Aryl-N-aryl derivatives for treating RNA virus infections

Abstract

The present invention relates to a compound of formula (I) below, or any one of its pharmaceutically acceptable salts: JPEG2022540941000170.jpg42170where, X 2 is -CO-NR k -group, -NR' k -CO- group, -O- group, -CO- group, -SO2- group, -CS-NH- group, -CH2-NH-, JPEG2022540941000171.jpg27170 group, or heterocyclyl, where the heterocyclyl is a 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and / or N; Y 2 is a morpholinyl group optionally substituted by a hydrogen atom, a halogen atom, a hydroxyl group, a (C1-C4) alkyl group or a trifluoromethyl group, a bridged morpholinyl group, a (C5-C 11 ) bicycloalkyl group, adamantyl group, piperidinyl group, (C1-C4) alkenyl group, -PO(OR a )(OR b ) group, a 5-membered heteroaromatic ring, or -CR 1 R 2 R 3 Represents a group. The present invention further relates to novel compounds, pharmaceutical compositions containing them, and synthetic methods for preparing them.

Description

[Technical field]

[0001] The present invention relates to novel compounds useful for preventing and / or treating RNA viral infections, most preferably RNA viral infections caused by RNA viruses belonging to Group V of the Baltimore classification, more particularly Respiratory Syncytial Virus (RSV) infections.

[0002] The present invention further relates to the use of the above compounds, in particular compounds useful for preventing and / or treating RNA viral infections, most preferably RNA viral infections caused by RNA viruses belonging to Group V of the Baltimore Classification, more particularly Respiratory Syncytial Virus (RSV) infections.

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

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

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

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

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

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

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

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

[0011] Representatives of viruses related to group V may include the Filoviridae virus family, which includes the Ebola virus, the Paramyxoviridae family, which includes the Respiratory Syncytial virus (RSV), the Rhabdoviridae family, and the Orthomyxoviridae family, which includes influenza A virus, influenza B virus, and influenza C virus.

[0012] A group within the virus family that is of particular focus within the framework of the present invention is the viruses that encompass the RNA viruses, in particular the single-stranded RNA viruses, and more particularly the RNA viruses belonging to group V of the Baltimore classification.

[0013] There are few treatments for diseases caused by RNA virus infections, especially single-stranded RNA viruses, more especially RNA virus infections from viruses belonging to group V of the Baltimore classification. Treatments are focused on alleviating symptoms. Therefore, there is still a need to identify new antiviral drugs, especially small chemical molecules, for treating RNA virus infections, such as RNA virus infections from group V, more especially respiratory syncytial virus (RSV) infections.

[0014] definition

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

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

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

[0018] In the context of the present invention, the term "treat" or "treatment" as used herein means reversing, alleviating, inhibiting the progression of a disease caused by an RNA virus infection, more particularly an RNA virus infection from group V, or one or more symptoms of such a disease, or preventing said disease or symptoms.

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

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

[0021] As used herein, the term "prevent" means reducing the risk or delaying the onset of a given phenomenon, i.e., a disease resulting from an RNA virus infection, in this invention, an RNA virus infection from group V, and even more particularly a respiratory syncytial virus (RSV) infection.

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

[0023] The term "prophylactically effective amount" refers to a concentration of a compound of the invention that, when administered prior to infection, i.e., before, during and / or shortly after the period of exposure to an RNA virus, more particularly an RNA virus from group V of the Baltimore classification, even more particularly Respiratory Syncytial Virus (RSV), is effective in inhibiting, preventing, reducing the likelihood of disease due to an RNA virus, more particularly an RNA virus from group V of the Baltimore classification, even more particularly Respiratory Syncytial Virus (RSV), or in preventing an RNA virus infection, more particularly an RNA virus from group V of the Baltimore classification, or in preventing the onset of disease due to an RNA virus, particularly an RNA virus from group V, more particularly Respiratory Syncytial Virus (RSV).

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

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

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

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

[0028] Viruses of the order Mononegavirales are also specifically considered by the present invention. The order Mononegavirales includes viruses belonging to group V of the Baltimore classification. As of 2018, this order mainly includes the following virus families: Bornaviridae, Mymonaviridae, Filoviridae, Nyamiviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, and Sunviridae.

[0029] Human respiratory syncytial virus (HRSV) is a syncytial virus that causes respiratory tract infections. It is a major cause of lower respiratory tract infections and hospital visits in infancy and childhood. HRSV virus may be particularly considered by the present invention and is related to group V of RNA viruses. More particularly, RSV virus is a (-)ssRNA virus belonging to group V of the Baltimore classification. It is a pneumovirus that is part of the family Paramyxoviridae, belonging to the order Mononegavirales. Among other viruses of the order Mononegavirales, those particularly considered by the present invention include measles virus, mumps virus, Nipah virus, rabies virus, and human parainfluenza virus (including HPIV-1, HPIV-2, HPIV-3, and HPIV). Of note, the subfamily of Paramyxoviridae has traditionally been integrated into the Paramyxoviridae family by reference to the 2016 updated classification of the Mononegavirales.

[0030] Viral genera of particular interest within the Paramyxoviridae family include the genera Aquaparamyxovirus, Avulavirus, Ferravirus, Henipavirus, Morbillivirus, Respirovirus, and Rubulavirus.

[0031] Viruses of the family Orthomyxoviridae are also specifically contemplated by the present invention. The family Orthomyxoviridae belongs to the order "Unassigned" according to the 2017 classification of viruses. Particularly contemplated virus genera in the family Orthomyxoviridae include Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus, Gammainfluenzavirus, Isavirus, Quaranjavirus, and Thogotovirus.

[0032] Influenza virus A, influenza virus B, influenza virus C are particularly considered by the present invention and may relate to the group V RNA viruses and the family Orthomyxoviridae, which can be defined as negative-sense single-stranded RNA or (-)ssRNA viruses. Isaviruses and Thogotoviruses also belong to the order Orthomyxovirales. Summary of the Invention [Problem to be solved by the invention]

[0033] The present inventors have surprisingly discovered that aryl-N-aryl compounds have broad spectrum activity against RNA viruses, more particularly single-stranded RNA viruses belonging to Group V of the Baltimore Classification. Group IV or Group V respectively include (+)ssRNA viruses and (-)ssRNA viruses, which also include (+)ssRNA viruses and (-)ssRNA viruses, which also refer to positive-sense single-stranded RNA viruses and negative-sense single-stranded RNA viruses.

[0034] For reference, the contents of the "Baltimore Classification" have been taken into account in the context of the classification and nomenclature of viruses as outlined in the 10th Report on Virus Taxonomy, 2017. [Means for solving the problem]

[0035] According to one aspect, the present invention relates to a compound of formula (I) below, or any one of its pharma- ceutically acceptable salts: [ka] Where: [ka] Ring and [ka] each ring independently represents a phenylene group or a pyridylene group; Z" represents a -CH2- group or a -CO- group; R g and R h each independently represents a hydrogen atom, a (C1-C4) alkyl group, a (C3-C6) cycloalkyl group, a -CH2CHF2 group, or a -COCH3 group; Q is NH or O; X 2 teeth, -CO-NR k - group, where R k represents a hydrogen atom or a methyl group; -NR' k -CO- group, where R' k represents a hydrogen atom or a methyl group; -O- group, -CO- group, -SO2- group, -CS-NH- group, -CH2-NH- group, [ka] base, Or, heterocyclyl, where the heterocyclyl is a 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and / or N, for example triazole, pyrazoline, oxazole, oxazoline, oxazolidine, imidazole, pyrazole, imidazoline, tetrazole or oxadiazole, which ring is optionally substituted by a (C1-C4) alkyl group, a halogen atom or =O; represents n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y 2 teeth, Hydrogen atom, Halogen atoms, Hydroxyl groups, a morpholinyl group optionally substituted by a (C1-C4) alkyl group or a trifluoromethyl group, a bridged morpholinyl group optionally substituted by a halogen atom; (C5~C 11 ) a bicycloalkyl group, a piperidinyl group, optionally interrupted by a SO group; (C1-C4) alkenyl group, -PO(OR a )(OR b ) group, Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that more than one of R is not a hydrogen atom, or 1 and R 2form a (C3-C8) cycloalkyl group together with the carbon atom to which they are attached, wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups optionally substituted by hydroxy groups, halogen atoms, trifluoromethyl groups, cyano groups, phosphonate groups, or (C1-C4) alkoxy groups, wherein the (C3-C8) cycloalkyl group is selected from the group represented by the above R 1 and / or R 2 may be interrupted by one or two oxygen atoms or by a -SO2- group, represents R and R' are independently a (C1-C4) alkyl group which may be substituted by a hydroxyl group and which may be interrupted by a -SO2- group or a -SO- group; (C1-C4) alkenyl group, (C3-C6) cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, Halogen atoms, Cyano group, Or, (C1-C5) alkoxy group represents R a and R b each independently represents a hydrogen atom or a (C1-C4) alkyl group.

[0036] According to one aspect, the present invention relates to a compound of formula (I) below, or any one of its pharma- ceutically acceptable salts: [ka] Where: [ka] Ring and [ka] each ring independently represents a phenylene group or a pyridylene group; Z" represents a -CH2- group or a -CO- group; R g and R h each independently represents a hydrogen atom, a (C1-C4) alkyl group, a (C3-C6) cycloalkyl group, or a -COCH3 group; Q is NH or O; X 2 teeth, -CO-NR k - group, where R k represents a hydrogen atom or a methyl group; -NR' k -CO- group, where R' k represents a hydrogen atom or a methyl group; -O- group, -CO- group, -SO2- group, -CS-NH- group, -CH2-NH- group, [ka] base, Or, Divalent 5-membered heteroaromatic rings containing 1, 2, 3 or 4 heteroatoms, such as triazole, imidazole, tetrazole, or oxadiazole. represents n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y 2 teeth, Hydrogen atom, Halogen atoms, Hydroxyl groups, a morpholinyl group optionally substituted by a (C1-C4) alkyl group; a piperidinyl group optionally substituted by a SO group; (C1-C4) alkenyl group, -PO(OR a )(OR b ) group, Or, -CR 1 R2 R 3 Group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that more than one of R is not a hydrogen atom. 1 and R 2 together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl group, wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms, trifluoromethyl groups, cyano groups, or (C1-C4) alkoxy groups, and wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms, trifluoromethyl groups, cyano groups, or (C1-C4) alkoxy groups, and wherein the (C3-C8) cycloalkyl group is 1 and / or R 2 may be interrupted by one or two oxygen atoms or by -SO2-, represents R and R' are independently a (C1-C4) alkyl group which may be substituted by a hydroxyl group and which may be interrupted by a -SO2- group or a -SO- group; (C1-C4) alkenyl group, (C3-C6) cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, Halogen atoms, Or, (C1-C5) alkoxy group represents R a and R b each independently represents a hydrogen atom or a (C1-C4) alkyl group.

[0037] In other words, [ka] is the following group (A) [ka] Or the following group (B): [ka]

[0038] Represents.

[0039] First perspective In accordance with the present invention, the present invention relates to a compound of formula (I) below, or any one of its pharma- ceutically acceptable salts: [ka] Where: [ka] Ring and [ka] each ring independently represents a phenylene group or a pyridylene group; Z" represents a -CH2- group or a -CO- group; R g and R h each independently represents a hydrogen atom, a (C1-C4) alkyl group, a (C3-C6) cycloalkyl group, a -CH2CHF2 group, or a -COCH3 group; Q is NH or O; X 2 teeth, -CO-NR k - group, where R k represents a hydrogen atom or a methyl group; -NR' k -CO- group, where R' k represents a hydrogen atom or a methyl group; -O- group, -CO- group, -SO2- group, -CS-NH- group, -CH2-NH-, [ka] base, Or, Heterocyclyl, where the heterocyclyl is a 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and / or N, such as triazolyl, pyrazolinyl, oxazolyl, oxazolinyl, oxazolidinyl, imidazolyl, dihydroimidazolyl, pyrazolyl, imidazolinyl, tetrazolyl, or oxadiazolyl, and the ring may be selected from (C1-C4) alkyl groups, halogen atoms, -COOR p R may be substituted by a group or ═O; p is a (C1-C4) alkyl group; represents n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y 2 teeth, Hydrogen atom, Halogen atoms, Hydroxyl groups, a morpholinyl group optionally substituted by a (C1-C4) alkyl group or a trifluoromethyl group, a bridged morpholinyl group optionally substituted by a halogen atom; (C5~C 11 ) a bicycloalkyl group, an adamantyl group, a piperidinyl group, which may be interrupted by a SO group; (C1-C4) alkenyl group, -PO(OR a )(OR b ) group, 5-membered heteroaromatic rings containing one or two heteroatoms selected from oxygen and nitrogen atoms, such as oxazolyl, isoxazolyl, pyrazolyl and imidazolyl, in particular oxazolyl; Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R2 and R 3 It is understood that more than one of R is not a hydrogen atom, or 1 and R 2 form a (C3-C8) cycloalkyl group together with the carbon atom to which they are bonded, wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups optionally substituted by hydroxy groups, halogen atoms, trifluoromethyl groups, cyano groups, phosphonate groups, oxo groups, or (C1-C4) alkoxy groups, wherein the (C3-C8) cycloalkyl group is selected from the group consisting of the above R 1 and / or R 2 may be interrupted by one or two oxygen atoms, by a sulfur atom, by a nitrogen atom or by a -SO2- group, represents R and R' are independently a (C1-C4) alkyl group which may be substituted by a hydroxyl group and which may be interrupted by a -SO2- group or a -SO- group; (C1-C4) alkenyl group, (C3-C6) cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, Halogen atoms, Cyano group, Or, (C1-C5) alkoxy group represents R a and R b each independently represents a hydrogen atom or a (C1-C4) alkyl group.

[0040] Second perspective Accordingly, the present invention relates to a compound of formula (I) as defined above, or any one of its pharma- ceutically acceptable salts, and to any one of compounds (1) to (181) as defined herein, or any one of their pharma-ceutically acceptable salts, for use as a medicament.

[0041] Third perspective Accordingly, the present invention relates to a compound of formula (I) as defined above, or any one of its pharma- ceutically acceptable salts, and to any one of compounds (1) to (181) as defined herein, or any one of its pharma-ceutically acceptable salts, for use in the treatment and / or prophylaxis of an RNA virus infection caused by an RNA virus belonging to group V of the Baltimore classification, in particular an RSV virus infection, or a virus-related condition.

[0042] The above-mentioned compound (I) is particularly suitable for treating or preventing a viral infection or associated condition, in particular an RNA virus infection or associated condition caused by an RNA virus belonging to group V of the Baltimore classification, more preferably an RSV virus infection or virus-associated condition.

[0043] According to a particular embodiment, the present invention provides a method for producing a composition comprising: [ka] Ring and [ka] both of the rings represent phenylene groups, or [ka] The ring represents a pyridylene group, and [ka] The present invention relates to a compound of formula (I) as defined above, wherein the ring represents a phenylene group, or any one of its pharma- ceutically acceptable salts.

[0044] In another embodiment, the invention relates to the compounds of formula (I) as defined above, or any one of its pharma- ceutically acceptable salts, wherein Q is an NH-group.

[0045] In another embodiment, the present invention provides a method for the preparation of a medicament comprising administering to a subject the g and Rh represents a hydrogen atom, or any one of its pharma- ceutically acceptable salts.

[0046] In another embodiment, the present invention provides X 2 but, -CO-NH- group, -NH-CO- group, -O- group, -CO- group, Or, heterocyclyl, where the heterocyclyl is a 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and / or N, for example triazole, imidazole, imidazoline, oxazoline, oxazolidine or tetrazole, which ring is optionally substituted by a (C1-C4) alkyl group, a halogen atom or =O; or any one of its pharma- ceutically acceptable salts.

[0047] In another embodiment, the present invention provides X 2 but, -CO-NH- group, -NH-CO- group, -O- group, -CO- group, Or, a divalent 5-membered heteroaromatic ring containing at least two nitrogen atoms, such as triazole, imidazole, or tetrazole; or any one of its pharma- ceutically acceptable salts.

[0048] In another embodiment, the present invention provides X 2 but, -CO-NH- group, -NH-CO- group, -O- group, -CO- group, Or, Heterocyclyl, where the heterocyclyl is a 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and / or N, such as triazolyl, imidazolyl, imidazolinyl, oxazolyl, oxazolinyl, oxazolidinyl, dihydroimidazolyl, or tetrazolyl, and the ring may be selected from (C1-C4) alkyl groups, halogen atoms, -COOR p R may be substituted by a group or ═O; p is a (C1-C4) alkyl group; or any one of its pharma- ceutically acceptable salts.

[0049] In another embodiment, the present invention provides Y 2 but, Hydrogen atom, Halogen atoms, a morpholinyl group optionally substituted by a (C1-C4) alkyl group or a trifluoromethyl group, a bridged morpholinyl group optionally substituted by a halogen atom; (C5~C 11 ) a bicycloalkyl group, (C1-C4) alkenyl group, -PO(OR a )(OR b ) group, Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that more than one of R is not a hydrogen atom, or 1 and R 2form, together with the carbon atom to which they are attached, a (C3-C8)cycloalkyl group, wherein the (C3-C8)cycloalkyl group is optionally substituted by one or two (C1-C4)alkyl groups which may be substituted by a hydroxy group, a halogen atom, a trifluoromethyl group, a cyano group, or a phosphonate group, and wherein the (C3-C8)cycloalkyl group is 1 and / or R 2 may be interrupted by one or two oxygen atoms or by a -SO2- group, represents R a and R b is as defined above, or any one of its pharma- ceutically acceptable salts.

[0050] In another embodiment, the present invention provides Y 2 but, Hydrogen atom, Halogen atoms, a morpholinyl group optionally substituted by a (C1-C4) alkyl group; (C1-C4) alkenyl group, -PO(OR a )(OR b ) group, Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3 It is understood that more than one of R is not a hydrogen atom, or 1 and R 2together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl group, wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms, trifluoromethyl groups, or cyano groups, and wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms, trifluoromethyl groups, or cyano groups, and wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups, halogen atoms, trifluoromethyl groups, or cyano groups, 1 and / or R 2 may be interrupted by one or two oxygen atoms or by a -SO2- group, represents R a and R b is as defined in claim 1, or any one of its pharma- ceutically acceptable salts.

[0051] In another embodiment, the present invention provides Y 2 but, Hydrogen atom, Halogen atoms, a morpholinyl group optionally substituted by a (C1-C4) alkyl group or a trifluoromethyl group, a bridged morpholinyl group optionally substituted by a halogen atom; (C5~C 11 ) a bicycloalkyl group, Adamantyl group, (C1-C4) alkenyl group, -PO(OR a )(OR b ) group, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, in particular oxazolyl; Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 each independently represents a hydrogen atom, a fluorine atom, or a (C1-C4) alkyl group; R 1 , R 2 and R 3It is understood that more than one of R is not a hydrogen atom, or 1 and R 2 form a (C3-C8) cycloalkyl group together with the carbon atom to which they are attached, wherein the (C3-C8) cycloalkyl group is optionally substituted by one or two (C1-C4) alkyl groups optionally substituted by hydroxy groups, halogen atoms, trifluoromethyl groups, cyano groups, phosphonate groups, or oxo groups, and wherein the (C3-C8) cycloalkyl group is 1 and / or R 2 may be interrupted by one or two oxygen atoms, by a sulfur atom, by a nitrogen atom or by a -SO2- group, represents R a and R b is as defined in claim 1, or any one of its pharma- ceutically acceptable salts.

[0052] In more specific embodiments, the polycyclic (bicyclic) alkyl group is selected from the group consisting of spiro[2.2]pentyl, spiro[5.5]undecanyl, spiro[3.4]octanyl, spiro[4.5]decanyl, bicyclo[1.1.0]butyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[1.1.1]pentyl, oxa ... It may be selected from the group consisting of cyclo[1.1.1]pentyl, oxabicyclo[2.1.1]hexyl, oxabicyclo[2.2.1]heptyl, oxabicyclo[4.1.0]heptyl, oxabicyclo[3.2.1]octyl, and cubyl, more particularly from the group consisting of bicyclo[1.1.1]pentyl, oxabicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, oxabicyclo[2.1.1]hexyl, and even more particularly bicyclo[1.1.1]pentyl.

[0053] In another embodiment, the present invention provides R and R' are independently a (C1-C4) alkyl group which may be substituted by a hydroxyl group and which may be interrupted by a -SO2- group or a -SO- group; (C3-C6) cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, A chlorine atom or a fluorine atom, Cyano group, Or, (C1-C5) alkoxy group or any one of its pharma- ceutically acceptable salts.

[0054] In another embodiment, the present invention provides R and R' are independently a (C1-C4) alkyl group which may be substituted by a hydroxyl group and which may be interrupted by a -SO2- group or a -SO- group; (C3-C6) cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, A chlorine atom or a fluorine atom, Or, (C1-C5) alkoxy group or any one of its pharma- ceutically acceptable salts.

[0055] In another embodiment, the present invention provides R and R' are independently a (C1-C4) alkyl group which may be substituted by a hydroxyl group and which may be interrupted by a -SO2- group or a -SO- group; (C3-C6) cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, A chlorine atom or a fluorine atom, Cyano group, Or, (C1-C5) alkoxy group or any one of its pharma- ceutically acceptable salts.

[0056] R, R', Z", R g , R h ,Q,m,m', [ka] ring, [ka] Tamaki, X 2 , n, and Y 2 Any combination of the above defined embodiments forms part of the present invention.

[0057] According to a preferred embodiment of the invention, the compounds of formula (I) and their pharma- ceutically acceptable salts are selected from: - (1) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-[(3-{[1-(propan-2-yl)cyclopropyl]carbamoyl}phenyl)amino]benzamide, - (2) 3-cyclopentyl-N-[(2E)-imidazolidin-2-ylidene]-4-{[3-(2-methylpropanamido)phenyl]amino}benzamide, - (3) 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-cyclopentyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (4) 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, (5) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-{[3-(4-methylpentanamido)phenyl]amino}benzamide, - (6) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[(4-methylpentan-2-yl)carbamoyl]phenyl}amino)benzamide, - (7) 2-cyclopropyl-3-[(2-cyclopropyl-4-{[(2E)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(3-methylbutyl)benzamide, (8) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[(3-methylbutyl)carbamoyl]phenyl}amino)benzamide, - (9) 3-tert-butyl-4-{[2-cyclopropyl-3-(morpholine-4-carbonyl)phenyl]amino}-N-[(2E)-imidazolidin-2-ylidene]benzamide, -(10) 4-({2-chloro-3-[(3-methylbutyl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (11) 4-({2-chloro-3-[(propan-2-yl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (12) 4-({2-chloro-3-[2-(1,4-dioxan-2-yl)ethoxy]phenyl}amino)-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (13) 4-[(3-cyclopropanamidophenyl)amino]-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (14) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)benzamide, (15) 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-N-[(2E)-imidazolidin-2-ylidene]-3-(oxolan-3-yl)benzamide, - (16) 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-N-[(2E)-imidazolidin-2-ylidene]-3-(trifluoromethyl)benzamide, - (17) 3-tert-butyl-N-[(2E)-1-methylimidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (18) 3-cyclobutyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)benzamide, - (19) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (20) 3-tert-butyl-4-{[3-(2,2-dimethylpropanamido)phenyl]amino}-N-[(2Z)-imidazolidin-2-ylidene]benzamide, (21) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-{[3-(1-methylcyclopropanamido)phenyl]amino}benzamide, - (22) 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (23) 4-({2-chloro-3-[(1,4-dioxan-2-yl)methoxy]phenyl}amino)-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (24) 3-tert-butyl-4-({3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-N-[(2E)-1-methylimidazolidin-2-ylidene]benzamide, - (25) 4-{[2-chloro-3-(cyclopropylcarbamoyl)phenyl]amino}-3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (26) 3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]-4-{[3-(2-methylpropanamido)phenyl]amino}benzamide, - (27) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({2-methoxy-3-[(3-methylbutyl)carbamoyl]phenyl}amino)benzamide, - (28) 4-({2-chloro-3-[(oxolan-3-yl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (29) N-[(2E)-imidazolidin-2-ylidene]-4-({3-[(3-methylbutyl)carbamoyl]phenyl}amino)-3-(prop-1-en-2-yl)benzamide, - (30) 3-(2-hydroxypropan-2-yl)-N-[(2E)-imidazolidin-2-ylidene]-4-{[3-(morpholine-4-carbonyl)-2-(trifluoromethyl)phenyl]amino}benzamide, - (31) 3-cyclopropyl-4-({3-[(1-ethylcyclopropyl)carbamoyl]phenyl}amino)-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (32) 3-cyclopropyl-4-({3-fluoro-5-[(propan-2-yl)carbamoyl]phenyl}amino)-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (33) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-[(3-{[2-(oxan-3-yl)ethyl]carbamoyl}phenyl)amino]benzamide, - (34) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamothioyl]phenyl}amino)benzamide, - (35) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-[(3-{[2-(oxan-2-yl)ethyl]carbamoyl}phenyl)amino]benzamide, - (36) 3-cyclopropyl-N-[(2E)-1-methylimidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (37) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-{[3-(2-methylpropanamido)phenyl]amino}benzamide, - (38) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[methyl(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (39) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-[(3-{[2-(oxan-4-yl)ethyl]carbamoyl}phenyl)amino]benzamide, - (40) 2-[(2-cyclopropyl-4-{[(2E)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-3-methyl-N-(3-methylbutyl)pyridine-4-carboxamide, - (41) 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-[(2E)-4-oxoimidazolidin-2-ylidene]benzamide, - (42) 4-{[2-cyclopropyl-3-(morpholine-4-carbonyl)phenyl]amino}-N-[(2Z)-imidazolidin-2-ylidene]-3-(trifluoromethyl)benzamide, - (43) 3-cyclopropyl-N-[(2E)-1-cyclopropylimidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (44) 3-(2-hydroxypropan-2-yl)-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[(3-methylbutyl)carbamoyl]phenyl}amino)benzamide, - (45) 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-(2-hydroxypropan-2-yl)-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (46) N-[(2E)-1-acetylimidazolidin-2-ylidene]-4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzamide, - (47) 3-cyclopropyl-4-({3-fluoro-5-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (48) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-[(3-{[2-(oxolan-3-yl)ethyl]carbamoyl}phenyl)amino]benzamide, - (49) 3-tert-butyl-N-[(2E)-4-oxoimidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (50) 4-({2-chloro-3-[(oxan-4-yl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (51) 3-cyclopentyl-4-({3-[(1,4-dioxan-2-yl)methoxy]phenyl}amino)-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (52) 3-tert-butyl-4-({3-[(1,4-dioxan-2-yl)methoxy]phenyl}amino)-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (53) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-[(3-{[1-(trifluoromethyl)cyclopropyl]carbamoyl}phenyl)amino]benzamide, - (54) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-({2-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (55) 2-[(2-tert-butyl-4-{[(2E)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(3-methylbutyl)pyridine-4-carboxamide, - (56) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-({2-[(2-methylpropyl)carbamoyl]phenyl}amino)benzamide, - (57) 4-{[3-(5-chloro-1H-imidazol-2-yl)-2-methylphenyl]amino}-3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (58) 3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]-4-[(3-{[2-(oxan-4-yl)ethyl]carbamoyl}phenyl)amino]benzamide, (59) N-[(2E)-imidazolidin-2-ylidene]-3-(oxolan-3-yl)-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (60) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[1-(3-methylbut-2-en-1-yl)-1H-1,2,3,4-tetrazol-5-yl]phenyl}amino)benzamide, - (61) 3-cyclopropyl-N-[(2E)-1-methyl-5-oxoimidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (62) 3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]-4-({2-[(3-methylbutyl)carbamoyl]phenyl}amino)benzamide, - (63) N-[(2E)-imidazolidin-2-ylidene]-4-{[3-(2-methylpropanamido)phenyl]amino}-3-(oxolan-3-yl)benzamide, - (64) 4-({3-[(1-cyanocyclopropyl)carbamoyl]-2-methylphenyl}amino)-3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (65) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]-5-(trifluoromethyl)phenyl}amino)benzamide, - (66) 3-cyclopropyl-4-({4-fluoro-3-[(propan-2-yl)carbamoyl]phenyl}amino)-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (67) 3-(2-hydroxypropan-2-yl)-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[3-(oxan-4-yl)propoxy]phenyl}amino)benzamide, - (68) N-{3-[(2-cyclopropyl-4-{[(2E)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-2-methylphenyl}-3-methyloxetane-3-carboxamide, (69) N-[(2Z)-imidazolidin-2-ylidene]-3-(oxan-4-yl)-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (70) 3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]-4-({2-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (71) 3-tert-butyl-N-[(2Z)-1,3-dimethylimidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (72) 3-chloro-N-[(2E)-imidazolidin-2-ylidene]-4-{[3-(2-methylpropanamido)phenyl]amino}benzamide, - (73) 3-cyclopropyl-4-{[3-fluoro-5-(morpholine-4-carbonyl)phenyl]amino}-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (74) 2-[(2-tert-butyl-4-{[(2E)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-[2-(oxan-4-yl)ethyl]pyridine-4-carboxamide, - (75) 3-cyclopropyl-4-{[3-(N,2-dimethylpropanamido)phenyl]amino}-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (76) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-[(3-{[(propan-2-yl)carbamoyl]methyl}phenyl)amino]benzamide, - (77) 3-cyclopropyl-4-({2-fluoro-5-[(propan-2-yl)carbamoyl]phenyl}amino)-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (78) 4-{[2-cyclopropyl-3-(morpholine-4-carbonyl)phenyl]amino}-3-(2-hydroxypropan-2-yl)-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (79) 3-(furan-3-yl)-N-[(2E)-imidazolidin-2-ylidene]-4-[(3-{[2-(oxan-4-yl)ethyl]carbamoyl}phenyl)amino]benzamide, - (80) 3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]-4-({2-[(2-methylpropyl)carbamoyl]phenyl}amino)benzamide, - (81) 3-cyclopropyl-N-[(2E)-1-methyl-4-oxoimidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (82) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-[(3-{3-[(propan-2-yl)amino]oxetan-3-yl}phenyl)amino]benzamide, - (83) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(2-methylpropanamido)methyl]phenyl}amino)benzamide, - (84) 3-(2-hydroxypropan-2-yl)-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[3-(oxan-4-yl)propanesulfonyl]phenyl}amino)benzamide, - (85) 3-(2-hydroxypropan-2-yl)-N-[(2E)-imidazolidin-2-ylidene]-4-({3-[2-(oxan-4-yl)ethoxy]phenyl}amino)benzamide, - (86) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(1-methylcyclopropyl)carbamoyl]-5-(trifluoromethyl)phenyl}amino)benzamide, - (87) 3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]-4-{2-[(3-methylbutyl)carbamoyl]phenoxy}benzamide, - (88) 4-({3-[2-(1,4-dioxan-2-yl)ethoxy]phenyl}amino)-3-(2-hydroxypropan-2-yl)-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (89) 3-[(2-cyclopropyl-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-2-methylphenyl diethyl phosphate, - (90) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[2-(3-methylbut-2-en-1-yl)-2H-1,2,3,4-tetrazol-5-yl]phenyl}amino)benzamide, - (91) 3-cyclopropyl-5-fluoro-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (92) 3-[(2-cyclopropyl-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-2-(furan-3-yl)-N-(propan-2-yl)benzamide, - (93) 3-tert-butyl-N-[(2E)-imidazolidin-2-ylidene]-4-[2-(4-methylpentanamido)phenoxy]benzamide, -(94) 4-({2-chloro-3-[(1,1-dioxo-1λ 6 -thian-4-yl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (95) 3-Cyclopentyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(oxolan-3-yl)carbamoyl]phenyl}amino)benzamide, - (96) 3-Cyclopentyl-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(oxan-4-yl)carbamoyl]phenyl}amino)benzamide, - (97) 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-N-[(2E)-imidazolidin-2-ylidene]-3-(oxolan-2-yl)benzamide, - (98) 3-cyclopropyl-4-({2-fluoro-3-[(propan-2-yl)carbamoyl]phenyl}amino)-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (99) 4-[(2-cyclopropyl-6-fluoro-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-3-fluoro-N-(1-methylcyclopropyl)pyridine-2-carboxamide, -(100) 3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]-4-[2-(4-methylpentanamido)phenoxy]benzamide, -(101) 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-N-[(2E)-imidazolidin-2-ylidene]-3-methanesulfinylbenzamide, - (102) 2-chloro-3-[(4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}-2-methanesulfonylphenyl)amino]-N-(1-methylcyclopropyl)benzamide, -(103) 4-{[2-chloro-3-(1,1-dioxo-1λ 6 -thiomorpholine-4-carbonyl)phenyl]amino}-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, - (104) 4-({2-chloro-3-[3-(propan-2-yl)morpholine-4-carbonyl]phenyl}amino)-3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (105) 4-({2-chloro-3-[2-(propan-2-yl)morpholine-4-carbonyl]phenyl}amino)-3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (106) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-5-methyl-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (107) 3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]-4-[(3-{[1-(2-methylpropyl)cyclopropyl]carbamoyl}phenyl)amino]benzamide, - (108) N-{3-[(2-cyclopropyl-4-{[(2E)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]phenyl}oxolane-2-carboxamide, - (109) 4-[(2-chloro-3-{[(oxolan-2-yl)methyl]carbamoyl}phenyl)amino]-3-cyclopropyl-N-[(2E)-imidazolidin-2-ylidene]benzamide, -(110) N-[(2E)-1-acetylimidazolidin-2-ylidene]-3-cyclopropyl-4-{[3-(2-methylpropanamido)phenyl]amino}benzamide, -(111) 4-({3-[(1-tert-butylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (112) 4-({3-cyano-5-[(propan-2-yl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (113) 3-cyclopropyl-N-[1-(2,2-difluoroethyl)imidazolidin-2-ylidene]-4-{[3-(2-methylpropanamido)phenyl]amino}benzamide, - (114) 4-[(2-chloro-3-{[1-(trifluoromethyl)cyclopropyl]carbamoyl}phenyl)amino]-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (115) 3-cyclopropyl-N-[imidazolidin-2-ylidene]-4-{[3-(morpholine-4-carbonyl)-2-(trifluoromethyl)phenyl]amino}benzamide, -(116) 3-cyclopropyl-4-{[3-(cyclopropylcarbamoyl)-2-(trifluoromethyl)phenyl]amino}-N-[imidazolidin-2-ylidene]benzamide, - (117) 3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]-4-({3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)benzamide, - (118) 4-{[2-chloro-5-fluoro-3-(morpholine-4-carbonyl)phenyl]amino}-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (119) 3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]-4-{[3-(morpholine-4-carbonyl)phenyl]amino}benzamide, - (120) 4-({2-chloro-3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]phenyl}amino)-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (121) 4-({2-chloro-3-[2-(trifluoromethyl)morpholine-4-carbonyl]phenyl}amino)-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (122) 4-({2-chloro-3-[3-(trifluoromethyl)morpholine-4-carbonyl]phenyl}amino)-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (123) 3-chloro-2-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(1-methylcyclopropyl)pyridine-4-carboxamide, -(124) N-{3-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]phenyl}-1,1-dioxo-1λ 6 -thiane-4-carboxamide, - (125) 3-fluoro-N-[imidazolidin-2-ylidene]-4-({3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-5-(oxolan-2-yl)benzamide, - (126) 4-{[2-chloro-3-(morpholine-4-sulfonyl)phenyl]amino}-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (127) 4-({3-[(1-cyanocyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]benzamide, - (128) 3-cyclopropyl-5-fluoro-4-({3-fluoro-5-[(propan-2-yl)carbamoyl]phenyl}amino)-N-[imidazolidin-2-ylidene]benzamide, - (129) 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]benzamide, - (130) 3-cyclopropyl-5-fluoro-4-({2-fluoro-3-[(propan-2-yl)carbamoyl]phenyl}amino)-N-[imidazolidin-2-ylidene]benzamide, - (131) 5-cyclopropyl-2-fluoro-N-[imidazolidin-2-ylidene]-4-({3-[(propan-2-yl)carbamoyl]phenyl}amino)benzamide, - (132) 3-tert-butyl-4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-N-[imidazolidin-2-ylidene]benzamide, - (133) 5-cyclopropyl-N-[imidazolidin-2-ylidene]-6-({3-[(propan-2-yl)carbamoyl]phenyl}amino)pyridine-3-carboxamide, - (134) 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-fluoro-N-[imidazolidin-2-ylidene]-5-(oxolan-3-yl)benzamide, - (135) 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-fluoro-N-[imidazolidin-2-ylidene]-5-(oxolan-2-yl)benzamide, - (136) 3-chloro-2-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(1-methylcyclopropyl)pyridine-4-carboxamide, - (137) 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-N-[imidazolidin-2-ylidene]-3-(oxolan-2-yl)benzamide, - (138) 3-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-2,5-difluoro N-(propan-2-yl)benzamide, - (139) 3-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-2,5-difluoro N-(1-methylcyclopropyl)benzamide, - (140) N-[imidazolidin-2-ylidene]-4-({3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-(oxolan-2-yl)benzamide, - (141) 4-{[3-(1-cyanocyclopropanamido)phenyl]amino}-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (142) 3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]-4-({3-[3-(trifluoromethyl)morpholine-4-carbonyl]phenyl}amino)benzamide, - (143) 3-cyclopropyl-5-fluoro-4-({2-fluoro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-N-[imidazolidin-2-ylidene]benzamide, - (144) 3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]-4-({3-[2-(trifluoromethyl)morpholine-4-carbonyl]phenyl}amino)benzamide, - (145) 3-Fluoro-N-[imidazolidin-2-ylidene]-4-{[3-(morpholine-4-carbonyl)phenyl]amino}-5-(oxolan-2-yl)benzamide, - (146) 6-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-5-cyclopropyl-N-[imidazolidin-2-ylidene]pyridine-3-carboxamide, - (147) 2-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-3-fluoro-N-(1-methylcyclopropyl)pyridine-4-carboxamide, - (148) 2-cyclopropyl-3-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-5-fluoro-N-(propan-2-yl)benzamide, - (149) 3-cyano-5-cyclopropyl-N-[imidazolidin-2-ylidene]-4-({3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)benzamide, - (150) 3-chloro-4-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide, - (151) 4-chloro-5-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(1-methylcyclopropyl)pyridine-3-carboxamide, - (152) N-(1-cyanocyclopropyl)-2-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-3-fluoropyridine-4-carboxamide, - (153) 4-{[3-chloro-4-(morpholine-4-carbonyl)pyridin-2-yl]amino}-3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]benzamide, - (154) 4-({3-chloro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]pyridin-2-yl}amino)-3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]benzamide, - (155) 4-({3-chloro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]pyridin-2-yl}amino)-3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]benzamide, - (156) 3-cyclopropyl-5-fluoro-4-{[3-fluoro-4-(morpholine-4-carbonyl)pyridin-2-yl]amino}-N-[imidazolidin-2-ylidene]benzamide, - (157) 3-chloro-4-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide, - (158) 3-cyclopropyl-5-fluoro-4-{[2-fluoro-3-(morpholine-4-carbonyl)phenyl]amino}-N-[imidazolidin-2-ylidene]benzamide, - (159) 3-cyclopropyl-5-fluoro-4-({3-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]pyridin-2-yl}amino)-N-[imidazolidin-2-ylidene]benzamide, - (160) 3-cyclopropyl-4-({3-[2-(3-methylbut-2-en-1-yl)-2H-1,2,3,4-tetrazol-5-yl]phenyl}amino)-N-[1-methylimidazolidin-2-ylidene]benzamide, - (161) N-{3-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]phenyl}-3-methyloxetane-3-carboxamide, - (162) 3-cyclopropyl-4-[(3-{[1-(hydroxymethyl)cyclopropyl]carbamoyl}phenyl)amino]-N-[imidazolidin-2-ylidene]benzamide, - (163) N-{3-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]phenyl}-3-methyloxetane-3-carboxamide, - (164) N-{bicyclo[1.1.1]pentan-2-yl}-3-chloro-2-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]pyridine-4-carboxamide, - (165) 3-cyclopropyl-4-{[3-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]amino}-5-fluoro-N-[imidazolidin-2-ylidene]benzamide, - (166) 3-chloro-2-[(2-cyclopropyl-6-fluoro-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-{3-fluorobicyclo[1.1.1]pentan-1-yl}pyridine-4-carboxamide, - (167) 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide, - (168) tert-butyl 2-{3-chloro-2-[(2-cyclopropyl-6-fluoro-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]pyridin-4-yl}-4,5-dihydro-1H-imidazole-1-carboxylate, - (169) 3-cyclopropyl-4-{[3-(4,5-dihydro-1H-imidazol-2-yl)phenyl]amino}-5-fluoro-N-[(2Z)-imidazolidin-2-ylidene]benzamide, - (170) 3-cyclopropyl-5-fluoro-N-[(2Z)-imidazolidin-2-ylidene]-4-{[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}benzamide, - (171) 3-cyclopropyl-5-fluoro-N-[(2Z)-imidazolidin-2-ylidene]-4-{[3-(thiomorpholine-4-carbonyl)phenyl]amino}benzamide, - (172) 3-chloro-2-[(2-cyclopropyl-6-fluoro-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-[(1s,3R,5S,7s)-adamantan-1-yl]pyridine-4-carboxamide, - (173) 3-cyclopropyl-5-fluoro-N-[(2Z)-imidazolidin-2-ylidene]-4-[(3-{[(1s,3R,5S,7s)-adamantan-1-yl]carbamoyl}phenyl)amino]benzamide, - (174) 3-cyclopropyl-5-fluoro-N-[(2E)-1-methylimidazolidin-2-ylidene]-4-[(3-{[(1s,3R,5S,7s)-adamantan-1-yl]carbamoyl}phenyl)amino]benzamide, -(175) (R)-N-(3-((2-cyclopropyl-6-fluoro-4-(imidazolidin-2-ylidenecarbamoyl)phenyl)amino)phenyl)pyrrolidine-2-carboxamide, - (176) 3-cyclopropyl-5-fluoro-N-[(2E)-1-methylimidazolidin-2-ylidene]-4-({3-[(oxetan-3-yl)carbamoyl]phenyl}amino)benzamide, - (177) 3-cyclopropyl-5-fluoro-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(oxetan-3-yl)carbamoyl]phenyl}amino)benzamide, - (178) 3-cyclopropyl-5-fluoro-N-[(2Z)-imidazolidin-2-ylidene]-4-({3-[(1,3-oxazol-2-yl)carbamoyl]phenyl}amino)benzamide, - (179) (2R)-N-{3-[(2-cyclopropyl-6-fluoro-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]phenyl}-5-oxopyrrolidine-2-carboxamide, - (180) N-{3-[(2-cyclopropyl-6-fluoro-4-{[(2Z)-imidazolidin-2-ylidene]carbamoyl}phenyl)amino]phenyl}-2-oxabicyclo[2.1.1]hexane-1-carboxamide, - (181) 4-({2-chloro-3-[(1-cyanocyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropyl-5-fluoro-N-[(2E)-imidazolidin-2-ylidene]benzamide.

[0058] Thus, the present invention extends to compounds (1)-(181) and pharma- ceutically acceptable salts thereof, such as the hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, triflate, maleate, mesylate, formate, acetate, and fumarate salts.

[0059] According to another aspect, the subject of the present invention relates to any one of the compounds (1) to (181), or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0060] According to another aspect, the subject of the present invention relates to a compound of formula (I) as defined above, or any one of its pharma- ceutically acceptable salts, and to any one of the compounds (1) to (181), or any one of its pharma-ceutically acceptable salts, for use in the treatment and / or prophylaxis of an RNA virus infection caused by an RNA virus belonging to group V of the Baltimore classification, in particular an RSV virus infection or a virus-associated condition.

[0061] The compounds of the present invention may exist in the form of a free base or in the form of an addition salt with a pharma- ceutically acceptable acid.

[0062] "Pharmaceutically acceptable salts thereof" refers to salts formed from acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) as well as salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.

[0063] Suitable physiologically acceptable acid addition salts of compounds of formula (I) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, triflate, maleate, mesylate, formate, acetate and fumarate salts.

[0064] The compound of formula (I), and any one of the compounds (1) to (181) or any one of the pharma- ceutically acceptable salts thereof, may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0065] The compounds of formula (I) can also exist in the form of tautomers and are part of the present invention. The terms "hydrate" and "solvate" simply mean that the compounds (I) according to the present invention can be in the form of hydrates or solvates, i.e. in the form of hydrates or solvates combined or associated with one or more water or solvent molecules. This is merely a chemical property of such compounds, which can be applied to all organic compounds of this type.

[0066] In the context of the present invention the following terms are defined as follows: "halogen atom" is understood to mean a chlorine, fluorine, bromine or iodine atom, and in particular to denote a chlorine, fluorine or bromine atom; - "(C1-Cx) alkyl" as used herein refers to a C1-Cx linear, secondary or tertiary saturated hydrocarbon, such as (C1-C6) alkyl. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl; - "Alkenylene" means a divalent (C1-C x ) alkyl radicals, more particularly the ethenylene radical, also known as vinylene or 1,2-ethenediyl; - "(C3-C6)cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; - "(C1~C x ")alkoxy" as used herein refers to an O-(C1-Cx)alkyl residue, where alkyl is as defined above, such as (C1-C6)alkoxy. Examples are, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy; - "5- or 6-membered heterocycle containing 1, 2, 3 or 4 heteroatoms" as used herein means an aromatic or non-aromatic ring containing 5 or 6 bonds and 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. In one particular embodiment, it is a "5-membered heterocycle containing 1, 2, 3 or 4 heteroatoms". In one embodiment, it contains at least one heteroatom, preferably at least one nitrogen atom. In another embodiment, it contains at least two heteroatoms, such as at least one nitrogen atom. In a further embodiment, it contains 2, 3 or 4 nitrogen atoms. According to yet a further embodiment, it contains one nitrogen atom and one oxygen atom or two nitrogen atoms and one oxygen atom. Examples are, but are not limited to, tetrazole, triazole, such as 1,2,3- or 1,2,4-triazole, and diazole, such as imidazole, pyrazole, 2- or 3-pyrazoline, dihydroimidazole or imidazoline, oxadiazole, such as 1,2,4-oxadiazole or 1,2,3-oxadiazole, oxazole, oxazoline, oxazolidine, oxazolidinone. According to a preferred embodiment, such a 5-membered heterocycle containing 2, 3 or 4 heteroatoms is triazole, tetrazole, imidazoline, or oxazoline. In one embodiment, the 5-membered heteroaromatic ring may contain one or two heteroatoms selected from oxygen and nitrogen atoms, in particular selected from oxazolyl, isoxazolyl, pyrazolyl and imidazolyl groups; - "Bicyclic alkyl" or "(C5-C 11A "bicyclic alkyl" compound refers to a bicyclic saturated monovalent hydrocarbon radical which may be selected from spirocyclic alkyl, fused bicyclic alkyl, and bridged bicyclic alkyl. Such bicyclic alkyls generally contain from 5 to 11 carbon atoms. Examples include, but are not limited to, spiro[2.2]pentyl, spiro[5.5]undecanyl, spiro[3.4]octanyl, spiro[4.5]decanyl, bicyclo[1.1.0]butyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[1.1.1]pentyl, oxabicyclo[1.1.1]pentyl, oxabicyclo[2.1.1]hexyl, oxabicyclo[2.2.1]heptyl, oxabicyclo[4.1.0]heptyl, oxabicyclo[3.2.1]octyl, and cubyl; and - "Bridged morpholinyl group" means a bicyclic compound in which one of the rings is a morpholinyl group, the two rings share three or more atoms, and the bridge contains at least one atom, e.g., one, two, or three atoms. As shown below, examples are as described herein below, but are not limited thereto. [ka]

[0067] The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, are included within the scope of the present invention.

[0068] The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below represent general methods useful for preparing the compounds of the present invention and are not meant to limit the scope or utility of the present invention.

[0069] Compounds of general formula (I) where Q is NH can be prepared according to Scheme 1 below. [ka]

[0070] The synthesis comprises a coupling reaction of a halogenoaromatic compound of formula (III) with an aniline derivative (II), where R, R', R c , R g , R h , m, m', [ka] ring, [ka] Tamaki, X 2 , n, Y 2 is as defined above, and X is a chlorine atom, an iodine atom or a bromine atom, followed by step (A1) or step (A2), followed by coupling the carboxylic acid derivative of the compound obtained after the above coupling step to a compound of the following formula [ka] Here, Z”, R g and R h is as defined above, The method is based on at least the further step of reacting with

[0071] R g =R h When =H and Z" is -CO-, the procedure first reacts compound (V) with guanidine, and then, in a cyclization step, R g =Rh ═H and Z″ is —CO— to produce the final cyclized derivative (I).

[0072] According to one embodiment, step (A1) comprises reacting the compound [ka] For -NH- groups, [ka] It may be advantageously used when in the meta or para position on the ring.

[0073] According to procedure (A1), the compound of formula (III) can be placed in an aprotic solvent, for example tert-butanol.The compound of formula (II) can then be added, for example, in the presence of an inorganic base, for example Cs2CO3 or K2CO3, in a molar ratio ranging from 1 to 1.5 relative to the compound of formula (III), for example, in the presence of a diphosphine, for example Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) or rac-BINAP, in particular in an amount ranging from 2 mol% to 15 mol% relative to the total amount of the compound of formula (III), and in the presence of an organometallic catalyst, for example Pd(OAc)2 or Pd2dba3, or BrettPhos Pd G3, in an amount ranging from 2 mol% to 25 mol% relative to the total amount of the compound of formula (III). The reaction mixture can then be heated at a temperature in the range of 80-130°C, for example 90°C, and stirred under an inert gas, for example argon, for a time period in the range of 15-25 hours, for example 20 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be diluted with an organic solvent, for example ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give the compound of formula (IV).

[0074] According to one embodiment, step (A2) comprises reacting the compound [ka] For -NH- groups, [ka] It may be advantageously used when in the ortho position on the ring.

[0075] According to procedure (A2), the compound of formula (II) can be placed in a polar aprotic solvent, for example dimethylsulfoxide. Then, the compound of formula (III) can be added, for example, in the presence of an inorganic base, for example Cs2CO3 or K2CO3, in a molar ratio ranging from 1 to 1.5 relative to the compound of formula (II), in the presence of a ligand, for example L-proline, in a molar ratio still ranging from 1 to 1.5 relative to the compound of formula (II), in particular in an amount ranging from 2 mol% to 25 mol% relative to the total amount of the compound of formula (II), and in the presence of an organometallic catalyst, for example CuI, in an amount ranging from 2 mol% to 25 mol% relative to the total amount of the compound of formula (II), then the reaction mixture can be heated at a temperature ranging from 80 to 130°C, for example at 90°C, and stirred under an inert gas, for example argon, for a time ranging from 15 to 25 hours, for example 20 hours. The reaction mixture can be diluted with an organic solvent, for example ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give the compound of formula (IV).

[0076] The starting compounds of formula (II) and (III) are available or can be prepared according to methods known to those skilled in the art. In particular, the method used to give the building block of formula (III), which further gives compound (166), is based on the synthesis of the intermediate (3-fluorobicyclo[1.1.1]pentane-1-ammonium chloride) described in Org. Biomol. Chem. 2015, 13, 11597-11601. In addition, the method used to give the building block of formula (III), which further gives compound (180), is based on the synthesis of the intermediate (2-oxabicyclo[2.1.1]hexane-1-carboxylic acid) described in Angew. Chem. Int. Ed. 2020, 59, 7161-7167. In addition, the methodology used to provide the required building blocks of formula (III) which further lead to compounds (165), (168) and (169) is based on the methodology described in Synlett 2006, 10, 1479-1484.

[0077] The present invention therefore relates to a synthetic process for preparing novel compounds of formula (I) as defined above, wherein Q is NH, comprising the steps of: (i) a compound of formula (II) [ka] with a compound of formula (III) [ka] in the presence of an inorganic base and a ligand, and in the presence of an organometallic catalyst to obtain a compound of formula (IV): where R, R', m, m', n, [ka] ring, [ka] Tamaki, X 2 , Y 2 is as defined above, and R cis an alkyl group, for example an ethyl or methyl group, and X is a chlorine, iodine or bromine atom; [ka] Here, R c is an alkyl group, for example an ethyl group or a methyl group, preferably a methyl group, and R, R', m, m', n, [ka] ring, [ka] Tamaki, X 2 , Y 2 is as defined above, followed by hydrolysis to give a compound of formula (V): [ka] Here, R c are hydrogen atoms, and R, R', m, m', n, [ka] ring, [ka] Tamaki, X 2 , Y 2 is as defined above, and (ii) reacting a compound of formula (V) with the compound [ka] Here, Z”, R g and R h is as defined above, in the presence of an organic base, such as N,N-diisopropylethylamine, and in the presence of a coupling agent, such as 1,1'-carbonyldiimidazole, to obtain a compound of formula (I) as defined above, wherein Q is NH.

[0078] The compound of general formula (I) where Q is O (oxygen atom) can be prepared according to the following scheme 1'. [ka] Scheme 1'

[0079] The synthesis is based on a coupling reaction starting from a halogenoaromatic compound of formula (III) and a phenol derivative of formula (II'), where R, R', R c , R g , R h ,Z”,m,m’, [ka] ring, [ka] Tamaki, X 2 , n, Y 2 is as defined above, and X is a fluorine atom.

[0080] According to procedure (D), the fluoroaryl derivative (III) can be placed in a polar solvent, such as N,N-dimethylformamide. Then, the phenol derivative (II') can be added in the presence of an inorganic base, such as Cs2CO3 or K2CO3, in a molar ratio ranging from 1 to 2, in particular in a molar ratio ranging from 1 to 5, relative to the fluoroaryl derivative (III). The reaction mixture can then be heated at a temperature ranging from 50 to 150°C, such as at 70°C, and stirred under an inert gas, such as argon, for a time ranging from 5 to 90 hours, such as 16 hours. The reaction mixture can be concentrated under reduced pressure, and the residue can be partitioned between an organic solvent, such as dichloromethane, and water. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and then purified to give the compound of formula (IV').

[0081] The present invention therefore relates to a synthetic process for preparing novel compounds of formula (I) as defined above, wherein Q is O (oxygen atom), comprising the steps of: (i) A compound of the following formula (II'): [ka] with a compound of formula (III) [ka] in the presence of an inorganic base to obtain a compound of formula (IV'): where R, R', and R c , R h , R g , m, m', n, [ka] ring, [ka] Tamaki, X 2 , Y 2is as defined above, and X is a fluorine atom; [ka] Here, R c means an alkyl group, for example an ethyl group or a methyl group, preferably a methyl group, and R, R', m, m', n, [ka] ring, [ka] Tamaki, X 2 , Y 2 is as defined above, followed by hydrolysis to give a compound of formula (V'): [ka] Here, R c are hydrogen atoms, and R, R', m, m', n, [ka] ring, [ka] Tamaki, X 2 , Y 2 is as defined above, and (ii) reacting a compound of formula (V') with [ka] Here, R g and R h is as defined above, where Q is O, as defined above; At least

[0082] Starting compounds of formula (II), (II'), (III) are available or can be prepared according to methods known to those skilled in the art.

[0083] More particularly, compounds of formula (II), when used to prepare compounds of formula (I), may be prepared according to Scheme 2 below. [ka]

[0084] According to step (E), a compound of formula (VI) and an organometallic catalyst, such as Pd(dppf)Cl2.CH2Cl2 or Pd(OAc), in an amount ranging from 2 mol % to 20 mol % relative to the amount of the compound of formula (VI) are reacted with each other. 2、 can be placed in a solvent, such as 1,4-dioxane, or a mixture of solvents, such as toluene and water. Then, the boronic acid R 1’ -B(OH)2 or organic trifluoroborate derivatives R 1’ -BF3K can be added in the presence of an inorganic base, such as K2CO3 or K3PO4, in a molar ratio ranging from 1 to 5, particularly in a molar ratio ranging from 2 to 5, to the compound of formula (VI), and in the presence of a ligand, such as RuPhos, in a molar ratio ranging from 2 to 5. The reaction mixture can then be heated at a temperature ranging from 50 to 150°C, for example at 110°C, and stirred under an inert gas, such as argon, for a time ranging from 2 to 70 hours, for example 3 hours. The reaction mixture can be concentrated under reduced pressure and purified to obtain the compound of formula (II).

[0085] More particularly, compounds of formula (II') may be prepared by a procedure similar to procedure (E) described above when used to prepare compounds of formula (I).

[0086] The chemical structures and spectroscopic data of some compounds of formula (I) of the present invention are shown in the following Tables I and II, respectively.

[0087] [Table 1] JPEG0007616609000058.jpg 255 132 JPEG0007616609000059.jpg 255 137 JPEG0007616609000060.jpg 255 135 JPEG0007616609000061.jpg 255 138 JPEG0007616609000062.jpg 255 136 JPEG0007616609000063.jpg 255 135 JPEG0007616609000064.jpg 255 137 JPEG0007616609000065.jpg 255 140 JPEG0007616609000066.jpg 255 136 JPEG0007616609000067.jpg 255 131 JPEG0007616609000068.jpg 255 134 JPEG0007616609000069.jpg 255 134 JPEG0007616609000070.jpg 255 135 JPEG0007616609000071.jpg 255 133 JPEG0007616609000072.jpg 255 135 JPEG0007616609000073.jpg 255 149 JPEG0007616609000074.jpg 255 130 JPEG0007616609000075.jpg 255 136 JPEG0007616609000076.jpg 255 129 JPEG0007616609000077.jpg 222 170 JPEG0007616609000078.jpg 255 160 JPEG0007616609000079.jpg 255 163 JPEG0007616609000080.jpg 236 170 JPEG0007616609000081.jpg 255 159 JPEG0007616609000082.jpg 255 164 JPEG0007616609000083.jpg 255 161 JPEG0007616609000084.jpg 255 166 JPEG0007616609000085.jpg 255 163 JPEG0007616609000086.jpg 255 159 JPEG0007616609000087.jpg 255 161 JPEG0007616609000088.jpg 104 170

[0088]

Table 2

[0089] The following examples are offered by way of illustration and are not intended to limit the scope of the present invention in any way.

[0090] The following examples detail the preparation of some compounds according to the invention. The structures of the products obtained are confirmed by NMR spectroscopy.

[0091] Working Example

[0092] Example 1 Compound (7) in Table I According to procedure (E), a solution of methyl 2-bromo-3-chlorobenzoate (500 mg, 2.0 mmol, 1 eq.) and (445 mg, 3.0 mmol, 1.5 eq.) in toluene (10 mL) and water (2 mL) was degassed with argon for 5 min, followed by the addition of tripotassium phosphate (1.08 g, 5.0 mmol, 2.5 eq.), RuPhos (37.4 mg, 80 μmol, 0.04 eq.) and palladium(II) acetate (9.1 mg, 40 μmol, 0.02 eq.). The reaction mixture was heated at 110° C. and stirred for 2 h 30 min under inert atmosphere. Upon cooling to room temperature, it was filtered on a pad of Celite and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give methyl 3-chloro-2-cyclopropybenzoate (201 mg, 47%).

[0093] 1 H NMR(400MHz,d6-DMSO) δ7.59(dd,J=8.0,1.3Hz,1H),7.46(dd,J=7.7,1.3Hz,1H),7.35(t,J=7.8Hz,1H) ,3.86(s,3H),1.94(tt,J=8.5,5.8Hz,1H),1.08-0.93(m,2H),0.47-0.34(m,2H)

[0094] According to procedure (B), methyl 3-chloro-2-cyclopropylbenzoate (200 mg, 949 μmol, 1 equiv.) was taken up in methanol (2 mL) and 4 M aqueous NaOH (1.2 mL, 4.75 mmol, 5 equiv.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and extracted with dichloromethane after adding 2 M aqueous HCl solution (10 equiv.). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-2-cyclopropylbenzoic acid (176 mg, 71%).

[0095] 1 H NMR(400MHz,d6-DMSO) δ13.16(s,1H),7.54(dd,J=7.9,1.3Hz,1H),7.43(dd,J=7.6,1.3Hz,1H),7.36- 7.27(m,1H),1.94(tt,J=8.5,5.7Hz,1H),1.08-0.93(m,2H),0.55-0.40(m,2H)

[0096] 3-Chloro-2-cyclopropylbenzoic acid (170 mg, 865 μmol, 1 equiv.) and 3-methylbutan-1-amine (110 μL, 951 μmol, 1.1 equiv.) were placed in anhydrous N,N-dimethylformamide (2 mL). HATU (329 mg, 865 μmol, 1 equiv.) and DIPEA (226 μL, 1.30 mmol, 1.5 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 phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-chloro-2-cyclopropyl-N-(3-methylbutyl)benzamide (168 mg, 73%).

[0097] 1 H NMR (400MHz,d6-DMSO) δ8.23(t,J=5.4Hz,1H),7.46(dd,J=7.9,1.3Hz,1H),7.27(t,J=7.8Hz,1H),7.18(dd,J=7.6,1.2Hz,1H),3.28-3.19(m,2H) ),1.92(tt,J=8.6,5.7Hz,1H),1.65(tq,J=13.3,6.7Hz,1H),1.42(q,J=7.0Hz,2H),0.98-0.88(m,8H),0.58-0.44(m,2H)

[0098] According to route (A1), a mixture of 3-chloro-2-cyclopropyl-N-(3-methylbutyl)benzamide (99.4 mg, 374 μmol, 1.1 equiv.), methyl 4-amino-3-cyclopropylbenzoate (65 mg, 340 μmol, 1 equiv.), Pd(OAc)2 (2.3 mg, 10.2 μmol, 3 mol %), rac-BINAP (4.2 mg, 6.8 μmol, 2 mol %) and K2CO3 (141 mg, 1.02 mmol, 3 equiv.) in anhydrous toluene (1 mL) was degassed with N2 and heated at 130 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature and filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 3-cyclopropyl-4-({2-cyclopropyl-3-[(3-methylbutyl)carbamoyl]phenyl}amino)benzoate (95 mg, 63%).

[0099] 1 H NMR (400MHz,d6-DMSO) δ8.17(t,J=5.6Hz,1H),7.67(dd,J=8.5,2.0Hz,1H),7.63(d,J=1.7Hz,1H),7.49(s,1H),7. 35-7.22(m,2H),6.98(dd,J=7.2,1.4Hz,1H),6.91(d,J=8.5Hz,1H),3.78(s,3H),3.29-3.2 1(m,2H),1.98-1.78(m,2H),1.66(dq,J=13.3,6.7Hz,1H),1.43(q,J=7.0Hz,2H),1.07-0.9 9(m,2H),0.92(d,J=6.6Hz,6H),0.83-0.75(m,2H),0.70-0.61(m,2H),0.42(q,J=5.7Hz,2H)

[0100] According to procedure (B), methyl 3-cyclopropyl-4-({2-cyclopropyl-3-[(3-methylbutyl)carbamoyl]phenyl}amino)benzoate (86.0 mg, 205 μmol, 1 equiv.) was placed in methanol (2 mL) and a 2 M aqueous solution of NaOH (1.03 mL, 2.05 mmol, 10 equiv.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and a 2 M aqueous solution of HCl (10 equiv.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-cyclopropyl-4-({2-cyclopropyl-3-[(3-methylbutyl)carbamoyl]phenyl}amino)benzoic acid (73.0 mg, 83%).

[0101] 1 H NMR (400MHz, d6-DMSO) δ12.32(s,1H),8.16(t,J=5.6Hz,1H),7.70-7.60(m,2H),7.41(s,1H),7.27(d t,J=15.3,7.3Hz,2H),6.99-6.91(m,2H),3.29-3.22(m,2H),1.98-1.78(m,2H ),1.67(dp,J=13.0,6.5Hz,1H),1.43(q,J=7.0Hz,2H),1.05-0.97(m,2H),0.9 2(d,J=6.6Hz,6H),0.86-0.78(m,2H),0.70-0.61(m,2H),0.43(q,J=5.8Hz,2H)

[0102] According to procedure (C), a reaction mixture of 3-cyclopropyl-4-({2-cyclopropyl-3-[(3-methylbutyl)carbamoyl]phenyl}amino)benzoic acid (66 mg, 154 μmol, 1.0 equiv.) and CDI (30.0 mg, 185 μmol, 1.2 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (53.9 mg, 309 μmol, 2 equiv.) and DIPEA (80.6 μL, 463 μmol, 3 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated in acetonitrile to give 2-cyclopropyl-3-({2-cyclopropyl-4-[(imidazolidin-2-ylidene)carbamoyl]phenyl}amino)-N-(3-methylbutyl)benzamide (7) (20.0 mg, 26%).

[0103] 1 H NMR (400MHz,d6-DMSO) δ8.14(t,J=5.5Hz,1H),8.08(s,2H),7.82(d,J=8.5Hz,2H),7.26-7.15(m,3H),7.03( d,J=8.2Hz,1H),6.84(d,J=6.2Hz,1H),3.51(s,4H),3.25(q,J=6.5Hz,2H),1.96-1.7 8(m,2H),1.67(dp,J=13.3,6.7Hz,1H),1.43(q,J=7.0Hz,2H),1.04-0.95(m,2H),0.9 2(d,J=6.6Hz,6H),0.87(d,J=8.6Hz,2H),0.62(q,J=5.4Hz,2H),0.45(q,J=5.4Hz,2H)

[0104] 13C NMR (151MHz,d6-DMSO) δ175.7,169.6,165.7,145.6,143.1,141.8,130.6,129.6,129.0,128.7,128.2 ,127.1,120.5,119.0,114.2,41.7,38.4,37.7,25.8,22.9,11.9,11.0,7.3,6.5

[0105] [M+H] + =474.2

[0106] Example 2 Compound (25) in Table I 3-Bromo-2-chlorobenzoic acid (500 mg, 2.1 mmol, 1 equiv.) and cyclopropanamine (173 μL, 2.5 mmol, 1.2 equiv.) were placed in anhydrous N,N-dimethylformamide (5 mL). HATU (1.24 g, 3.1 mmol, 1.5 equiv.) and DIPEA (1.1 mL, 6.2 mmol, 3 equiv.) were added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-bromo-2-chloro-N-cyclopropylbenzamide (375 mg, 60%).

[0107] 1 H NMR (400MHz,d6-DMSO) δ8.54(d,J=4.0Hz,1H),7.82(dd,J=8.0,1.6Hz,1H),7.40(dd,J=7.6,1.6Hz,1H),7.32(t, J=7.8Hz,1H),2.81(td,J=7.3,4.0Hz,1H),0.70(td,J=7.0,4.8Hz,2H),0.54-0.49(m,2H)

[0108] According to route (A1), a reaction mixture of 3-bromo-2-chloro-N-cyclopropylbenzamide (108 mg, 0.392 mmol, 1.0 equiv.), methyl 4-amino-3-cyclopropylbenzoate (75 mg, 0.392 mmol, 1.0 equiv.), BrettPhos Pd G3 (26.7 mg, 29.4 μmol, 7.5 mol %) and Cs2CO3 (153 mg, 0.471 mmol, 1.2 equiv.) in anhydrous DMF (2 mL) was degassed with N2 and heated at 80 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature, filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-{[2-chloro-3-(cyclopropylcarbamoyl)phenyl]amino}-3-cyclopropylbenzoate (75 mg, 41%).

[0109] 1 H NMR (500MHz,d6-DMSO) δ8.47(d,J=4.4Hz,1H),7.69(dd,J=8.5,2.0Hz,1H),7.63-7.58(m,2H),7.36-7.29(m,2H),7.08(s,1H),6.89(d,J=8.5Hz,1H),3.79(s,3H),2. 82(td,J=7.3,3.8Hz,1H),1.88(s,1H),1.01-0.96(m,2H),0.69(dd,J=7.1,2.2Hz,2H),0.64(dd,J=5.4,1.7Hz,2H),0.53(dd,J=3.9,2.4Hz,2H)

[0110] According to procedure (B), methyl 4-{[2-chloro-3-(cyclopropylcarbamoyl)phenyl]amino}-3-cyclopropylbenzoate (75 mg, 0.195 mmol, 1 equiv.) was placed in methanol (3 mL) and an aqueous solution of 2 M NaOH (0.808 mL, 1.62 mmol, 10 equiv.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and an aqueous solution of 2 M HCl (10 equiv.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4-{[2-chloro-3-(cyclopropylcarbamoyl)phenyl]amino}-3-cyclopropylbenzoic acid (70 mg, 97%).

[0111] 1 H NMR (400MHz,d6-DMSO) δ12.46(s,1H),8.48(d,J=4.4Hz,1H),7.69(dd,J=8.4,2.0Hz,1H),7.60(d,J=1.8Hz,1H) ,7.54(s,1H),7.35-7.29(m,1H),7.27(dd,J=8.1,1.8Hz,1H),7.04(dd,J=7.2,1.8Hz,1H ),6.93(d,J=8.4Hz,1H),2.83(td,J=7.3,4.0Hz,1H),1.93-1.84(m,1H),1.01-0.95(m,2 H),0.69(dt,J=7.0,3.4Hz,2H),0.64(dd,J=5.4,1.8Hz,2H),0.53(dd,J=4.0,2.3Hz,2H)

[0112] According to procedure (C), a reaction mixture of 4-{[2-chloro-3-(cyclopropylcarbamoyl)phenyl]amino}-3-cyclopropylbenzoic acid (70 mg, 188 μmol, 1.0 equiv.) and CDI (36.5 mg, 225 μmol, 1.2 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (39.4 mg, 225 μmol, 1.2 equiv.) and DIPEA (98 μL, 563 μmol, 3 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-{[2-chloro-3-(cyclopropylcarbamoyl)phenyl]amino}-3-cyclopropyl-N-(imidazolidin-2-ylidene)benzamide (25) (18.2 mg, 22%).

[0113] 1 H NMR (400MHz, d6-DMSO) δ8.45(d,J=4.5Hz,1H),8.11(s,2H),7.85(dd,J=8.3,1.9Hz,1H),7.79(d,J=1. 8Hz,1H),7.33(s,1H),7.23(s,1H),7.10(d,J=1.5Hz,1H),7.04(d,J=8.3Hz,1H) ,6.92-6.85(m,1H),3.52(s,4H),2.87-2.79(m,1H),1.87(s,1H),0.98-0.91(m, 2H),0.70(td,J=7.1,4.8Hz,2H),0.60(dd,J=5.5,1.8Hz,2H),0.56-0.50(m,2H)

[0114] 13C NMR (151MHz,d6-DMSO) δ175.5,168.1,165.8,144.0,140.9,138.9,132.9,132.6,127.9,127.8,120.3,119.5,118.8,118.1,41.7,23.1,11.7,7.3,6.1

[0115] [M+H] + =438.0

[0116] Example 3 Compound (26) in Table I 2-Methylpropanoic acid (461 mg, 5.23 mmol, 1.2 equiv.) and 3-bromoaniline (475 μL, 4.36 mmol, 1.0 equiv.) were placed in anhydrous N,N-dimethylformamide (10 mL). HATU (2.59 g, 6.54 mmol, 1.5 equiv.) and DIPEA (2.30 mL, 13.1 mmol, 3.0 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 phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-(3-bromophenyl)-2-methylpropanamide (979 mg, 88%).

[0117] 1 H NMR (400MHz,d6-DMSO) δ9.98(s,1H),7.98(d,J=1.8Hz,1H),7.51(d,J=7.9Hz,1H),7.26(t,J=7.9 Hz,1H),7.21(d,J=8.1Hz,1H),2.58(p,J=6.8Hz,1H),1.10(d,J=6.8Hz,6H)

[0118] According to route (A1), a reaction mixture of N-(3-bromophenyl)-2-methylpropanamide (279 mg, 1.15 mmol, 1.1 equiv), methyl 4-amino-3-cyclopropyl-benzoate (200 mg, 1.05 mmol, 1.0 equiv), BrettPhos Pd G3 (47.4 mg, 52.3 μmol, 5 mol%) and Cs2CO3 (409 mg, 1.26 mmol, 1.2 equiv) in anhydrous DMF (3 mL) was degassed with N2 and heated at 80 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature, filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 3-cyclopropyl-4-{[3-(2-methylpropanamido)phenyl]amino}benzoate (368 mg, 99%).

[0119] 1 H NMR (400MHz,d6-DMSO) δ9.77(s,1H),7.86(s,1H),7.66(dd,J=8.5,2.1Hz,1H),7.59(d,J=1.9Hz,1H),7.54(d,J=2.0Hz,1H),7.25-7.17(m,2H),7.14(d,J=8.5Hz,1H) ,6.85(d,J=7.3Hz,1H),3.78(s,3H),2.63-2.53(m,1H),1.95(s,1H),1.09(d,J=6.8Hz,6H),0.98(dd,J=8.3,2.0Hz,2H),0.60(d,J=3.6Hz,2H)

[0120] According to procedure (B), methyl 3-cyclopropyl-4-{[3-(2-methylpropanamido)phenyl]amino}benzoate (368 mg, 1.04 mmol, 1 equiv.) was taken up in methanol (3 mL) and an aqueous solution of 2 M NaOH (2.61 mL, 5.21 mmol, 5 equiv.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure, an aqueous solution of 2 M HCl (10 equiv.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-cyclopropyl-4-{[3-(2-methylpropanamido)phenyl]amino}benzoic acid (278 mg, 79%).

[0121] 1 H NMR (400MHz,d6-DMSO) δ12.34(s,1H),9.75(s,1H),7.80(s,1H),7.64(dd,J=8.5,2.0Hz,1H),7.54(dd,J=12.8,1.9Hz,2H),7.24-7.10(m,3H),6.84(dt,J=7. 3,1.9Hz,1H),2.58(p,J=6.8Hz,1H),1.95(tt,J=8.4,5.4Hz,1H),1.09(d,J=6.8Hz,6H),0.97(dd,J=8.3,2.0Hz,2H),0.63-0.56(m,2H)

[0122] According to procedure (C), a reaction mixture of 3-cyclopropyl-4-{[3-(2-methylpropanamido)phenyl]amino}benzoic acid (178 mg, 526 μmol, 1.0 equiv.) and CDI (102 mg, 631 μmol, 1.2 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (110 mg, 631 μmol, 1.2 equiv.) and DIPEA (276 μL, 1.58 mmol, 3 equiv.) in anhydrous DMF (1.0 mL) and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel and subjected to preparative TLC to give 3-cyclopropyl-N-(imidazolidin-2-ylidene)-4-{[3-(2-methylpropanamido)phenyl]amino}benzamide (26) (25.7 mg, 12%).

[0123] 1 H NMR (400MHz,d6-DMSO) δ9.71(s,1H),8.21(s,2H),7.82-7.73(m,1H),7.69(s,2H),7.51(s,1H),7.13(dt,J=13.7,7.3Hz,3H),6.78(d,J=7.7Hz,1H) ,3.56(s,4H),2.61-2.54(m,1H),1.98(d,J=14.4Hz,1H),1.08(d,J=6.8Hz,6H),0.95(d,J=8.4Hz,2H),0.58(d,J=4.0Hz,2H)

[0124] 13 C NMR (151MHz,d6-DMSO) δ175.6,146.1,144.0,140.6,131.1,129.5,127.8,127.5,116.0,114.2,112.2,109.9,41.9,35.3,19.9,11.6,7.6

[0125] [M+H] + =406.0

[0126] Example 4 Compound (41) in Table I According to procedure (E), a solution of methyl 4-amino-3-bromobenzoate (3.00 g, 12.8 mmol, 1 eq.) and potassium cyclopropyltrifluoroborate (2.84 g, 19.2 mmol, 1.5 eq.) in toluene (52.5 mL) and water (13.5 mL) was degassed with argon for 5 min, then tripotassium phosphate (6.88 g, 31.9 mmol, 2.5 eq.), RuPhos (239 mg, 511 μmol, 0.04 eq.) and palladium(II) acetate (57.9 mg, 256 μmol, 0.02 eq.) were added. The reaction mixture was heated at 110° C. and stirred under an inert atmosphere for 2 h 30 min. Upon cooling to room temperature, it was filtered on a pad of Celite and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-amino-3-cyclopropylbenzoate (2.02 g, 81%).

[0127] 1 H NMR (400MHz,d6-DMSO) δ7.53(dd,J=8.4,2.0Hz,1H),7.42(d,J=1.9Hz,1H),6.63(d,J=8.4Hz,1H),5.87(s, 2H),3.73(s,3H),1.65(tt,J=8.3,5.4Hz,1H),0.95-0.82(m,2H),0.54-0.40(m,2H)

[0128] 3-Bromophenol (701 mg, 3.97 mmol, 1.2 equiv.) was placed in N,N-dimethylformamide (4 mL) with Cs2CO3 (1.3 g, 3.97 mmol, 1.2 equiv.). Upon addition of (3-bromopropyl)cyclohexane (715 mg, 3.31 mmol, 1 equiv.), the reaction mixture was stirred at room temperature for 16 h under an inert atmosphere of argon. A saturated aqueous solution of NaHCO3 was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 1-bromo-3-(3-cyclohexylpropoxy)benzene (882 mg, 90%).

[0129] 1 H NMR (500MHz,d6-DMSO) δ7.22(t,J=8.1Hz,1H),7.14-7.08(m,2H),6.93(dd,J=8.3,2.3Hz,1H),3.95(t, J=6.5Hz,2H),1.68(tt,J=15.1,9.2Hz,7H),1.32-1.06(m,6H),0.92-0.82(m,2H)

[0130] According to procedure (A1), a reaction mixture of 1-bromo-3-(3-cyclohexylpropoxy)benzene (547 mg, 1.84 mmol, 1.1 equiv.), methyl 4-amino-3-cyclopropyl-benzoate (320 mg, 1.67 mmol, 1 equiv.), BrettPhos Pd G3 (31.9 mg, 33.5 μmol, 2 mol%) and Cs2CO3 (818 mg, 2.51 mmol, 1.5 equiv.) in anhydrous DMF (8 mL) was degassed with N2 and heated at 80 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature, filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoate (1.35 g, 80%).

[0131] 1 H NMR (400MHz,d6-DMSO) δ7.82(s,1H),7.66(dd,J=8.5,2.0Hz,1H),7.54(d,J=2.0Hz,1H),7.24-7.14(m,2H) ,6.76(d,J=7.9Hz,1H),6.73(t,J=2.1Hz,1H),6.56(dd,J=8.1,2.2Hz,1H),3.92(t, J=6.5Hz,2H),3.78(s,3H),1.94(ddd,J=13.8,8.3,5.4Hz,1H),1.75-1.58(m,7H),1 .35-1.08(m,6H),1.04-0.94(m,2H),0.88(q,J=10.0,9.3Hz,2H),0.65-0.56(m,2H)

[0132] According to procedure (B), 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 2 M 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 an aqueous solution of 2 M HCl (7 mL, 14 mmol, 10.5 equiv.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (540 mg, 97%).

[0133] 1 H NMR (400MHz,d6-DMSO) δ12.37(s,1H),7.76(s,1H),7.64(dd,J=8.5,2.0Hz,1H),7.52(d,J=1.9Hz,1H),7.18(t ,J=8.6Hz,2H),6.74(d,J=7.9Hz,1H),6.71(d,J=2.1Hz,1H),6.53(dd,J=8.1,2.1Hz,1H ),3.91(t,J=6.5Hz,2H),1.94(ddd,J=13.6,8.4,5.4Hz,1H),1.75-1.58(m,7H),1.35-1 .09(m,6H),0.98(dd,J=4.0,2.0Hz,2H),0.88(q,J=10.1,9.3Hz,2H),0.65-0.56(m,2H)

[0134] According to procedure (C), a reaction mixture of 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (150 mg, 362 μmol, 1 equiv.) and CDI (70.5 mg, 435 μmol, 1.2 equiv.) in anhydrous DMF (3.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of guanidine carbonate (2:1 salt) (130 mg, 724 μmol, 2 equiv.) and DIPEA (158 μL, 905 μmol, 2.5 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-(diaminomethylidene)benzamide (135 mg, 82%).

[0135] 1 H NMR (400MHz,d6-DMSO) δ7.79(d,J=8.4Hz,1H),7.70(s,1H),7.57(s,1H),7.12(dd,J=11.2,8.5Hz,2H),6.64(d,J=8.0Hz,1H),6.60(s,1H),6.41(d,J=8.2Hz,1H) ,3.89(t,J=6.4Hz,2H),2.00-1.88(m,1H),1.68(t,J=13.7Hz,7H),1.34-1.09(m,6H),0.91(dd,J=28.4,9.6Hz,4H),0.58(d,J=5.0Hz,2H)

[0136] To a solution of 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-(diaminomethylidene)benzamide (69.0 mg, 151 μmol, 1 equiv.) and DIPEA (131 μL, 754 μmol, 5 equiv.) in anhydrous DMF (1.5 mL) was added 2-chloroacetyl chloride (23.7 μL, 226 μmol, 1.5 equiv.). The resulting reaction mixture was stirred at room temperature for 2 h and then heated at 90° C. and stirred for 2 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with DCM. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-[(2E)-4-oxoimidazolidin-2-ylidene]benzamide (41) (4.0 mg, 5%).

[0137] 1 H NMR (400MHz,d6-DMSO) δ11.24(s,1H),9.35(s,1H),7.81(d,J=9.6Hz,1H),7.75(s,2H),7.16(t,J=8.2Hz,2H),6.78-6.64(m,2H),6.50(d,J=8.5Hz,1H),4.06(s,2H) ),3.91(t,J=6.5Hz,2H),1.93(d,J=13.8Hz,1H),1.67(d,J=14.8Hz,7H),1.30-1.16(m,6H),0.98(d,J=8.6Hz,2H),0.86(s,2H),0.61(s,2H)

[0138] [M+H] + =475.1

[0139] Example 5 Compound (45) in Table I 3-Bromo-2-chlorobenzoic acid (200 mg, 832 μmol, 1 equiv.) and morpholine (87.0 mg, 999 μmol, 1.2 equiv.) were placed in anhydrous N,N-dimethylformamide (4 mL). HATU (495 mg, 1.25 mmol, 1.5 equiv.) and DIPEA (438 μL, 2.50 mmol, 3 equiv.) were added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-(3-bromo-2-chlorobenzoyl)morpholine (216 mg, 85%).

[0140] 1 H NMR (400MHz,d6-DMSO) δ7.84(dd,J=7.8,1.7Hz,1H),7.46-7.33(m,2H),3.66(qd,J=8.3,7.2,3.8Hz,4H),3.56-3.51(m,2H),3.15-3.10(m,2H)

[0141] The experimental set-up was dried with a heat gun under a stream of nitrogen, kept under an inert atmosphere, and then cooled to room temperature. Methyl 3-acetyl-4-aminobenzoate (1.10 g, 5.41 mmol, 1 equiv.) and anhydrous THF (40 mL) were then added and the reaction mixture was cooled to -10°C. A 3M solution of methylmagnesium bromide in diethyl ether (3.79 mL, 11.4 mmol, 2.1 equiv.) was added dropwise and the reaction mixture was stirred at -10°C for 30 min, then an additional 3M solution of methylmagnesium bromide in diethyl ether (1.80 mL, 5.43 mmol, 1 equiv.) was added dropwise and the reaction mixture was further stirred at -10°C for 30 min. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride at -10°C, then warmed to room temperature and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give methyl 4-amino-3-(2-hydroxypropan-2-yl)benzoate (986 mg, 87%).

[0142] 1 H NMR (400MHz,d6-DMSO) δ7.64(s,1H),7.55(d,J=8.4Hz,1H),6.64(d,J=8.4Hz,1H),6.22(s,2H),5.37(s,1H),3.74(s,3H),1.51(s,6H)

[0143] According to route (A1), a mixture of 4-(3-bromo-2-chlorobenzoyl)morpholine (218 mg, 717 μmol, 1.5 equiv.), methyl 4-amino-3-(2-hydroxypropan-2-yl)benzoate (100 mg, 478 μmol, 1 equiv.), Pd(OAc)2 (3.2 mg, 14.3 μmol, 3 mol %), rac-BINAP (6.0 mg, 9.6 μmol, 2 mol %) and K2CO3 (198 mg, 1.43 mmol, 3 equiv.) in anhydrous toluene (3 mL) was degassed with N2 and heated at 110 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature and filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give methyl 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-(2-hydroxypropan-2-yl)benzoate (278 mg, 99%).

[0144] 1 H NMR (400MHz,d6-DMSO) δ9.53(s,1H),7.86(d,J=2.0Hz,1H),7.79(dd,J=8.5,2.0Hz,1H),7.47(dd,J=8.2,1.4Hz,1H),7.33(dd,J=8.3,4.5Hz,2H),6. 95(dd,J=7.4,1.4Hz,1H),6.18(s,1H),3.82(s,3H),3.67(s,4H),3.58-3.54(m,2H),3.22-3.18(m,2H),1.58(d,J=5.8Hz,6H)

[0145] According to procedure (B), methyl 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-(2-hydroxypropan-2-yl)benzoate (278 mg, 642 μmol, 1 equiv.) was placed in methanol (5 mL) and a 2 M aqueous solution of NaOH (1.61 mL, 3.21 mmol, 5 equiv.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and a 2 M aqueous solution of HCl (10 equiv.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-(2-hydroxypropan-2-yl)benzoic acid (240 mg, 55%).

[0146] 1 H NMR (400MHz,d6-DMSO) δ12.56(s,1H),9.48(s,1H),7.86(d,J=1.9Hz,1H),7.77(dd,J=8.5,1.9Hz,1H),7.46(d,J=8.2Hz,1H),7.33(d,J=1.9Hz ,2H),6.92(dd,J=7.4,1.3Hz,1H),6.14(s,1H),3.67(s,4H),3.58-3.54(m,2H),3.22-3.18(m,2H),1.58(d,J=6.5Hz,6H)

[0147] According to procedure (C), a reaction mixture of 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-(2-hydroxypropan-2-yl)benzoic acid (80 mg, 191 μmol, 1.0 equiv.) and CDI (37.2 mg, 229 μmol, 1.2 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (63.4 mg, 382 μmol, 2 equiv.) and DIPEA (100 μL, 573 μmol, 3 equiv.) in anhydrous DMF (1.0 mL) and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-{[2-chloro-3-(morpholine-4-carbonyl)phenyl]amino}-3-(2-hydroxypropan-2-yl)-N-(imidazolidin-2-ylidene)benzamide (45) (9.9 mg, 11%).

[0148] 1 H NMR (400MHz,d6-DMSO) δ9.33(s,1H),8.13(s,2H),8.05(s,1H),7.92(d,J=8.2Hz,1H),7.42(d,J=7.4Hz,1H),7.29(dd,J=8.1,3.9Hz,2H) ,6.85(d,J=7.7Hz,1H),6.04(s,1H),3.67(s,4H),3.59-3.50(m,6H),3.21(d,J=5.1Hz,2H),1.56(d,J=10.1Hz,6H)

[0149] 13 C NMR (151MHz,d6-DMSO) δ166.3,140.3,137.3,135.5,128.8,128.6,127.1,118.9,118.2,117.9,116.9,72.8,66.6,66.4,47.1,41.9,41.7,29.9

[0150] [M+H] + =486.2

[0151] Example 6 Compound (46) in Table I According to procedure (C), a reaction mixture of 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (100 mg, 241 μmol, 1 equiv.) and CDI (47.0 mg, 290 μmol, 1.2 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (84.4 mg, 483 μmol, 2 equiv.) and DIPEA (126 μL, 724 μmol, 3 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-(imidazolidin-2-ylidene)benzamide (27.0 mg, 23%).

[0152] 1 H NMR (400MHz,d6-DMSO) δ8.08(s,2H),7.79(dd,J=8.4,1.9Hz,1H),7.70(d,J=1.8Hz,1H),7.58(s,1H),7.18 -7.07(m,2H),6.65(d,J=8.0Hz,1H),6.61(t,J=2.1Hz,1H),6.43(dd,J=8.1,2.2Hz,1 H),3.89(t,J=6.5Hz,2H),3.51(s,4H),1.94(ddd,J=13.7,8.4,5.5Hz,1H),1.74-1.5 8(m,7H),1.21(ddt,J=36.1,21.2,10.0Hz,6H),0.98-0.83(m,4H),0.61-0.52(m,2H)

[0153] [M+H] + =431.3

[0154] To a solution of 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-(imidazolidin-2-ylidene)benzamide (84.0 mg, 109 μmol, 1 equiv.) and DIPEA (95 μL, 547 μmol, 5 equiv.) in DCM (2.0 mL) was added acetyl chloride (16 μL, 219 μmol, 2.0 equiv.). The resulting reaction mixture was stirred at room temperature for 20 min and then quenched with a saturated aqueous solution of brine and extracted with DCM. The combined organic layers were then dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-[(2E)-1-acetylimidazolidin-2-ylidene]-4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzamide (46) (12.0 mg, 20%).

[0155] 1 H NMR (400MHz,d6-DMSO) δ9.70(s,1H),7.81(d,J=8.4Hz,1H),7.73(d,J=10.6Hz,2H),7.16(dd,J=14.6,8.2Hz,2H),6 .71(d,J=8.1Hz,1H),6.67(s,1H),6.48(d,J=8.4Hz,1H),3.91(t,J=6.5Hz,2H),3.87-3.78(m ,2H),3.59(t,J=8.5Hz,2H),2.72(s,3H),1.96(t,J=5.3Hz,1H),1.68(t,J=14.8Hz,7H),1.3 3-1.09(m,6H),0.98(q,J=5.1,4.5Hz,2H),0.88(q,J=10.2,9.2Hz,2H),0.58(q,J=5.1Hz,2H)

[0156] 13C NMR (151MHz,d6-DMSO) δ176.3,170.0,160.0,158.4,146.5,144.8,131.1,130.2,129.6,128.1,127.8,115.8 ,111.5,107.6,105.5,68.1,42.5,37.2,33.7,33.3,26.6,26.5,26.3,25.9,11.4,7.7

[0157] [M+H] + =503.1

[0158] Example 7 Compound (123) in Table I 2,3-Dichloropyridine-4-carboxylic acid (288 mg, 1.5 mmol, 1 equiv.) and 1-methylcyclopropan-1-amine hydrochloride (178 mg, 1.58 mmol, 1.05 equiv.) were placed in anhydrous N,N-dimethylformamide (4 mL). HATU (570 mg, 1.5 mmol, 1.0 equiv.) and DIPEA (523 μL, 3.75 mmol, 2.5 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 phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 2,3-dichloro-N-(1-methylcyclopropyl)pyridine-4-carboxamide (213 mg, 58%).

[0159] 1 H NMR (400MHz,d6-DMSO) δ8.88(s,1H),8.43(d,J=4.8Hz,1H),7.46(d,J=4.8Hz,1H),1.39(s,3H),0.77-0.72(m,2H),0.65-0.60(m,2H)

[0160] According to route (A1), a reaction mixture of 2,3-dichloroN-(1-methylcyclopropyl)pyridine-4-carboxamide (100 mg, 0.408 mmol, 1.0 equiv.), methyl 4-amino-3-cyclopropyl-benzoate (78 mg, 0.408 mmol, 1.0 equiv.), BrettPhos Pd G3 (18.5 mg, 20.4 μmol, 5 mol%) and Cs2CO3 (199 mg, 0.612 mmol, 1.5 equiv.) in anhydrous DMF (2 mL) was degassed with N2 and heated at 80 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature and filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropylbenzoate (56 mg, 34%).

[0161] According to procedure (B), methyl 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropylbenzoate (56 mg, 0.140 mmol, 1 equiv.) was taken up in methanol (2 mL) and an aqueous solution of 1 M NaOH (0.700 mL, 0.700 mmol, 5 equiv.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and an aqueous solution of 1 M HCl (5 equiv.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropylbenzoic acid (51 mg, 94%).

[0162] According to procedure (C), a reaction mixture of 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropylbenzoic acid (51 mg, 132 μmol, 1.0 equiv.) and CDI (32.1 mg, 198 μmol, 1.5 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (46.2 mg, 264 μmol, 2.0 equiv.) and DIPEA (69.3 μL, 397 μmol, 3 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give 3-chloro-2-[(2-cyclopropyl-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(1-methylcyclopropyl)pyridine-4-carboxamide (123) (9.0 mg, 14%).

[0163] 1 H NMR (400MHz,d6-DMSO) δ8.79(s,1H),8.30(s,1H),8.15(dd,J=9.0,4.2Hz,4H),7.92(dd,J=8.4,1.9Hz,1H),7.90-7.87(m,1H),6.80(d,J=4.9Hz, 1H),3.53(s,4H),1.91(ddd,J=13.6,8.4,5.4Hz,1H),1.40(s,3H),1.05-1.00(m,2H),0.77-0.73(m,2H),0.64-0.59(m,4H)

[0164] [M+H] + =453.2

[0165] Example 8 Compound (136) in Table I According to procedure (E), a solution of methyl amino-3-bromo-5-fluorobenzoate (1.00 g, 4.03 mmol, 1 eq.) and potassium cyclopropyltrifluoroborate (895 mg, 6.04 mmol, 1.5 eq.) in toluene (16 mL) and water (4 mL) was degassed with argon for 5 min, then tripotassium phosphate (2.17 g, 10.1 mmol, 2.5 eq.), RuPhos (75.2 mg, 161 μmol, 0.04 eq.) and palladium(II) acetate (18.3 mg, 80.6 μmol, 0.02 eq.) were added. The reaction mixture was heated at 110° C. and stirred under an inert atmosphere for 2 h 30 min. Upon cooling to room temperature, it was filtered on a pad of Celite and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (847 mg, 100%).

[0166] 1 H NMR (400MHz,d6-DMSO) δ7.39(dd,J=11.8,1.9Hz,1H),7.28(d,J=1.7Hz,1H),5.91(s,2H),3.75( s,3H),1.77(tt,J=8.3,5.4Hz,1H),1.00-0.90(m,2H),0.59-0.45(m,2H)

[0167] According to route (A1), a reaction mixture of 2,3-dichloroN-(1-methylcyclopropyl)pyridine-4-carboxamide (100 mg, 0.408 mmol, 1.0 equiv.), methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (85 mg, 0.408 mmol, 1.0 equiv.), BrettPhos Pd G3 (39.0 mg, 40.8 μmol, 10 mol%) and Cs2CO3 (199 mg, 0.612 mmol, 1.5 equiv.) in anhydrous DMF (2 mL) was degassed with N2 and heated at 80 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature and filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropyl-5-fluorobenzoate (40 mg, 24%).

[0168] 1 H NMR (400MHz,d6-DMSO) δ8.78(s,1H),8.42(s,1H),7.91(d,J=4.9Hz,1H),7.55(dd,J=9.9,1.8Hz,1H),7.33(s,1H),6.67(d,J=4.9Hz,1H),3.86(s ,3H),2.08-2.00(m,1H),1.40(s,3H),0.95-0.88(m,2H),0.77-0.72(m,2H),0.65(q,J=5.1,4.5Hz,2H),0.63-0.59(m,2H)

[0169] According to procedure (B), methyl 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropyl-5-fluorobenzoate (40 mg, 0.096 mmol, 1 eq.) was placed in methanol (2 mL) and an aqueous solution of 1 M NaOH (0.479 mL, 0.479 mmol, 5 eq.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and an aqueous solution of 1 M HCl (5 eq.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropyl-5-fluorobenzoic acid (38.6 mg, 100%).

[0170] According to procedure (C), a reaction mixture of 4-({3-chloro-4-[(1-methylcyclopropyl)carbamoyl]pyridin-2-yl}amino)-3-cyclopropyl-5-fluorobenzoic acid (38.6 mg, 96 μmol, 1.0 equiv.) and CDI (23.3 mg, 144 μmol, 1.5 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (33.4 mg, 191 μmol, 2.0 equiv.) and DIPEA (50.1 μL, 287 μmol, 3 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give 3-chloro-2-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]-N-(1-methylcyclopropyl)pyridine-4-carboxamide (136) (14.1 mg, 30%).

[0171] 1 H NMR (400MHz,d6-DMSO) δ8.76(s,1H),8.26(s,1H),8.17(s,2H),7.89(d,J=4.9Hz,1H),7.59(dd,J=10.6,1.7Hz,1H),7.49(d,J=1.2Hz,1H),6.62(d,J=4 .9Hz,1H),3.54(s,4H),2.00(ddd,J=13.8,8.4,5.3Hz,1H),1.40(s,3H),0.94-0.84(m,2H),0.78-0.70(m,2H),0.64-0.54(m,4H)

[0172] 13 C NMR (151MHz,d6-DMSO) δ174.1,166.1,159.3,157.7,153.6,146.3,145.4,143.2,138.2,129.6(d ,J=13.2Hz),120.6,113.0,112.8,111.2,41.8,29.2,22.8,14.0,11.7,8.9

[0173] [M+H] + =471.1

[0174] Example 9 : Compound (153) in Table I To a solution of 2,3-dichloropyridine-4-carboxylic acid (288 mg, 1.5 mmol, 1 equiv.) and anhydrous DMF (2 drops) in anhydrous DCM (10 mL) was added oxalyl dichloride (193 μL, 2.25 mmol, 1.5 equiv.). The resulting reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting residue was taken up in anhydrous DCM (8 mL). The resulting solution was added dropwise to a solution of morpholine (182 μL, 1.50 mmol, 1 equiv.) and triethylamine (523 μL, 3.75 mmol, 2.5 equiv.) in anhydrous DCM (2 mL). The resulting reaction mixture was stirred at room temperature for 2 h 30 min. The reaction was quenched with water and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give 4-(2,3-dichloropyridine-4-carbonyl)morpholine (364 mg, 93%).

[0175] 1 H NMR (400MHz,d6-DMSO) δ8.48(d,J=4.8Hz,1H),7.54(d,J=4.8Hz,1H),3.74-3.67(m,2H),3.67-3.58(m,2H),3.53(ddd,J=16.4,10.5,4.8Hz,2H),3.18(t,J=4.9Hz,2H)

[0176] According to route (A1), a reaction mixture of 4-(2,3-dichloropyridine-4-carbonyl)morpholine (75 mg, 0.287 mmol, 1.0 equiv.), methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (60 mg, 0.287 mmol, 1.0 equiv.), Pd(OAc)2 (7.8 mg, 34.5 μmol, 12 mol%), rac-BINAP (14.3 mg, 23 μmol, 8 mol%) and Cs2CO3 (187 mg, 575 μmol, 2 equiv.) in anhydrous toluene (2 mL) was degassed with N2 and heated at 110 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature and filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give methyl 4-{[3-chloro-4-(morpholine-4-carbonyl)pyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoate (64.0 mg, 51%).

[0177] 1 H NMR (400MHz,d6-DMSO) δ8.51(s,1H),7.98(d,J=4.9Hz,1H),7.56(dd,J=10.0,1.8Hz,1H),7.33(s,1H),6.74(d,J=4.9Hz,1H),3.87(s,3H),3.72-3.62(m,4H) ),3.62-3.54(m,2H),3.25-3.18(m,2H),2.06(ddd,J=13.7,8.4,5.2Hz,1H),0.92(dd,J=8.4,2.0Hz,2H),0.65(td,J=5.1,2.4Hz,2H)

[0178] According to procedure (B), methyl 4-{[3-chloro-4-(morpholine-4-carbonyl)pyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoate (64.0 mg, 0.148 mmol, 1 eq.) was placed in methanol (2 mL) and an aqueous solution of 1 M NaOH (0.738 mL, 0.738 mmol, 5 eq.) was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and an aqueous solution of 1 M HCl (5 eq.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-{[3-chloro-4-(morpholine-4-carbonyl)pyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoic acid (62.0 mg, 100%).

[0179] According to procedure (C), a reaction mixture of 4-{[3-chloro-4-(morpholine-4-carbonyl)pyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoic acid (62.0 mg, 148 μmol, 1.0 equiv.) and CDI (35.9 mg, 222 μmol, 1.5 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (51.6 mg, 295 μmol, 2.0 equiv.) and DIPEA (77.4 μL, 443 μmol, 3 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative PLC to give 4-{[3-chloro-4-(morpholine-4-carbonyl)pyridin-2-yl]amino}-3-cyclopropyl-5-fluoro-N-[imidazolidin-2-ylidene]benzamide (153) (36.6 mg, 48%).

[0180] 1 H NMR (400MHz,d6-DMSO) δ8.35(s,1H),8.18(s,2H),7.96(d,J=4.9Hz,1H),7.61(dd,J=10.7,1.6Hz,1H),7.49(s,1H),6.69(d,J=4.9Hz,1H),3.71-3.63(m,4H) ,3.61-3.57(m,2H),3.55(s,4H),3.24-3.18(m,2H),2.02(ddd,J=13.9,8.5,5.4Hz,1H),0.89(dd,J=8.4,2.0Hz,2H),0.63-0.52(m,2H)

[0181] 13 C NMR (151MHz,d6-DMSO) δ174.1,165.8,164.8,158.5(d,J=244.9Hz),153.7,146.9,144.0,143.3,138.4(d,J=7.1Hz),129.4(d, J=13.4Hz),120.6,113.0,112.8,112.1,110.6,66.6,66.4,47.0,41.9,41.8,11.7(d,J=2.8Hz),9.0,8.9

[0182] [M+H] + =487.1

[0183] Example 10 : Compound (163) in Table I According to procedure (E), methyl 4-amino-3-bromo-5-fluorobenzoate (4.0 g, 16.13 mmol, 1 eq.) was placed in anhydrous 1,4-dioxane (60 mL) with Pd(dppf)Cl2.CH2Cl2 (1.3 g, 1.61 mmol, 0.1 eq.). Upon addition of K3PO4 (12.0 g, 56.44 mmol, 3.5 eq.) and cyclopropylboronic acid (1.8 g, 20.96 mmol, 1.3 eq.), the reaction mixture was heated at 100° C. and stirred under an inert atmosphere of argon for 3 h. Upon filtration through a pad of Celite, the reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (2.8 g, 83%).

[0184] 1 H NMR (300MHz,CDCl3) δ7.57-7.54(m,J=4.8Hz,2H),4.40 (br s,2H),3.85(s,3H),1.76-1.60(m,1H),1.03-0.88(m,2H),0.69-0.60(m,2H)

[0185] 3-Methyloxetane-3-carboxylic acid (1 g, 8.61 mmol, 1 equiv.) was placed in anhydrous dichloromethane (34.5 mL). PyBOP (6.7 g, 12.92 mmol, 1.5 equiv.), DIPEA (5.7 mL, 34.45 mmol, 4 equiv.) and 3-bromoaniline (940 μL, 8.61 mmol, 1 equiv.) were added and the resulting reaction mixture was stirred at room temperature for 16 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 a saturated aqueous solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-(3-bromophenyl)-3-methyloxetane-3-carboxamide (1.3 g, 56%).

[0186] 1H NMR (300MHz, CDCl3) δ7.83(t,J=1.9Hz,1H),7.71(brs,1H),7.50-7.44(m,1H),7.30-7.17(m,3H),4.92(d,J=6.2Hz,1H),4.58(d,J=6.3Hz,2H),1.65(s,3H)

[0187] According to route (A1), a reaction mixture of methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (542 mg, 2.59 mmol, 1 eq.), N-(3-bromophenyl)-3-methyloxetane-3-carboxamide (700 mg, 2.59 mmol, 1 eq.), Pd2(dba)3 (237 mg, 0.26 mmol, 0.1 eq.), XPhos (247 mg, 0.52 mmol, 0.2 eq.) and K2CO3 (1.4 g, 10.37 mmol, 4 eq.) in t-BuOH (10.5 mL) was heated at 90° C. and stirred for 16 h under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with dichloromethane. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 3-cyclopropyl-5-fluoro-4-{[3-(3-methyloxetan-3-amido)phenyl]amino}benzoate (694 mg, 67%).

[0188] 1 H NMR (300MHz, CDCl3) δ7.63(dd,J=11.1,1.8Hz,1H),7.52(s,2H),7.19(t,J=8.0Hz,1H),6.99(d,J=7.9Hz,1H),6.59(d,J=8.0Hz,1H),5.94(s,1H),4.93 (d,J=6.0Hz,2H),4.56(d,J=6.1Hz,2H),3.90(s,3H),1.88-1.79(m,1H),1.65(s,3H),0.96(q,J=6.0Hz,2H),0.72(q,J=6.0Hz,2H)

[0189] According to procedure (B), methyl 3-cyclopropyl-5-fluoro-4-{[3-(3-methyloxetan-3-amido)phenyl]amino}benzoate (694 mg, 1.74 mmol, 1 equiv.) was placed in a mixture of THF (10 mL), methanol (1.9 mL) and water (1.9 mL) and LiOH.HO (365 mg, 8.71 mmol, 5 equiv.) was added. The reaction mixture was stirred for 16 h at room temperature. It was then concentrated under reduced pressure and an aqueous solution of 6 M HCl (5 equiv.) was added and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with a saturated aqueous solution of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-cyclopropyl-5-fluoro-4-{[3-(3-methyloxetan-3-amido)phenyl]amino}benzoic acid (537 mg, 80%).

[0190] 1 H NMR (300MHz, CDCl3) δ7.71(s,1H),7.67(dd,J=11.0,1.7Hz,1H),7.60(brs,1H),7.31(brs,1H),7.21(t,J=8.1Hz,1H),7.04(d,J=7.9Hz,1H),6.63(d,J=8.2Hz,1 H),6.05(s,1H),4.97(d,J=6.1Hz,2H),4.57(d,J=6.1Hz,2H),1.88-1.78(m,1H),1.66(s,3H),0.96(q,J=5.4Hz,2H).),0.73(q,J=5.4Hz,2H)

[0191] According to procedure (C), a reaction mixture of 3-cyclopropyl-5-fluoro-4-{[3-(3-methyloxetan-3-amido)phenyl]amino}benzoic acid (200 mg, 520 μmol, 1.0 eq.) and CDI (101 mg, 620 μmol, 1.2 eq.) in anhydrous DMF (2.6 mL) was stirred at room temperature for 3 h. The mixture was then added to a solution of 4,5-dihydro-1H-imidazol-2-amine (66.5 mg, 780 μmol, 1.5 eq.) and DIPEA (430 μL, 2.60 mmol, 5 eq.) in anhydrous DMF (2.7 mL), and the resulting mixture was heated at 60° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in EtOAc, and then the organic phase was washed with a saturated aqueous solution of NH4Cl, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give, after trituration in diethyl ether, N-{3-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]phenyl}-3-methyloxetane-3-carboxamide (163) (109 mg, 46%).

[0192] 1 H NMR (300MHz, CDCl3) δ7.75(d,J=11.3Hz,1H),7.63(s,1H),7.49(s,1H),7.18(t,J=8.0Hz,1H),7.06(d,J=7.7Hz,2H),6.57(d,J=7.4Hz,1H),5.83(s,1H),4 .94(d,J=6.0Hz,2H),4.53(d,J=6.0Hz,2H),3.72(s,4H),1.91-1.78(m,1H),1.65(s,3H),0.91(q,J=5.3Hz,2H),0.75(q,J=5.3Hz,2H)

[0193] 13C NMR (75MHz, CDCl3) δ176.1,172.7,165.6,157.5,154.2,145.2,138.6,133.9,133.8,131.9,131.7,1 29.6,122.5,114.5,114.2,112.4,111.9,107.6,80.1,46.4,41.9,22.0,12.0,7.9

[0194] [M+H] + =452.5

[0195] Example 11 Compound (164) in Table I According to procedure (E), methyl 4-amino-3-bromo-5-fluorobenzoate (4.0 g, 16.13 mmol, 1 eq.) was placed in anhydrous 1,4-dioxane (60 mL) with Pd(dppf)Cl2.CH2Cl2 (1.3 g, 1.61 mmol, 0.1 eq.). Upon addition of K3PO4 (12.0 g, 56.44 mmol, 3.5 eq.) and cyclopropylboronic acid (1.8 g, 20.96 mmol, 1.3 eq.), the reaction mixture was heated at 100° C. and stirred under an inert atmosphere of argon for 3 h. Upon filtration through a pad of Celite, the reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (2.8 g, 83%).

[0196] 1 H NMR (300MHz,CDCl3) δ7.57-7.54(m,J=4.8Hz,2H),4.40(brs,2H),3.85(s,3H),1.76-1.60(m,1H),1.03-0.88(m,2H),0.69-0.60(m,2H)

[0197] 2,3-Dichloropyridine-4-carboxylic acid (730 mg, 3.80 mmol, 1 equiv.) was placed in anhydrous dichloromethane (15.5 mL). PyBOP (3.0 g, 5.70 mmol, 1.5 equiv.), DIPEA (2.5 mL, 15.20 mmol, 4 equiv.) and bicyclo[1.1.1]pentan-1-amine hydrochloride (500 mg, 4.18 mmol, 1.1 equiv.) were added and the resulting reaction mixture was stirred at room temperature for 16 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 a saturated aqueous solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-{bicyclo[1.1.1]pentan-1-yl}-2,3-dichloropyridine-4-carboxamide (728 mg, 74%).

[0198] 1 H NMR (300MHz,CDCl3) δ8.34(d,J=4.8Hz,1H),7.40(d,J=4.8Hz,1H),7.26(s,1H),6.42(s,1H),2.55(s,1H),2.21(s,6H)

[0199] According to route (A1), a reaction mixture of N-{bicyclo[1.1.1]pentan-1-yl}-2,3-dichloropyridine-4-carboxamide (386 mg, 1.5 mmol, 1.0 equiv.), methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (314 mg, 1.5 mmol, 1.0 equiv.), Pd(OAc)2 (41 mg, 180 μmol, 12 mol %), rac-BINAP (75 mg, 120 μmol, 8 mol %) and Cs2CO3 (977 mg, 3.0 mmol, 2 equiv.) in anhydrous toluene (9.5 mL) was degassed with argon and heated at 110° C. for 16 h under an inert atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in dichloromethane, and then the organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-{[4-({bicyclo[1.1.1]pentan-1-yl}carbamoyl)-3-chloropyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoate (220 mg, 34%).

[0200] 1 H NMR (300MHz, CDCl3) δ8.07(d,J=5.0Hz,1H),7.65(dd,J=10.2,1.7Hz,1H),7.55(s,1H),6.86(d,J=5.0Hz,1H),6.83(s,1H),6.29( s,1H),3.91(s,3H),2.54(s,1H),2.22(s,6H),1.93-1.84(m,1H),0.96(q,J=5.3Hz,2H),0.74(q,J=5.3Hz,2H)

[0201] According to procedure (B), methyl 4-{[4-({bicyclo[1.1.1]pentan-1-yl}carbamoyl)-3-chloropyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoate (220 mg, 0.51 mmol, 1 eq.) was placed in a mixture of THF (3 mL), methanol (560 μL) and water (560 μL) and LiOH.H2O (107 mg, 2.56 mmol, 5 eq.) was added. The reaction mixture was stirred at room temperature for 16 h. It was then concentrated under reduced pressure and an aqueous solution of 6 M HCl (5 eq.) was added and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated aqueous solution of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-{[4-({bicyclo[1.1.1]pentan-1-yl}carbamoyl)-3-chloropyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoic acid (130 mg, 61%).

[0202] 1 H NMR (300MHz,d6-DMSO) δ9.12(s,1H),8.44(s,1H),7.92(d,J=4.9Hz,1H),7.51(dd,J=10.0,1.6Hz,1H),7.32(s,1H),6.69(d,J =4.9Hz,1H),2.47(s,1H),2.08(s,6H),2.06-1.99(m,1H),0.91(q,J=5.3Hz,2H),0.64(q,J=5.3Hz,2H)

[0203] According to procedure (C), a reaction mixture of 4-{[4-({bicyclo[1.1.1]pentan-1-yl}carbamoyl)-3-chloropyridin-2-yl]amino}-3-cyclopropyl-5-fluorobenzoic acid (130 mg, 310 μmol, 1.0 equiv.) and CDI (61 mg, 370 μmol, 1.2 equiv.) in anhydrous DMF (1.6 mL) was stirred at room temperature for 3 h. The mixture was then added to a solution of 4,5-dihydro-1H-imidazol-2-amine (40 mg, 470 μmol, 1.5 equiv.) and DIPEA (260 μL, 1.56 mmol, 5 equiv.) in anhydrous DMF (1.6 mL), and the resulting mixture was heated at 60° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in EtOAc, and then the organic phase was washed with a saturated aqueous solution of NH4Cl, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-{bicyclo[1.1.1]pentan-2-yl}-3-chloro-2-[(2-cyclopropyl-6-fluoro-4-{[imidazolidin-2-ylidene]carbamoyl}phenyl)amino]pyridine-4-carboxamide (164) (66 mg, 44%).

[0204] 1 H NMR (300MHz, CDCl3) δ8.03(d,J=4.9Hz,1H),7.89(brs,1H),7.73(dd,J=10.6,1.4Hz,1H),7.62(s,1H),6.80(d,J=5.0Hz,1H),6.78(s,1H) ,6.38(s,1H),3.64(s,4H),2.53(s,1H),2.21(s,6H),1.92-1.83(m,1H),0.91(q,J=5.3Hz,2H),0.76(q,J=5.3Hz,2H)

[0205] 13C NMR (75MHz, CDCl3) δ176.3,166.0,165.3,158.9,155.6,152.5,146.6,143.3,140.7,136.8,136.7,1 29.1,128.9,122.2,114.3,114.0,113.8,112.2,53.1,48.8,41.9,25.1,12.1,7.7

[0206] [M+H] + =483.4

[0207] Example 12 Compound (167) in Table I 3-Bromo-2-chlorobenzoic acid (500 mg, 2.1 mmol, 1 equiv.) and 1-methylcyclopropan-1-amine hydrochloride (247 mg, 2.2 mmol, 1.05 equiv.) were placed in anhydrous N,N-dimethylformamide (5 mL). HATU (907 mg, 2.3 mmol, 1.1 equiv.) and DIPEA (544 μL, 3.1 mmol, 1.5 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 phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-bromo-2-chloro-N-(1-methylcyclopropyl)benzamide (370 mg, 62%).

[0208] 1 H NMR (400MHz,d6-DMSO) δ8.67(s,1H),7.80(dd,J=7.8,1.7Hz,1H),7.35(dd,J=7.5,1.7Hz,1H),7.30(t,J=7.7Hz,1H),1.39(s,3H),0.76-0.68(m,2H),0.64-0.56(m,2H)

[0209] According to route (A1), a reaction mixture of 3-bromo-2-chloro-N-(1-methylcyclopropyl)benzamide (226 mg, 0.784 mmol, 1.0 equiv.), methyl 4-amino-3-cyclopropyl-benzoate (150 mg, 0.784 mmol, 1.0 equiv.), BrettPhosPdG3 (35.6 mg, 39.2 μmol, 5 mol%) and Cs2CO3 (383 mg, 1.18 mmol, 1.5 equiv.) in anhydrous DMF (4 mL) was degassed with N2 and heated at 80 °C for 75 min under inert atmosphere. The reaction mixture was cooled to room temperature and filtered on a pad of Celite, and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropylbenzoate (77 mg, 25%).

[0210] 1 H NMR (400MHz,d6-DMSO) δ8.61(s,1H),7.70(dd,J=8.5,2.1Hz,1H),7.63-7.59(m,2H),7.35-7.29(m,2H),7.04(dd,J=6.3,2.7Hz,1H),6.90(d,J=8.5Hz,1H),3. 80(s,3H),1.89(ddd,J=13.5,8.3,5.4Hz,1H),1.40(s,3H),1.02-0.95(m,2H),0.78-0.70(m,2H),0.67-0.62(m,2H),0.62-0.57(m,2H).

[0211] According to procedure (B), methyl 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropylbenzoate (77 mg, 0.193 mmol, 1 equiv.) was taken up in methanol (3 mL) and 1 M NaOH was added. The reaction mixture was heated at 80° C. and stirred for 3 h. It was then concentrated under reduced pressure and an aqueous solution of 1 M HCl (5 equiv.) was added and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropylbenzoic acid (71 mg, 96%).

[0212] 1 H NMR (400MHz,d6-DMSO) δ12.47(s,1H),8.61(s,1H),7.69(dd,J=8.4,2.0Hz,1H),7.60(d,J=1.9Hz,1H),7.52(s,1H),7.35-7.22(m,2H),6.99(dd,J=7.2,1.8 Hz,1H),6.93(d,J=8.4Hz,1H),1.88(s,1H),1.40(s,3H),1.03-0.93(m,2H),0.78-0.70(m,2H),0.66-0.62(m,2H),0.61-0.58(m,2H)

[0213] According to procedure (C), a reaction mixture of 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropylbenzoic acid (35 mg, 91 μmol, 1.0 equiv.) and CDI (22.1 mg, 136 μmol, 1.5 equiv.) in anhydrous DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then added to a solution of imidazolidin-2-imine hydrobromide (31.8 mg, 182 μmol, 2 equiv.) and DIPEA (47.6 μL, 273 μmol, 3 equiv.) in anhydrous DMF (1.0 mL), and the resulting mixture was heated at 75° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-({2-chloro-3-[(1-methylcyclopropyl)carbamoyl]phenyl}amino)-3-cyclopropyl-N-[imidazolidin-2-ylidene]benzamide (167) (7.7 mg, 18%).

[0214] 1 H NMR (400MHz,d6-DMSO) δ8.58(s,1H),8.11(s,2H),7.85(dd,J=8.3,1.9Hz,1H),7.80(s,1H),7.31(s,1H),7.22(t,J=7.8Hz,1H),7.09(dd,J=8.2,1.4Hz,1H),7.04( d,J=8.3Hz,1H),6.85(dd,J=7.4,1.4Hz,1H),3.52(s,4H),1.87(s,1H),1.40(s,3H),0.99-0.90(m,2H),0.77-0.71(m,2H),0.63-0.54(m,4H)

[0215] 13C NMR (151MHz,d6-DMSO) δ175.5,167.5,165.8,144.0,140.9,139.2,132.9,132.5,128.0,127. 9,127.8,120.2,119.5,118.7,118.0,41.7,29.2,22.9,14.1,11.7,7.2

[0216] [M+H] + =452.1

[0217] Example 13 Compound (169) in Table I According to procedure (E), methyl 4-amino-3-bromo-5-fluorobenzoate (4.0 g, 16.13 mmol, 1 eq.) was placed in anhydrous 1,4-dioxane (60 mL) with Pd(dppf)Cl2.CH2Cl2 (1.3 g, 1.61 mmol, 0.1 eq.). Upon addition of K3PO4 (12.0 g, 56.44 mmol, 3.5 eq.) and cyclopropylboronic acid (1.8 g, 20.96 mmol, 1.3 eq.), the reaction mixture was heated at 100° C. and stirred under an inert atmosphere of argon for 3 h. Then, upon filtration through a pad of Celite, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (2.8 g, 83%).

[0218] 1 H NMR (300MHz,CDCl3) δ7.57-7.54(m,J=4.8Hz,2H),4.40(br s,2H),3.85(s,3H),1.76-1.60(m,1H),1.03-0.88(m,2H),0.69-0.60(m,2H)

[0219] 3-Bromobenzaldehyde (1.2 mL, 10 mmol, 1 equiv.) was placed in water (240 mL). Ethylenediamine (4.0 mL, 60 mmol, 6 equiv.) and pyridinium bromide perbromide (6.4 g, 20 mmol, 2 equiv.) were added and the resulting reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then treated with an aqueous solution of 3 M NaOH and the resulting aqueous phase was extracted with dichloromethane. The combined organic layers were then dried over MgSO4, filtered and concentrated under reduced pressure to give 2-(3-bromophenyl)-4,5-dihydro-1H-imidazole (1.1 g, 49%).

[0220] 1 H NMR (300MHz,CDCl3) δ7.96-7.94(m,1H),7.70(d,J=7.7Hz,1H),7.57(d,J=7.7Hz,1H),7.28(t,J=7.7Hz,1H),3.80(s,4H)

[0221] 2-(3-Bromophenyl)-4,5-dihydro-1H-imidazole (1.1 g, 4.88 mmol, 1 equiv.) was placed in a 1 / 1 mixture of water / dichloromethane (30 mL) at 0° C. NaHCO3 (1.6 g, 19.55 mmol, 4 equiv.) and Boc2O (1.6 g, 7.33 mmol, 1.5 equiv.) were added and the resulting reaction mixture was stirred at room temperature for 21 h. Upon decantation, the aqueous layer was extracted with dichloromethane. The combined organic layers were then washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(3-bromophenyl)-4,5-dihydro-1H-imidazole-1-carboxylate (1.5 g, 94%).

[0222] 1 H NMR (300MHz,CDCl3) δ7.65(s,1H),7.53(d,J=7.8Hz,1H),7.45(d,J=7.8Hz,1H),7.25(t,J=7.8Hz,1H),3.97(s,4H),1.27(s,9H)

[0223] According to route (A1), a reaction mixture of methyl 4-amino-3-cyclopropyl-5-fluorobenzoate (418 mg, 2 mmol, 1 equiv.), tert-butyl 2-(3-bromophenyl)-4,5-dihydro-1H-imidazole-1-carboxylate (650 mg, 2 mmol, 1 equiv.), Pd2(dba)3 (183 mg, 0.2 mmol, 0.1 equiv.), XPhos (191 mg, 0.4 mmol, 0.2 equiv.) and K2CO3 (1.1 g, 8 mmol, 4 equiv.) in t-BuOH (10.5 mL) was heated at 90° C. and stirred for 20 h under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give tert-butyl 2-(3-{[2-cyclopropyl-6-fluoro-4-(methoxycarbonyl)phenyl]amino}phenyl)-4,5-dihydro-1H-imidazole-1-carboxylate (320 mg, 35%).

[0224] 1 H NMR (300MHz, CDCl3) δ7.62(dd,J=11.0,1.7Hz,1H),7.52(s,1H),7.23(t,J=7.9Hz,1H),7.04(d,J=7.8Hz,1H),7.01(s,1H),6.85(d,J=7.8Hz,1H),5. 97(s,1H),3.95(dd,J=6.2,4.6Hz,4H),3.90(s,3H),1.84-1.75(m,1H),1.25(s,9H),0.93(q,J=5.3Hz,2H),0.71(q,J=5.3Hz,2H)

[0225] According to procedure (B), tert-butyl 2-(3-{[2-cyclopropyl-6-fluoro-4-(methoxycarbonyl)phenyl]amino}phenyl)-4,5-dihydro-1H-imidazole-1-carboxylate (320 mg, 0.70 mmol, 1 eq.) was placed in a mixture of THF (4.2 mL), methanol (0.8 mL) and water (0.8 mL) and LiOH.HO (148 mg, 3.53 mmol, 5 eq.) was added. The reaction mixture was stirred for 16 h at room temperature. It was then concentrated under reduced pressure and an aqueous solution of 6 M HCl (5 eq.) was added and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated aqueous solution of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-[(3-{1-[(tert-butoxy)carbonyl]-4,5-dihydro-1H-imidazol-2-yl}phenyl)amino]-3-cyclopropyl-5-fluorobenzoic acid (294 mg, 95%).

[0226] 1 H NMR (300MHz, CDCl3) δ7.54(d,J=6.9Hz,2H),7.28(t,J=7.8Hz,1H),7.04(d,J=8.0Hz,2H),6.99(d,J=7.8Hz,1H),6.01 (s,1H),4.04(s,4H),1.84-1.79(m,1H),1.29(s,9H),0.93(q,J=5.3Hz,2H),0.72(q,J=5.3Hz,2H)

[0227] According to procedure (C), a reaction mixture of 4-[(3-{1-[(tert-butoxy)carbonyl]-4,5-dihydro-1H-imidazol-2-yl}phenyl)amino]-3-cyclopropyl-5-fluorobenzoic acid (250 mg, 0.57 mmol, 1 eq.) and CDI (111 mg, 0.68 mmol, 1.2 eq.) in anhydrous DMF (2.9 mL) was stirred at room temperature for 5 h. The mixture was then added to a solution of 4,5-dihydro-1H-imidazol-2-amine (73 mg, 0.85 mmol, 1.5 eq.) and DIPEA (470 μL, 2.84 mmol, 5 eq.) in anhydrous DMF (2.9 mL), and the resulting mixture was heated at 60° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to give tert-butyl-2-[3-({2-cyclopropyl-6-fluoro-4-[(imidazolidin-2-ylidene)carbamoyl]phenyl}amino)phenyl]-4,5-dihydro-1H-imidazole-1-carboxylate (127 mg, 44%).

[0228] 1 H NMR (300MHz, CDCl3) δ7.72(dd,J=11.2,1.6Hz,1H),7.66(brs,1H),7.60(s,1H),7.19(t,J=7.8Hz,1H),6.98(d,J=7.8Hz,1H),6.95(s,1H),6.80(d,J=7.8Hz, 1H),5.83(s,1H),3.93(dd,J=6.6,4.8Hz,4H),3.67(s,4H),1.88-1.76(m,1H),1.23(s,9H),0.89(q,J=5.3Hz,2H),0.74(q,J=5.3Hz,2H)

[0229] To a solution of tert-butyl-2-[3-({2-cyclopropyl-6-fluoro-4-[(imidazolidin-2-ylidene)carbamoyl]phenyl}amino)phenyl]-4,5-dihydro-1H-imidazole-1-carboxylate (100 mg, 0.20 mmol, 1 equiv.) in anhydrous DCM (600 μL) was added a 4N solution of HCl in dioxane (250 μL, 0.99 mmol, 5 equiv.) and the reaction mixture was stirred at room temperature for 6 h. The resulting precipitate was filtered and after washing it with dichloromethane, 20 mg was loaded onto an SCX cartridge and eluted with MeOH and then with 2N ammonia solution in MeOH to give 3-cyclopropyl-4-{[3-(4,5-dihydro-1H-imidazol-2-yl)phenyl]amino}-5-fluoro-N-(imidazolidin-2-ylidene)benzamide (169) (15 mg, 59% extrapolated).

[0230] 1 H NMR (300MHz,d6-DMSO) δ8.16(s,2H),7.84(s,1H),7.61(d,J=11.5Hz,1H),7.48(s,1H),7.22-7.08(m,3H),6.75(d,J=7.7 Hz,1H),3.53(s,4H),3.33(s,4H),2.04-1.94(m,1H),0.90(q,J=5.3Hz,2H),0.60(q,J=5.3Hz,2H).

[0231] 13 C NMR (75MHz,d6-DMSO) δ173.8,165.3,164.2,156.6(d,J=242.4Hz),145.6,140.3,135.6(d,J=6.8Hz),131.3,130 .5(d,J=12.8Hz),128.5,120.6,117.0,116.2,113.1(d,J=21.0Hz),112.8,41.3,11.3,8.8

[0232] [M+H] + =407.3

[0233] Pharmacological Data

[0234] Example 14: RSV virus The compounds according to the invention have been the subject of pharmacological tests which have demonstrated their relevance as active substances in therapy, in particular for preventing, inhibiting or treating RSV viral infections.

[0235] Materials and Methods A protocol for screening antiviral compounds for RSV inhibition and cytotoxicity using the viral ToxGlo assay HEp-2 cells were maintained in Eagle's minimum essential medium (EMEM) containing Earle's BSS adjusted to contain 2 mM L-glutamine, 10% fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin. For the purposes of the screening assay, they were grown to 90% confluency, trypsinized, and harvested. Trypsin was neutralized with cell culture medium, and cells were centrifuged at 150 x g for 5 min, the supernatant was discarded, and the cell pellet was resuspended in assay medium (EMEM containing 2 mM L-glutamine, 2% fetal bovine serum, and Earle's BSS adjusted to contain 100 U / ml penicillin, and 100 μg / ml streptomycin). Cells were plated at 1.5x10 in 50μl in 96-well and 384-well plates, respectively. 4 4x10 cells / well, and 25 μl 3 Cells were seeded into white clear bottom cell culture plates at a density of 100 cells / well. Only assay medium was added to the media / background control columns. The cell plates were placed in a humidified chamber and incubated overnight at 37°C / 5% CO2. After overnight incubation, cells were checked for confluency and healthy appearance.

[0236] Test articles were made up at 10x the test concentration with a maximum DMSO concentration of 10% (final assay concentration of DMSO up to 1%) and added to cell plates in volumes of 10 μl for 96-well plates and 5 μl for 384-well plates. For cell and virus control wells, only test article solvent was added. Assay medium for virus or cytotoxicity test wells and media / cell control wells was added immediately after test article at an MOI of 0.5, 40 or 20 μl for 96-well and 384-well plates, respectively. Virus suspensions were prepared by thawing RSV A2 frozen stocks and diluting to the required concentration of plaque forming units in assay medium on ice.

[0237] The cell plates were further incubated at 37°C / 5% CO2 in a humidified chamber for 72 hours pi. After the incubation period, the cells were observed under a microscope to check for characteristic cytopathic effects in virus control wells and healthy cells in cell control wells. After the plates were adjusted to room temperature, 20 / 40 μl of Viral ToxGlo (Promega) was added to each well of the 384 / 96-well cell plates. The plates were incubated at room temperature and luminescence was measured in a spectrophotometer (Biotek Synergy HTX) for 20 minutes protected from light on a plate rocker.

[0238] RSV inhibition was calculated as the percentage of cytopathic effect inhibition relative to virus control and cytotoxicity was calculated as the percentage of cell viability relative to cell control wells. This represents the EC of each test article at which a virus inhibition or cytotoxicity dose response was determined. 50 This allows the calculation of EC values ​​ranging from 0.001 μM to 2.5 μM. 50The values ​​are more particularly for compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 69, 70, 71, 72, 73, 74, 91, 92, 94, 95, 96, 97, 98, 99, 100, Found for 102, 103, 104, 105, 106, 107, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 125, 127, 128, 129, 130, 131, 132, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 163, 164 and 167.

[0239] [Table 3] JPEG0007616609000111.jpg255134JPEG0007616609000112.jpg255134JPEG0007616609000113.jpg255132JPEG0007616609000114.jpg134134

[0240] conclusion Based on the previous results, it can be concluded that the compounds of formula (I) are suitable compounds for treating and / or preventing RNA viral infections caused by group V RNA viruses, more particularly pneumovirus infections, most particularly RSV viral infections.

[0241] The present invention further relates to a pharmaceutical composition comprising at least one of the novel compounds defined above or any one of their pharma- ceutically acceptable salts, or at least one of the compounds (1) to (181) defined above or any one of their pharma- ceutically acceptable salts, and also at least one pharma- ceutically acceptable excipient.

[0242] The pharmaceutical compositions of the present invention may contain one or more compounds of the present invention in any of the forms described herein.

[0243] A still further object of the invention consists of the use of at least one of the compounds of formula (I) as defined above according to the invention, as well as any one of the compounds (1) to (181) as defined above, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment in a patient of an RNA viral infection caused by an RNA virus from group V according to the Baltimore classification, such as an RSV infection.

[0244] The present invention therefore relates to one compound of formula (I) as defined above, and any one of the compounds (1) to (181), or a pharma- ceutically acceptable salt thereof, as an agent for inhibiting, preventing or treating an RNA virus infection, more preferably an RNA virus infection from group V, such as an RSV infection.

[0245] According to a particular embodiment, the treatment is continuous or discontinuous.

[0246] "Continuous treatment" refers to long-term treatment which can be performed at various dosing frequencies, for example, once a day, every third day, once a week or once every two weeks, or once a month.

[0247] According to one embodiment, the compound of formula (I), or any one of its pharma- ceutically acceptable salts, is administered in a dose varying from 0.1 to 1000 mg, in particular from 0.1 to 10 mg, or for example from 10 to 200 mg, for example from 200 to 1000 mg.

[0248] Another object of the present invention relates to a therapeutic method for treating and / or preventing a patient from an RNA viral infection, most preferably an RNA viral infection caused by an RNA virus belonging to group V of the Baltimore classification, comprising administering a therapeutically effective amount of a compound of formula (I) as defined above or of any one of the compounds (1) to (181), or of their acceptable salts.

[0249] In a particular embodiment, the present invention provides the use of a compound of formula (I) according to the present invention, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically active derivative thereof, or a method according to the present invention, in which the compound of formula (I) is to be administered in combination with a co-agent useful in the treatment of said RNA virus infection, more preferably said RNA virus infection from group V, such as RSV infection.

[0250] The compounds can be administered via any mode of administration, such as intramuscular, intravenous, intranasal or oral routes.

[0251] The compounds of the present invention may be administered as prodrugs, e.g., esters, of the compounds involved in the present invention, where appropriate. "Prodrug" means a compound that is convertible in vivo to a compound of the present invention by metabolic means (e.g., by hydrolysis, reduction, or oxidation). For example, an ester prodrug of a compound of the present invention may be convertible to the parent molecule by hydrolysis in vivo. Suitable esters of the compounds of the present invention are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthate, gentisate, isethionate, di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate, and quinate. Examples of ester prodrugs are those described by FJ Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, reference to the compounds of the invention is meant to also encompass any prodrug or metabolite forms.

[0252] The composition of the present invention may further comprise one or more additives, such as diluents, excipients, stabilizers and preservatives. Such additives are well known to those skilled in the art and are described in particular in Ullmann's Encyclopedia of Industrial Chemistry, Vol. 6, No. 6, pp. 111-115, 2002. th Ed. (various editors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0253] The above additives are selected according to the dosage form and the desired mode of administration.

[0254] According to other embodiments, the pharma- ceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.

[0255] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, intravaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0256] The compositions of the present invention can be administered in any manner, including but not limited to oral, parenteral, sublingual, transdermal, vaginal, rectal, transmucosal, topical, intranasal, buccal or intranasal administration by inhalation, or any combination thereof. Parenteral administration includes but is not limited to intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular. The compositions of the present invention can also be administered in the form of an implant, which allows for slow release of the composition and slow controlled intravenous (iv) infusion.

[0257] For example, the compounds of formula (I) can be present, in association with suitable excipients, in any pharmaceutical form suitable for enteral or parenteral administration, for example in the form of plain or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories, or drinks, e.g. suspensions, syrups, or injectable solutions or suspensions, in doses allowing the daily administration of 0.1 to 1000 mg of active substance.

[0258] In a particular embodiment, the compounds of formula (I) according to the present invention are administered orally.

[0259] The oral administration route is particularly preferred in the prophylactic or therapeutic aspects of the present invention.

Claims

1. Any one of the compounds of formula (I) below, or a pharma- ceutically acceptable salt thereof: 【Chemistry 01】 Where: 【Chemistry 02】 Ring and 【Chemistry 03】 each ring independently represents a phenylene group or a pyridylene group; Z” is -CH 2 - or -CO- group, R g and R h are independently a hydrogen atom, (C 1 ~C 4 ) alkyl group, (C 3 ~C 6 ) cycloalkyl group, -CH 2 CHF 2 group, or -COCH 3 represents a group, Q is NH or O; X 2 teeth, -CO-NR k Group, where R k represents a hydrogen atom or a methyl group; -NR' k -CO- group, where R' k represents a hydrogen atom or a methyl group; -O- group, -CO- group, -SO 2 -Group, -CS-NH- group, -CH 2 -NH- 【Chemistry 04】 basis, Or, Heterocyclyl, where the heterocyclyl is a 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and / or N, said ring being selected from (C 1 ~C 4 ) alkyl group, halogen atom, -COOR p R may be substituted by a group or ═O; p (C 1 ~C 4 ) alkyl group, represents n is 0, 1, 2 or 3; m and m' are independently 0, 1 or 2; Y 2 teeth, Hydrogen atom, Halogen atoms, Hydroxyl groups, (C 1 ~C 4 ) a morpholinyl group optionally substituted by an alkyl group or a trifluoromethyl group; a bridged morpholinyl group optionally substituted by a halogen atom; (C 5 ~C 11 ) a bicycloalkyl group, SO 2 an adamantyl group, a piperidinyl group, (C 1 ~C 4 ) an alkenyl group, -PO(OR a )(OR b ) group, a 5-membered heteroaromatic ring containing one or two heteroatoms selected from an oxygen atom and a nitrogen atom; Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 are independently a hydrogen atom, a fluorine atom, or (C 1 ~C 4 ) represents an alkyl group, R 1 , R 2 and R 3 It is understood that more than one of R is not a hydrogen atom, or 1 and R 2 together with the carbon atoms to which they are attached (C 3 ~C 8 ) cycloalkyl group, wherein (C 3 ~C 8 The cycloalkyl group may be substituted with one or two hydroxy groups (C 1 ~C 4 ) an alkyl group, a halogen atom, a trifluoromethyl group, a cyano group, a phosphonate group, an oxo group, or (C 1 ~C 4 ) alkoxy group, wherein the (C 3 ~C 8 The cycloalkyl group is as defined above for R 1 and / or R 2 by one or two oxygen atoms, by a sulfur atom, by a nitrogen atom, or by -SO 2 - groups, represents R and R' are independently may be substituted with a hydroxyl group, and may be -SO 2 - or -SO- group, (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) an alkenyl group, (C 3 ~C 6 ) a cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, Halogen atoms, Cyano group, Or, (C 1 ~C 5 ) Alkoxy group represents R a and R b are independently a hydrogen atom or (C 1 ~C 4 ) represents an alkyl group.

2. The compound of claim 1, or any one of its pharma- ceutically acceptable salts, wherein the heterocyclyl is triazolyl, pyrazolinyl, oxazolyl, oxazolinyl, oxazolidinyl, imidazolyl, dihydroimidazolyl, pyrazolyl, imidazolinyl, tetrazolyl, or oxadiazolyl, and / or the 5-membered heteroaromatic ring is oxazolyl, isoxazolyl, pyrazolyl, or imidazolyl. 【Request 3】 【Chemical 05】 Ring and 【Chemistry 06】 both of the rings represent phenylene groups, or 【Chemistry 07】 The ring represents a pyridylene group, and 【Chemistry 08】 The ring represents a phenylene group; 3. Any one of the compounds according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

4. 4. The compound of formula (I) according to claim 1, wherein Q is an NH-group, or any one of its pharma- ceutically acceptable salts.

5. R g and R h A compound of formula (I) according to any one of claims 1 to 4, or any one of its pharma- ceutically acceptable salts, wherein represents a hydrogen atom.

6. X 2 but, -CO-NH- group, -NH-CO- group, -O- group, -CO- group, Or, heterocyclyl, wherein the heterocyclyl is a 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and / or N, the ring being selected from triazolyl, imidazolyl, imidazolinyl, oxazolyl, oxazolinyl, oxazolidinyl, dihydroimidazolyl and tetrazolyl, said ring being selected from (C 1 ~C 4 ) alkyl group, halogen atom, -COOR p R may be substituted by a group or ═O; p (C 1 ~C 4 ) alkyl group, Represents, A compound of formula (I) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

7. Y 2 but, Hydrogen atom, Halogen atoms, (C 1 ~C 4 ) a morpholinyl group optionally substituted by an alkyl group or a trifluoromethyl group; a bridged morpholinyl group optionally substituted by a halogen atom; (C 5 ~C 11 ) a bicycloalkyl group, Adamantyl group, (C 1 ~C 4 ) an alkenyl group, -PO(OR a )(OR b ) group, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, Or, -CR 1 R 2 R 3 Group, where R 1 , R 2 and R 3 are independently a hydrogen atom, a fluorine atom, or (C 1 ~C 4 ) represents an alkyl group, R 1 , R 2 and R 3 It is understood that more than one of R is not a hydrogen atom, or 1 and R 2 together with the carbon atoms to which they are attached (C 3 ~C 8 ) cycloalkyl group, wherein (C 3 ~C 8 The cycloalkyl group may be substituted with one or two hydroxy groups (C 1 ~C 4 ) may be substituted by an alkyl group, a halogen atom, a trifluoromethyl group, a cyano group, a phosphonate group, or an oxo group, 3 ~C 8 The cycloalkyl group is the same as R 1 and / or R 2 by one or two oxygen atoms, by a sulfur atom, by a nitrogen atom, or by -SO 2 - groups, represents R a and R b is as defined in claim 1, A compound of formula (I) according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. R and R' are independently may be substituted with a hydroxyl group, and may be -SO 2 - or -SO- group, (C 1 ~C 4 ) alkyl group, (C 3 ~C 6 ) a cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, Trifluoromethyl group, Furanyl group, A chlorine atom or a fluorine atom, Cyano group, Or, (C 1 ~C 5 ) Alkoxy group Represents, A compound of formula (I) according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof.

9. 2. A compound of formula (I) according to claim 1, selected from the following compounds, or any pharma- ceutically acceptable salts thereof: 【Table 1】

10. A pharmaceutical used for the treatment and / or prevention of an RNA virus infection caused by an RNA virus belonging to group V of the Baltimore classification, comprising at least one of the compounds of formula (I) according to any one of claims 1 to 8, or a pharmaceutical acceptable salt thereof, and at least one of the compounds (1) to (181) according to claim 9, or a pharmaceutical acceptable salt thereof.

11. A pharmaceutical for use in the treatment and / or prevention of RSV infection or virus-related conditions caused by an RNA virus belonging to group V of the Baltimore classification, comprising at least one of the compounds of formula (I) as defined in any one of claims 1 to 8, or a pharmaceutical acceptable salt thereof, and at least one of the compounds (1) to (181) as defined in claim 9, or a pharmaceutical acceptable salt thereof.

12. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 8, or any one of its pharma- ceutically acceptable salts, and any one of compounds (1) to (181) according to claim 9, or any one of its pharma- ceutically acceptable salts, and at least one pharma- ceutically acceptable excipient.

13. A synthetic process for preparing a compound of formula (I) according to any one of claims 1 to 8, wherein Q is NH, comprising the steps of: (i) a compound of formula (II) 【Chemistry 09】 with a compound of formula (III) 【Chemistry 10】 in the presence of an inorganic base and a diphosphine and in the presence of an organometallic catalyst to obtain a compound of formula (IV): where R, R', m, m', n, 【Chemistry 11】 ring, 【Chemistry 12】 Tamaki, X 2 , Y 2 is as defined in any one of claims 1 to 8, and R c is an alkyl group, and X is a chlorine atom, an iodine atom, or a bromine atom; 【Chemistry 13】 Here, R c is an alkyl group, and R, R', m, m', n, 【Chemistry 14】 ring, 【Chemistry 15】 Tamaki, X 2 , Y 2 is as defined in any one of claims 1 to 8, followed by hydrolysis to give a compound of formula (V): 【Chemistry 16】 Here, R c are hydrogen atoms, and R, R', m, m', n, 【Chemistry 17】 ring, 【Chemistry 18】 Tamaki, X 2 , Y 2 is as defined in any one of claims 1 to 8, and (ii) reacting a compound of formula (V) with the compound 【Chemistry 19】 Here, Z”, R g and R h is as defined in claim 1, in the presence of an organic base and in the presence of a coupling agent to obtain a compound of formula (I) according to any one of claims 1 to 8, wherein Q is NH. The synthesis method,

14. A synthetic process for preparing novel compounds of formula (I) according to any one of claims 1 to 8, wherein Q is O (oxygen atom), said process comprising: (i) A compound of the following formula (II'): 【Chemistry 20】 with a compound of formula (III) 【Chemistry 21】 in the presence of an inorganic base to obtain a compound of formula (IV') where R, R', and R c , R h , R g , m, m', n, 【Chemical 22】 ring, 【Chemistry 23】 Tamaki, X 2 , Y 2 is as defined in any one of claims 1 to 8, and X is a fluorine atom. 【Chemistry 24】 where R c represents an alkyl group, and R, R′, m, m′, n, 【Chemistry 25】 ring, 【Chemistry 26】 The ring, X2 and Y2 are as defined in claim 1. followed by hydrolysis to give a compound of formula (V'): 【Chemical 27】 where R c is a hydrogen atom, and R, R′, m, m′, n, 【Chemistry 28】 ring, 【Chemical 29】 the ring, X2, Y2 are as defined in any one of claims 1 to 8, and (ii) reacting a compound of formula (V') with 【Chemistry 30】 wherein Z″, R g and R h are as defined in claim 1, and wherein Q is O, as defined in claim 1; To obtain said compound of formula (I) wherein Q is O. The method comprises at least the steps of:

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