Aryl-N-aryl derivatives for treating RNA virus infections

Abstract

The present invention relates to any one of compounds of formula (I) or pharmaceutically acceptable salts thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification: wherein X 1 represents an alkenylene group, a -NH-CO- group, a -CO-NH- group, Y 1 represents an aryl group selected from a pyridyl group, a pyrazinyl group or a pyrimidinyl group, X 2 represents an -O- group, a -CO-NH- group, a -NH-CO-NH- group, -OCH 2 - group, a -NH-CO- group, a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms or a -SO 2 -NH- group, and Y 2 represents a hydrogen atom, a hydroxyl group, a morpholinyl group, a piperidinyl group (optionally substituted by a (C 1 -C 4 )alkyl group), a piperazinyl group (optionally substituted by a (C 1 -C 4 )alkyl group) or a -CR 1 R 2 R 3 group, or alternatively X 2 -Y 2 represents a group -CONR c R d , wherein R c and R d together with the nitrogen atom form a heterocycle which is optionally substituted by one or two (C 1 -C 4 )alkyl groups, substituted by a cyclopentyl group (thereby forming a spirocyclopentyl) or substituted by a trifluoromethyl group. The present invention further relates to new compounds, to pharmaceutical compositions containing them, and to synthetic methods for preparing them.

Description

[0001] The present invention relates to compounds that can be used for the prevention and / or treatment of RNA virus infections, and most preferably RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification.

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

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

[0004] Background

[0005] Viruses are one of the main causes of diseases worldwide. Viruses are generally defined as small, non-living infection agents that replicate only within living cells because they do not have a fully autonomous replication mechanism. Although they vary in shape and size, they generally consist of viral particles (called "virions"), which are made up of a protein coat containing at least one nucleic acid molecule and optionally one or more proteins or nucleoproteins depending on the virus type.

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

[0007] Although their replication cycles vary widely between different species, it is generally accepted that the life cycle of a virus includes six basic steps: attachment, penetration, uncoating, replication, assembly, and release.

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

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

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

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

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

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

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

[0015] - Group V: (-) strand or antisense RNA viruses ((-) ssRNA);

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

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

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

[0019] As representatives of viruses belonging to Group IV, one can cite Picornaviruses (a virus family that includes well-known viruses such as hepatitis A virus, enteroviruses, rhinoviruses, polioviruses, and foot-and-mouth disease virus), SARS virus, hepatitis C virus, yellow fever virus, and rubella virus. The Togaviridae also belongs to Group IV, and one of its known genera is alphavirus, which encompasses the Chikungunya virus. The Flaviridae is also a family belonging to Group IV, which encompasses the well-known mosquito-borne viruses, namely the Dengue virus.

[0020] As representatives of viruses belonging to Group V, there may be mentioned the Filoviridae family, which encompasses the Ebola virus, the Paramyxoviridae family, which encompasses the respiratory syncytial virus (RSV), the Rhabdoviridae family, and the Orthomyxoviridae family, which encompasses influenza virus A, influenza virus B, and influenza virus C.

[0021] The groups included within the viral families of particular interest within the framework of the present invention are those groups that encompass RNA viruses, particularly single-stranded RNA viruses, and more specifically RNA viruses belonging to Groups IV and V of the Baltimore classification.

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

[0023] Definition

[0024] As used herein, the term "patient" refers to an animal that has or is at risk of having one or more of the diseases and disorders described herein, such as valuable animals for breeding, companionship, or conservation purposes, or preferably a human or a human child.

[0025] Specifically, as used in this application, the term "patient" refers to mammals such as rodents, cats, dogs, primates, or humans, preferably the subject is a human, and also extends to avians.

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

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

[0028] As used herein, "effective amount" refers to the amount of a compound of the present invention that effectively prevents, reduces, eliminates, treats, or controls the symptoms of the diseases and disorders described herein (i.e., RNA virus infections, and more particularly RNA virus infections from groups IV or V). The term "control" is intended to mean all processes in which the progression of the diseases and disorders described herein may be slowed, interrupted, halted, or stopped, but does not necessarily indicate complete elimination of all symptoms of the diseases and disorders, and is intended to include prophylactic treatment.

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

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

[0031] "Prevent" as used herein also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence".

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

[0033] Similarly, the term "therapeutically effective amount" refers to the concentration of a compound that effectively treats RNA virus infection, such as when administered after infection has occurred, and after examination, results in a reduction in RNA virus infection.

[0034] As used herein, the term "pharmaceutically acceptable" refers to a compound, material, excipient, composition, or dosage form that, within the scope of reasonable medical judgment, is suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem complications, commensurate with a reasonable benefit / risk ratio.

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

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

[0037] In particular, the present invention may contemplate alphaviruses, which belong to Group IV RNA viruses and the family Togaviridae, and which may be defined as positive-sense single-stranded RNA viruses or (+) ssRNA viruses. According to the 2017 virus taxonomy, their order is "not assigned". The family Togaviridae includes the genus Alphavirus and the genus Rubivirus.

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

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

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

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

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

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

[0044] Joint pain is often debilitating and can vary in duration.

[0045] The proximity of mosquito breeding sites to human settlements is an important risk factor for chikungunya.

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

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

[0048] The present invention also particularly contemplates viruses of the order Mononegavirales. 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.

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

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

[0051] The invention also specifically considers viruses of the Orthomyxoviridae family. According to the 2017 virus taxonomy, the Orthomyxoviridae family belongs to the "unassigned" order. Virus genera that are specifically considered within the Orthomyxoviridae family include: Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus, Gammainfluenzavirus, Isavirus, Quaranjavirus, and Thogotovirus.

[0052] Influenza A virus, Influenza B virus, and Influenza C virus can especially be considered by the present invention and belong to Group V RNA viruses and the Orthomyxoviridae family, which can be defined as negative-sense single-stranded RNA or (-)ss RNA viruses. Isavirus and Thogotovirus also belong to the Orthomyxovirales order. Detailed Description of the Invention

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

[0055] For reference, we have considered the content of the "Baltimore classification" according to the virus classification and nomenclature described in the tenth report on virus taxonomy in 2017.

[0056] This document discloses any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to Groups IV or V of the Baltimore classification, and especially Flexivirus infections, Dengue virus infections, Influenza virus infections, or RSV virus infections, or virus-related disorders

[0057]

[0058] wherein:

[0059] ring sum rings independently denote a phenylene or pyridylene group,

[0060] wherein the group is in the meta or para position on the ring relative to the -NH- group, especially in the meta position,

[0061] X 1 represents an alkenylene group, especially a vinylidene group, -NH-CO- group, -CO-NH- group, -CR a R b O- group,

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

[0063] or alternatively X 1 -Y 1 represents a group (A) of the following formula

[0064]

[0065] X 2 represents a -CO-NH- group, -NH-CO-NH- group, -OCH 2 - group, -NH-CO- group or -SO 2 -NH- group,

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

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

[0068] Y 2 represents a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 group, wherein R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 4 ) alkyl group, it being understood that no more than one of R 1 , R 2 and R 3 is a hydrogen atom, or R 1 ​and R 2 together with the carbon atom(s) to which they are attached form a (C 3 -C 8 ) cycloalkyl group, said (C 3 -C 8 ) cycloalkyl being optionally substituted by one or two (C 1 -C 4 ) alkyl, halogen atom or (C 1 -C 4 ) alkoxy, and said (C 3 -C 8 ) cycloalkyl being optionally interrupted by an oxygen atom on said R 1 and / or R 2 .

[0069] R and R’ independently represent a halogen atom, (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 5 ) alkoxy, -SO 2 -NR a R b group, -SO 3 H group, -OH group, -O-SO 2 -OR c group or -O-P(=O)-(OR c )(OR d ).

[0070] R a 、R b 、R c and R d independently represent a hydrogen atom or a (C 1 -C 4 ) alkyl group.

[0071] Provided that when X 1 is -CR a R b O-, Y 1 may further be 3-pyridyl, 4-pyridyl or phenyl, which is optionally substituted by one or two substituents selected from: halogen atom, (C 1 -C 4 ) alkyl, cyano group, (C 1 -C 5 ) alkoxy, trifluoromethyl group, trifluoromethoxy group, -SO 2 -NR a R b group, -SO 3The H group, -OH group, -O-SO 2 -OR c group or -O-P(=O)-(OR c )(OR d ) group.

[0072] According to First aspect, the present invention relates to any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification

[0073]

[0074] wherein

[0075] ring and ring independently refer to a phenylene or pyridinylene group,

[0076] X 1 represents an alkenylene group, -NH-CO- group, -CO-NH- group,

[0077] Y 1 represents an aryl group selected from a pyridyl group, a pyrazinyl group or a pyrimidinyl group,

[0078] X 2 represents

[0079] -O- group,

[0080] -CO-NH- group,

[0081] -NH-CO-NH- group,

[0082] -OCH 2 - group,

[0083] -NH-CO- group,

[0084] a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, such as triazole or diazole,

[0085] or

[0086] -SO 2 -NH- group,

[0087] n is 0, 1, 2 or 3,

[0088] m and m' are independently 0, 1 or 2,

[0089] Y 2 represents

[0090] a hydrogen atom

[0091] a hydroxy group

[0092] a morpholino group

[0093] a piperidyl group, optionally substituted with a (C 1 -C 4 )alkyl group

[0094] a piperazinyl group, optionally substituted with a (C 1 -C 4 )alkyl group

[0095] or

[0096] -CR 1 R 2 R 3 group, wherein R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 4 )alkyl group, it being understood that no more than one of R 1 , R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 )cycloalkyl group, said (C 3 -C 8 )cycloalkyl being optionally substituted with one or two (C 1 -C 4 )alkyl, halogen atoms or (C 1 -C 4 )alkoxy, and said (C 3 -C 8 )cycloalkyl being optionally interrupted by an oxygen atom on said R 1 and / or R 2

[0097] or alternatively X 2 -Y 2 represents the group -C(=O)-NR c R d , wherein R c and R d together with the nitrogen atom form a saturated heterocycle, the group being optionally substituted with one or two (C 1 -C 4 )alkyl groups, substituted with a cyclopentyl group to form a spirocyclopentyl derivative, or substituted with a trifluoromethyl group​

[0098] R and R' independently represent

[0099] (C 1 -C 4 ) alkyl group,

[0100] (C 3 -C 6 ) cycloalkyl group,

[0101] a halogen atom,

[0102] (C 1 -C 5 ) alkoxy group,

[0103] -SO 2 -NR a R b group,

[0104] -SO 3 H group,

[0105] -OH group, or

[0106] -O-SO 2 -OR c group,

[0107] provided that when X 1 is the -NH-CO- group, Y 1 can further be a phenyl group, optionally substituted by one or two substituents selected from: a halogen atom, (C 1 -C 4 ) alkyl, a cyano group, (C 1 -C 5 ) alkoxy, a trifluoromethyl group, a trifluoromethoxy group, -SO 2 -NR a R b group, -SO 3 H group, -OH group, -O-SO 2 -OR c group or -O-P(=O)-(OR c )(OR d ) group.

[0108] According to Second aspect,The present invention relates to a compound of formula (I) as defined above, which is used for treating and / or preventing RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, in particular hepacivirus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders, and even more particularly RSV virus infections, hepacivirus infections and dengue virus infections or virus-related disorders.

[0109] According to Third aspect, The present invention relates to any one of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for treating and / or preventing RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular hepacivirus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders

[0110]

[0111] wherein

[0112] Y 1 、R, R', m, m', ring, X 2 、n and Y 2 are as defined above.

[0113] Still according to this third aspect, the present invention relates to any one of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for the use as defined above, wherein

[0114] the ring is a phenylene group or a pyridinylene group,

[0115] Y 1 represents a 2-pyridyl group, a 3-pyridyl group or a pyrazinyl group,

[0116] n is 1, 2 or 3, m is 0,

[0117] R' is a halogen atom, a (C 1 -C 2 ) alkoxy group or a (C 1 -C 2 ) alkyl group,

[0118] X 2 represents a -CO-NH- group, a -SO 2 NH- group or a divalent triazole group,

[0119] Y 2 represents

[0120] a morpholinyl group, a piperidinyl group or a piperazinyl group, which is optionally substituted by (C 1 -C4 ) substituted by an alkyl group,

[0121] -CR 1 R 2 R 3 group, where R 1 , R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, it should be understood that no more than one of R 1 , R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group,

[0122] or alternatively X 2 -Y 2 represents the group -C(=O)-NR c R d , where R c and R d together with the nitrogen atom form a saturated heterocycle, and the group is optionally substituted by one or two (C 1 -C 4 ) alkyl groups, substituted by cyclopentyl to form a spirocyclopentyl derivative, or substituted by a trifluoromethyl group.

[0123] Still according to the third aspect, the present invention further relates to any one of the compounds of formula (Ia) as defined above or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular hepatitis C virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related diseases, where

[0124] the ring is a phenylene group or a pyridinylene group,

[0125] Y 1 represents a 2-pyridyl group,

[0126] n is 2, m is 0, R' is a halogen atom, a (C 1 -C 2 ) alkoxy group or a (C 1 -C 2 ) alkyl group,

[0127] Y 2 represents -CR 1 R 2R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, it being understood that no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group.

[0128] According to Fourth aspect, the present invention relates to any one of the compounds of formula (Ib) or a pharmaceutically acceptable salt thereof for the treatment and / or prophylaxis of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular hepatitis C virus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders,

[0129]

[0130] wherein

[0131] Y 1 、R, R’, m, m’, ring, X 2 、n and Y 2 are as defined above.

[0132] Still according to this fourth aspect, the present invention relates to any one of the compounds of formula (Ib) or a pharmaceutically acceptable salt thereof for the use as defined above, wherein

[0133] the ring is a phenylene group,

[0134] Y 1 is a phenyl group, a 2-pyridyl group or a pyrimidinyl group, one of the nitrogen atoms of the pyrimidinyl group being in the ortho position relative to the -NH-CO- group,

[0135] n is 1, 2 or 3, m is 0, m’ is 0 or 1,

[0136] R’ is a (C 3 -C 6 ) cycloalkyl group,

[0137] X 2 represents a -CO-NH- group, an -O- group or a divalent triazole,

[0138] Y2 represents

[0139] a hydroxy group,

[0140] a morpholino group, a piperidino group or a piperazino group, optionally substituted with a (C 1 -C 4 )alkyl group,

[0141] -CR 1 R 2 R 3 group, where R 1 , R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 )alkyl group, it being understood that no more than one of R 1 , R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 )cycloalkyl group, said (C 3 -C 6 )cycloalkyl being optionally interrupted by an oxygen atom on said R 1 and / or R 2 .

[0142] Still according to the fourth aspect, the present invention further relates to any one of the compounds of formula (Ib) as defined above or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular kunjin virus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders,

[0143] wherein the ring is a phenylene group,

[0144] Y 1 is a 2-pyridyl group or a pyrimidinyl group, one of the nitrogen atoms of said pyrimidinyl group being in the ortho position relative to the -NH-CO- group,

[0145] n is 1 or 2, m and m' are 0,

[0146] X 2 represents a -CO-NH- group,

[0147] Y 2 represents a -CR 1 R 2 R 3 group, where R1 , R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, it being understood that not more than one of R 1 , R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group, said (C 3 -C 6 ) cycloalkyl being optionally interrupted by an oxygen atom on said R 1 and / or R 2 .

[0148] According to Fifth aspect, the present invention relates to any one of the compounds of formula (Id) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular hepatitis C virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders,

[0149]

[0150] wherein

[0151] Y 1 , R, R’, m, m’, ring, X 2 , n and Y 2 are as defined above.

[0152] Still according to this fifth aspect, the present invention relates to any one of the compounds of formula (Id) or a pharmaceutically acceptable salt thereof for use as defined above, wherein

[0153] the ring is a phenylene group,

[0154] Y 1 represents a 2-pyridyl group or a 3-pyridyl group,

[0155] X 2 represents a -CO-NH- group, a -SO 2 -NH- group or a divalent triazole,

[0156] m’ and m are 0, n is 1, 2 or 3,

[0157] Y 2 represents a hydroxyl group or -CR 1 R2 R 3 group, where R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, it should be understood that no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom carrying them form a (C 3 -C 6 ) cycloalkyl group.

[0158] Still according to the fifth aspect, the present invention further relates to any one of the compounds of formula (Id) or their pharmaceutically acceptable salts for treating and / or preventing RNA virus infections caused by RNA viruses belonging to Group IV or V of the Baltimore classification, and especially infections by hepaciviruses, dengue viruses, influenza viruses or RSV viruses or virus-related diseases, wherein the ring is a phenylene group,

[0159] group is in the meta position on the ring relative to the -NH- group,

[0160] Y 1 represents a 2-pyridyl group,

[0161] m’ and m are 0, n is 2,

[0162] Y 2 represents a -CR 1 R 2 R 3 group, where R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, it should be understood that no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom carrying them form a (C 3 -C 6 ) cycloalkyl group.

[0163] The above-mentioned compounds (I), (Ia), (Ib) and (Id) are particularly suitable for treating or preventing viral infections or related disorders, especially RNA viral infections or related disorders caused by RNA viruses belonging to Group IV or V of the Baltimore classification, and most preferably hepacivirus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders.

[0164] The above-mentioned compounds are even more particularly suitable for treating or preventing hepacivirus infection, dengue virus infection or RSV virus infection or virus-related disorders, and most particularly RSV virus infection.

[0165] After the application of novel compounds such as formula (I), (Ia), (Ib) and (Id) as medicaments, pharmaceutical compositions and synthetic methods, other aspects of the present invention will be described herein.

[0166] According to a specific embodiment, one subject of this document describes any of the compounds of formula (I) as defined above or a pharmaceutically acceptable salt thereof for treating and / or preventing RNA viral infections caused by RNA viruses belonging to Group IV or V of the Baltimore classification, and especially hepacivirus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders, wherein the alkenylene group is an (E)-alkenylene group,

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

[0168] Y 2 represents -CR 1 R 2 R 3 group, wherein R 1 , R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 2 ) alkyl group, it being understood that no more than one of R 1 , R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group, said (C 3 -C 6 ) cycloalkyl being optionally substituted by one or two halogen atoms, and said (C 3 -C 6 ) cycloalkyl being optionally interrupted by an oxygen atom on said R 1 and / or R 2 ,

[0169] R and R’ independently represent a halogen atom, (C 1 -C 2 )alkyl, (C 3 -C 6 )cycloalkyl or (C 1 -C 2 )alkoxy group.

[0170] According to another embodiment, this document describes any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for treating and / or preventing RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification

[0171]

[0172] wherein:

[0173] ring and ring independently refer to a phenylene or pyridinylene group,

[0174] wherein the group is in the meta or para position on the ring relative to the -NH- group,

[0175] X 1 represents an alkenylene group, -NH-CO- group, -CO-NH- group, -CR a R b O- group,

[0176] Y 1 represents an aryl group selected from a 2-pyridyl group or a pyrimidinyl group, wherein one of the nitrogen atoms of the pyrimidinyl group is in the ortho position relative to X 1 or alternatively X

[0177] -Y 1 represents a group (A) of the following formula 1

[0178]

[0179]

[0180] 2 represents a -CO-NH- group, -NH-CO-NH- group, -OCH 2 - group, -NH-CO- group or -SO 2 -NH- group,

[0180] n is 0, 1, 2 or 3,

[0181] m and m’ are independently 0, 1 or 2,

[0182] Y​2 represents a hydrogen atom, a hydroxyl group or -CR 1 R 2 R 3 group, where R 1 、R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or (C 1 -C 4 ) alkyl group, it should be understood that no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 ) cycloalkyl group, and the (C 3 -C 8 ) cycloalkyl is optionally substituted by one or two (C 1 -C 4 ) alkyl, halogen atom or (C 1 -C 4 ) alkoxy, and the (C 3 -C 8 ) cycloalkyl is optionally interrupted by an oxygen atom on the R 1 and / or R 2 ,

[0183] R and R’ independently represent a halogen atom, (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 5 ) alkoxy, -SO 2 -NR a R b group, -SO 3 H group, -OH group, -O-SO 2 -OR c group or -O-P(=O)-(OR c )(OR d ) group,

[0184] R a 、R b 、R c and R d independently represent a hydrogen atom or (C 1 -C 4 ) alkyl group,

[0185] provided that when X 1 is -CR aR b When it is an O-group, Y 1 can further be 3-pyridyl, 4-pyridyl or phenyl, which is optionally substituted by one or two substituents selected from the following: a halogen atom, (C 1 -C 4 ) alkyl, a cyano group, (C 1 -C 5 ) alkoxy, a trifluoromethyl group, a trifluoromethoxy group, -SO 2 -NR a R b group, -SO 3 H group, -OH group, -O-SO 2 -OR c group or -O-P(=O)-(OR c )(OR d ) group,

[0186] And provided that when Y 1 -X 1 represents a 2-pyridylvinyl group, X 2 represents a -CO-NH- group and Y 2 represents a -CR 1 R 2 R 3 group, where R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 4 ) alkyl group, and m' is different from 0.

[0187] Still according to a specific embodiment, the present invention relates to new compounds covered by formula (I).

[0188] The said new compounds (which can also be in the form of acceptable salts) are selected from

[0189] (1) Compounds of formula (Ia) as defined above with respect to formula (I)

[0190] Wherein

[0191] Y 1 is a 2-pyridyl group, 3-pyridyl or pyrazinyl group,

[0192] group is in the meta position on the ring with respect to the -NH- group,

[0193] X 2 、Y 2 、n、R、R’, m and m' are as defined above,

[0194] The ring is a phenylene group, and

[0195] the precondition is that compounds 1 and 2 as defined below are not included,

[0196] (2) A compound of formula (Ib) as defined above for formula (I)

[0197] wherein

[0198] Y 1 is a phenyl group, a 2-pyridyl group or a pyrimidinyl group, wherein one of the nitrogens of the pyrimidinyl group is in the ortho position relative to X 1 ortho,

[0199] X 2 Y 2 n, R, R', the ring, m and m' are as defined above, and

[0200] (4) A compound of formula (Id) as defined above for formula (I)

[0201] wherein

[0202] Y 1 is a 2-pyridyl group or a 3-pyridyl group, and

[0203] R, R', m, m', the ring, X 2 n and Y 2 are as defined above.

[0204] According to another aspect, a subject of the present invention relates to any one of the new compounds of formula (Ia), (Ib) and (Id) as just defined above for use as a medicament or a pharmaceutically acceptable salt thereof, and any one of compounds (3) to (18), (32) to (35), (91) to (122) as defined below or a pharmaceutically acceptable salt thereof.

[0205] Regarding any combination of the above-defined embodiments of R, R', m, m', the ring, the ring, X 1 X 2 n, Y 1 Y 2 with each other actually forms a part of the present invention.

[0206] According to a specific embodiment, the present invention relates to any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for the use as defined above, wherein

[0207] the ring and Each ring represents a phenylene group.

[0208] According to a particular embodiment, one subject of this document describes a compound of formula (Ia) as defined above,

[0209] wherein

[0210] the alkenylene group is an (E)-alkenylene group,

[0211] m and m’ are independently 0 or 1,

[0212] Y 2 represents -CR 1 R 2 R 3 group, where R 1 、R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 2 ) alkyl group, it should be understood that no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom carrying them form a (C 3 -C 6 ) cycloalkyl group, the (C 3 -C 6 ) cycloalkyl is optionally substituted by one or two halogen atoms, and the (C 3 -C 6 ) cycloalkyl is optionally interrupted by an oxygen atom on the R 1 and / or R 2 ,

[0213] R and R’ independently represent a halogen atom, a (C 1 -C 2 ) alkyl, a (C 3 -C 6 ) cycloalkyl or a (C 1 -C 2 ) alkoxy group,

[0214] They are used for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular hepatitis C virus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related diseases.

[0215] According to certain embodiments, one subject of this document describes any of the compounds of formula (Ib) as defined above or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular hepatitis C virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders.

[0216] wherein

[0217] m and m' are independently 0 or 1,

[0218] Y 2 represents -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 2 ) alkyl group, it being understood that no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom carrying them form a (C 3 -C 6 ) cycloalkyl group, said (C 3 -C 6 ) cycloalkyl being optionally substituted by one or two halogen atoms, and said (C 3 -C 6 ) cycloalkyl being optionally interrupted by an oxygen atom on said R 1 and / or R 2 .

[0219] R and R' independently represent a halogen atom, a (C 1 -C 2 ) alkyl, a (C 3 -C 6 ) cycloalkyl or a (C 1 -C 2 ) alkoxy group.

[0220] According to certain embodiments, one subject of this document describes any of the compounds of formula (Id) as defined above or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification, and in particular hepatitis C virus infection, dengue virus infection, influenza virus infection or RSV virus infection or virus-related disorders.

[0221] wherein

[0222] m and m' are independently 0 or 1,

[0223] Y 2 represents -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 2 ) alkyl group, it being understood that not more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group, said (C 3 -C 6 ) cycloalkyl being optionally substituted by one or two halogen atoms, and said (C 3 -C 6 ) cycloalkyl being optionally interrupted by an oxygen atom on said R 1 and / or R 2 .

[0224] R and R' independently represent a halogen atom, a (C 1 -C 2 ) alkyl, a (C 3 -C 6 ) cycloalkyl or a (C 1 -C 2 ) alkoxy group.

[0225] In another embodiment, the present invention relates to any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for use as defined above,

[0226] wherein

[0227] Y 1 represents

[0228] a 2-pyridyl group or a 3-pyridyl group,

[0229] a pyrimidinyl group or a pyrazinyl group, wherein one of the nitrogen atoms is in the ortho position relative to X 1 .

[0230] Provided that when X 1 is a -NH-CO- group, Y 1 can further be a phenyl group.

[0231] In another embodiment, in any of the compounds of formula (I) or their pharmaceutically acceptable salts for use as defined above, wherein

[0232] X 2 represents

[0233] an -O- group,

[0234] a -CO-NH- group,

[0235] a divalent triazole,

[0236] or

[0237] -SO 2 -NH- group.

[0238] In another embodiment, the present invention relates to any of the compounds of formula (I) or their pharmaceutically acceptable salts for use as defined above, wherein

[0239] Y 2 represents

[0240] a hydroxy group,

[0241] a morpholinyl group,

[0242] a piperidinyl group, optionally substituted with a (C 1 -C 4 )alkyl group,

[0243] a piperazinyl group, optionally substituted with a (C 1 -C 4 )alkyl group,

[0244] or

[0245] -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 4 )alkyl group, it being understood that no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 )cycloalkyl group.

[0246] In another embodiment, the present invention relates to any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for use as defined above, wherein

[0247] R and R’ independently represent

[0248] (C 1 -C 4 )alkyl group,

[0249] (C 3 -C 6 )cycloalkyl group,

[0250] a halogen atom, or

[0251] (C 1 -C 5 )alkoxy group.

[0252] Regarding any combination of the above-defined embodiments of R, R’, m, m’, ring, ring, X 1 、X 2 、n, Y 1 、Y 2 with each other actually forms part of the present invention.

[0253] In another embodiment, the present invention relates to any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for use as defined above, wherein

[0254] ring and ring both represent a phenylene group,

[0255] R” is a hydrogen atom,

[0256] Y 1 represents a 2-pyridyl group, provided that when X 1 is a -NH-CO- group, Y 1 can further be a phenyl group,

[0257] X 2 represents an -O- group, a -CO-NH- group,

[0258] Y 2 represents a -CR 1 R 2 R 3 group, wherein R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 )cycloalkyl group, and R 3 represents a hydrogen atom or (C1 -C 4 ) alkyl group, and

[0259] R and R' represent a hydrogen atom or (C 3 -C 6 ) cycloalkyl group such as a cyclopropyl group.

[0260] According to a preferred embodiment of the present invention, the compounds of formula (I) are selected from:

[0261] -(1) (E)-N-isopentyl-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0262] -(2) (E)-N-isopentyl-4-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0263] -(3) (E)-N-isopentyl-3-((3-methoxy-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0264] -(4) (E)-N-(2-cyclohexylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0265] -(5) (E)-N-neopentyl-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0266] -(6) (E)-N-(2-cyclopentylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0267] -(7) (E)-N-isopentyl-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzenesulfonamide

[0268] -(8) (E)-N-(2-cyclopropylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0269] -(9) (E)-N-(2-cyclobutylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0270] -(10) (E)-N-(2-cyclopentylethyl)-6-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)pyridinecarboxamide

[0271] -(11) (E)-N-(2-cyclohexylethyl)-3-((3-fluoro-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0272] -(12)(E)-N-(2-Cyclopentylethyl)-3-((2-methyl-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0273] -(13)(E)-N-Isopentyl-3-((2-methyl-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide

[0274] -(14)N-Isopentyl-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide

[0275] -(15)N-(2-Cyclopentylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide

[0276] -(16)N-(2-Cyclohexylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide

[0277] -(17)N-(2-Cyclopentylethyl)-3-((4-(pyrimidin-4-ylcarbamoyl)phenyl)amino)benzamide

[0278] -(18)N-Isopentyl-3-((4-(pyrimidin-2-ylcarbamoyl)phenyl)amino)benzamide

[0279] -(32)N-(4-((3-(Isopentylcarbamoyl)phenyl)amino)phenyl)pyridinecarboxamide

[0280] -(33)N-(4-((3-(Neopentylcarbamoyl)phenyl)amino)phenyl)pyridinecarboxamide

[0281] -(34)N-(4-((3-(N-Isopentylsulfamoyl)phenyl)amino)phenyl)pyridinecarboxamide

[0282] -(35)N-(4-((3-((2-Cyclopentylethyl)carbamoyl)phenyl)amino)phenyl)pyridinecarboxamide

[0283] -(91)3-({3-Methoxy-4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)-N-[3-(morpholin-4-yl)propyl]benzamide

[0284] -(92)3-({2-Methyl-4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)-N-[3-(morpholin-4-yl)propyl]benzamide

[0285] -(93)N-(2-Cyclopentylethyl)-3-({4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)benzene-1-sulfonamide

[0286] -(94)4-[(E)-2-(Pyridin-2-yl)vinyl]-N-{3-[4-(trifluoromethyl)piperidine-1-carbonyl]phenyl}aniline

[0287] -(95)N-(3-Methylbutyl)-3-({4-[(E)-2-(pyrazin-2-yl)vinyl]phenyl}amino)benzamide

[0288] -(96)N-(2-Cyclopentylethyl)-3-({4-[(E)-2-(pyrazin-2-yl)vinyl]phenyl}amino)benzamide

[0289] -(97)N-[3-(4,4-Dimethylpiperidine-1-carbonyl)phenyl]-4-[(E)-2-(pyridin-2-yl)vinyl]aniline

[0290] -(98)N-(3-{8-Azaspiro[4.5]decane-8-carbonyl}phenyl)-4-[(E)-2-(pyridin-2-yl)vinyl]aniline

[0291] -(99)3-[4-(2-Methylpropyl)-1H-1,2,3-triazol-1-yl]-N-{4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}aniline

[0292] -(100)3-[4-(2-Methylpropyl)-1H-1,2,3-triazol-1-yl]-N-{4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}aniline

[0293] -(101)N-(3-Methylbutyl)-3-({4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)benzamide

[0294] -(102)N-(3-Methylbutyl)-3-({4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)benzene-1-sulfonamide

[0295] -(103)N-(2-Cyclopentylethyl)-3-({4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)benzamide

[0296] -(104)N-(2,2-Dimethylpropyl)-3-({4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)benzamide

[0297] -(105)N-(2-Cyclohexylethyl)-3-({4-[(E)-2-(pyridin-3-yl)vinyl]phenyl}amino)benzamide

[0298] -(106)N-[3-(Morpholin-4-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)benzene-1-sulfonamide

[0299] -(107)N-[3-(Morpholin-4-yl)propyl]-2-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)pyridine-4-carboxamide

[0300] -(108)N-[3-(Morpholin-4-yl)propyl]-6-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)pyridine-2-carboxamide

[0301] -(109)N-[3-(4-Methylpiperazin-1-yl)propyl]-2-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)pyridine-4-carboxamide

[0302] -(110)N-[3-(4-Methylpiperazin-1-yl)propyl]-6-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)pyridine-2-carboxamide

[0303] -(111)N-[3-(Morpholin-4-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)benzamide

[0304] -(112)N-[3-(Piperidin-1-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)benzamide

[0305] -(113)N-[3-(4-Methylpiperazin-1-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}amino)benzamide

[0306] -(114)3-{4-[(Diethylamino)methyl]-1H-1,2,3-triazol-1-yl}-N-{4-[(E)-2-(pyridin-2-yl)vinyl]phenyl}aniline

[0307] -(115)4-{[3-(3-Cyclopropylpropoxy)phenyl]amino}-3-cyclopropyl-N-phenylbenzamide

[0308] -(116)3-Cyclopropyl-4-({2-[(3-methylbutyl)carbamoyl]phenyl}amino)-N-(pyrimidin-2-yl)benzamide

[0309] -(117) 3-Cyclopropyl-N-(pyrimidin-2-yl)-4-({2-[(3,3,3-trifluoropropyl)carbamoyl]phenyl}amino)benzamide

[0310] -(118) 4-[(3-{[3-(morpholin-4-yl)propyl]carbamoyl}phenyl)amino]-N-(pyridin-2-yl)benzamide

[0311] -(119) 4-[(3-{[3-(piperidin-1-yl)propyl]carbamoyl}phenyl)amino]-N-(pyridin-2-yl)benzamide

[0312] -(120) 4-[(3-{[3-(4-methylpiperazin-1-yl)propyl]carbamoyl}phenyl)amino]-N-(pyridin-2-yl)benzamide

[0313] -(121) 4-({3-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}amino)-N-(pyridin-2-yl)benzamide

[0314] -(122) N-[4-({3-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]phenyl}amino)phenyl]pyridine-2-carboxamide

[0315] and pharmaceutically acceptable salts thereof.

[0316] The present invention extends to compounds (3) to (18), (32) to (35), (91) to (122) and pharmaceutically acceptable salts thereof, such as hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, toluenesulfonate, trifluoromethanesulfonate, maleate, mesylate, formate, acetate and fumarate.

[0317] According to another aspect, a subject of the present invention relates to any one of the compounds of formula (I), (Ia), (Ib) and (Id) as defined above or a pharmaceutically acceptable salt thereof, and any one of compounds (1) to (18), (32) to (35) and (91) to (122) or a pharmaceutically acceptable salt thereof, which are used as medicaments for preventing, inhibiting or treating RNA virus infections caused by RNA viruses belonging to group IV or V of the Baltimore classification.

[0318] Any one of the compounds of formula (I) as defined above or a pharmaceutically acceptable salt thereof, wherein

[0319] ring and ring both represent a phenylene group,

[0320] Y 1 represents a 2-pyridyl group, provided that when X 1 is an -NH-CO- group, Y 1 may further be a phenyl group,

[0321] X 2 represents an -O- group, a -CO-NH- group,

[0322] Y 2 represents

[0323] -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 4 ) alkyl group, it being understood that not more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 ) cycloalkyl group, and R 3 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group, or

[0324] a morpholinyl group, and

[0325] R and R’ independently represent a hydrogen atom, a (C 1 -C 4 ) alkyl group such as a methyl group, or a (C 3 -C 6 ) cycloalkyl group such as a cyclopropyl group,

[0326] may be particularly suitable for use as a medicament for preventing, inhibiting or treating RNA virus infections caused by RNA viruses belonging to groups IV or V of the Baltimore classification.

[0327] Any one of compounds (12), (13), (15) and (35) or a pharmaceutically acceptable salt thereof may be particularly useful for preventing, inhibiting or treating dengue infection.

[0328] Any one of compounds (12), (13), (16) and (115) or a pharmaceutically acceptable salt thereof may be particularly useful for preventing, inhibiting or treating RSV infection.

[0329] Any one of compounds (1), (2), (4), (6), (9), (12), (13), (14), (15), (16), (32), (35) or a pharmaceutically acceptable salt thereof may be particularly useful for preventing, inhibiting or treating flexion infection.

[0330] The compounds of the present invention may exist in the form of a free base or an addition salt with a pharmaceutically acceptable acid.

[0331] "Its pharmaceutically acceptable salts" refers to salts formed from acid addition salts formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed from organic acids (such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid and poly-galacturonic acid).

[0332] Suitable physiologically acceptable acid addition salts of the compounds of formula (I) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, toluenesulfonate, trifluoromethylsulfonate, maleate, mesylate, formate, acetate and fumarate.

[0333] Any one of the compounds of formula (I), (Ia), (Ib) and (Id) and any one of compounds (1) to (18), (32) to (35) and (91) to (122) or a pharmaceutically acceptable salt thereof may form a solvate or hydrate, and the present invention includes all such solvates and hydrates.

[0334] The terms "hydrate" and "solvate" simply mean that the compounds (I), (Ia), (Ib) and (Id) according to the present invention may exist in the form of a hydrate or solvate, that is, combined or associated with one or more water or solvent molecules. This is merely a chemical characteristic of such compounds, which can be applied to all organic compounds of this kind.

[0335] In the context of the present invention, the terms:

[0336] - "Halogen" is understood to mean chlorine, fluorine, bromine or iodine, and particularly means chlorine, fluorine or bromine,

[0337] - "(C 1 -C x )alkyl" respectively represents C 1 -C x normal, secondary or tertiary saturated hydrocarbons, such as (C 1 -C 6)Alkyl. Examples are, but not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,

[0338] - “Alkenylene” means a divalent (C 1 -C x ) alkyl group containing a double bond, and more specifically a vinylene group, also referred to as vinylidene or 1,2-ethylenediyl,

[0339] - As used herein, “(C 3 -C 6 ) cycloalkyl” represents a cyclic saturated hydrocarbon. Examples are, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0340] - As used herein, “(C 3 -C 6 ) cycloalkenyl” represents a cyclic non-aromatic hydrocarbon containing at least one unsaturated bond. Examples are, but not limited to, cyclopentenyl and cyclohexenyl,

[0341] - As used herein, “(C 1 -C x ) alkoxy” represents an O-(C 1 -Cx) alkyl moiety, where the alkyl is as defined above, for example (C 1 -C 6 ) alkoxy group. Examples are, but not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy, pentyloxy,

[0342] - As used herein, “aryl” represents a monocyclic aromatic group containing 6 carbon atoms and containing 0-2 heteroatoms (such as nitrogen, oxygen or sulfur, and especially nitrogen). As examples of aryl groups, mention may be made, but not limited to, phenyl, pyridine, pyrimidine, pyridazine, pyrazine, etc. Within the framework of the present invention, the aryl is advantageously phenyl, pyridazine, pyrazine, pyridine, such as 2-pyridine or 3-pyridine and pyrimidine. The aryl is even more advantageously phenyl and pyridine, such as 2-pyridine or 3-pyridine.

[0343] - As used herein, “divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms” means a divalent ring composed of an aromatic ring containing 5 chains and 1, 2, 3 or 4 heteroatoms selected from nitrogen and oxygen atoms. In one embodiment, it contains at least 1 heteroatom, and preferably at least one nitrogen atom. In another embodiment, it contains at least 2 heteroatoms, and for example at least one nitrogen atom. According to another embodiment, it contains 2, 3 or 4 nitrogen atoms, preferably 3 nitrogen atoms. According to still another embodiment, it contains one nitrogen atom and one oxygen atom, or two nitrogen atoms and one oxygen atom. Examples are, but not limited to, divalent triazoles such as 1,2,3- or 1,2,4-triazole, Diazoles such as 1,2,4- diazole or 1,2,3- diazole, and divalent diazoles such as divalent diazole and divalent imidazole. According to a preferred embodiment, such a divalent 5-membered heteroaromatic ring containing 2 or 3 heteroatoms is divalent triazole.

[0344] The compounds of formula (I), (Ia), (Ib) and (Id) may contain one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof (including racemic mixtures) are encompassed within the scope of the present invention.

[0345] 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 described below represent general methods that can be used to prepare the compounds of the present invention and are not intended to be limiting in scope or utility.

[0346] The compounds of general formula (I) can be prepared according to Scheme 1 below.

[0347]

[0348] Scheme 1

[0349] The synthesis is based on a coupling reaction starting from a haloaromatic compound of formula (III), wherein R, R’, m, m’, ring, ring, X 1 、X 2 、n、Y 1 、Y 2 are as defined above, and X is a chlorine atom, an iodine atom or a bromine atom.

[0350] According to one embodiment, when the group is in the meta or para position on the ring relative to the -NH- group, protocol (A1) can be advantageously used.

[0351] According to protocol (A1), the compound of formula (III) can be placed in a protic solvent such as tert-butanol. Then an inorganic base such as Cs 2 CO 3 or K 2 CO 3in the presence of, for example, still in a molar ratio in the range of 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), in particular in an amount in the range of 2 mol% to 15 mol% relative to the total amount of the compound of formula (III), and in an amount in the range of 2 mol% to 25 mol% relative to the total amount of the compound of formula (III) of an organometallic catalyst such as Pd(OAc) 2 or Pd 2 dba 3 in the presence of, a compound of formula (II) is added, for example, in a molar ratio in the range of 1 - 1.5 relative to the compound of formula (III). Then the reaction mixture can be heated at a temperature in the range of 80 - 130 °C, for example, at 90 °C, and stirred for a time in the range of 15 - 25 hours, for example, 20 hours, under an inert gas and, for example, argon. The reaction mixture can be concentrated under reduced pressure and the residue can be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to obtain the compound of formula (I).

[0352] According to one embodiment, when the group is ortho on the ring relative to the -NH- group, protocol (A2) can be advantageously used.

[0353] According to protocol (A2), the compound of formula (II) can be placed in a polar aprotic solvent such as dimethyl sulfoxide. Then, in the presence of an inorganic base such as Cs 2 CO 3 or K 2 CO 3 in the presence of, for example, still in a molar ratio in the range of 1 - 5 relative to the compound of formula (II), in the presence of a ligand such as L-proline, in particular in an amount in the range of 2 mol% to 25 mol% relative to the total amount of the compound of formula (II), and in an amount in the range of 2 mol% to 25 mol% relative to the total amount of the compound of formula (II) of an organometallic catalyst such as CuI, a compound of formula (III) is added, for example, in a molar ratio in the range of 1 - 1.5 relative to the compound of formula (II). Then the reaction mixture can be heated at a temperature in the range of 80 - 130 °C, for example, at 90 °C, and stirred for a time in the range of 15 - 25 hours, for example, 20 hours. The reaction mixture can be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to obtain the compound of formula (I). ​

[0354] The starting compounds of formula (II) and (III) are available or can be prepared according to methods known to those skilled in the art.

[0355] Accordingly, the present invention further relates to a method for synthesizing new compounds of formula (I), (I), (Ia), (Ib) and (Id) as defined above, more particularly new compounds of formula (Ia), (Ib) or (Id), which comprises at least the following steps: in the presence of an inorganic base and a ligand and in the presence of an organometallic catalyst, reacting a compound of formula (II)

[0356]

[0357] with a compound of formula (III)

[0358]

[0359] wherein X 1 , Y 1 , R, R’, m, m’, ring, ring, X 2 , Y 2 are as defined above, and X is a chlorine atom, an iodine atom or a bromine atom,

[0360] to obtain a new compound of formula (I), (I), (Ia), (Ib) or (Id), more particularly a new compound of formula (Ia), (Ib) or (Id).

[0361] More specifically, when used for preparing a compound of formula (Ia), the compound of formula (IIa) can be prepared according to Scheme 2 below.

[0362] Preparation of (IIa) for (Ia)

[0363]

[0364] Scheme 2

[0365] According to the present invention, the intermediate compounds of formula (IIa) and (IVa) can be used for preparing the compound of formula (Ia).

[0366] According to procedure (B), a bromonitrobenzene derivative can be placed in a polar solvent such as N,N-dimethylformamide. Then, in the presence of an inorganic base such as sodium acetate or potassium acetate, especially still relative to the compound of formula (III) in a molar ratio in the range of 1 - 3, in the presence of a phosphine such as triphenylphosphine, for example, in an amount in the range of 5 mol% to 15 mol% relative to the amount of the bromonitrobenzene derivative, and in the presence of an organometallic catalyst such as Pd(OAc) 2 or Pd 2 dba 3 vinylaryl (wherein aryl has the same meaning as defined above) is added, for example, in a molar ratio in the range of 1 - 1.5 relative to the bromonitrobenzene derivative. Then, the reaction mixture can be heated at a temperature in the range of 80 - 140 °C, for example, at 135 °C, and stirred for a time in the range of 15 - 30 hours, for example, for 24 hours under an inert gas such as argon. The reaction mixture can be concentrated under reduced pressure, and the residue can be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the compound of formula (IVa).

[0367] According to procedure (C), the compound of formula (IVa) and tin(II) chloride dihydrate can be placed in a protic solvent such as ethanol in a ratio in the range of 3 - 8 equivalents. Then, the reaction mixture can be heated at a temperature in the range of 40 - 80 °C, for example, at 60 °C, and stirred for a time in the range of 15 - 25 hours, for example, for 20 hours. The mixture can be poured into 1N aqueous NaOH solution and extracted with an organic solvent such as ethyl acetate. Then, the organic phase can be washed with water and saturated brine solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the compound of formula (IIa).

[0368] More specifically, when used for the preparation of the compound of formula (Ib), the intermediate compound of formula (IIb) (wherein W 1 or W 2 at least one of which is CH) can be prepared according to Scheme 3 below.

[0369] For the preparation of (IIb) for (Ib), wherein at least (W 1 or W 2 = CH)

[0370]

[0371] Scheme 3

[0372] According to the present invention, the intermediate compounds of formula (IIb) and (IVb) can be used for the preparation of the compound of formula (Ib).

[0373] According to procedure (D1), 2-aminopyridine (W 1 and W 2 =CH) (e.g., added in a molar ratio in the range of 1 - 1.5 relative to the nitrobenzoyl chloride derivative) can be placed in an aqueous solution of an inorganic base such as sodium hydroxide, e.g., at a molar concentration in the range of 2M to 5M. A polar aprotic solvent such as dichloromethane can be added to the solution, the reaction mixture can be cooled to 0 °C with an ice bath, and a solution of the nitrobenzoyl chloride derivative in a polar aprotic solvent such as dichloromethane can be added dropwise. Then the reaction mixture can be stirred under an inert gas such as argon at room temperature for a time in the range of 15 - 24 hours, e.g., 18 hours. The resulting precipitate can be filtered, washed with water and dichloromethane, and dried under vacuum overnight to obtain the compound of formula (IVb).

[0374] According to procedure (D2), 2-aminopyrimidine (W 1 or W 2 =N and the other W 1 or W 2 =CH) can be placed in a polar aprotic solvent such as dichloromethane. Then, in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine, e.g., still in a molar ratio in the range of 1 - 2 relative to the aminopyrimidine, and in the presence of a nucleophilic catalyst such as dimethylaminopyridine, e.g., still in a molar ratio in the range of 0.1 - 1 relative to the aminopyrimidine, the nitrobenzoyl chloride derivative can be added, e.g., in a molar ratio in the range of 1 - 1.5 relative to the aminopyrimidine. Then the reaction mixture can be stirred under an inert gas and such as argon at room temperature for a time in the range of 5 - 20 hours, e.g., 18 hours. The organic phase can be washed with water, and the resulting precipitate can be filtered, washed with water and dichloromethane, and dried under vacuum overnight to obtain the compound of formula (IVb).

[0375] According to procedure (C), the compound of formula (IVb) and tin(II) chloride dihydrate can be placed in a protic solvent such as ethanol in a ratio in the range of 3 - 8 equivalents. Then the reaction mixture can be heated at a temperature in the range of 40 - 80 °C, e.g., at 60 °C, and stirred for a time in the range of 15 - 25 hours, e.g., 20 hours. The mixture can be poured into 1N aqueous NaOH, and extracted with an organic solvent such as ethyl acetate. Then the organic phase can be washed with water and a saturated aqueous brine solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the compound of formula (IIb).

[0376] In the case where X 1 is an -NH-CO- group, another route can be followed to prepare the compound of formula (Ib) and is shown in Scheme X below.

[0377]

[0378] Scheme X

[0379] This synthesis begins with the coupling reaction of a haloaromatic compound of formula (IIIb) with an aniline derivative (Vb) according to protocol (A1) or (A2), where R, R’, m, m’, X 1 、X 2 、n、Y 1 、Y 2 are as defined above, and X is a chlorine atom, an iodine atom or a bromine atom.

[0380] According to protocol (K), the compound of formula (VIb) can be placed in a protic solvent such as methanol, and an aqueous solution of 2M NaOH can be added in a ratio within the range of 3 - 10 equivalents. Then the reaction mixture can be heated at a temperature within the range of 50 - 90 °C, for example at 80 °C, and stirred for a time within the range of 1 - 24 hours, for example 3 hours. The mixture can be concentrated under reduced pressure, and after adding an aqueous solution of 2M HCl, it can be extracted with an organic solvent such as dichloromethane. Then the combined organic phases can be dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the compound of formula (VIIb).

[0381] According to protocol (L), the compound of formula (VIIb) and the amine derivative Y 1 -NH 2 can be placed in an anhydrous polar solvent such as N,N-dimethylformamide in a ratio within the range of 1.0 - 3 equivalents, for example 1.2 equivalents. Then, in the presence of an organic base such as triethylamine or N,N-diisopropylethylamine, for example still in a molar ratio within the range of 2 - 5 relative to the compound (VIIb), a coupling agent such as HATU can be added, for example in a molar ratio within the range of 1 - 2 relative to the compound (VIIb). Then the reaction mixture can be stirred at room temperature for a time within the range of 5 - 20 hours, for example 16 hours. The reaction can be quenched after adding an aqueous solution of 1M hydrochloric acid, and the mixture can be extracted with an organic solvent such as ethyl acetate. Then the combined organic phases can be dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the compound of formula (Ib).

[0382] More specifically, when used for the preparation of the compound of formula (Id), the compound of formula (IId) can be prepared according to Scheme 5 below.

[0383] Preparation of (IId) for (Id)

[0384]

[0385] Scheme 5

[0386] The intermediate compounds of formula (IId), (IVd) and (Vd) can be used to prepare the compounds of formula (Id) according to the present invention.

[0387] According to protocol (F), 1,4-phenylenediamine derivatives can be placed in a mixture of polar solvents such as N,N-dimethylformamide and tetrahydrofuran, for example, at a ratio in the range of 1 / 4 to 1 / 2. Then, in the presence of an inorganic base such as Cs 2 CO 3 or K 2 CO 3 aqueous solution (with a concentration in the range of 2M to 3M), and for example, still relative to the 1,4-phenylenediamine derivative at a molar ratio in the range of 0.5 - 1, Boc 2 O (di-tert-butyl dicarbonate) is added dropwise, for example, at a molar ratio in the range of 0.25 - 0.75 relative to the 1,4-phenylenediamine derivative. Then the reaction mixture can be stirred under an inert gas and for example, argon, at room temperature for a time in the range of 10 - 70 hours, for example, 64 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the compound of formula (IVd).

[0388] According to protocol (G), the amino derivative (IVd) can be placed in a polar aprotic solvent such as dichloromethane. Then, in the presence of a coupling agent such as EDCI.HCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), for example, at a molar ratio in the range of 1 - 3, in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine, for example, still relative to the amino derivative (IVd) at a molar ratio in the range of 1 - 5, and in the presence of HOBt (1-hydroxybenzotriazole hydrate), for example, still relative to the amino derivative (IVd) at a molar ratio in the range of 1 - 3, a carboxylic acid derivative is added, for example, at a molar ratio in the range of 1 - 1.5 relative to the amino derivative (IVd). Then the reaction mixture can be stirred under an inert gas and for example, argon, at room temperature for a time in the range of 5 - 30 hours, for example, 24 hours. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the compound of formula (Vd).

[0389] According to protocol (H), the compound of formula (Vd) can be placed in a polar aprotic solvent such as dichloromethane. Then trifluoroacetic acid can be added, for example, in a molar ratio in the range of 10 - 30 relative to the amino derivative (IVd). The reaction mixture can be stirred at room temperature for a time in the range of 1 - 7 hours and then cooled to 0 °C using an ice bath. Water and an inorganic base such as sodium carbonate or potassium carbonate can be added until a pH > 7 is reached. The aqueous phase can be extracted with an organic solvent such as dichloromethane. The organic phase can be collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the compound of formula (IId).

[0390] The chemical structures and spectral data of some compounds of formula (I) of the present invention are illustrated in Tables I and II below, respectively.

[0391] Table I

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399] Table II

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413] The following examples are provided by way of illustration and in no way limit the scope of the invention.

[0414] The following examples illustrate in detail the preparation of some compounds according to the present invention. The structures of the products obtained have been confirmed by NMR analysis. Example

[0415] Example 1 : Compound (6) in Table I

[0416] According to Procedure (B), 2-vinylpyridine (2.32 mL, 22 mmol, 1.1 eq) was combined with 1-bromo-4-nitrobenzene (4 g, 20 mmol, 1 eq), NaOAc (3.3 g, 40 mmol, 2 eq), Pd(OAc) 2 (450 mg, 2 mmol, 10 mol%), PPh 3 (525 mg, 2 mmol, 10 mol%) in N,N-dimethylformamide (20 mL). The reaction mixture was heated at 135 °C and stirred under an argon inert atmosphere for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. After decantation, the aqueous phase was further extracted with dichloromethane. The organic phase was further washed with water, dried over MgSO 4 and filtered, collected and concentrated under reduced pressure to give (E)-2-[2-(4-nitrophenyl)vinyl]pyridine (1.9 g, 42%).

[0417] 1 H NMR (300 MHz, CDCl 3 ) δ 8.65 (d, J = 4.1 Hz, 1H), 8.24 (d, J = 9.0 Hz, 2H), 7.75 - 7.69 (m, 4H), 7.42 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 16.2 Hz, 1H), 7.27 - 7.20 (m, 1H).

[0418] According to procedure (C), (E)-2-[2-(4-nitrophenyl)vinyl]pyridine (1.9 g, 8.4 mmol, 1 equiv) and tin(II) chloride dihydrate (9.5 g, 42 mmol, 5 equiv) were placed in EtOH (84 mL). The reaction mixture was heated at 60 °C and stirred under an argon inert atmosphere for 88 h. 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 and then with saturated aqueous brine, dried over MgSO 4 and filtered and concentrated under reduced pressure to give (E)-4-[2-(pyridin-2-yl)vinyl]aniline (1.59 g, 96%).

[0419] 1 H NMR (300 MHz, CDCl 3 ) δ 8.56 (d, J = 4.5 Hz, 1H), 7.62 (td, J = 7.9, 1.8 Hz, 1H), 7.53 (d, J = 16.1 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 7.9 Hz, 1H), 7.09 (dd, J = 7.0, 4.5 Hz, 1H), 6.98 (d, J = 16.1 Hz, 1H), 6.68 (d, J = 8.5 Hz, 2H), 3.80 (s, 2H).

[0420] 2-Cyclopentylethan-1-amine hydrochloride (3.0 g, 19.1 mmol, 1.1 equiv) was placed in 3N aqueous NaOH solution (13 mL), and dichloromethane (3.2 mL) was added to the solution. The reaction mixture was cooled to 0 °C with an ice bath, and a solution of 3-bromobenzoyl chloride (2.3 mL, 17.4 mmol, 1 equiv) in dichloromethane (5.5 mL) was added dropwise. The reaction mixture was then stirred at room temperature under an argon inert atmosphere for 18 h. After decantation, the organic phase was washed with saturated aqueous brine, dried over MgSO 4 and filtered and concentrated under reduced pressure to give 3-bromo-N-(2-cyclopentylethyl)benzamide (5.1 g, 99%).

[0421] 1 H NMR (300 MHz, CDCl 3 ) δ 7.89 (t, J = 1.7 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.07 (s, 1H), 3.46 (dt, J = 7.4, 5.9 Hz, 2H), 1.93 - 1.77 (m, 3H), 1.67 - 1.52 (m, 6H), 1.25 - 1.06 (m, 2H).

[0422] According to procedure (A), 3-bromo-N-(2-cyclopentylethyl)benzamide (755 mg, 2.55 mmol, 1 equiv), (E)-4-[2-(pyridin-2-yl)vinyl]aniline (500 mg, 2.55 mmol, 1 equiv), Pd 2 (dba) 3 (233 mg, 255 μmol, 10 mol%), XPhos (243 mg, 510 μmol, 20 mol%) and K 2 CO 3 (1.41 g, 10.2 mmol, 4 equiv) in a reaction mixture in t-BuOH (10.2 mL) was heated at 90 °C and stirred under an argon inert atmosphere for 20 h. 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 brine solution, dried over MgSO 4 and filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give fractions which, upon trituration with diethyl ether, gave (E)-N-(2-cyclopentylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide (6) (613 mg, 58%).

[0423] 1 H NMR (300 MHz, d 6 -DMSO) δ 8.59 (s, 1H), 8.54 (d, J = 3.8 Hz, 1H), 8.40 (t, J = 5.5 Hz, 1H), 7.75 (td, J = 7.7, 1.6 Hz, 1H), 7.60 (dd, J = 8.5, 7.7 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.21 (ddd, J = 12.2, 5.5, 1.6 Hz, 2H), 7.14 (s, 1H), 7.11 (d, J = 8.5 Hz, 2H), 3.26 (dd, J = 13.8, 6.2 Hz, 2H), 1.85 - 1.72 (m, 3H), 1.66 - 1.42 (m, 6H), 1.18 - 0.99 (m, 2H).

[0424] 13 C NMR (75 MHz, d 6-DMSO) δ 164.2, 153.6, 147.5, 141.6, 140.9, 134.8, 134.1, 130.1, 127.2, 126.4, 126.0, 122.8, 119.9, 119.8, 117.8, 116.8, 114.5, 114.2, 77.9, 35.5, 33.6, 30.3, 22.8

[0425] [M+H] + = 412.3

[0426] Example 2 : in compound (15) in Table I

[0427] According to procedure (D1), 2-pyridinamine (4.7 g, 50 mmol, 1.1 eq) was placed in 3N aqueous NaOH (56 mL) and dichloromethane (24 mL) was added to the solution. The reaction mixture was cooled to 0 °C with an ice bath and a solution of 4-nitrobenzoyl chloride (8.4 g, 45 mmol, 1 eq) in dichloromethane (40 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 h under an argon inert atmosphere. The resulting precipitate was filtered and washed with water and dichloromethane to give 4-nitro-N-(pyridin-2-yl)benzamide (6.7 g, 61%).

[0428] 1 H NMR (300 MHz, d 6 -DMSO) δ 10.91 (s, 1H), 8.80 (s, 1H), 8.52 (d, J = 5.5 Hz, 2H), 8.47 (d, J = 7.9 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.79 (d, J = 5.5 Hz, 2H).

[0429] According to procedure (C), 4-nitro-N-(pyridin-2-yl)benzamide (1.5 g, 6.2 mmol, 1 eq) and tin(II) chloride dihydrate (7.0 g, 30.8 mmol, 5 eq) were placed in EtOH (62 mL). The reaction mixture was heated at 60 °C and stirred for 16 h under an argon 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 and then with water, dried over MgSO 4 and filtered and concentrated under reduced pressure to give 4-amino-N-(pyridin-2-yl)benzamide (273 mg, 21%).

[0430] 1 H NMR (300 MHz, d 6-DMSO) δ 10.44 (s, 1H), 8.44 (d, J = 6.3 Hz, 2H), 7.77 (d, J = 6.3 Hz, 2H), 7.18 (t, J = 7.9 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.78 (d, J = 7.9 Hz, 1H), 5.38 (s, 2H).

[0431] 2-Cyclopentylethane-1-amine hydrochloride (1.0 g, 7 mmol, 1.1 eq) was placed in 3N aqueous NaOH (4.6 mL) and dichloromethane (1.1 mL) was added to the solution. The reaction mixture was cooled to 0 °C with an ice bath and a solution of 3-bromobenzoyl chloride (0.8 mL, 6 mmol, 1 eq) in dichloromethane (1.9 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 h under an argon inert atmosphere. After decantation, the organic phase was washed with saturated aqueous brine, dried over MgSO 4 and filtered and concentrated under reduced pressure to give 3-bromo-N-(2-cyclopentylethyl)benzamide (1.77 g, 98%).

[0432] 1 1H NMR (300 MHz, CDCl 3 ) δ 7.89 (t, J = 1.7 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.07 (s, 1H), 3.46 (dt, J = 7.4, 5.9 Hz, 2H), 1.93 - 1.77 (m, 3H), 1.67 - 1.52 (m, 6H), 1.25 - 1.06 (m, 2H).

[0433] According to procedure (A), a reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (296 mg, 1.0 mmol, 1 eq), 4-amino-N-(pyridin-2-yl)benzamide (213 mg, 1.0 mmol, 1 eq), Pd 2 (dba) 3 (92 mg, 0.1 mmol, 10 mol%), XPhos (95 mg, 0.2 mmol, 20 mol%) and K 2 2CO 3 (553 mg, 4.0 mmol, 4 eq) in t-BuOH (4 mL) was heated in a microwave reactor at 120 °C for 60 min. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO 4Dry, filter and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-(2-cyclopentylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide (15) (30 mg, 7%).

[0434] 1 H NMR (300 MHz, d 6 -DMSO) δ 10.46 (s, 1H), 8.83 (s, 1H), 8.44 (t, J = 5.5 Hz, 1H), 8.37 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.87 - 7.77 (m, 1H), 7.65 (s, 1H), 7.45 - 7.36 (m, 2H), 7.30 (dt, J = 6.5, 2.2 Hz, 1H), 7.15 (d, J = 5.5 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 3.26 (dd, J = 13.7, 6.4 Hz, 2H), 1.87 - 1.72 (m, 3H), 1.67 - 1.40 (m, 6H), 1.07 (m, 2H).

[0435] 13 C NMR (75 MHz, d 6 -DMSO) δ 164.2, 163.5, 150.8, 146.1, 145.3, 140.1, 136.2, 134.3, 128.1, 127.5, 122.3, 119.3, 118.1, 117.6, 117.5, 115.7, 112.8, 112.7, 35.7, 33.7, 30.5, 23.0

[0436] [M + H] + = 429.1

[0437] Example 3 : For the compound (16) in Table I

[0438] According to procedure (D1), 2-pyridinamine (5.0 g, 53.1 mmol, 1 equiv) was placed in an aqueous solution of 3N NaOH (65.5 mL) and dichloromethane (5 mL) was added to the solution. The reaction mixture was cooled to 0 °C with an ice bath and a solution of 4-nitrobenzoyl chloride (9.8 g, 53.1 mmol, 1 equiv) in dichloromethane (70 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 h under an argon inert atmosphere. The resulting precipitate was filtered and washed with water and dichloromethane to give 4-nitro-N-(pyridin-2-yl)benzamide (5.8 g, 45%).

[0439] 1 H NMR (300 MHz, d 6 -DMSO) δ 11.16 (s, 1H), 8.40 (dd, J = 4.8, 1.6 Hz, 1H), 8.32 (d, J = 8.9 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H), 8.17 (d, J = 8.4 Hz, 1H), 7.90 - 7.82 (m, 1H), 7.23 - 7.15 (m, 1H).

[0440] According to procedure (C), 4-nitro-N-(pyridin-2-yl)benzamide (5.8 g, 23.8 mmol, 1 equiv) and tin(II) chloride dihydrate (27 g, 119 mmol, 5 equiv) were placed in EtOH (240 mL). The reaction mixture was heated at 60 °C and stirred under an argon inert atmosphere for 16 h. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane. The organic phase was washed with 1 N aqueous NaOH solution and then with saturated aqueous saline solution, dried over MgSO 4 and filtered and concentrated under reduced pressure to give 4-amino-N-(pyridin-2-yl)benzamide (955 mg, 19%).

[0441] 1 H NMR (300 MHz, d 6 -DMSO) δ 10.17 (s, 1H), 8.34 (d, J = 3.8 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.80 - 7.75 (m, 3H), 7.09 (dd, J = 6.4, 5.0 Hz, 1H), 6.57 (d, J = 8.6 Hz, 2H), 5.82 (br s, 2H).

[0442] 2-Cyclohexylethan-1-amine (1.1 mL, 7.9 mmol, 1.1 equiv) was placed in 3 N aqueous NaOH solution (5.3 mL) and dichloromethane (1 mL) was added to the solution. The reaction mixture was cooled to 0 °C in an ice bath and a solution of 3-bromobenzoyl chloride (945 μL, 7.1 mmol, 1 equiv) in dichloromethane (2.5 mL) was added dropwise. The reaction mixture was then stirred at room temperature under an argon inert atmosphere for 18 h. After decantation, the organic phase was washed with saturated aqueous saline solution, dried over MgSO 4 and filtered and concentrated under reduced pressure to give 3-bromo-N-(2-cyclohexylethyl)benzamide (2.0 g, 90%).

[0443] 1 H NMR (300 MHz, CDCl 3)δ 7.89 (t, J = 1.7 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 6.00 (bs, 1H), 3.47 (dt, J = 7.5, 5.8 Hz, 2H), 1.81 - 1.62 (m, 4H), 1.51 (dd, J = 14.6, 7.1 Hz, 2H), 1.31 - 1.12 (m, 5H), 1.04 - 0.85 (m, 2H).

[0444] According to procedure (A), a reaction mixture of 3-bromo-N-(2-cyclohexylethyl)benzamide (310 mg, 1.0 mmol, 1 equiv), 4-amino-N-(pyridin-2-yl)benzamide (213 mg, 1.0 mmol, 1 equiv), Pd 2 (dba) 3 (92 mg, 0.1 mmol, 10 mol%), XPhos (95 mg, 0.2 mmol, 20 mol%) and K 2 CO 3 (553 mg, 4.0 mmol, 4 equiv) in t-BuOH (4 mL) was heated in a microwave reactor at 120 °C for 60 minutes. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with saturated aqueous brine, dried over MgSO 4 and filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel and then triturated with ether to give N-(2-cyclohexylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide (16) (78 mg, 18%).

[0445] 1 1H NMR (300 MHz, d 6 -DMSO) δ 10.46 (s, 1H), 8.83 (s, 1H), 8.42 - 8.37 (m, 2H), 8.19 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.82 (t, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.42 - 7.35 (m, 2H), 7.32 - 7..29 (m1H), 7.17 - 7.13 (m, 1H), 7.10 (d, J = 8.6 Hz, 2H), 3.28 (dd, J = 13.3, 6.8 Hz, 2H), 1.78 - 1.57 (m, 5H), 1.43 (dd, J = 14.2, 6.9 Hz, 2H), 1.34 - 1.12 (m, 4H), 0.99 - 0.82 (m, 2H).

[0446] 13 C NMR (75 MHz, d 6 -DMSO) δ 166.4, 165.7, 152.9, 148.3, 147.5, 142.3, 138.4, 136.5, 130.2, 129.7, 124.5, 121.5, 120.3, 119.8, 117.9, 115.0, 114.9, 37.5, 37.1, 35.3, 33.2, 26.5, 26.2

[0447] [M + H] + = 429.1

[0448] Example 4 : In the compound (115) in Table I

[0449] According to procedure (J), a solution of methyl 4 - amino - 3 - bromobenzoate (3.00 g, 12.8 mmol, 1 equiv) and potassium cyclopropyltrifluoroborate (2.84 g, 19.2 mmol, 1.5 equiv) in toluene (52.5 mL) and water (13.5 mL) was degassed with argon for 5 minutes, then potassium phosphate tribasic (6.88 g, 31.9 mmol, 2.5 equiv), RuPhos (239 mg, 511 μmol, 0.04 equiv) and palladium(II) acetate (57.9 mg, 256 μmol, 0.02 equiv) were added. The reaction mixture was heated and stirred at 110 °C for 2 h 30 in an inert atmosphere. After cooling to room temperature, it was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc. Then a saturated aqueous saline solution was added to the filtrate and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO 4 dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4 - amino - 3 - cyclopropylbenzoate (2.02 g, 81%).

[0450] 1 H NMR (400 MHz, d 6 -DMSO) δ 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 5.87 (s, 2H), 3.73 (s, 3H), 1.65 (tt, J = 8.3, 5.4 Hz, 1H), 0.95 - 0.82 (m, 2H), 0.54 - 0.40 (m, 2H).

[0451] 3 - Bromophenol (701 mg, 3.97 mmol, 1.2 equiv) was combined with Cs 2 CO 3(1.30 g, 3.97 mmol, 1.2 equiv) were placed together in N,N-dimethylformamide (4 mL). After the addition of (3-bromopropyl)cyclohexane (715 mg, 3.31 mmol, 1.0 equiv), the reaction mixture was stirred for 16 h under an argon inert atmosphere. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO 3 aqueous solution. After extraction with ethyl acetate, the combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 1-bromo-3-(3-cyclohexylpropoxy)benzene (882 mg, 90%).

[0452] 1 H NMR (500 MHz, d 6 -DMSO) δ 7.22 (t, J = 8.1 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.93 (dd, J = 8.3, 2.3 Hz, 1H), 3.95 (t, J = 6.5 Hz, 2H), 1.68 (tt, J = 15.1, 9.2 Hz, 7H), 1.32 - 1.06 (m, 6H), 0.92 - 0.82 (m, 2H).

[0453] According to procedure (A), a reaction mixture of 1-bromo-3-(3-cyclohexylpropoxy)benzene (547 mg, 1.84 mmol, 1.1 equiv), methyl 4-amino-3-cyclopropylbenzoate (320 mg, 1.67 mmol, 1.0 equiv), BrettPhos Pd G3 (31.9 mg, 33.5 μmol, 0.02 equiv) and Cs 2 CO 3 (818 mg, 2.51 mmol, 1.5 equiv) in anhydrous DMF (8 mL) was degassed with argon and heated at 80 °C for 75 min under an inert atmosphere. The reaction mixture was then cooled to room temperature, filtered through a pad of Celite, and the pad was washed with EtOAc. Then brine was added to the filtrate and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford methyl 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoate (1.35 g, 80%).

[0454] 1 H NMR (400 MHz, d 6-DMSO) δ 7.82 (s, 1H), 7.66 (dd, J = 8.5, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.24 - 7.14 (m, 2H), 6.76 (d, J = 7.9 Hz, 1H), 6.73 (t, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.1, 2.2 Hz, 1H), 3.92 (t, J = 6.5 Hz, 2H), 3.78 (s, 3H), 1.94 (ddd, J = 13.8, 8.3, 5.4 Hz, 1H), 1.75 - 1.58 (m, 7H), 1.35 - 1.08 (m, 6H), 1.04 - 0.94 (m, 2H), 0.88 (q, J = 10.0, 9.3 Hz, 2H), 0.65 - 0.56 (m, 2H).

[0455] According to procedure (E), methyl 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoate (575 mg, 1.34 mmol, 1 equiv) was placed in methanol (10 mL) and an aqueous solution of 2M NaOH (4.7 mL, 9.4 mmol, 7 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 2M HCl (7.0 mL, 14 mmol, 10.5 equiv). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (540 mg, 97%).

[0456] 1 H NMR (400 MHz, d 6 -DMSO) δ 12.37 (s, 1H), 7.76 (s, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.18 (t, J = 8.6 Hz, 2H), 6.74 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 6.53 (dd, J = 8.1, 2.1 Hz, 1H), 3.91 (t, J = 6.5 Hz, 2H), 1.94 (ddd, J = 13.6, 8.4, 5.4 Hz, 1H), 1.75 - 1.58 (m, 7H), 1.35 - 1.09 (m, 6H), 0.98 (dd, J = 4.0, 2.0 Hz, 2H), 0.88 (q, J = 10.1, 9.3 Hz, 2H), 0.65 - 0.56 (m, 2H).

[0457] According to protocol (F), 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (50.0 mg, 127 μmol, 1 equiv) and aniline (12.2 μL, 133 μmol, 1.05 equiv) were placed in anhydrous N,N-dimethylformamide (650 μL). HATU (48.3 mg, 127 μmol, 1 equiv) and DIPEA (44.4 μL, 254 μmol, 2 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. The resulting residue was purified by column chromatography on silica gel to afford 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-phenylbenzamide (115) (42.0 mg, 67%).

[0458] 1 H NMR (400 MHz, d 6 -DMSO) δ 9.96 (s, 1H), 7.78 - 7.67 (m, 4H), 7.57 (d, J = 2.0 Hz, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.23 (d, J = 8.5 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.74 - 6.68 (m, 1H), 6.67 (t, J = 2.1 Hz, 1H), 6.48 (dd, J = 8.1, 2.1 Hz, 1H), 3.91 (t, J = 6.5 Hz, 2H), 2.04 - 1.92 (m, 1H), 1.75 - 1.57 (m, 7H), 1.35 - 1.09 (m, 6H), 1.04 - 0.95 (m, 2H), 0.88 (q, J = 10.1, 9.5 Hz, 2H), 0.76 - 0.67 (m, 2H).

[0459] 13 C NMR (151 MHz, d 6 -DMSO) δ 165.6, 160.0, 146.2, 144.9, 139.9, 131.8, 130.2, 128.9, 126.8, 126.7, 126.4, 123.7, 120.9, 116.2, 111.4, 107.5, 105.3, 68.0, 37.2, 33.7, 33.3, 26.6, 26.6, 26.3, 11.6, 7.8

[0460] [M+H] + = 469.2

[0461] Example 5: The compound (35) in Table I

[0462] According to procedure (F), 1,4-phenylenediamine (4.0 g, 37 mmol, 3.0 eq) was placed in tetrahydrofuran (37 mL) and N,N-dimethylformamide (12 mL). 2.2 M K 2 CO 3 aqueous solution (6.8 mL, 13.6 mmol, 1.1 eq) was added to the solution, and then Boc 2 O (2.6 mL, 12.3 mmol, 1.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 64 h. Then the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give tert-butyl (4-aminophenyl)carbamate (1.6 g, 62%).

[0463] 1 H NMR (300 MHz, CDCl 3 ) δ 7.13 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 6.32 (s, 1H), 3.54 (s, 2H), 1.50 (s, 9H).

[0464] According to procedure (G), a reaction mixture of tert-butyl (4-aminophenyl)carbamate (1.6 g, 7.7 mmol, 1.0 eq), 2-pyridinecarboxylic acid (1.0 g, 8.5 mmol, 1.1 eq), EDCI·HCl (1.6 g, 8.5 mmol, 1.1 eq), N,N-diisopropylethylamine (3.8 mL, 23 mmol, 3.0 eq) and HOBt (1.1 g, 8.5 mmol, 1.1 eq) in anhydrous dichloromethane (15 mL) was stirred at room temperature for 24 h under an argon inert atmosphere. The organic phase was washed with water, dried over MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give tert-butyl N-[4-(pyridin-2-ylamino)phenyl]carbamate (983 mg, 41%).

[0465] 1 H NMR (300 MHz, CDCl 3)δ9.98(s,1H),8.61(d,J=4.5Hz,1H),8.29(d,J=7.7Hz,1H),7.91(td,J=7.7,1.5Hz,1H),7.72(d,J=8.8Hz,2H),7.48(ddd,J=7.7,4.5,1.5Hz,1H),7.40(d,J=8.8Hz,2H),6.61(s,1H),1.52(s,9H).

[0466] According to procedure (H), tert-butyl N-[4-(pyridin-2-ylamino)phenyl]carbamate (983 mg, 3.1 mmol, 1 equiv) was placed in dichloromethane (6.3 mL) and trifluoroacetic acid (5.1 mL, 68.2 mmol, 22 equiv) was added to the solution. The reaction mixture was stirred at room temperature for 1 h and then cooled to 0 °C with an ice bath. Water was added and then K 2 CO 3 was added until pH>7 was reached. The aqueous phase was extracted with dichloromethane. The organic phase was collected, dried over MgSO 4 4, filtered and concentrated under reduced pressure to give N-(4-aminophenyl)pyridine-2-carboxamide (659 mg, 99%).

[0467] 1 1H NMR (300 MHz, CDCl 3 )δ9.85(s,1H),8.60(d,J=4.5Hz,1H),8.29(d,J=7.7Hz,1H),7.89(td,J=7.7,1.5Hz,1H),7.57(d,J=8.7Hz,2H),7.46(ddd,J=7.7,4.5,1.5Hz,1H),6.72(d,J=8.7Hz,2H),3.63(s,2H).

[0468] 2-Cyclopentylethan-1-amine hydrochloride (1.0 g, 7 mmol, 1.1 equiv) was placed in 3N aqueous NaOH (4.6 mL) and dichloromethane (1.1 mL) was added to the solution. The reaction mixture was cooled to 0 °C with an ice bath and a solution of 3-bromobenzoyl chloride (0.8 mL, 6 mmol, 1 equiv) in dichloromethane (1.9 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 h under an argon inert atmosphere. After decantation, the organic phase was washed with saturated aqueous brine, dried over MgSO 4 4, filtered and concentrated under reduced pressure to give 3-bromo-N-(2-cyclopentylethyl)benzamide (1.77 g, 98%).

[0469] 1 1H NMR (300 MHz, CDCl3 ) δ 7.89 (t, J = 1.7 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.07 (s, 1H), 3.46 (dt, J = 7.4, 5.9 Hz, 2H), 1.93 - 1.77 (m, 3H), 1.67 - 1.52 (m, 6H), 1.25 - 1.06 (m, 2H).

[0470] According to procedure (A), 3-bromo-N-(2-cyclopentylethyl)benzamide (296 mg, 1.0 mmol, 1 equiv), N-(4-aminophenyl)pyridine-2-carboxamide (213 mg, 1.0 mmol, 1 equiv), Pd 2 (dba) 3 (92 mg, 0.1 mmol, 10 mol%), XPhos (95 mg, 0.2 mmol, 20 mol%) and K 2 CO 3 (553 mg, 4.0 mmol, 4 equiv) in a reaction mixture in t-BuOH (4 mL) was heated in a microwave reactor at 120 °C for 60 minutes. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO 4 and filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-(4-((3-((2-cyclopentylethyl)carbamoyl)phenyl)amino)phenyl)pyridinecarboxamide (35) (89 mg, 21%).

[0471] 1 H NMR (300 MHz, d 6 -DMSO) δ 10.54 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.36 (t, J = 5.4 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 8.07 (td, J = 7.7, 1.5 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.71 - 7.62 (m, 1H), 7.51 (s, 1H), 7.34 - 7.20 (m, 2H), 7.16 - 7.10 (m, 3H), 3.25 (dd, J = 13.4, 6.5 Hz, 2H), 1.82 - 1.72 (m, 3H), 1.68 - 1.45 (m, 6H), 1.12 - 1.08 (m, 2H).

[0472] 13 C NMR (75 MHz, d 6-DMSO) δ 164.9, 160.5, 148.7, 146.9, 142.6, 137.6, 136.6, 134.5, 130.0, 127.6, 125.3, 120.8, 120.0, 116.7, 116.4, 116.1, 113.1, 35.9, 34.0, 30.7, 23.2

[0473] [M+H] + = 429.1

[0474] Pharmacological Data

[0475] Example 6: Chikungunya virus

[0476] The compounds of the present invention have been the subject of pharmacological tests, which have demonstrated their relevance as active substances in therapy, particularly for the prevention, inhibition or treatment of Flavivirus infections.

[0477] Materials and Methods

[0478] Inhibition of Chikungunya virus (CHIKV) production in infected HEK293T cell line.

[0479] The ability of the compounds to inhibit virus replication was evaluated experimentally, where infected cells were treated with 1 μM of the compound of formula (I). Ribavirin was used as a positive control for the inhibition of Flavi. The toxicity of the compounds was evaluated in parallel.

[0480] · Amplification of cells

[0481] Human embryonic kidney cells 293T (HEK293T, CRL-11268) were maintained in Dulbecco's Modified Eagle Medium (DMEM, 31966-021, Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (FBS), penicillin and streptomycin. After removing the medium, the cells were washed with a salt solution without Ca 2+ and Mg 2+ to remove all traces of serum. After aspirating the wash solution, the cells were dissociated with 0.25% trypsin-EDTA solution and incubated in a 37 °C incubator for at least 30 s. The concentration of the cell suspension was determined by an automated cell counter (EVE, NanoEntek), and if necessary, adjusted to 0.33×10 6 cells / mL with DMEM medium supplemented with 10% FBS.

[0482] · Preparation of compounds

[0483] Dispense 100 μL of the cell suspension into a ViewPlate-96 Black (6005182, PerkinElmer) and a transparent 96-well cell culture plate (655180, Greiner bio-one). After incubation at 37 °C for 24 h under 5% CO 2 2, add the compound at an appropriate concentration.

[0484] · Screening at 1 μM

[0485] Prepare intermediate dilutions from the stock solution at 2 mM in DMSO (D8418, Sigma) in a 96-well V-bottom microculture plate:

[0486] Mix 1 μL of the 50 mM stock solution library in 25 μL of DMSO.

[0487] Mix 2 μL of the 25 mM stock solution library in 25 μL of DMSO.

[0488] ·IC 50 Determination of value

[0489] Prepare intermediate dilutions from the stock solution at 25 mM in DMSO (D8418, Sigma) in a 96-well V-bottom microculture plate:

[0490] Mix 2 μL of the 50 mM stock solution library in 2 μL of DMSO.

[0491] Perform serial dilutions 13 times in 2 μL of DMSO to reach 0.0015 mM. As shown in Table III below:

[0492] Table III

[0493]

[0494] Regarding the screening and determination of IC 50 , add 1 μL of each solution to 1 mL of DMEM medium in a 1 mL Masterblock 96-well (Greiner bio-one, 780261). As a positive control, add 5 μL of an 80 mM ribavirin solution (R9644, Sigma) to 1 mL of DMEM. On the other hand, DMSO is used as a negative control.

[0495] · Infection

[0496] Infect cells with 30 μL of the La Réunion outbreak CHIKV strain (LR2006-OPY1) (CHIK 5’LR) modified with GFP at the 5’ end (Tsetsarkin K, Higgs S, McGee CE, De Lamballerie X, Charrel RN, Vanlandingham DL. Infectious Clones of Chikungunya Virus (La Réunion Isolate- Ref-SKU:001N-EVA249 (PMID: 17187566 ) and available at: https: / / www.european-virus-archive.com / nucleic-acid / chikv-lr-5gfp-infectious-clone) for Vector Competence Studies. Vector Borne Zoonotic Dis. 2006;6(4)). Use the modified virus to infect cells at an MOI of 0.1. The LR2006-OPY1 strain of CHIKV (CHIKV-LR) was obtained from the World Reference Center for Arboviruses at the University of Texas Medical Branch, Galveston, TX. This strain was originally isolated from the serum of febrile French patients returning from La Réunion Island.

[0497] · Cell lysis

[0498] After maintaining at 37 °C for 22 h under 5% CO 2 , remove the medium and wash the cells as described above. Add 60 μL of RIPA buffer (50 mM Tris-HCl pH 8, 100 mM NaCl, 1 mM MgCl 2 , 1% Triton X-100) to the cells and incubate for at least 20 min, then read the fluorescence signal. Use Pierce 660 nm Protein Assay Reagent (22660, Thermo scientific) to normalize the fluorescence signal by protein amount.

[0499] Use CellTiter AQueous One Solution Cell Proliferation Assay (MTS) (G3581, Promega) was used to examine the toxicity of the compounds. We added 20 μL of the MTS solution and read the absorbance at 492 nm after 1 hour.

[0500] Results

[0501] - has been performed First round of experiments , where the results were expressed as percentage inhibition, which was calculated as follows by the following steps:

[0502] 1. Fluorescence intensity (FI) / Absorbance at 660 nm (A660) = A

[0503] This ratio allows the infection (GFP virus) to be considered as the amount of protein.

[0504] 2. A’ = A - background noise of the uninfected plate,

[0505] 3. B = Fluorescence intensity (FI) / Absorbance at 660 nm (A660) of the infected but untreated plate,

[0506] 4. C = A’ / B, which was then converted to the percentage of infection after treatment relative to the untreated sample and subsequently expressed as the percentage of infection. For example, a value of 100 in Table IV below means that after treatment, the signal caused by GFP fluorescence was eliminated, which is related to the absence of infection.

[0507] 5. C’ = 100 - C

[0508] This value corresponds to the percentage of inhibition.

[0509] Table IV below covers the C’ values (calculated as the average of 2 experiments as above) of some compounds and the corresponding standard deviations.

[0510] Some values were initially higher than 100. In these cases, the values were reduced to 100. This means that some molecules also have an impact on cell viability. In other words, the A value may be lower than the background noise.

[0511] In addition, for each measurement, ribavirin was used as a control for the test. The value of the percentage of inhibition was checked, which gave 100%.

[0512] Table IV

[0513]

[0514] - has been performed Second round of experiments , and the results were given as IC 50Value

[0515] IC 50 The value is in the range between 0.1 nM and 1 μM, especially between 0.5 and 500 nM, and even more particularly between 1 - 400 nM, for example between 1 - 200 nM, and especially for compounds 6, 14, 15, 16, 32 and 35, whose IC 50 value is in the range between 200 - 500 nM. For example, compounds 12 and 13 have an IC 50 value

[0516] Conclusion

[0517] Based on the foregoing results, it can be concluded that the compounds of formula (I) are suitable chemical compounds for the treatment and / or prevention of RNA virus infections caused by RNA viruses of group IV, more specifically alphavirus infections and most particularly rubivirus infections

[0518] Example 7: RSV virus

[0519] The compounds of the present invention have been the subject of pharmacological tests, which have demonstrated their relevance as active substances in the treatment and especially for the prevention, inhibition or treatment of RSV virus infections

[0520] Materials and Methods

[0521] Protocol for screening antiviral compounds for RSV inhibition and cytotoxicity using the Viral ToxGlo assay

[0522] HEp - 2 cells are maintained in Eagle's Minimum Essential Medium (EMEM) containing Earle's BSS, which is adjusted to contain 2 mM L - glutamine, 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin. For the purpose of screening assays, they are grown to 90% confluence, treated with trypsin and harvested. The trypsin is neutralized with cell medium and the cells are centrifuged at 150 x g for 5 minutes, then the supernatant is discarded and the cell pellet is resuspended in assay medium (EMEM containing Earle's BSS, which is adjusted to contain 2 mM L - glutamine, 2% fetal bovine serum and 100 U / ml penicillin and 100 μg / ml streptomycin). For 96 - well plates and 384 - well plates, at a density of 1.5 x 10 4 cells / well in 50 μl and 4 x 10 3Seed cells into a white clear-bottom cell culture plate at a density of cells / well. For the media / background control columns, add only the assay media. Place the cell plate in a humidity-controlled chamber and incubate overnight at 37 °C / 5% CO 2 Incubate overnight. After overnight incubation, examine the cells for confluence and healthy appearance.

[0523] Prepare test articles at 10-fold assay concentrations up to a maximum DMSO concentration of 10% (final assay concentration up to 1% DMSO) and add to the cell plate in volumes of 10 μl (for 96-well plates) and 5 μl (for 384-well plates). For the cell control and virus control wells, add only the test article vehicle. For 96- and 384-well plates, add virus or assay media at 40 or 20 μl, respectively, immediately after the test article to the cytotoxicity test wells and media / cell control wells at an MOI of 0.5. Prepare the virus suspension by thawing the RSV A2 frozen stock and diluting it in assay media on ice to the desired plaque-forming unit concentration.

[0524] Place the cell plate in a humidity-controlled chamber and incubate further at 37 °C / 5% CO 2 for 72 h. After the incubation period, observe the cells under a microscope to examine for characteristic cytopathic effects in the virus control wells and healthy cells in the cell control wells. After bringing the plate to room temperature, add 20 / 40 μl Viral ToxGlo (Promega) to each well of the 384 / 96-well cell plate. Incubate the plate on a plate shaker for 20 min at room temperature in the dark and then measure luminescence on a spectrophotometer (Biotek Synergy HTX).

[0525] Calculate RSV inhibition as the percentage of cytopathic effect inhibition relative to the virus control, and calculate cytotoxicity as the percentage of cell survival relative to the cell control wells. This allows calculation of the EC 50 values, where virus inhibition or cytotoxicity dose responses are identified. EC 50 values were found in the range between 0.001 μM and 2.5 μM, and more particularly for compounds 12, 13, 16, and 115.

[0526] Table V

[0527] Examples <![CDATA[EC 50 (nM)]]> 12 <![CDATA[370<EC 50 <2500]]> 13 <![CDATA[370<EC 50 <2500]]> 16 1168 115 229

[0528] Conclusion

[0529] Based on the foregoing results, it can be concluded that the compounds of formula (I) are suitable chemical compounds for the treatment and / or prevention of RNA virus infections caused by RNA viruses of group V, more specifically pneumovirus infections, and most particularly RSV virus infections.

[0530] Example 8: Dengue 2 virus

[0531] The compounds of the present invention have been the subject of pharmacological tests, and they have been shown to be relevant as active substances in therapy and especially for the prevention, inhibition or treatment of dengue 2 virus infection.

[0532] Materials and Methods

[0533] Protocol for screening antiviral compounds for DENV-2 inhibition and cytotoxicity using the Viral ToxGlo assay

[0534] A549 cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin. For the purpose of screening assays, they were grown to 90% confluence, treated with trypsin and harvested. The trypsin was neutralized with cell medium and the cells were centrifuged at 150 x g for 5 minutes, then the supernatant was discarded and the cell pellet was resuspended in assay medium (DMEM supplemented with 2% fetal bovine serum and 100 U / ml penicillin and 100 μg / ml streptomycin). The cells were seeded into 96-well white clear-bottom cell culture plates at a density of 1.0 x 10 4 cells / well in 50 μl. For the media / background control columns, only assay medium was added. The cell plates were placed in a humidified chamber and incubated overnight at 37 °C / 5% CO 2 After incubation overnight, the cells were examined for confluence and healthy appearance.

[0535] Test compounds were prepared at a final concentration of 10 μM at a maximum DMSO concentration of 1% (final assay concentration maximum 0.1% DMSO) and added to the cell plates in a volume of 10 μl. For the cell control and virus control wells, only the test article vehicle was added. As a positive inhibition control, 7-deaza-2'-C-methyladenosine was added at 100 μM in 3 wells. For 96-well plates, virus (DENV-2 strain 16681) or assay medium was added to the cytotoxicity test wells and media / cell control wells immediately after the test article at an MOI of 0.5 in 40 μl (40 for 96 well plates). The virus suspension was prepared by thawing the DENV-2 frozen stock and diluting it in assay medium to the required plaque-forming unit concentration.

[0536] The cell plates were placed in a humidified chamber at 37 °C / 5% CO 2Incubate for an additional 5 days. After the incubation period, cells are observed under a microscope to check for the characteristic cytopathic effect in the virus control wells and healthy cells in the cell control wells. After bringing the plate to room temperature, 20 μl of Viral ToxGlo (Promega) is added to each well of a 96-well cell plate. The plate is incubated at room temperature for 5 minutes and then luminescence is measured on a spectrophotometer (Envision, PerkinElmer).

[0537] DENV-2 inhibition is calculated as the percentage of inhibition of the cytopathic effect relative to the virus control, and cytotoxicity is calculated as the percentage of cell survival relative to the cell control wells.

[0538] Table VI

[0539]

[0540]

[0541] Conclusion

[0542] Based on the foregoing results, it can be concluded that the compounds of formula (I) are suitable chemical compounds for the treatment and / or prevention of RNA virus infections caused by RNA viruses of group IV, more particularly yellow virus infections, and most particularly dengue 2 virus infections.

[0543] The present invention further relates to a pharmaceutical composition comprising at least one of the new compounds as defined above or any of its pharmaceutically acceptable salts, or at least one of the compounds (3) to (18), (32) to (35), (91) to (125) as defined above or any of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

[0544] The pharmaceutical composition of the present invention may contain one or more compounds of the present invention in any form described herein.

[0545] Another object of the present invention consists of the use of at least one compound of formula (I) as defined above, and the compounds (1) to (18) and (32) to (35) and (91) to (122) as defined above, or one of its pharmaceutically acceptable salts according to the present invention, for the preparation of a medicament for the prevention or treatment of RNA virus infections in a subject caused by RNA viruses from group IV or group V according to the Baltimore classification, and such as Zika infection, dengue infection, influenza infection or RSV infection.

[0546] Accordingly, the present invention relates to a compound of formula (I) as defined above and compounds (1) to (18) and (32) to (35) and (91) to (122) or one of its acceptable salts, as a medicament for inhibiting, preventing or treating RNA virus infections, and most preferably RNA virus infections from Group IV or V, and for example Kyasanur Forest disease infection, dengue infection, influenza infection or RSV infection.

[0547] According to a particular embodiment, the treatment is continuous or discontinuous.

[0548] "Continuous treatment" refers to a long-term treatment that can be achieved at various administration frequencies, such as once a day, once every three days, once a week, or once every two weeks or once a month.

[0549] According to one embodiment, any one of the compounds of formula (I) or its pharmaceutically acceptable salts is administered at a specific dose, which varies between 0.1 - 1000 mg, particularly between 0.1 - 10 mg, or for example between 10 - 200 mg, or for example between 200 - 1000 mg.

[0550] Another object of the present invention relates to a method of treatment for treating and / or preventing RNA virus infections in a subject, and most preferably RNA virus infections caused by viruses belonging to Group IV or V of the Baltimore classification, which comprises administering a therapeutically effective amount of a compound of formula (I) as defined above, compounds (1) to (18) and (32) to (35) and (91) to (122) or one of its acceptable salts.

[0551] In a specific embodiment, the present invention provides the use of a compound of formula (I) according to the present invention or its pharmaceutically acceptable salt or its pharmaceutically active derivative or according to the method of the present invention, wherein the compound of formula (I) is to be administered in combination with a co-agent that can be used to treat said RNA virus infection, and most preferably said RNA virus infection from Group IV or V, and for example Kyasanur Forest disease infection, dengue infection, influenza infection or RSV infection.

[0552] The compound can be administered by any mode of administration, such as intramuscular, intravenous, intranasal or oral route, etc.

[0553] In suitable cases, the compounds of the present invention can be administered as prodrugs (such as esters) of the compounds involved in the present invention. A "prodrug" refers to a compound that can be converted in vivo into the compound of the present invention by metabolic means (such as by hydrolysis, reduction or oxidation). For example, an ester prodrug of the compound of the present invention can be converted into the parent molecule by in vivo hydrolysis. 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-hydroxynaphthoate, gentisate, hydroxyethylsulfonate, di-p-toluoyl tartrate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate and quinic acid ester. Examples of ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, reference to the compounds of the present invention is also intended to include any prodrug or metabolite form.

[0554] The compositions of the present invention may also include one or more additives such as diluents, excipients, stabilizers and preservatives. Such additives are well known to those skilled in the art and are particularly described in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition" (multiple editors, 1989 - 1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0555] The foregoing excipients are selected according to the dosage form and the desired mode of administration.

[0556] According to another embodiment, the pharmaceutically acceptable compositions of the present invention can be administered orally, rectally, parenterally, intrathecally, vaginally, intraperitoneally, topically (such as by powders, ointments or drops), sublingually, as oral or nasal sprays, etc. to humans and other animals, depending on the severity of the infection to be treated.

[0557] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oleaginous suspension. 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, such as a solution in 1,3-butanediol. Acceptable media and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly employed as a solvent or suspending medium.

[0558] The compositions of the present invention can be administered in any manner, including, but not limited to, orally, parenterally, sublingually, transdermally, vaginally, rectally, transmucosally, topically, nasally, by inhalation, by buccal administration or intranasally or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, arterial, intraperitoneal, subcutaneous, intramuscular, intrathecal and intra-articular. The compositions of the present invention may also be administered in the form of an implant which permits slow release of the composition as well as slow controlled intravenous infusion.

[0559] For example, the compounds of formula (I) can be present in any pharmaceutical form suitable for enteral or parenteral administration, together with suitable excipients, such as in the form of plain or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories or potions such as suspensions, syrups or injectable solutions or suspensions, in a dose such that 0.1 - 1000 mg of the active substance can be administered daily.

[0560] In a particular embodiment, the compounds of formula (I) according to the present invention are administered orally.

[0561] The oral route of administration is particularly preferred in the prophylactic or therapeutic aspects of the present invention.

Claims

Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for 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, 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, Torque teno virus infection, influenza virus infection and dengue virus infection: wherein: Ring sum The rings independently refer to phenylene or pyridylene groups, X 1 represents an alkenylene group, -NH-CO- group, -CO-NH- group, Y 1 represents an aryl group selected from a pyridyl group, a pyrazinyl group or a pyrimidinyl group, X 2 represent -O-group, -CO-NH-group, -NH-CO-NH-group, -OCH 2 - group -NH-CO-group, a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, or -SO 2 -NH-group, n is 0, 1, 2 or 3, m and m' are independently 0, 1 or 2, Y 2 represent a hydrogen atom, a hydroxy group, a morpholino group, A piperidyl group, which is optionally substituted by a (C 1 -C 4 ) alkyl group, A piperazinyl group, which is optionally substituted with a (C 1 -C 4 )alkyl group, or -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 4 ) alkyl group, and no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 ) cycloalkyl group, and the (C 3 -C 8 ) cycloalkyl group is optionally substituted by one or two (C 1 -C 4 ) alkyl groups, a halogen atom or a (C 1 -C 4 ) alkoxy group, and the (C 3 -C 8 ) cycloalkyl group is optionally interrupted by an oxygen atom on the R 1 and / or R 2 . Alternatively X 2 -(CH 2 ) n -Y 2 represents the group -C(=O)-NR c R d , where R c and R d together with the nitrogen atom form a saturated heterocycle, and the group is optionally substituted with one or two (C 1 -C 4 ) alkyl groups, substituted with a cyclopentyl group to form a spirocyclopentyl derivative, or substituted with a trifluoromethyl group R and R' independently represent (C 1 -C 4 ) alkyl group, (C 3 -C 6 ) cycloalkyl group, a halogen atom, (C 1 -C 5 ) alkoxy group, -SO 2 -NR a R b group -SO 3 H group -OH group, or -O-SO 2 -OR c group R a , R b , R c and R d independently represent a hydrogen atom or (C 1 -C 4 ) an alkyl group, Provided that when X 1 is an -NH-CO- group, Y 1 may further be a phenyl group, which is optionally substituted by one or two substituents selected from the following: 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, -SO 2 -NR a R b group, -SO 3 H group, -OH group, -O-SO 2 -OR c group or -O-P(=O)-(OR c )(OR d ) group.

2. The use according to claim 1, wherein the divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms is triazole or diazole.

3. Use according to claim 1, wherein Ring sum The rings each represent a phenylene group, or a ring represents a pyridylene group and a ring represents a phenylene group.

4. Use according to claim 1, wherein Y 1 represent 2-pyridyl group or 3-pyridyl group, a pyrimidinyl group or a pyrazinyl group, in which one of the nitrogen atoms is in the ortho position relative to X 1 to Provided that when X 1 is an -NH-CO- group, Y 1 may further be a phenyl group.

5. Use according to claim 1, wherein X 2 represents -O-group, -CO-NH-group, divalent triazole, or -SO 2 -NH-group.

6. Use according to claim 1, wherein Y 2 represent hydroxy group, morpholino group, A piperidinyl group, which is optionally substituted with a (C 1 -C 4 )alkyl group, A piperazinyl group, which is optionally substituted with a (C 1 -C 4 ) alkyl group, or -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom, a fluorine atom or a (C 1 -C 4 ) alkyl group, and no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 ) cycloalkyl group.

7. Use according to claim 1, wherein R and R' independently represent (C 1 -C 4 ) alkyl group, (C 3 -C 6 ) cycloalkyl group, a halogen atom, or (C 1 -C 5 ) alkoxy group.

8. Use according to claim 1, wherein Ring sum The rings all represent phenylene groups, Y 1 represents a 2-pyridyl group, provided that when X 1 is an -NH-CO- group, Y 1 may further be a phenyl group, X 2 represents an -O- group, a -CO-NH- group, Y 2 represent -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 4 ) alkyl group, and no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 8 ) cycloalkyl group, and R 3 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group, or morpholino group, and R and R' independently represent (C 1 -C 4 ) alkyl groups or (C 3 -C 6 ) cycloalkyl groups.

9. Use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for 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, 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, Torque teno virus infection, influenza virus infection and dengue virus infection, wherein Y 1 , R, R’, m, m’, ring, X 2 , n and Y 2 as defined in claim 1.

10. Use according to claim 9, wherein The ring is a phenylene group or a pyridylene group, Y 1 represents a 2-pyridyl group, a 3-pyridyl group or a pyrazinyl group, n is 1, 2 or 3, m is 0, R’ is a halogen atom, a (C 1 -C 2 ) alkoxy group or a (C 1 -C 2 ) alkyl group, X 2 represents a -CO-NH- group, -SO 2 NH- group or a divalent triazole, Y 2 represent a morpholinyl group, a piperidinyl group or a piperazinyl group, which is optionally substituted with a (C 1 -C 4 )alkyl group, -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, and no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group, Alternatively X 2 -(CH 2 ) n -Y 2 represents the group -C(=O)-NR c R d , where R c and R d together with the nitrogen atom form a saturated heterocycle, and the group is optionally substituted with one or two (C 1 -C 4 ) alkyl groups, substituted with a cyclopentyl group to form a spirocyclopentyl derivative, or substituted with a trifluoromethyl group.

11. Use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for 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, 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, Torque teno virus infection, influenza virus infection and dengue virus infection, wherein Y 1 , R, R’, m, m’, ring, X 2 , n and Y 2 as defined in claim 1.

12. Use according to claim 11, wherein The ring is a phenylene group, Y 1 is a phenyl group, a 2-pyridyl group or a pyrimidinyl group, wherein one of the nitrogen atoms of the pyrimidinyl group is in the ortho position relative to the -NH-CO- group, n is 1, 2 or 3, m is 0, m' is 0 or 1, R’ is a (C 3 -C 6 ) cycloalkyl group, X 2 represents a -CO-NH- group, an -O- group or a divalent triazole, Y 2 represent hydroxy group, a morpholinyl group, a piperidinyl group or a piperazinyl group, which is optionally substituted with a (C 1 -C 4 )alkyl group, -CR 1 R 2 R 3 group, wherein R 1 、R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, and no more than one of R 1 、R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group, and the (C 3 -C 6 ) cycloalkyl is optionally interrupted by an oxygen atom on the R 1 and / or R 2 .

13. Use of a compound of formula (Id) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for 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, 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, Torque teno virus infection, influenza virus infection and dengue virus infection, wherein Y 1 , R, R’, m, m’, ring, X 2 , n and Y 2 as defined in claim 1.

14. Use according to claim 13, wherein the ring is a phenylene group, Y 1 represents a 2-pyridyl group or a 3-pyridyl group, X 2 represents a -CO-NH- group, -SO 2 -NH- group or a divalent triazole, where m’ and m are 0, and n is 1, 2 or 3, Y 2 represents a hydroxyl group or -CR 1 R 2 R 3 group, where R 1 , R 2 and R 3 independently represent a hydrogen atom or a (C 1 -C 2 ) alkyl group, and no more than one of R 1 , R 2 and R 3 is a hydrogen atom, or R 1 and R 2 together with the carbon atom bearing them form a (C 3 -C 6 ) cycloalkyl group.

15. Use of any one of the compounds of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prophylaxis of an RNA virus infection caused by an RNA virus belonging to Baltimore classification groups IV or V, wherein the RNA virus infection caused by an RNA virus belonging to Baltimore classification groups IV or V is selected from RSV virus infection, Flexivirus infection, influenza virus infection and dengue virus infection, and wherein the compound of formula (I) is selected from:

16. Use of compound (114) and its pharmaceutically acceptable salts in the preparation of a medicament for the prevention and / or treatment of an RNA virus infection caused by an RNA virus belonging to Baltimore classification groups IV or V, wherein the RNA virus infection caused by an RNA virus belonging to Baltimore classification groups IV or V is selected from RSV virus infection, Flexivirus infection, influenza virus infection and dengue virus infection, 17. Any one of the compounds of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, which is selected from (1) a compound of formula (Ia) as defined in claim 9 wherein Y 1 is a 2-pyridyl group, 3-pyridyl or pyrazinyl group, group meta to the -NH- group on the ring The ring is a phenylene group, and provided that compounds 1 and 2 as defined in claim 15 are excluded, (2) a compound of formula (Ib) as defined in claim 11 wherein Y 1 is a phenyl group, a 2-pyridyl group or a pyrimidinyl group, one of the nitrogens of said pyrimidinyl group being in the ortho position relative to the -NH-CO- group, provided that the following compounds are excluded: and (3) a compound of formula (Id) as defined in claim 13 wherein Y 1 is a 2-pyridyl group, provided that the following compounds are excluded:

18. Use of any one of the compounds of formula (Ia), (Ib) and (Id) as defined in claim 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of an RNA virus infection caused by an RNA virus belonging to Baltimore classification groups IV or V, wherein the RNA virus infection caused by an RNA virus belonging to Baltimore classification groups IV or V is selected from RSV virus infection, Flexivirus infection, influenza virus infection and dengue virus infection.

19. Compounds as defined in claim 15 or 16, other than compound numbers 1 and 2, and their pharmaceutically acceptable salts.

20. The compound according to claim 19, wherein the pharmaceutically acceptable salt is selected from hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, trifluoromethanesulfonate, maleate, mesylate, formate, acetate and fumarate.

21. A pharmaceutical composition comprising at least one of the compounds as defined in claim 17 or a pharmaceutically acceptable salt thereof, or at least one of the compounds (3) to (18), (32) to (35), (91) to (122) as defined in claim 15 or 16 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

22. A synthetic method for preparing the compounds of formula (Ia), (Ib) and (Id) as defined in claim 17, which at least comprises the following steps: coupling a compound of formula (II) with a compound of formula (III) in the presence of an inorganic base and a diphosphine and in the presence of an organometallic catalyst to obtain a compound of formula (Ia), (Ib) or (Id) as defined in claim 17 ​ wherein X 1 , Y 1 , R, R’, m, m’, n, ring, ring, X 2 , Y 2 as defined in claim 17, and X is a chlorine atom, an iodine atom or a bromine atom.

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