and concentrated under reduced pressure, and the resulting 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-cyclohexylpropanamide (131 mg, 76%).

[0185] 1 H NMR(400MHz,d6-DMSO) δ 7.52~7.22(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).

[0186] [M+H] + =495.3

[0187] A 0.025 M solution of N-(3-{[4-(benzyloxy)-2-(cyclopent-1-en-1-yl)phenyl]amino}phenyl)-3-cyclohexylpropanamide (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 and the resulting residue was purified by column chromatography on silica gel to give N-(3-{[4-(benzyloxy)-2-cyclopentylphenyl]amino}phenyl)-3-cyclohexylpropanamide (93) (50.0 mg, 50%).

[0188] 1 H NMR(400MHz,d6-DMSO) δ 9.55(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). [M+H] + =497.3

[0189] Example 7 Compound (101) in Table I

[0190] According to route (I), 4-amino-3-tert-butylphenol (100 mg, 0.581 mmol, 1 equiv.) was placed in anhydrous N,N-dimethylformamide (2 mL) with Cs2CO3 (227 mg, 0.697 mmol, 1.2 equiv.). Upon addition of bromomethylbenzene (75.9 μL, 0.639 mmol, 1 equiv.), the reaction mixture was stirred at room temperature for 16 h under inert atmosphere. The reaction was quenched with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a mixture of O and N poly-benzylated products. The residue was taken up in methanol (15 mL) and hydrogenated using an H-cube apparatus (Pd / C 10%, 1 bar hydrogen pressure, 1 mL / min flow). The solvent was then concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give 4-(benzyloxy)-2-tert-butylaniline (23.8 mg, 21%).

[0191] 1 H NMR(400MHz,d6-DMSO) δ 7.42(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,1 H),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).

[0192] According to procedure (A1), a reaction mixture of methyl 2-bromobenzoate (11.0 μL, 78.3 μmol, 1.0 equiv.), 4-(benzyloxy)-2-tert-butylaniline (20.0 mg, 78.3 μmol, 1.0 equiv.), Pd(OAc) (0.53 mg, 2.3 μmol, 3 mol%), rac-BINAP (0.98 mg, 1.6 μmol, 2 mol%) and KCO (32.5 mg, 235 μmol, 3 equiv.) in anhydrous toluene (1.0 mL) was degassed with N and heated at 110° C. for 75 min under an inert atmosphere. The reaction mixture was cooled to room temperature and 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 MgSO4, filtered, and concentrated under reduced pressure to give methyl 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}benzoate (50.0 mg, 47% purity, 77%).

[0193] Methyl 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}benzoate (50.0 mg, 47% purity, 60.3 μmol, 1 equiv.) was placed in methanol (2 mL) and an aqueous solution of 2 M NaOH (151 μL, 302 μmol, 5 equiv.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and extracted with dichloromethane after addition of an aqueous solution of 2 M HCl (10 equiv.). 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%).

[0194] 2-{[4-(benzyloxy)-2-tert-butylphenyl]amino}benzoic acid (28.0 mg, 42% purity, 74.6 μmol, 1 equiv.) and 2-cyclohexylethanamine (12.5 μL, 89.5 μmol, 1.2 equiv.) were placed in anhydrous N,N-dimethylformamide (1.0 mL). HATU (44.3 mg, 112 μmol, 1.5 equiv.) and DIPEA (39.1 μL, 224 μmol, 3 equiv.) were added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and 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%).

[0195] 1 H NMR(400MHz,d6-DMSO) δ 9.47(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,2H),7.34(t,J=7.2 Hz,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=8.6,2.8Hz,1H),6.6 1(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(d d,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).

[0196] [M+H] + =485.3

[0197] Pharmacological Data Example 8: Chikungunya virus The compounds of the invention have been the subject of pharmacological tests which have demonstrated their relevance as active substances in therapy, in particular for preventing, inhibiting or treating Chikungunya virus infection.

[0198] Materials and Methods Inhibition of Chikungunya virus (CHIKV) production in infected HEK293T cell lines The ability of the compounds to inhibit viral replication was evaluated in an experiment in which infected cells were tested with 1 μM of the compound of formula (Ie). Ribavirin was used as a positive control for inhibition of chikungunya. The toxicity of the compounds was evaluated in parallel.

[0199] · Cell proliferation Human embryonic kidney cells 293T (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 2+ and Mg 2+ The cells were washed with 0.25% trypsin-EDTA solution to remove all traces of serum. After aspirating the wash, the cells were dissociated with 0.25% trypsin-EDTA solution and incubated for at least 30 seconds in a 37°C incubator. The concentration of the cell suspension was measured with an automated cell counter (EVE, NanoEntek) and, where necessary, adjusted to a concentration of 0.33 × 10 in DMEM medium supplemented with 10% FBS. 6 Adjusted to cells / mL.

[0200] · Preparation of compounds 100 μL of cell suspension was dispatched to ViewPlate-96 Black (6005182, PerkinElmer) and clear 96-well cell culture plates (655180, Greiner bio-one). After incubation at 37°C under 5% CO2 for 24 hours, compounds were added at appropriate concentrations.

[0201] · Screening at 1μM Intermediate dilutions were prepared from the stock solution in 96-well V-bottom microplates using DMSO (D8418, Sigma) at 2 mM. Mix 1 μL of 50 mM stock library in 25 μL of DMSO 2 μL of 25 mM stock library mixed in 25 μL of DMSO

[0202] · I C 50 Determining Values Intermediate dilutions were prepared from the stock solution in 96-well V-bottom microplates using DMSO (D8418, Sigma) at 25 mM. 2 μL of 50 mM stock library mixed with 2 μL of DMSO

[0203] Thirteen serial dilutions were made with 2 μL of DMSO to arrive at 0.0015 mM as shown in Table III below.

[0204] [Table 3]

[0205] Screening and IC 50 For both determinations, 1 μL of each solution was added to 1 mL of Masterblock 96-well (Greiner bio-one, 780261) containing 1 mL of DMEM medium. As a positive control, 5 μL of 80 mM Ribavirin solution (R9644, Sigma) was added to 1 mL of DMEM, while DMSO was used as a negative control.

[0206] · infection Cells were infected with 30 μL of a CHIKV strain (LR2006-OPY1) originating from La Reunion modified with GFP at the 5' (CHIK 5'LR) (Tsetsarkin K, Higgs S, McGee CE, De Lamballerie X, Charrel RN, Vanlandingham DL. Infectious Clones of Chikungunya Virus (La Reunion solate- Ref-SKU:001N-EVA249 (PMID: 17187566 ).Vector Borne Zoonotic Dis.2006;6(4)). The modified virus was used to infect cells at an MOI of 0.1. CHIKV strain LR2006-OPY1 (CHIKV-LR) was obtained from the World Reference Center for Arboviruses at the University of Texas Medical Branch, Galveston, Texas. The strain was originally isolated from serum of a febrile French patient returning from La Réunion island.

[0207] · cell lysis The medium was removed after 22 hours at 37°C under 5% CO2, and the cells were washed as above. 60μL of RIPA buffer (50mM Tris-HCl pH8, 100mM NaCl, 1mM MgCl2, 1% Triton X-100) was added to the cells and incubated for at least 20 minutes, and the fluorescent signal was read. Pierce 660nm Protein Assay Reagent (22660, Thermo scientific) was used to normalize the fluorescent signal by protein amount.

[0208] CellTiter 96® Aqueous One Solution Cell Proliferation Assay (MTS) (G3581, Promega) was used to check the toxicity of the compounds. We added 20 μL of MTS solution and read the absorbance at 492 nm after 1 hour.

[0209] result First round of experiments is performed, where the results are expressed as a percentage of inhibition calculated as follows: 1. Fluorescence intensity (FI) 509 nm / absorbance 660 nm (A660) = A This ratio makes it possible to take into account the amount of infection (GFP virus) relative to the amount of protein. 2. A' = A - background noise of uninfected plate 3.B = Fluorescence intensity (FI) / Absorbance at 660 nm (A660) of infected but untreated plate. 4. C=A' / B, which is then converted as the infection percentage after treatment compared to the untreated sample, and subsequently converted as the infection percentage. For example, a value of 100 in Table IV herein below means that after treatment, the signal due to GFP fluorescence disappears, which correlates to the absence of infection. 5. C'=100-C

[0210] This value corresponds to the percentage of inhibition.

[0211] Table IV below contains the above C' values ​​for several compounds, averaged over two experiments, and the corresponding standard deviations, as calculated above.

[0212] Some values ​​were originally above 100. In these cases, the values ​​were lowered to 100. This means that some molecules also affect cell viability. In other words, the A value can be lower than the background noise.

[0213] Furthermore, for each measurement, the test was performed with ribavirin as a control, and the inhibition percentage values ​​were checked and assigned a value of 100%.

[0214] [Table 4]

[0215] Second experiment The results are then compared with the IC 50 was given as.

[0216] I C 50 The values ​​are from 0.1 nM to 1 μM, in particular from 0.5 to 500 nM, even more particularly from 1 to 400 nM, for example from 1 to 200 nM, in particular for compounds 6, 14, 15, 16, 32 and 35, IC 50 For example, compounds (36)-(41), (53), (54), (57), (58), (60)-(62), (64), (68), (70), and (71) have IC values ​​of 1-400 nM. 50 It has a value.

[0217] conclusion Based on the previous results it can be concluded that the compounds of formula (Ie) are suitable compounds for treating and / or preventing RNA virus infections caused by group IV RNA viruses, more particularly alpha virus infections, most particularly Chikungunya virus infections.

[0218] Example 9: RSV virus 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 preventing, inhibiting or treating RSV viral infections.

[0219] Materials and Methods Protocol for screening antiviral compounds for RSV inhibition and cytotoxicity using the viral ToxGlo assay HEp-2 cells were maintained in Eagle's minimum essential medium (EMEM) containing Earle's BSS adjusted to contain 2 mM L-glutamine, 10% fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin. For the purposes of the screening assay, they were grown to 90% confluency, trypsinized, and harvested. Trypsin was neutralized with cell culture medium, cells were centrifuged at 150 x g for 5 min, and the supernatant was discarded and the cell pellet was resuspended in assay medium (EMEM containing Earle's BSS adjusted to contain 2 mM L-glutamine, 2% fetal bovine serum, and 100 U / ml penicillin and 100 μg / ml streptomycin). Cells were plated at 1.5x10 in 50μl in white clear bottom cell culture plates in 96-well and 384-well plates, respectively. 4 4x10 cells / well and 25 μl 3Cells were seeded at a density of 1000 cells / well. Only medium / background control column assay medium was added. The cell plates were placed in a humidified chamber and incubated overnight at 37°C / 5% CO2. After overnight incubation, cells were checked for confluency and healthy appearance.

[0220] Test articles were made up at 10x the test concentration with a maximum DMSO concentration of 10% (final assay concentration of DMSO up to 1%) and added to cell plates in volumes of 10 μl for 96-well plates and 5 μl for 384-well plates. For cell and virus control wells, only test article solvent was added. Assay medium for virus or cytotoxicity test wells and media / cell control wells was added immediately after test article at an MOI of 0.5, 40 or 20 μl for 96-well and 384-well plates, respectively. Virus suspensions were prepared by thawing RSV A2 frozen stocks and diluting to the required concentration of plaque forming units with assay medium on ice.

[0221] The cell plates were further incubated at 37°C / 5% CO2 in a humidified chamber for 72 hours pi. After the incubation period, the cells were observed under a microscope to check for characteristic cytopathic effects in virus control wells and healthy cells in cell control wells. After the plates were adjusted to room temperature, 20 / 40 μl of Viral ToxGlo (Promega) was added to each well of the 384 / 96-well cell plates. The plates were incubated at room temperature and luminescence was measured in a spectrophotometer (Biotek Synergy HTX) for 20 minutes protected from light on a plate rocker.

[0222] RSV inhibition was calculated as the percentage of cytopathic effect inhibition relative to virus control and cytotoxicity was calculated as the percentage of cell viability relative to cell control wells. This represents the EC for each test article at which a virus inhibition or cytotoxicity dose response was observed. 50It was possible to calculate EC values ​​from 0.001 μM to 2.5 μM. 50 Values ​​were found more particularly for compounds (36), (38), (39), (45), (46), (47), (54), (57), (60), (61), (64), (68), (70), (71), (72), (75) through (80), (82) through (86), (88) through (142), (147) through (156), (164) through (166), and (179).

[0223] [Table 5] JPEG0007634847000086.jpg25567JPEG0007634847000087.jpg25568JPEG0007634847000088.jpg25576

[0224] conclusion Based on the above results, it can be concluded that the compounds of formula (Ie) are suitable compounds for treating and / or preventing RNA viral infections caused by group V RNA viruses, more particularly pneumovirus infections, most particularly RSV viral infections.

[0225] Example 10: Dengue 2 virus 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 preventing, inhibiting or treating dengue 2 virus infection.

[0226] Materials and Methods A Protocol for Screening Antiviral Compounds for DENV-2 Inhibition and Cytotoxicity Using the Viral ToxGlo Assay A549 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin. For the screening assay, they were grown to 90% confluency, trypsinized, and harvested. Trypsin was neutralized in cell culture medium and cells were centrifuged at 150 x g for 5 min, the supernatant was discarded, and the cell pellet was resuspended in assay medium (DMEM supplemented with 2% fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin). Cells were plated at 1.0x10 in 50 μl in 96-well white clear-bottom cell culture plates. 4 Cells were seeded at a density of 1000 cells / well. Only medium / background control column assay medium was added. The cell plates were placed in a humidified chamber and incubated overnight at 37°C / 5% CO2. After overnight incubation, cells were checked for confluency and healthy appearance.

[0227] Test compounds were prepared at a final concentration of 10 μM with a maximum DMSO concentration of 1% (max 0.1% DMSO final assay concentration) and added to the cell plates in a volume of 10 μl. For cell control and virus control wells, only the test article solvent was added. As a positive inhibition control, 7-deaza-2'-C-methyladenosine was added at 100 μM to three wells. Virus (DENV-2 strain 16681) or assay medium for cytotoxicity test wells and medium / cell control wells were added immediately after the test article at an MOI of 0.5 and 40, respectively, for the 96-well plate. Virus suspensions were prepared by thawing DENV-2 frozen stocks and diluting to the required concentration of plaque forming units with assay medium.

[0228] The cell plates were further incubated at 37°C / 5% CO2 in a humidified chamber for 5 days pi. After the incubation period, the cells were observed under a microscope to check for characteristic cytopathic effects in virus control wells and healthy cells in 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. After the plates were incubated at room temperature for 5 minutes, luminescence was measured with a spectrophotometer (Envision, PerkinElmer).

[0229] DENV-2 inhibition was calculated as the percentage of cytopathic effect inhibition relative to virus control, and cytotoxicity was calculated as the percentage of cell viability relative to cell control wells.

[0230] [Table 6]

[0231] conclusion Based on the above results, it can be concluded that the compounds of formula (Ie) are suitable compounds for treating and / or preventing RNA viral infections caused by group IV RNA viruses, more particularly Flavivirus infections, most particularly Dengue 2 virus infections.

[0232] The present invention further relates to a pharmaceutical composition comprising at least one of the novel compounds defined above, or any one of their pharma- ceutically acceptable salts, or at least one of the compounds (36) to (206) defined above, or any one of their pharma- ceutically acceptable salts, and also at least one pharma- ceutically acceptable excipient.

[0233] The pharmaceutical compositions of the present invention may contain one or more compounds of the present invention in any of the forms described herein.

[0234] A still further object of the present invention is the use according to the present invention of at least one compound of formula (Ie) as defined above, or any one of the compounds (36) to (206) as defined above, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment and / or prevention in a subject of an RNA virus infection caused by an RNA virus from group IV or V according to the Baltimore classification, such as a chikungunya infection, a dengue infection, an influenza infection or an RSV infection.

[0235] The present invention therefore relates to one compound of formula (Ie) as defined above, and any one of the compounds (36) to (206), or a pharma- ceutically acceptable salt thereof, as an agent for inhibiting, preventing or treating an RNA virus infection, more preferably an RNA virus infection from group IV or V, such as a chikungunya infection, a dengue infection, an influenza infection or an RSV infection.

[0236] According to certain embodiments, the treatment is continuous or discontinuous.

[0237] "Continuous treatment" refers to long-term treatment which can be performed at various dosing frequencies, for example, once a day, every third day, once a week or once every two weeks, or once a month.

[0238] In one embodiment, the compound of formula (Ie), or any one of its pharma- ceutically acceptable salts, is administered at a dose ranging from 0.1 to 1000 mg, in particular from 0.1 to 10 mg, or at a dose varying, for example, from 10 to 200 mg, for example from 200 to 1000 mg.

[0239] Another object of the present invention relates to a therapeutic method for treating and / or preventing an RNA virus infection in a subject, more preferably an RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification, comprising administering a therapeutically effective amount of a compound of formula (Ie), compounds (36) to (206), or an acceptable salt thereof, as defined above.

[0240] In a particular embodiment, the present invention provides the use of a compound of formula (Ie) according to the invention, or any one of its pharma- ceutically acceptable salts, or a pharma- ceutically active derivatives thereof, or a method according to the invention, wherein the compound of formula (Ie) is to be administered in combination with an adjuvant that is useful in the treatment of said RNA virus infections, more preferably said RNA virus infections from group IV or V, such as chikungunya infection, dengue infection, influenza infection or RSV infection.

[0241] The compounds can be administered via any mode of administration, such as intramuscular, intravenous, intranasal or oral routes.

[0242] The compounds of the present invention may be administered as prodrugs, e.g., esters, of the compounds involved in the present invention, where appropriate. "Prodrug" means a compound that is convertible in vivo to a compound of the present invention by metabolic means (e.g., by hydrolysis, reduction, or oxidation). For example, an ester prodrug of a compound of the present invention may be convertible to the 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-bis-β-hydroxynaphthate, gentisate, isethionate, di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate, and quinate. Examples of ester prodrugs are those described by FJ Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, reference to the compounds of the invention is meant to also encompass any prodrug or metabolite forms.

[0243] The composition of the present invention may further comprise one or more additives, such as diluents, excipients, stabilizers and preservatives. Such additives are well known to those skilled in the art and are described in particular in Ullmann's Encyclopedia of Industrial Chemistry, Vol. 6, No. 6, pp. 111-115, 2002. th Ed. (various editors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0244] The above additives are selected according to the dosage form and the desired mode of administration.

[0245] The compositions of the present invention can be administered in any manner, including but not limited to oral, parenteral, sublingual, transdermal, vaginal, rectal, transmucosal, topical, intranasal, buccal or intranasal administration by inhalation, or combinations 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 slow release of the composition and slow controlled intravenous (iv) infusion.

[0246] According to other embodiments, the pharma- ceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.

[0247] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, intravaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0248] For example, the compounds of formula (Ie), in association with suitable excipients, can be present in any pharmaceutical form suitable for enteral or parenteral administration, for example in the form of plain or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories, or drinks, e.g. suspensions, syrups, or injectable solutions or suspensions, in doses allowing the daily administration of 0.1 to 1000 mg of active substance.

[0249] In a particular embodiment, the compounds of formula (Ie) according to the invention are administered orally.

[0250] The oral administration route is particularly preferred in the prophylactic or therapeutic aspects of the present invention.

Claims

1. Any one of the compounds of formula (Ie) below, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 Where: 【Chemistry 2】 Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, and a pyrimidinyl group, and the aryl group is not limited to a halogen atom, (C 1 ~C 4 ) alkyl group, cyano group, (C 1 ~C 5 ) Alkoxy group, trifluoromethyl group, trifluoromethoxy group, -SO 2 -NR a R b Group, -SO 3 H group, -OH group, -O-SO 2 -OR c Group or -OP(=O)-(OR c )(OR d ) groups, R a , R b , R c and R d are independently a hydrogen atom or (C 1 ~C 4 ) an alkyl group; X 2 teeth, -O- group, -NH- group, -S- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, -CH(OH)- group, -CH(COOH)NH- group, -CH(COOCH 3 )NH-, -C(OH)(CH 2 OH)-、 【Chemistry 3】 a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, -SO 2 -Group, Or, -SO 2 -NH- group represents n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y 2 teeth, Hydroxyl groups, (C 1 ~C 4 ) an alkoxy group, -CHC(OH) 2 、 COOR f , where R f is a hydrogen atom or (C 1 ~C 4 ) an alkyl group; morpholinyl group, Dihydropyranyl group, 【Chemistry 4】 【Chemistry 5】 -PO(OR f )(OR' f ) group, where R f and R' f are independently a hydrogen atom or (C 1 ~C 4 ) an alkyl group; Oxetanyl group, -Si(CH 3 ) 3 base, -NHCOO-(C 1 ~C 4 ) alkyl group, Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 are independently a hydrogen atom, a fluorine atom or (C 1 ~C 4 ) represents an alkyl group, R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached (C 3 ~C 8 ) cycloalkyl group, 3 ~C 8 ) Cycloalkyl groups are (C 1 ~C 4 ) an alkyl group, a halogen atom or (C 1 ~C 4 ) alkoxy groups, and the (C 3 ~C 8 ) The cycloalkyl group is linked to the above R by an oxygen atom. 1 and / or R 2 Optionally, interposed on or alternatively, X 2 -Y 2 -CONR c R d represents a group, where R c and R d together with the nitrogen atom form a heterocyclic group, which is a hydroxy group or (C 1 ~C 4 ) optionally substituted by an alkyl group; R and R' are independently (C 1 ~C 4 ) alkyl group, -S-(C 1 ~C 4 ) alkyl group, (C 3 ~C 6 ) a cycloalkyl group, Halogen atoms, Trifluoromethyl group, -SO 2 (C 1 ~C 4 ) alkyl group, (C 3 ~C 6 ) a cycloalkenyl group, (C 1 -C 5 ) an alkoxy group, -SO 2 -NR a R b base, -SO 3 H or SO 2 -CH 3 basis, -OH group, -CONHR g , where R g is a hydrogen atom or (C 1 ~C 4 ) an alkyl group; -O-SO 2 -OR c basis, An azetidinyl group, a morpholinyl group, or Cyano group represents R″ may be substituted by a hydrogen atom or a —COOH group (C 1 ~C 4 ) an alkyl group; However, the following compounds are excluded: 【Chemistry 6】 。

2. 2. The compound of formula (Ie) according to claim 1, wherein the divalent 5-membered heteroaromatic ring is triazole, tetrazole or oxadiazole, or any one of its pharma- ceutically acceptable salts.

3. 3. A compound of formula (Ie) according to claim 1 or 2, or any one of its pharma- ceutically acceptable salts, wherein R'' is a hydrogen atom.

4. Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, and a pyrimidinyl group, and the aryl group is not limited to a halogen atom, (C 1 ~C 4 ) alkyl group, cyano group, (C 1 ~C 5 ) optionally substituted by one or two substituents selected from an alkoxy group, a trifluoromethyl group, and a trifluoromethoxy group; A compound of formula (Ie) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. X 2 but, -O- group, -NH- group, -S- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, -SO 2 -Group, or -SO 2 -NH- group, Represents, A compound of formula (Ie) according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

6. Y 2 but, Hydroxyl groups, -PO(OR f )(R' f ) group, where R f and R' f are independently a hydrogen atom or (C 1 ~C 4 ) an alkyl group; or -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 are independently a hydrogen atom, a fluorine atom or (C 1 ~C 4 ) represents an alkyl group, R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached (C 3 ~C 8 ) cycloalkyl group, 3 ~C 8 ) Cycloalkyl groups are (C 1 ~C 4 ) an alkyl group, a halogen atom or (C 1 ~C 4 ) alkoxy groups, 3 ~C 8 ) The cycloalkyl group is linked to the above R by an oxygen atom. 1 and / or R 2 Optionally, interposed on A compound of formula (Ie) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

7. R and R' are independently (C 1 ~C 4 ) alkyl group, (C 3 ~C 6 ) a cycloalkyl group, Halogen atoms, a trifluoromethyl group, or -SO 3 H or SO 2 -CH 3 basis Represents, A compound of formula (Ie) according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. 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, and a pyrimidinyl group, and the aryl group is not limited to a halogen atom, (C 1 ~C 4 ) alkyl group, cyano group, (C 1 ~C 5 ) optionally substituted by one or two groups selected from an alkoxy group, a trifluoromethyl group, and a trifluoromethoxy group; X 2 but, -O- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, Or, -SO 2 -NH- group represents Y 2 but, Hydroxyl group, -PO(OR f )(R' f ) group, where R f and R' f are independently a hydrogen atom or (C 1 ~C 4 ) an alkyl group; Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 are independently a hydrogen atom, a fluorine atom or (C 1 ~C 4 ) represents an alkyl group, R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached (C 3 ~C 8 ) cycloalkyl group, 3 ~C 8 ) Cycloalkyl groups are (C 1 ~C 4 ) an alkyl group, a halogen atom or (C 1 ~C 4 ) alkoxy groups, and the (C 3 ~C 8 ) The cycloalkyl group is linked to the above R by an oxygen atom. 1 and / or R 2 Optionally, interposed on and, R and R' are independently (C 1 ~C 4 ) alkyl group, (C 3 ~C 6 ) a cycloalkyl group, Halogen atoms, Trifluoromethyl group, -SO 3 H or SO 2 -CH 3 Group, or Morpholinyl group Represents, A compound of formula (Ie) according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof.

9. R'' is a hydrogen atom, Y 1 represents a phenyl group or a pyridyl group; X 2 but, -O- group, -CO-NH- group, -NH-CO- group, Or, A divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms represents Y 2 but, -PO(OR f )(R' f ) group, where R f and R' f are independently a hydrogen atom or (C 1 ~C 4 ) an alkyl group; Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 are independently a hydrogen atom, a fluorine atom or (C 1 ~C 4 ) represents an alkyl group, R 1 , R 2 and R 3 It is understood that two or more of R 1 and R 2 together with the carbon atom to which they are attached (C 3 ~C 8 ) forming a cycloalkyl group, and, R and R' are independently (C 1 ~C 4 ) alkyl group, (C 3 ~C 6 ) a cycloalkyl group, or morpholinyl group, Represents, A compound of formula (Ie) according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof.

10. 2. Any one of the compounds of formula (Ie) according to claim 1 selected from the following: or a pharma- ceutically acceptable salt thereof. 【Table 1】

11. Any one of the compounds selected from the following, or a pharma- ceutically acceptable salt thereof: 【Table 2】

12. 12. A compound of formula (Ie) as defined in any one of claims 1 to 9, or any one of its pharma- ceutically acceptable salts, or any one of the compounds as defined in claims 10 or 11, or any one of its pharma-ceutically acceptable salts, for use as a medicament.

13. A pharmaceutical for use in the treatment and / or prevention of an RNA viral infection caused by an RNA virus belonging to group IV or group V of the Baltimore classification, comprising any one of the compounds of formula (Ie) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or any one of the compounds according to claim 10 or 11, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical product according to claim 13, wherein the RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification is selected from among RSV virus infection, chikungunya virus infection, influenza virus infection and dengue virus infection.

15. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9, or any one of its pharma- ceutically acceptable salts, or at least one compound according to claim 10 or 11, or any one of its pharma- ceutically acceptable salts, and also at least one pharma- ceutically acceptable excipient.

16. A synthetic process for preparing a compound of formula (Ie) according to any one of claims 1 to 9, or any one of its pharma- ceutically acceptable salts, or a compound according to claim 10 or 11, or any one of its pharma- ceutically acceptable salts, comprising: A compound of formula (IIe) 【Chemistry 10】 with a compound of formula (IIIe) 【Chemistry 11】 in the presence of an inorganic base and a diphosphine and in the presence of an organometallic catalyst to obtain a compound of formula (Ie) according to any one of claims 1 to 9, or any one of its pharma-ceutically acceptable salts, or a compound according to claim 10 or 11, or any one of its pharma-ceutically acceptable salts, 【Chemistry 12】 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; The method.

17. A pharmaceutical for use in the treatment and / or prevention of an RNA viral infection caused by an RNA virus belonging to Group IV or Group V of the Baltimore Classification, comprising any one of the compounds of the following formula (Ie) or a pharmaceutical acceptable salt thereof: 【Chemistry 13】 Where: 【Chemistry 14】 Y 1 represents an aryl group selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, and a pyrimidinyl group, the aryl group being optionally substituted by one or two groups selected from a halogen atom, a (C 1 -C 4 ) alkyl group, a cyano group, a (C 1 -C 5 ) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SO 2 -NR a R b group, a -SO 3 H group, a -OH group, a -O-SO 2 -OR c group, and a -OP(═O)-(OR c )(OR d ) group; R a , R b , R c and R d independently represent a hydrogen atom or a (C 1 -C 4 ) alkyl group; X2 is -O- group, -NH- group, -S- group, -CO-NH- group, -NH-CO-NH- group, -NH-CO- group, -CH(OH)- group, -CH(COOH)NH- group, -CH(COOCH 3 )NH- group, -C(OH)(CH2OH)-, 【Chemistry 15】 divalent 5-membered heteroaromatic rings containing 1, 2, 3 or 4 heteroatoms, such as triazole, tetrazole or oxadiazole; -SO2- group, Or, -SO 2 -NH- group represents n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y2 is Hydrogen atom, Hydroxyl groups, (C1-C4) alkoxy groups, -CHC(OH)2, COOR f , where R f represents a hydrogen atom or a (C 1 -C 4 ) alkyl group; morpholinyl group, Dihydropyranyl group, 【Chemistry 16】 【Chemistry 17】 the -PO(ORf)(OR'f) group, where Rf and R'f independently represent a hydrogen atom or a (C1-C4) alkyl group; Oxetanyl group, -Si(CH 3 ) 3 groups, -NHCOO-(C1-C4)alkyl group, Or, -CR1R2R3 radical, where R1, R2 and R3 independently represent a hydrogen atom, a fluorine atom or a (C1-C4) alkyl group, it being understood that two or more of R1, R2 and R3 are not hydrogen atoms, or R1 and R2 together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl group, which (C3-C8) cycloalkyl group may be substituted by one or two (C1-C4) alkyl groups, halogen atoms or (C1-C4) alkoxy groups, and which (C3-C8) cycloalkyl group may be interrupted on said R1 and / or R2 by an oxygen atom, or alternatively, X 2 -Y 2 represents a group -CONR c R d , where R c and R d together with the nitrogen atom form a heterocyclic group, which is optionally substituted by a hydroxy group or a (C 1 -C 4 ) alkyl group; R and R' are independently (C1-C4) alkyl groups, -S-(C1-C4)alkyl groups, (C3-C6)cycloalkyl groups, Halogen atoms, Trifluoromethyl group, -SO2(C1-C4)alkyl groups, (C3-C6)cycloalkenyl groups, (C1-C5) alkoxy groups, the group -SO2-NRaRb; -SO3H or SO2-CH3 groups, -OH group, -CONHR g , where R g represents a hydrogen atom or a (C 1 -C 4 ) alkyl group; the -O-SO2-ORc group, An azetidinyl group, a morpholinyl group, or Cyano group represents R'' represents a hydrogen atom or a (C 1 -C 4 ) alkyl group which may be substituted with a -COOH group.

18. The pharmaceutical product described in claim 17, wherein the RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification is selected from RSV virus infection, chikungunya virus infection, influenza virus infection and dengue virus infection.

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