phenyl/pyridyl-N-phenyl/pyridyl derivatives for the treatment of RNA viral infections

文档序号：788655 发布日期：2021-04-09 浏览：26次中文

阅读说明：本技术 用于治疗rna病毒感染的苯基/吡啶基-n-苯基/吡啶基衍生物 (phenyl/pyridyl-N-phenyl/pyridyl derivatives for the treatment of RNA viral infections ) 是由 D·谢雷 J·塔齐 F·马于托-贝茨尔 R·纳日曼 J·桑托 C·阿波利特于 2019-07-09 设计创作，主要内容包括：本发明涉及式(Ic)的化合物或其药学上可接受的盐中的任一种其中X～2代表-CO-NR-k-基团,其中R-k代表氢原子或甲基、-NH-CO-NH-基团、-OCH-2-基团、-CH(OH)-基团、-NH-CO-基团、-O-基团、-O-(CH-2)-s-O-、-CO-基团、-SO-2-基团、包含1、2、3或4个杂原子的二价5-元杂芳族环、-NH-SO-2-或-SO-2-NH-基团；Y～2代表氢原子、卤素原子、羟基、(C-1-C-4)烷氧基、基团、基团、任选地被(C-1-C-4)烷基基团取代的吗啉基基团、哌嗪基基团、哌啶基基团或-CR～1R～2R～3基团。本发明进一步涉及新化合物,涉及含有它们的药物组合物,并涉及用于制备它们的合成方法。(The present invention relates to any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof Wherein X 2 represents-CO-NR k A group in which R k Represents a hydrogen atom or a methyl group, -NH-CO-NH-group, -OCH 2 -a group, -CH (OH) -a group, -NH-CO-a group, -O- (CH) 2 ) s -O-, -CO-groups, -SO 2 -a group, a divalent 5-membered heteroaromatic ring comprising 1,2,3 or 4 heteroatoms, -NH-SO 2 -or-SO 2 -an NH-group; y is 2 Represents a hydrogen atom, a halogen atom, a hydroxyl group, or (C) 1 ‑C 4 ) Alkoxy radical, A group, Radical, optionally substituted (C) 1 ‑C 4 ) Morpholinyl radicals, piperazinyl radicals, piperidinyl radicals or-CR substituted by alkyl radicals 1 R 2 R 3 A group. The invention further relates to novel compounds, to pharmaceutical compositions containing them and to synthetic processes for preparing them.)

1. Any one of a compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

wherein:

ring andring independently refers to a phenylene or pyridylene group,

z' represents-CH₂-a group or a-CO-group,

R_gand R_hIndependently represents a hydrogen atom or (C)₁-C₄) An alkyl group, a carboxyl group,

X²represents

-CO-NR_kA group in which R_kRepresents a hydrogen atom or a methyl group,

-a NH-CO-NH-group,

-OCH₂-a group of,

-a CH (OH) -group,

-NH-CO-group

-an O-group, in which,

-O-(CH₂)_s-O-wherein s is 2 or 3,

-a CO-group, in which,

-SO₂-a group of,

a divalent 5-membered heteroaromatic ring containing 1,2,3 or 4 heteroatoms, such as triazole, imidazole, tetrazole orThe oxadiazole is a compound of two or more of the compounds of formula (I),

-NH-SO₂-，

-an NH-group,

-SO₂-an NH-group,

n is 0, 1,2 or 3,

m and m' are independently 0, 1 or 2,

Y²represents

A hydrogen atom, and a nitrogen atom,

a halogen atom,

a hydroxyl group(s),

(C₁-C₄) An alkoxy group, a carboxyl group,

wherein R is_fIs represented by (C)₁-C₄) An alkyl group, a cyano group,

the radical(s) is (are),

group, wherein R_qAnd R'_qIndependently represents a hydrogen atom or a methyl group,

a morpholinyl radical, optionally substituted by (C)₁-C₄) The substitution of the alkyl group is carried out,

a piperazinyl group, a phenyl group,

a piperidinyl group,

-CR¹R²R³Group, wherein R¹、R²And R³Independently represent hydrogenAtom, fluorine atom or (C)₁-C₄) An alkyl group of said (C)₁-C₄) The alkyl group is optionally substituted by trifluoromethyl and/or optionally substituted by a hydroxyl group, it being understood that R is¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) Cycloalkyl group of (C)₃-C₈) Cycloalkyl radicals optionally substituted by one or two (C)₁-C₄) Alkyl group, halogen atom, hydroxy group or (C)₁-C₄) Alkoxy group is substituted, and the (C)₃-C₈) Cycloalkyl groups optionally at said R¹And/or R²Interrupted by one or two oxygen atoms,

r and R' independently represent

(C₁-C₄) Alkyl radical, optionally substituted by-SO₂-a radical or-SO-radical interruption,

(C₃-C₆) A cycloalkyl group,

a trifluoromethyl group,

a halogen atom,

(C₁-C₅) An alkoxy group, a carboxyl group,

-SO₂-NR_aR_bthe radical(s) is (are),

-SO₃the radical of H is a radical of hydrogen,

-an OH group, a hydroxyl group or a hydroxyl group,

-O-SO₂-OR_ca group, or

-O-P(＝O)-(OR_c)(OR_d) The radical(s) is (are),

R_a、R_b、R_cand R_dIndependently represents a hydrogen atom or (C)₁-C₄) An alkyl group.

2. The compound of formula (Ic) or any of its pharmaceutically acceptable salts according to claim 1, wherein

Ring andthe rings all represent a phenylene group, orThe ring represents a pyridylene group andthe ring represents a phenylene group.

3. The compound of formula (Ic) or any of its pharmaceutically acceptable salts according to any one of claims 1-2, wherein

R_gIs a hydrogen atom and R_hRepresents a hydrogen atom or (C)₁-C₄) Alkyl groups such as methyl groups.

4. The compound of formula (Ic) or any of its pharmaceutically acceptable salts according to any one of claims 1-3, wherein

X²Represents

-CO-NR_kA group in which R_kRepresents a hydrogen atom or a methyl group,

-NH-CO-group

-an O-group, in which,

-a CO-group, in which,

-a CH (OH) -group,

-SO₂-a group of,

-an NH-group,

a divalent 5-membered heteroaromatic ring containing 1,2,3 or 4 heteroatoms, such as triazole, imidazole, tetrazole orThe oxadiazole is a compound of two or more of the compounds of formula (I),

-NH-SO₂-，

-SO₂-NH-groups.

5. The compound of formula (Ic) or any of its pharmaceutically acceptable salts according to any one of claims 1-4, wherein

Y²Represents

A hydrogen atom, and a nitrogen atom,

a halogen atom,

wherein R is_fIs represented by (C)₁-C₄) An alkyl group, a cyano group,

group, wherein R_qAnd R'_qIndependently represents a hydrogen atom or a methyl group,

a morpholinyl radical, optionally substituted by (C)₁-C₄) The substitution of the alkyl group is carried out,

the radical(s) is (are),

(C₁-C₄) An alkoxy group, a carboxyl group,

-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom, a fluorine atom or (C)₁-C₄) An alkyl group of said (C)₁-C₄) The alkyl group is optionally substituted with a trifluoromethyl group, optionally with a hydroxyl group, it being understood that R is¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) Cycloalkyl group of (C)₃-C₈) Cycloalkyl radicals optionally substituted by one or two (C)₁-C₄) Alkyl radicalHalogen atom, hydroxy group or (C)₁-C₄) Alkoxy group is substituted, and the (C)₃-C₈) Cycloalkyl groups optionally at said R¹And/or R²Interrupted by one or two oxygen atoms.

6. The compound of formula (Ic) or any of its pharmaceutically acceptable salts according to any one of claims 1-5, wherein

R and R' independently represent

(C₁-C₄) Alkyl radical, optionally substituted by-SO₂-a radical or-SO-radical interruption,

(C₃-C₆) A cycloalkyl group,

a trifluoromethyl group, or

A halogen atom.

7. The compound of formula (Ic) or any of its pharmaceutically acceptable salts according to any one of claims 1-6, wherein

Ring andthe rings all represent a phenylene group, orThe ring represents a pyridylene group andthe ring represents a phenylene group, and the ring represents a phenylene group,

m is 0 or 1, n is 0 or 1,

X²represents

-a CO-NH-group,

-CO-N(CH₃) -a group of,

-a NH-CO-group,

-O-group or

-a CO-group, in which,

-NH-SO₂-a group of,

-a CH (OH) -group,

-SO₂-a group of,

a divalent triazole, or a salt thereof,

a divalent imidazole, which is a divalent imidazole,

the divalent tetrazole is, in turn,

divalentThe oxadiazole is a compound of two or more of the compounds of formula (I),

-an NH-group,

Y²represents

The presence of hydrogen in the presence of hydrogen,

a morpholinyl radical, optionally substituted by (C)₁-C₄) The substitution of the alkyl group is carried out,

the radical(s) is (are),

group, wherein R_qAnd R'_qIndependently represents a hydrogen atom or a methyl group,

wherein R is_fIs represented by (C)₁-C₄) An alkyl group, a cyano group,

(C₁-C₄) An alkoxy group, a carboxyl group,

-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom, a fluorine atom or (C)₁-C₄) An alkyl group of said (C)₁-C₄) The alkyl group being optionally substituted by trifluoromethyl, optionallySubstituted by hydroxy groups, it being understood that R is¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) Cycloalkyl group of (C)₃-C₈) Cycloalkyl radicals optionally substituted by one or two (C)₁-C₄) Alkyl group, halogen atom, hydroxy group or (C)₁-C₄) Alkoxy group is substituted, and the (C)₃-C₈) Cycloalkyl groups optionally at said R¹And/or R²Interrupted by one or two oxygen atoms,

and is

R and R' independently represent

(C₁-C₄) An alkyl group, a carboxyl group,

(C₃-C₆) A cycloalkyl group such as a cyclopropyl group,

a trifluoromethyl group, or

A halogen atom.

8. The compound of formula (Ic) or any of its pharmaceutically acceptable salts according to any one of claims 1-7, wherein

Ring andthe rings all represent a phenylene group or a phenylene group,

m is 0, n is 1,

X²represents

-CO-NH-group, or

-an O-group, in which,

Y²represents

-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom or (C)₁-C₄) Alkyl radical, it being understood that R¹、R²And R³Not more than one of which is a hydrogen atom, such as an isopropyl group, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) A cycloalkyl group such as a cyclopropyl group,

and is

R' represents

(C₁-C₄) An alkyl group such as a tert-butyl group, or

(C₃-C₆) Cycloalkyl groups such as cyclopropyl.

9. The compound of formula (Ic) according to claim 1, selected from

Or any of its pharmaceutically acceptable salts.

10. Any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, and any one of the compounds (19) to (31) and (91) to (181) or a pharmaceutically acceptable salt thereof as defined in claim 9 for use as a medicament.

11. A compound of formula (Ic) according to any one of claims 1 to 8 or any one of its pharmaceutically acceptable salts, or a compound according to claim 10, or any one of compounds (19) to (31) and (91) to (181) as defined in claim 9 or any one of its pharmaceutically acceptable salts, for use in the treatment and/or prevention of an RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore classification.

12. The compound of formula (Ic) according to the preceding claim, wherein the RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore classification is caused by an RNA virus selected from: RSV, flexor, influenza and dengue, and more particularly selected from RSV and flexor.

13. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 8 or any one of its pharmaceutically acceptable salts, or at least any one of compounds (19) to (31) and (91) to (181) as defined in claim 9 or any one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

14. A synthetic process for the preparation of any of the compounds of formula (Ic) or any of their pharmaceutically acceptable salts as defined in any one of claims 1 to 8, or any of the compounds or any of their pharmaceutically acceptable salts as defined in claim 9, comprising at least the following steps: reacting a compound of formula (IIc) in the presence of an inorganic base and a diphosphine and in the presence of an organometallic catalyst

Coupling with a compound of formula (IIIc) to obtain a compound of formula (Ic) as defined in any one of claims 1 to 8 or any one of its pharmaceutically acceptable salts, or a compound as defined in claim 9 or any one of its pharmaceutically acceptable salts

Wherein R, R ', m'),A ring,Ring, X²、Y²、R_h、R_gAnd Z' is as defined in claim 1, X is a chlorine atom, an iodine atom or a bromine atom.

Background

Viruses are one of the leading causes of disease worldwide. Viruses are generally defined as small, non-living infectious agents (infection agents) that replicate only in living cells, because they do not have a completely autonomous replication mechanism. Although differing in shape and size, they generally consist of viral particles (referred to as "virions") made of a protein coat comprising at least one nucleic acid molecule and optionally one or more proteins or nucleoproteins depending on the virus type.

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

Although their replication cycle varies widely between species, it is widely accepted that the viral life cycle comprises six basic steps: attachment, invasion, dehulling, replication, assembly and release.

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

The replication step involves, among other things, not only the propagation of the viral genome, but also the synthesis of viral messenger RNA, the synthesis of viral proteins and the regulation of the transcription or translation machinery of the host. However, it is also clear that the type of genome (single-stranded, double-stranded, RNA, DNA.) is a significant feature of this replication step. For example, most DNA viruses assemble in the nucleus, while most RNA viruses develop only in the cytoplasm. Also, there is increasing evidence that single-stranded RNA viruses (such as influenza) use host RNA splicing and maturation mechanisms.

Thus, and in view of the implications of a given type of genome in the replication step, a Baltimore virus classification was developed. This classification divides viruses into families (or "groups") according to their genomic type. As in 2018, the current virus classification includes 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 RNA virus ((+) 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 RNA intermediates (dsDNA-RT).

According to this classification, strictly speaking, viruses belonging to group VI are not RNA viruses. For the same reason, strictly speaking, the viruses belonging to group VII are not DNA viruses. One well studied example of a virus family belonging to group VI is the family of Retroviridae (Retroviridae) (retroviruses), including HIV. An example of a well studied family of viruses belonging to group VII is the Hepadnaviridae (Hepadnaviridae) including Hepatitis B Virus (HBV).

As representative viruses belonging to group IV, there can be cited Picornaviruses (Picornaviruses), which are a family of viruses including well-known viruses such as hepatitis A virus, enterovirus, rhinovirus, poliovirus and foot and mouth disease virus, SARS virus, hepatitis C virus, yellow fever virus and rubella virus. Togaviridae (Togaviridae) also belongs to group IV, and one of its known genera is alphavirus (alphavirus), which encompasses Chikungunya (Chikungunya) virus. The flaviviridae family (Flaviridae), also a family belonging to group IV, covers the famous virus transmitted by mosquitoes, i.e. the dengue virus.

As representatives of viruses belonging to group V, the Filoviridae family (Filoviridae) encompassing ebola viruses, the Paramyxoviridae family (Paramyxoviridae) encompassing Respiratory Syncytial Virus (RSV), the Rhabdoviridae family (Rhabdoviridae), the Orthomyxoviridae family (Orthomyxoviridae) encompassing influenza a, influenza B and influenza C viruses may be cited.

Groups included within the virus family of particular interest within the framework of the present invention are such groups: it encompasses RNA viruses, in particular single-stranded RNA viruses, and more particularly RNA viruses belonging to group IV and group V of the Baltimore classification.

There is little cure for diseases caused by RNA virus infection, particularly with single-stranded RNA viruses, and more particularly with RNA virus infections of viruses belonging to groups IV and V of the Baltimore classification. Treatment is focused on alleviating the symptoms. Thus, there remains a need to identify new antiviral drugs to treat RNA viral infections, such as RNA viral infections from groups IV and V, in particular small chemical molecules.

Definition of

The term "patient" as used herein means an animal, such as a valuable animal for breeding, companion, or preservation purposes, or preferably a human or human child, suffering from, or having the potential to suffer from, one or more of the diseases and disorders described herein.

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

The identification of those patients in need of treatment for the diseases and conditions described herein is well within the abilities and knowledge of those skilled in the art. Those patients in need of such treatment can be readily identified by veterinarians or physicians in the art by using clinical trials, physical examinations, medical/family history or biological and diagnostic tests.

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

As used herein, "effective amount" means an amount of a compound of the invention effective to prevent, reduce, eliminate, treat or control the symptoms of the diseases and disorders described herein (i.e., RNA viral infection, and more particularly RNA viral infection from group IV or V). The term "control" is intended to mean all such processes: wherein the progression of the diseases and conditions described herein may be slowed, interrupted, arrested or halted, but does not necessarily indicate a complete elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.

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

The term "prevention" as used herein means reducing the risk of occurrence of, or slowing down the occurrence of, a given phenomenon, which in the present invention is a disease caused by infection with an RNA virus, and more particularly an RNA virus from group IV or V.

"preventing" as used herein also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence".

The term "prophylactically effective amount" means the concentration of a compound of the present invention: when administered prior to infection (i.e., prior to, during, and/or shortly after the exposure phase to RNA viruses, and particularly RNA viruses from group IV or V), it is effective to inhibit, prevent, reduce the likelihood of, or prevent infection by RNA viruses, and more particularly RNA viruses from group IV or V of the Baltimore classification, or prevent infection by RNA viruses, and particularly RNA viruses from group IV or V, or prevent delayed onset of disease caused by RNA viruses, and more particularly RNA viruses from group IV or V.

Likewise, the term "therapeutically effective amount" means the concentration of such compound: it is effective in treating RNA viral infections, e.g. when administered after an infection has occurred, resulting in a reduction of RNA viral infections after examination.

The term "pharmaceutically acceptable" as used herein means a compound, material, excipient, composition, or dosage form that: which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications, commensurate with a reasonable benefit/risk ratio.

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

For reference, the contents of the "Baltimore Classification" reported herein further refer to the viral Taxonomy listed in the 2017International Committee of Taxomy of Virus (ICTV) database published online on 12.3.2018 on http:// ictvonline. This classification is incorporated herein in its entirety.

The invention may especially consider alphaviruses belonging to the group IV RNA viruses and togaviridae family, which may be defined as plus-sense single-stranded RNA viruses or (+) ssRNA viruses. Their purpose was "unspecified" according to 2017 virus taxonomy. Togaviridae include alphaviruses (alphaviruses) and Rubivirus (Rubivirus).

Examples of alphaviruses contemplated by the present invention include: barmah Forest virus, chikungunya virus, equine Asia virus, Ardisia virus (O 'nyong' nyong virus), Ross river virus, Simplek Forest virus, Wuna virus, eastern equine encephalitis virus, Tornate virus, Venezuelan equine encephalitis virus, and Western equine encephalitis virus.

Most preferably, according to the present invention, the alphavirus infection or alphavirus-related disorder is Chikungunya virus infection (Chikungunya virus infection) or a Chikungunya virus-related disorder.

More specifically, chikungunya virus (CHIKV) is an RNA virus belonging to the genus alphavirus, which in turn belongs to the family togaviridae, i.e. group IV from the Baltimore classification. Bucking is a mosquito-transmitted viral disease that was first described in the southern outbreak of tanzania in 1952. CHIKV is an enveloped, positive-sense, single-stranded RNA virus whose genome has a nucleotide length of approximately 12 kb. The genome of CHIKV is organized as follows: 5'-cap-nsPl-nsP2-nsP3-nsP4- (joining region) -C-E3-E2-6k-El-poly (A) -3', wherein the first four proteins (nsPl-4) are non-structural proteins and the structural proteins are capsid (C) and envelope (E) proteins. There were no significant serotype differences between CHIKV isolated from islands in africa, asia and indian ocean. Phylogenetic analysis based on the El gene sequences can classify CHIKV into three genotypes (lineages): asia, east/central/south africa (ECSA) and west africa. Asian genotypes differed from ECSA and West African genotypes at nucleotide levels of-5% and-15%, respectively. African genotypes (ECSA vs west africa) differ by-15%. Amino acid identity between the three genotypes varied between 95.2-99.8%.

Chikungunya virus may cause outbreaks associated with severe morbidity.

Bucking is a viral disease that is transmitted to humans by infected mosquitoes. Aedes aegypti (ae. aegypti) and aedes albopictus (ae. albopictus) are both associated with a large burst of flexion. Aedes aegypti is restricted to tropical and subtropical zones, and aedes albopictus occurs in temperate and even cold temperate zones (cold temperature zones). In recent decades, the Aedes albopictus has spread from Asia to African, European and American regions.

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

Joint pain is often debilitating and can vary in duration.

The proximity of mosquito breeding sites to human habitats is an important risk factor for buckling.

The distribution of chikungunya virus occurs mainly in africa, india and southeast asia. In the last decades, bucking mosquito vectors have been transmitted to europe and america. In 2007, disease transmission was first reported in a local outbreak in northeast italy. Outbreaks have since been recorded in france and crohn's.

Dengue viruses with multiple serotypes are also contemplated by the present invention and belong to the group IV RNA viruses and flaviviridae families, which may be defined as positive-sense single-stranded RNA or (+) ss RNA viruses. More particularly, the dengue virus is a (+) ssRNA virus belonging to group IV of the Baltimore classification. It is part of the flavivirus genus, which belongs to the family flaviviridae. Other viruses belonging to the flaviviridae family are hepatitis c virus and yellow fever virus.

Viruses of the order Mononegavirales (Mononegaviridales) are also specifically contemplated by the present invention. Mononegavirales include viruses belonging to group V of the Baltimore classification. By 2018, this order mainly includes the following virus families: bornaviridae (Bornaveridae), Mymonaviridae, Filoviridae (Filoviridae), Niamaviridae (Nyamiviridae), Paramyxoviridae (Paramyxoviridae), Pneumoviridae (Pneumoviridae), Rhabdoviridae (Rhabdoviridae), and Sun Viridae (Sunveridae).

Human Respiratory Syncytial Virus (HRSV) is a syncytial virus that causes respiratory infections. It is the main cause of lower respiratory tract infections and hospital visits during infancy and childhood. HRSV viruses are specifically contemplated by the present invention and belong to group V of RNA viruses. More specifically, the 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, which belongs to the order mononegavirales. Among other viruses of the order mononegavirales, those viruses specifically contemplated by the present invention include: measles virus, mumps virus, nipah virus, rabies virus and human parainfluenza virus (which includes HPIV-1, HPIV-2, HPIV-3 and HPIV-4). Notably, the subfamily paramyxovirus (Paramyxovirinae) was routinely incorporated into the Paramyxoviridae based on the taxonomy of Mononegavirales updated in 2016.

Genera of viruses specifically contemplated in the Paramyxoviridae family include: aquatic animal paramyxoviruses (aquaparamyxoviruses), avian paramyxoviruses (avilavirus), Serpentis paramyxoviruses (Ferlavirus), Henipavirus, Morbillivirus (morblivirus), Respirovirus (Respirovirus), and mumps virus (Rubulavirus).

Viruses of the orthomyxoviridae family are also specifically contemplated by the present invention. Orthomyxoviridae belong to the order "unspecified" according to the 2017 virus taxonomy. Genera of viruses specifically contemplated within the orthomyxoviridae family include: influenza A (Alphanfluenzavirus), influenza B (Betainfluenzavirus), influenza D (Deltainfluenzavirus), influenza C (Gamma influenzavirus), Isavirus, Quaranjavirus, and Thogotovirus.

Influenza a (inflenzavirus a), influenza b (inflenzavirus b), influenza c (inflenzavirus c) are especially contemplated by the present invention and belong to the group V RNA viruses and orthomyxoviridae, which may be defined as negative-sense single stranded RNA or (-) ss RNA viruses. The genera isavurus and toruloviruses also belong to the order orthomyxoviridae.

Detailed Description

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

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

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

Wherein:

ring andring independently refers to a phenylene or pyridylene group,

wherein the radicalsRelative to the-NH-group isThe ring is substituted with one or more substituents selected from the group consisting of meta-and para-positions on the ring, especially meta,

X¹represents an alkenylene radical, in particular a vinylene radical, an-NH-CO-radical, a-CO-NH-radical, a-CR_aR_bA group of O-is selected from the group consisting of,

Y¹represents an aryl group selected from a 2-pyridyl group or a pyrimidinyl group, wherein one of the nitrogen atoms of the pyrimidinyl group is in a position relative to X¹The ortho-position of (a) is,

or alternatively X¹-Y¹Represents a group of the formula (A)

X²Represents a-CO-NH-group, -NH-CO-NH-group, -OCH₂-groups, -NH-CO-groups or-SO₂-an NH-group,

n is 0, 1,2 or 3,

m and m' are independently 0, 1 or 2,

Y²represents a hydrogen atom, a hydroxyl group or-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom, a fluorine atom or (C)₁-C₄) Alkyl radical, it being understood that R¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) Cycloalkyl group of (C)₃-C₈) Cycloalkyl radicals optionally substituted by one or two (C)₁-C₄) An alkyl group, a halogen atom or (C)₁-C₄) Alkoxy group is substituted, and the (C)₃-C₈) Cycloalkyl groups optionally at said R¹And/or R²Is interrupted by an oxygen atom, and is,

r and R' independently represent a halogen atom, (C)₁-C₄) Alkyl radical, (C)₃-C₆) Cycloalkyl radical, (C)₁-C₅) Alkoxy radical, -SO₂-NR_aR_bGroup, -SO₃H group, -OH group, -O-SO₂-OR_cA radical OR-O-P (═ O) - (OR)_c)(OR_d) The radical(s) is (are),

R_a、R_b、R_cand R_dIndependently represents a hydrogen atom or (C)₁-C₄) An alkyl group, a carboxyl group,

with the proviso that when X¹is-CR_aR_bWhen the group is O-, Y¹May further be a 3-pyridyl, 4-pyridyl or phenyl group, optionally substituted with one or two substituents selected from the group consisting of: halogen atom, (C)₁-C₄) Alkyl group, cyano group, (C)₁-C₅) Alkoxy radical, trifluoromethyl radical, trifluoromethoxy radical, -SO₂-NR_aR_bGroup, -SO₃H group, -OH group, -O-SO₂-OR_cA radical OR-O-P (═ O) - (OR)_c)(OR_d) A group.

According toFirst aspectThe present invention relates to any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof

Wherein

Y¹、R、R’、R_a、R_b、m、m’、A ring,Ring, X²N and Y²As defined above with respect to formula (I).

Still according to said firstAspect(s)The invention further relates to any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein said groupRelative to the-NH-group isMeta or para and preferably meta on the ring,

m is 0, n is 0, 1,2 or 3,

Y¹represents a pyridyl or phenyl group, optionally substituted with one or two substituents selected from: halogen atom, (C)₁-C₄) Alkyl and cyano groups, (C)₁-C₅) Alkoxy radical, trifluoromethyl radical, trifluoromethoxy radical, -SO₂-NR_aR_bGroup, -SO₃H group, -OH group, -O-SO₂-OR_cA radical OR-O-P (═ O) - (OR)_c)(OR_d) The radical(s) is (are),

Y²represents a hydrogen atom, a hydroxyl group or-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom or (C)₁-C₂) Alkyl radical, it being understood that R¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²And is provided withThe carbon atoms of which together form (C)₃-C₆) Cycloalkyl group of (C)₃-C₆) Cycloalkyl group is optionally substituted by one or two halogen atoms, and said (C)₃-C₆) Cycloalkyl groups optionally at said R¹And/or R²Interrupted by oxygen atoms.

According toSecond aspect of the inventionThe present invention relates to compounds of formula (Ic) as defined above for use in the treatment and/or prevention of RNA viral infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular chikungunya virus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders.

According toThird aspect of the inventionThe present invention relates to any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof:

wherein:

ring andring independently refers to a phenylene or pyridylene group,

z' represents-CH₂-a group or a-CO-group,

R_gand R_hIndependently represents a hydrogen atom or (C)₁-C₄) An alkyl group, a carboxyl group,

X²represents

-CO-NR_kA group in which R_kRepresents a hydrogen atom or a methyl group,

-a NH-CO-NH-group,

-OCH₂-a group of,

-a CH (OH) -group,

-NH-CO-group

-an O-group, in which,

-O-(CH₂)_s-O-wherein s is 2 or 3,

-a CO-group, in which,

-SO₂-a group of,

a divalent 5-membered heteroaromatic ring containing 1,2,3 or 4 heteroatoms, such as triazole, imidazole, tetrazole orThe oxadiazole is a compound of two or more of the compounds of formula (I),

-NH-SO₂-，

-an NH-group,

-SO₂-an NH-group,

n is 0, 1,2 or 3,

m and m' are independently 0, 1 or 2,

Y²represents

A hydrogen atom, and a nitrogen atom,

a halogen atom,

a hydroxyl group, a carboxyl group,

(C₁-C₄) An alkoxy group, a carboxyl group,

wherein R is_fIs represented by (C)₁-C₄) An alkyl group, a cyano group,

the radical(s) is (are),

group, wherein R_qAnd R'_qIndependently represents a hydrogen atom or a methyl group,

a morpholinyl radical, optionally substituted by (C)₁-C₄) The substitution of the alkyl group is carried out,

a piperazinyl group, a phenyl group,

a piperidinyl group,

-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom, a fluorine atom or (C)₁-C₄) An alkyl group of said (C)₁-C₄) The alkyl group is optionally substituted by trifluoromethyl and/or optionally substituted by a hydroxyl group, it being understood that R is¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) Cycloalkyl group of (C)₃-C₈) Cycloalkyl radicals optionally substituted by one or two (C)₁-C₄) Alkyl group, halogen atom, hydroxy group or (C)₁-C₄) Alkoxy group is substituted, and the (C)₃-C₈) Cycloalkyl groups optionally at said R¹And/or R²Interrupted by one or two oxygen atoms,

r and R' independently represent

(C₁-C₄) Alkyl radical, optionally substituted by-SO₂-a radical or-SO-radical interruption,

(C₃-C₆) A cycloalkyl group,

a trifluoromethyl group,

a halogen atom,

(C₁-C₅) An alkoxy group, a carboxyl group,

-SO₂-NR_aR_bthe radical(s) is (are),

-SO₃the radical of H is a radical of hydrogen,

-an OH group, a hydroxyl group or a hydroxyl group,

-O-SO₂-OR_ca group, or

-O-P(＝O)-(OR_c)(OR_d) The radical(s) is (are),

R_a、R_b、R_cand R_dIndependently represents a hydrogen atom or (C)₁-C₄) An alkyl group.

In other words,representative formula(A) A group A or formula(B) The group B of (1).

According toFourth aspect of the inventionThe present invention relates to any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof as defined above, and any one of the compounds (19) to (31) and (91) to (181) defined below, for use as a medicament.

According toFifth aspect of the inventionThe present invention relates to compounds of formula (Ic) as defined above for use in the treatment and/or prevention of RNA viral infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular chikungunya virus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders.

The above-mentioned compounds (I) and (Ic) are particularly suitable for the treatment or prophylaxis of viral infections or associated disorders, in particular RNA viral infections or associated disorders caused by RNA viruses belonging to group IV or V of the Baltimore classification, and most preferably chikungunya viral infections, dengue viral infections, influenza viral infections or RSV viral infections or viral associated disorders.

The above compounds are even more particularly suitable for use in the treatment or prevention of chikungunya virus infection or RSV virus infection or virus-related disorder, most particularly RSV virus infection.

Other aspects of the invention will be described herein after the application of the novel compounds, such as formula (Ic), as pharmaceuticals, pharmaceutical compositions and synthetic methods.

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

m and m' are independently 0 or 1,

Y²represents-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom, a fluorine atom or (C)₁-C₂) Alkyl radical, it being understood that R¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₆) Cycloalkyl group of (C)₃-C₆) Cycloalkyl group is optionally substituted by one or two halogen atoms, and said (C)₃-C₆) Cycloalkyl groups optionally at said R¹And/or R²Is interrupted by an oxygen atom, and is,

r and R' independently represent a halogen atom, (C)₁-C₂) Alkyl radical, (C)₃-C₆) Cycloalkyl radical or (C)₁-C₂) An alkoxy group.

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

Wherein:

ring andring independently refers to a phenylene or pyridylene group,

wherein the radicalsRelative to the-NH-group isThe meta-or para-position on the ring,

X¹represents an alkenylene radical, an-NH-CO-radical, a-CO-NH-radical, or a-CR radical_aR_bA group of O-is selected from the group consisting of,

or alternatively X¹-Y¹Represents a group of the formula (A)

X²Represents a-CO-NH-group, -NH-CO-NH-group, -OCH₂-groups, -NH-CO-groups or-SO₂-an NH-group,

n is 0, 1,2 or 3,

m and m' are independently 0, 1 or 2,

R_a、R_b、R_cand R_dIndependently represents a hydrogen atom or (C)₁-C₄) An alkyl group, a carboxyl group,

with the proviso that when Y is¹-X¹When it represents a 2-pyridinylvinylene group, X²Represents a-CO-NH-group and Y²represents-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom or (C)₁-C₄) An alkyl group, and m' is different from 0.

According to a particular embodiment, another subject of the invention is any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of RNA viral infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular chikungunya virus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders

Wherein

R、R’、m、m’、Ring, X²N and Y²As defined above.

Still according to said specific embodiment, the present invention further relates to any one of the compounds of formula (Ic) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of RNA viral infections caused by RNA viruses belonging to group IV or V of the Baltimore classification, and in particular chikungunya virus infections, dengue virus infections, influenza virus infections or RSV virus infections or virus-related disorders, wherein

m is 0, m' is 0 or 1,

X²represents a-CO-NH-group or-SO₂-an NH-group,

Y²represents-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom or (C)₁-C₂) Alkyl radical, it being understood that R¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₆) A cycloalkyl group.

According to a particular embodiment, the present invention relates to any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof as defined above, wherein

Ring andthe rings all represent a phenylene group, orThe ring represents a pyridylene group andthe ring represents a phenylene group.

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

m and m' are independently 0 or 1,

r and R' independently represent a halogen atom, (C)₁-C₂) Alkyl radical, (C)₃-C₆) Cycloalkyl radical or (C)₁-C₂) An alkoxy group.

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

R_gIs a hydrogen atom and R_hRepresents a hydrogen atom or (C)₁-C₄) Alkyl groups such as methyl groups.

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

X²Represents

-CO-NR_kA group in which R_kRepresents a hydrogen atom or a methyl group,

-NH-CO-group

-an O-group, in which,

-a CO-group, in which,

-a CH (OH) -group,

-SO₂-a group of,

-an NH-group,

a divalent 5-membered heteroaromatic ring containing 1,2,3 or 4 heteroatoms, such as triazole, imidazole, tetrazole orThe oxadiazole is a compound of two or more of the compounds of formula (I),

-NH-SO₂-，

-SO₂-NH-groups.

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

Y²Represents

A hydrogen atom, and a nitrogen atom,

a halogen atom,

wherein R is_fIs represented by (C)₁-C₄) An alkyl group, a cyano group,

group, wherein R_qAnd R'_qIndependently represents a hydrogen atom or a methyl group,

a morpholinyl radical, optionally substituted by (C)₁-C₄) The substitution of the alkyl group is carried out,

the radical(s) is (are),

(C₁-C₄) An alkoxy group, a carboxyl group,

-CR¹R²R³Group, wherein R¹、R²And R³Independently represents a hydrogen atom, a fluorine atom or (C)₁-C₄) An alkyl group of said (C)₁-C₄) The alkyl group being optionally trifluoroMethyl, optionally substituted with a hydroxy group, it being understood that R¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) Cycloalkyl group of (C)₃-C₈) Cycloalkyl radicals optionally substituted by one or two (C)₁-C₄) Alkyl group, halogen atom, hydroxy group or (C)₁-C₄) Alkoxy group is substituted, and the (C)₃-C₈) Cycloalkyl groups optionally at said R¹And/or R²Interrupted by one or two oxygen atoms.

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

R and R' independently represent

(C₁-C₄) Alkyl radical, optionally substituted by-SO₂-a radical or-SO-radical interruption,

(C₃-C₆) A cycloalkyl group,

a trifluoromethyl group, or

A halogen atom.

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

Ring andthe rings all represent a phenylene group, orThe ring represents a pyridylene group andthe ring represents a phenylene group, and the ring represents a phenylene group,

m is 0 or 1, n is 0 or 1,

X²represents

-a CO-NH-group,

-CO-N(CH₃) -a group of,

-a NH-CO-group,

-O-group or

-a CO-group, in which,

-NH-SO₂-a group of,

-a CH (OH) -group,

-SO₂-a group of,

a divalent triazole, or a salt thereof,

a divalent imidazole, which is a divalent imidazole,

the divalent tetrazole is, in turn,

divalentThe oxadiazole is a compound of two or more of the compounds of formula (I),

-an NH-group,

Y²represents

The presence of hydrogen in the presence of hydrogen,

a morpholinyl radical, optionally substituted by (C)₁-C₄) The substitution of the alkyl group is carried out,

the radical(s) is (are),

group, wherein R_qAnd R'_qIndependently represents a hydrogen atom or a methyl group,

wherein R is_fIs represented by (C)₁-C₄) An alkyl group, a cyano group,

(C₁-C₄) An alkoxy group, a carboxyl group,

-CR¹R²R³The radical(s) is (are),wherein R is¹、R²And R³Independently represents a hydrogen atom, a fluorine atom or (C)₁-C₄) An alkyl group of said (C)₁-C₄) The alkyl group is optionally substituted with a trifluoromethyl group, optionally with a hydroxyl group, it being understood that R is¹、R²And R³Not more than one of which is a hydrogen atom, or R¹And R²Together with the carbon atom bearing them to form (C)₃-C₈) Cycloalkyl group of (C)₃-C₈) Cycloalkyl radicals optionally substituted by one or two (C)₁-C₄) Alkyl group, halogen atom, hydroxy group or (C)₁-C₄) Alkoxy group is substituted, and the (C)₃-C₈) Cycloalkyl groups optionally at said R¹And/or R²Interrupted by one or two oxygen atoms,

and is

R and R' independently represent

(C₁-C₄) An alkyl group, a carboxyl group,

(C₃-C₆) A cycloalkyl group such as a cyclopropyl group,

a trifluoromethyl group, or

A halogen atom.

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

Ring andthe rings all represent a phenylene group or a phenylene group,

m is 0, n is 1,

X²represents

-CO-NH-group, or

-an O-group, in which,

Y²represents

and is

R' represents

(C₁-C₄) Alkyl radicals such as the tert-butyl radical (tertiobutyl group), or

(C₃-C₆) Cycloalkyl groups such as cyclopropyl.

With respect to R, R', mA ring,Ring, X¹、X²、n、Y¹、Y²Any combination of the above-defined embodiments with each other actually forms part of the invention.

According to a preferred embodiment of the invention, the compound of formula (Ic) is selected from:

- (19)4- ((3- (N- (2-cyclopentylethyl) sulfamoyl) phenyl) amino) -N- (tetrahydropyrimidin-2 (1H) -ylidene (yliden)) benzamide

- (20) N- (cyclopentylmethyl) -3- ((4- ((tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl) phenyl) amino) benzamide

- (21) N- ((3-methyloxetan-3-yl) methyl) -3- ((4- ((tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl) phenyl) amino) benzamide

- (22) N- (2-cyclopentylethyl) -3- ((4- ((tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl) phenyl) amino) benzamide

- (23) N-isoamyl-3- ((4- ((tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl) phenyl) amino) benzamide

- (24) N- (2-cyclohexylethyl) -3- ((4- ((tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl) phenyl) amino) benzamide

- (25) N- (2-cyclopropylethyl) -3- ((4- ((tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl) phenyl) amino) benzamide

- (26) N- (2-cyclobutylethyl) -3- ((4- ((tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl) phenyl) amino) benzamide

- (27)4- ((3- (isopentylcarbamoyl) phenyl) amino) -3-methyl-N- (tetrahydropyrimidin-2 (1H) -ylidene) benzamide

- (28)4- ((3- ((2-cyclopentylethyl) carbamoyl) phenyl) amino) -3-methyl-N- (tetrahydropyrimidin-2 (1H) -ylidene) benzamide

- (29)4- ((3- (N- (3-methylbutyl) sulfamoyl) phenyl) amino) -N- (tetrahydropyrimidin-2 (1H) -ylidene) benzamide

- (30)4- ((3- (N- (1-methylbutyl) sulfamoyl) phenyl) amino) -N- (tetrahydropyrimidin-2 (1H) -ylidene) benzamide

- (31) 3-methyl-4- ((3- (N- (2-cyclopentylethyl) sulfamoyl) phenyl) amino) -N- (tetrahydropyrimidin-2 (1H) -ylidene) benzamide

- (91)4- { [ 2-chloro-3- (3-methylmorpholine-4-carbonyl) phenyl ] amino } -3-cyclopropyl-N- [ (2E) -4-oxo-1, 3-diazine (diazina) -2-ylidene ] benzamide

- (92)4- { [ 2-chloro-3- (2-methylmorpholine-4-carbonyl) phenyl ] amino } -3-cyclopropyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (93)4- ({ 2-chloro-3- [ (1, 4-di)Alk-2-yl) methoxy]Phenyl } amino) -3-cyclopropyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide derivatives

- (94) 3-tert-butyl-4- { [3- (3-methylbutanesulfonamido) phenyl ] amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (95)4- { [ 2-chloro-3- (morpholine-4-carbonyl) phenyl ] amino } -3-cyclopropyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (96) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({ 2-methyl-3- [ (3-methylbutyl) carbamoyl ] phenyl } amino) benzamide

- (97)4- { [3- (3-cyclohexylpropoxy) phenyl ] amino } -3-cyclopropyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (98) 3-tert-butyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] -4- ({3- [ (propan-2-yl) carbamoyl ] phenyl } amino) benzamide

- (99) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (1-methylcyclopropyl) carbamoyl ] phenyl } amino) benzamide

- (100) 3-tert-butyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] -4- ({2- [ (propan-2-yl) carbamoyl ] phenyl } amino) benzamide

- (101)4- ({3- [ (but-2-yl) carbamoyl ] phenyl } amino) -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (102) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (propan-2-yl) carbamoyl ] phenyl } amino) benzamide

- (103)4- { [3- (4-cyclohexyl-1-hydroxybutyl) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (104) N- (1, 3-diazine-2-ylidene) -4- ({3- [ (3-methylbutyl) carbamoyl ] phenyl } amino) -3- (trifluoromethyl) benzamide

- (105) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (4-methylpentyl) carbamoyl ] phenyl } amino) benzamide

- (106)4- { [2- (3-cyclohexylpropanesulfonyl) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (107) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (5-methylhexyl) carbamoyl ] phenyl } amino) benzamide

- (108) 3-cyclopropyl-N- [ (2E) -1-methyl-1, 3-diazine-2-ylidene ] -4- ({3- [ (propan-2-yl) carbamoyl ] phenyl } amino) benzamide

- (109) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (1,1, 1-trifluoropropan-2-yl) carbamoyl ] phenyl } amino) benzamide

- (110) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (pentan-3-yl) carbamoyl ] phenyl } amino) benzamide

- (111) N- (2-cyclohexylethyl) -2- ({4- [ (1, 3-diazine-2-ylidene) carbamoyl ] -2- (trifluoromethyl) phenyl } amino) pyridine-4-carboxamide

- (112) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (difluoromethoxy) phenyl ] amino } benzamide

- (113) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (3-methylbutyl) carbamoyl ] phenyl } amino) benzamide

- (114) 3-cyclopropyl-4- { [3- (cyclopropylcarbamoyl) phenyl ] amino } -N- (1, 3-diazine-2-ylidene) benzamide

- (115)4- { [3- (3-cyclohexylpropoxy) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (116) 3-cyclopropyl-4- { [3- (2-methylpropionylamino) phenyl ] amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (117)4- { [3- (cyclohexylcarbamoyl) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (118) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ methyl (3-methylbutyl) carbamoyl ] phenyl } amino) benzamide

- (119)4- ({3- [4- (cyclohexylmethyl) -1H-1,2, 3-triazol-1-yl ] phenyl } amino) -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (120) 3-cyclopropyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] -4- ({3- [ (propan-2-yl) carbamoyl ] phenyl } amino) benzamide

- (121) 3-cyclopropyl-4- ({3- [ (1-methylcyclopropyl) carbamoyl ] phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (122) 3-cyclopropyl-4- { [ 2-cyclopropyl-3- (2-methylpropionylamino) phenyl ] amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (123)4- { [3- (tert-butylcarbamoyl) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (124) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (2,2, 2-trifluoroethoxy) phenyl ] amino } benzamide

- (125) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (2, 2-difluoroethoxy) phenyl ] amino } benzamide

- (126) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- [ (3- { [2-, (Alk-4-yl) ethyl]Carbamoyl } phenyl) amino]Benzamide derivatives

- (127)4- { [3- (cyclohexylmethoxy) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (128) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [ 2-methyl-3- (4-methylpentanoylamino) phenyl ] amino } benzamide

- (129)4- [ (3-cyclobutoxyphenyl) amino ] -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (130)4- { [3- (2-cyclohexylethoxy) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (131) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (2-methylpropyl) carbamoyl ] phenyl } amino) benzamide

- (132) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (4-methylpentyl) oxy ] phenyl } amino) benzamide

- (133) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (2,2, 2-trifluoroethyl) carbamoyl ] phenyl } amino) benzamide

- (134) 3-cyclopropyl-4- ({3- [ (3- [)Alk-3-yl) methoxy]Phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide derivatives

- (135)4- [ (3-amino-2-methylphenyl) amino ] -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (136)4- [ (3- { 3-azabicyclo [3.1.0] hexane-3-carbonyl } phenyl) amino ] -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (137) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (trifluoromethoxy) phenyl ] amino } benzamide

- (138) N- (2-cyclohexylethyl) -4- ({ 2-cyclopropyl-4- [ (1, 3-diazine-2-ylidene) carbamoyl ] phenyl } amino) pyridine-2-carboxamide

- (139) 3-cyclopropyl-N- (1, 3-diazinon-2-ylidene) -4- ({3- [2- (propan-2-yloxy) ethoxy ] phenyl } amino) benzamide

- (140)4- { [3- (4-cyclohexylbutoxy) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (141)4- { [3- (5-chloro-1H-imidazol-2-yl) -2-methylphenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (142)4- { [3- (5-chloro-1H-imidazol-2-yl) -2-methylphenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (143)4- { [3- (3-cyclohexylpropanesulfonyl) phenyl ] amino } -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (144) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (oxetan-3-yloxy) phenyl ] amino } benzamide

- (145) 3-cyclopropyl-4- { [3- (cyclopropylcarbamoyl) phenyl ] amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (146) 3-cyclopropyl-4- ({3- [ (3- [))Alk-4-yl) methoxy]Phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide derivatives

- (147) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({2- [ (3-methylbutyl) carbamoyl ] phenyl } amino) benzamide

- (148)4- { [3- (3-cyclohexylpropionylamino) -4-fluorophenyl ] amino } -N- (1, 3-diazine-2-ylidene) -3- (trifluoromethyl) benzamide

- (149)4- ({3- [2- (3-cyclohexylpropyl) -2H-1,2,3, 4-tetrazol-5-yl ] phenyl } amino) -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (150) 3-cyclopropyl-4- ({3-, [2 ]2- (1, 4-diAlk-2-yl) ethoxy]Phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide derivatives

- (151) 3-cyclopropyl-4- ({3- [ ((151)Alk-2-yl) methoxy]Phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide derivatives

- (152) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (3, 3-difluorocyclobutyl) carbamoyl ] phenyl } amino) benzamide

- (153)4- { [3- (3-cyclohexylpropionylamino) phenyl ] amino } -N- (1, 3-diazine-2-ylidene) -3-methylbenzamide

- (154) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (2, 2-Dimethylazepine-1-carbonyl) phenyl ] amino } benzamide

- (155) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (Oxetan-3-yl) carbamoyl ] phenyl } amino) benzamide

- (156)4- { [3- (3-cyclohexylpropoxy) phenyl ] amino } -N- (1, 3-diazine-2-ylidene) -3-methylbenzamide

- (157) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (1, 3-diazine-2-ylidene)Alk-4-yl) carbamoyl]Phenyl } amino) benzamides

- (158) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (morpholine-4-carbonyl) phenyl ] amino } benzamide

- (159) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({2- [ (3,3, 3-trifluoropropyl) carbamoyl ] phenyl } amino) benzamide

- (160) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [2- (2-methoxyethyl) -2H-1,2,3, 4-tetrazol-5-yl ] phenyl } amino) benzamide

- (161) 3-cyclopropyl-4- ({3- [ (1, 4-bis)Alk-2-yl) methoxy]Phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide derivatives

- (162) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (2-methylazepan-1-carbonyl) phenyl ] amino } benzamide

- (163) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (dimethylcarbamoyl) phenyl ] amino } benzamide

- (164) 3-cyclopropyl-4- { [3- (morpholine-4-carbonyl) phenyl ] amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (165)4- ({3- [ (1-cyanocyclopropyl) carbamoyl ] -2-methylphenyl } amino) -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (166) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (oxetan-3-yl) carbamoyl ] phenyl } amino) benzamide

- (167) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (4-methylpiperazine-1-carbonyl) phenyl ] amino } benzamide

- (168)4- ({3- [ (1-methylcyclopropyl) carbamoyl ] phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] -3- (propane-2-sulfonyl) benzamide

- (169) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [ 4-methyl-3- (4-methylpentanoylamino) phenyl ] amino } benzamide

- (170) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({ 4-methyl-3- [ (3-methylbutyl) carbamoyl ] phenyl } amino) benzamide

- (171) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [1- (2-methoxyethyl) -1H-1,2,3, 4-tetrazol-5-yl ] phenyl } amino) benzamide

- (172)4- ({3- [ (1-cyanocyclopropyl) carbamoyl ] phenyl } amino) -3-cyclopropyl-N- (1, 3-diazine-2-ylidene) benzamide

- (173)4- ({3- [ (1-methylcyclopropyl) carbamoyl ] phenyl } amino) -3- (2-methylpropane-2-sulfonyl) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (174)4- ({3- [ (1-methylcyclopropyl) carbamoyl ] phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] -3- (propane-2-sulfinyl) benzamide

- (175) 3-methyl-4- { [3- (morpholine-4-carbonyl) phenyl ] amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

- (176) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (1-hydroxypropan-2-yl) carbamoyl ] phenyl } amino) benzamide

- (177) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (3-hydroxycyclobutyl) carbamoyl ] phenyl } amino) benzamide

- (178) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (piperazine-1-carbonyl) phenyl ] amino } benzamide

- (179) 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- ({3- [ (piperidin-4-yl) methoxy ] phenyl } amino) benzamide

- (180) N- (1, 3-diazine-2-ylidene) -3-methyl-4- [ (3- { [3- (morpholin-4-yl) propyl ] carbamoyl } phenyl) amino ] benzamide

- (181) 3-methanesulfonyl-4- ({3- [ (1-methylcyclopropyl) carbamoyl ] phenyl } amino) -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene ] benzamide

And pharmaceutically acceptable salts thereof.

Thus, the present invention extends to compounds (19) to (31) and (91) to (181) and their pharmaceutically acceptable salts, such as the hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tosylate, triflate, maleate, mesylate, formate, acetate and fumarate salts.

According to anotherAspect(s)One subject of the present invention relates to any of compounds (19) to (31) and (91) to (181) or pharmaceutically acceptable salts thereof for use as a medicament.

According to anotherAspect(s)One subject of the present invention relates to any one of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, and any one of compounds (19) to (31) and (91) to (181) or a pharmaceutically acceptable salt thereof, as defined above, for use as a medicamentAny one of the salts for use in the prevention, inhibition or treatment of an RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification.

Any of compounds (27), (28), (91) - (166), or a pharmaceutically acceptable salt thereof, can be particularly useful for preventing, inhibiting, or treating RSV infection.

Any of compounds (22), (23), (24), (26), (27), and (28), or pharmaceutically acceptable salts thereof, may be particularly useful for preventing, inhibiting, or treating a chikungunya infection.

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

"pharmaceutically acceptable salts thereof" means salts formed from acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed from organic acids (such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid (palmoic acid), alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and poly-galacturonic acid).

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

Any one of the compound of formula (Ic) and any one of compounds (19) to (31) and (91) to (181), or a pharmaceutically acceptable salt thereof, may form a solvate or a hydrate, and the present invention includes all such solvates and hydrates.

The compounds of formula (Ic) may also exist in tautomeric forms and are part of the present invention. The terms "hydrate" and "solvate" simply mean that compound (Ic) according to the invention may be in the form of a hydrate or solvate, i.e. in combination or association with one or more water or solvent molecules. This is merely a chemical feature of such compounds, which can be applied to all organic compounds of this class.

In the context of the present invention, the term:

"halogen" is understood to mean chlorine, fluorine, bromine or iodine, and especially chlorine, fluorine or bromine,

as used herein "(C)₁-C_x) Alkyl "independently represents C₁-C_xNormal (normal), secondary or tertiary saturated hydrocarbons, e.g. (C)₁-C₆) An alkyl group. Examples are, but not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,

- "alkenylene" means a divalent radical (C) containing a double bond₁-C_x) Alkyl groups, and more specifically ethenylene groups, also known as ethenylene or 1, 2-ethenediyl,

as used herein "(C)₃-C₆) Cycloalkyl group "means a cyclic saturated hydrocarbon. Examples are, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

as used herein "(C)₁-C_x) Alkoxy "denotes O- (C)₁-Cx) alkyl moiety wherein alkyl is as defined above, e.g. (C)₁-C₆) An alkoxy group. Examples are, but not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy, pentoxy,

"aryl" as used herein denotes a monocyclic aromatic radical containing 6 carbon atoms and containing 0 to 2 heteroatoms, such as nitrogen, oxygen or sulfur, and in particular nitrogen. As examples of aryl groups, mention may be made, without being limited thereto, of phenyl, pyridine, pyrimidine, pyridazine, pyrazine and the like. Within the framework of the invention, the aryl radicals are advantageously phenyl, pyridazine, pyrazine, pyridine, such as 2-pyridine or 3-pyridine and pyrimidine. The aryl groups are even more advantageously phenyl and pyridine, such as 2-pyridine or 3-pyridine.

As used herein, "a divalent 5-membered heteroaromatic ring containing 1,2,3 or 4 heteroatoms" refers to a divalent ring consisting of an aromatic ring containing 5 chains and 1,2,3 or 4 heteroatoms selected from nitrogen and oxygen atoms. In one embodiment, it comprises at least 1 heteroatom, and preferably at least one nitrogen atom.In another embodiment, it comprises at least 2 heteroatoms, and for example at least one nitrogen atom. According to another embodiment, it comprises 2,3 or 4 nitrogen atoms, preferably 3 nitrogen atoms. According to yet another embodiment, it comprises one nitrogen atom and one oxygen atom, or two nitrogen atoms and one oxygen atom. Examples are, but are not limited to, divalent triazoles such as 1,2, 3-or 1,2, 4-triazole,diazoles such as 1,2,4-Oxadiazoles or 1,2,3-Diazoles, and divalent diazoles such as divalent diazoles and divalent imidazoles. According to a preferred embodiment, such a divalent 5-membered heteroaromatic ring comprising 2 or 3 heteroatoms is a divalent triazole.

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

The compounds of the present invention may be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences described below represent general procedures that may be used to prepare the compounds of the invention and are not intended to be limiting in scope or utility.

The compounds of general formulae (I) and (Ic) can be prepared according to scheme 1 below.

The synthesis is based on a coupling reaction starting from a haloaromatic compound of formula (III) in which R, R ', m'A ring,Ring, X¹、X²、n、Y¹、Y²As defined above, and X is a chlorine atom, an iodine atom or a bromine atom.

According to one embodiment, the groupRelative to the-NH-group isThe procedure (A1) can advantageously be used in the meta-or para-position on the ring.

According to scheme (a1), the compound of formula (III) can be placed in a protic solvent such as tert-butanol. May then be in the presence of an inorganic base such as Cs₂CO₃Or K₂CO₃In the presence of a diphosphine such as Xantphos (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) or X-Phos (2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl) or rac-BINAP, in particular in an amount ranging from 2 to 15 mol% relative to the total amount of compounds of formula (III), and an organometallic catalyst such as Pd (OAc) in an amount ranging from 2 to 25 mol% relative to the total amount of compounds of formula (III), for example still in a molar ratio ranging from 1 to 5 relative to compounds of formula (III)₂Or Pd₂dba₃Or BrettPhos Pd G3, in a molar ratio, for example in the range from 1 to 1.5, relative to the compound of formula (III). The reaction mixture may then be heated at a temperature in the range of 80-130 c, for example at 90 c, and stirred under an inert gas, for example argon, for a time in the range of 15-25 hours, for example 20 hours. The reaction mixture may be concentrated under reduced pressure, and the residue may be diluted with an organic solvent such as ethyl acetate. The organic phase may be washed with water, decanted, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give the compounds of formula (I) and (Ic).

According to one embodiment, the groupRelative to the-NH-group isWhen ortho on the ring, the procedure (A2) can advantageously be used.

According to procedure (a2), the compound of formula (II) may be placed in a polar aprotic solvent such as dimethyl sulfoxide. May then be in the presence of an inorganic base such as Cs₂CO₃Or K₂CO₃The compound of formula (III) is added in the presence of a ligand such as L-proline, in particular in an amount ranging from 2 to 25 mol% relative to the total amount of the compound of formula (II), and in the presence of an organometallic catalyst such as CuI in an amount ranging from 2 to 25 mol% relative to the total amount of the compound of formula (II), for example in a molar ratio ranging from 1 to 1.5 relative to the compound of formula (II), for example still in a molar ratio ranging from 1 to 5 relative to the compound of formula (II). The reaction mixture may then be heated at a temperature in the range of 80-130 c, for example at 90 c, and stirred under an inert gas, for example argon, for a time in the range of 15-25 hours, for example 20 hours. The reaction mixture may be diluted with an organic solvent such as ethyl acetate. The organic phase may be washed with water, decanted, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give the compounds of formula (I) and (Ic).

The starting compounds of the formulae (II), (III) are available or can be prepared according to methods known to the person skilled in the art.

Thus, this document further describes synthetic processes for the preparation of the novel compounds of formulae (I) and (Ic) as defined above, comprising at least the following steps: reacting a compound of formula (II) in the presence of an inorganic base and a ligand and in the presence of an organometallic catalyst

Coupling with compounds of the formula (III)

Wherein X¹、Y¹、R、R’、m、m’、A ring,Ring, X²、Y²As defined above, and X is a chlorine atom, an iodine atom or a bromine atom,

to give compounds of formulae (I) and (Ic).

The compounds of general formula (Ic) can be prepared according to scheme 1' below.

More specifically, the present invention relates to a synthetic process for the preparation of a compound of formula (Ic) as defined above, comprising at least the following steps: reacting a compound of formula (IIc) in the presence of an inorganic base and a ligand and in the presence of an organometallic catalyst

Coupling with compounds of the formula (IIIc)

Wherein R, R ', m'),A ring,Ring, X²、Y²、R_h、R_gAnd Z' is as defined above, X is a chlorine atom, an iodine atom or a bromine atom,

to give a compound of formula (Ic).

More particularly when used in the preparation of compounds of formula (Ic) (wherein Z ═ CH)₂) When the compound of formula (IIc) is prepared according to scheme 4 below.

Preparation of (IIc) for (Ic)

The intermediate compounds of formulae (IIc) and (IVc) may be used to prepare compounds of formula (Ic) according to the invention.

According to the scheme (D2), aminopyrimidines can be placed in a polar aprotic solvent such as dichloromethane. The nitrobenzoyl chloride derivative may then be added, for example, in a molar ratio in the range of 1 to 1.5 relative to aminopyrimidine in the presence of an organic base such as N, N-diisopropylethylamine or triethylamine, for example, still in a molar ratio in the range of 1 to 2 relative to aminopyrimidine, in the presence of a nucleophilic catalyst such as dimethylaminopyridine, for example, still in a molar ratio in the range of 0.1 to 1 relative to aminopyrimidine. The reaction mixture may then be stirred under an inert gas and, for example, argon at room temperature for a period in the range of 5-20 hours, for example, 18 hours. The organic phase may be washed with water and the resulting precipitate may be filtered, washed with water and dichloromethane, and dried under vacuum overnight to provide the compound of formula (IVc).

According to scheme (E), the compound of formula (IVc) and the amount of 10% Pd/C with respect to benzamide can be placed in a protic solvent such as ethanol in a ratio ranging from 2% to 10%. The reaction mixture can then be reacted in H₂Stirring is carried out at room temperature under an atmosphere for a period in the range of 5-20 hours, for example 16 hours. The reaction mixture may then be filtered, and the filtrate may be concentrated under reduced pressureTo give the compound of formula (IIc).

According to one embodiment, in case Z "is a-CO-group, another route can be followed to prepare the compound of formula (Ic) and shown in scheme X below.

The synthesis starts with the coupling reaction of a halogenated aromatic compound of formula (IIIc) according to the protocol (A1) or (A2) with an aniline derivative (Vc), in which R, R', R_a、m、m’、X¹、X²、n、Y¹、Y²Z, Z ', Z' are as defined above and X is a chlorine atom, an iodine atom or a bromine atom.

According to procedure (K), the compound of formula (VIc) may be placed in a protic solvent such as methanol and 2M aqueous NaOH solution may be added at a rate in the range of 3-10 equivalents. The reaction mixture may then be heated at a temperature in the range of 50-90 c, for example at 80 c, and stirred for a time in the range of 1-24 hours, for example 3 hours. The mixture can be concentrated under reduced pressure and, after addition of 2M aqueous HCl, extracted with an organic solvent such as dichloromethane. The combined organic phases may then be dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the compound of formula (VIIc).

According to procedure (L), the compound of formula (VIIc) and Carbonyldiimidazole (CDI) can be placed in an anhydrous polar solvent such as N, N-dimethylformamide in a ratio ranging from 1.0 to 3 equivalents, for example 1.2 equivalents. The reaction mixture may then be stirred at room temperature for a time in the range of 1-3 hours, for example 1 hour. The amine derivative Y can then be added in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine, for example still in a molar ratio ranging from 2 to 5 with respect to compound (VIIc)¹-NH₂For example in a molar ratio ranging from 1 to 2.5 with respect to compound (VIIc). The reaction mixture may then be heated at a temperature in the range of 50-90 c, for example at 75 c, and stirred for a time in the range of 1-24 hours, for example 16 hours. After adding the hydrogen carbonateAfter a saturated aqueous solution of sodium, the reaction can be quenched and the mixture extracted with an organic solvent such as ethyl acetate. The combined organic phases may then be dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the compound of formula (Ic).

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

TABLE I

TABLE II

The following examples are provided as illustrations and in no way limit the scope of the invention.

The following examples illustrate in detail the preparation of certain compounds according to the invention. The structure of the product obtained has been confirmed by NMR spectroscopy.

Examples

Example 1Compound (22) in Table I

According to scheme (D2), a reaction mixture of 2-aminopyrimidine (2.0g,21.0mmol,1.0 equiv.), 4-nitrobenzoyl chloride (4.68g,25.2mmol,1.2 equiv.), N-diisopropylethylamine (5.21mL,31.5mmol,1.5 equiv.), and dimethylaminopyridine (2.6g,21.0mmol,1 equiv.) in dichloromethane (45mL) was stirred under an argon inert atmosphere at room temperature for 18 h. After washing the organic phase with water, the resulting precipitate formed was filtered, washed with diethyl ether and dried under reduced pressure to give 4-nitro-N- (pyrimidin-2-yl) benzamide (2.0g, 39%).

¹H NMR(300MHz,d₆-DMSO)δ11.39(s,1H),8.76(d,J＝4.8Hz,2H),8.34(d,J＝8.8Hz,2H),8.16(d,J＝8.8Hz,2H),7.30(t,J＝4.8Hz,1H)。

According to scheme (E), 4-nitro-N- (pyrimidin-2-yl) benzamide (1g,4.1mmol,1 eq) and 10% Pd/C (2.2g) were placed in EtOH (20.5 mL). The reaction mixture is reacted in H₂Stirred at room temperature under an atmosphere for 16 hours. The reaction mixture was then filtered over celite, washed with EtOH, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-amino-N- (tetrahydropyrimidin-2 (1H) -ylidene) benzamide (580mg, 65%).

¹H NMR(300MHz,d₆-DMSO)δ8.77(s,2H),7.75(d,J＝8.5Hz,2H),6.48(d,J＝8.5Hz,2H),5.50(s,2H),3.28(t,J＝5.7Hz,4H),1.86-1.76(m,2H)。

2-Cyclopentylethane-1-amine hydrochloride (3.0g,19.1mmol,1.1 equiv.) was placed in 3N aqueous NaOH (13mL) and dichloromethane (3.2mL) was added to the solutionAnd (4) liquid. The reaction mixture was cooled to 0 ℃ with an ice bath and a solution of 3-bromobenzoyl chloride (2.3mL,17.4mmol,1 eq) in dichloromethane (5.5mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. After decantation, the organic phase is washed with a saturated aqueous brine solution over MgSO₄Dried, filtered and concentrated under reduced pressure to give 3-bromo-N- (2-cyclopentylethyl) benzamide (4.6g, 89%).

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

According to scheme (A1), 3-bromo-N- (2-cyclopentylethyl) benzamide (296mg,1.0mmol,1 equiv.), 4-amino-N- (tetrahydropyrimidin-2 (1H) -ylidene) benzamide (218mg,1.0mmol,1 equiv.), Pd₂(dba)₃(92mg,0.1mmol,10 mol%), XPhos (95mg,0.2mmol,20 mol%) and K₂CO₃(553mg,4.0mmol,4 equiv.) of the reaction mixture in t-BuOH (4mL) was heated in a microwave reactor at 120 ℃ for 60 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase is washed with water and over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N- (2-cyclopentylethyl) -3- ({4- [ (tetrahydropyrimidin-2 (1H) -ylidene) carbamoyl]Phenyl } amino) benzamide (22) (240mg, 55%).

¹H NMR(300MHz,d₆-DMSO)δ8.77(s,2H),8.55(s,1H),8.37(t,J＝5.6Hz,1H),7.93(d,J＝8.7Hz,2H),7.59(s,1H),7.37-7.29(m,2H),7.27-7.21(m,1H),7.02(d,J＝8.7Hz,2H),3.51-3.39(m,1H),3.29-3.22(m,6H),1.84-1.75(m,5H),1.58-1.47(m,7H)。

¹³C NMR(75MHz,d₆-DMSO)δ175.0,166.6,159.1,145.8,143.1,136.5,131.1,130.4,129.6,120.5,119.7,119.4,116.9,115.1,38.6,37.9,35.9,32.7,25.2,20.5

[M+H]⁺＝434.0

Example 2In Table ICompound (97)

3-bromophenol (701mg,3.97mmol,1.2 equiv.) with Cs₂CO₃(1.3g,3.97mmol,1.2 eq.) were placed together in N, N-dimethylformamide (4 mL). After addition of (3-bromopropyl) cyclohexane (715mg,3.31mmol,1 eq.) the reaction mixture was stirred at room temperature for 16 h under an inert atmosphere of argon. Adding saturated NaHCO to the reaction mixture₃Aqueous solution, and it was 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 (882mg, 90%).

¹H 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)。

According to the protocol (A1), 1-bromo-3- (3-cyclohexylpropoxy) benzene (547mg,1.84mmol,1.1 equiv.), methyl 4-amino-3-cyclopropyl-benzoate (320mg,1.67mmol,1 equiv.), Brettphos Pd G3(31.9mg, 33.5. mu. mol,2 mol%) and Cs₂CO₃(818mg,2.51mmol,1.5 equiv.) of the reaction mixture in anhydrous DMF (8mL) with N₂Degassed and heated at 80 ℃ for 75 minutes under an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the pad was washed with EtOAc. Saturated aqueous brine was then added to the filtrate, and the mixture was extracted with EtOAc. The combined organic phases were passed over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4- { [3- (3-cyclohexylpropoxy) phenyl group]Amino } -3-cyclopropylbenzoic acid methyl ester (1.35g, 80%).

¹H 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)。

Methyl 4- { [3- (3-cyclohexylpropoxy) phenyl ] amino } -3-cyclopropylbenzoate (575mg,1.34mmol,1 equiv.) was placed in methanol (10mL) according to procedure (K) and 2M aqueous NaOH (4.7mL,9.4mmol,7 equiv.) was added. The reaction mixture was heated at 80 ℃ and stirred for 3 hours. It was then concentrated under reduced pressure and, after addition of 2M aqueous HCl (7mL,14mmol,10.5 equiv.), 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 (540mg, 97%).

¹H 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)。

According to procedure (L), 4- { [3- (3-cyclohexylpropoxy) phenyl]A reaction mixture of amino } -3-cyclopropylbenzoic acid (100mg, 241. mu. mol,1 equivalent) and CDI (47.0mg, 290. mu. mol,1.2 equivalents) in dry DMF (1.0mL) was stirred at room temperature for 1 hour. The mixture was then added to a solution of β -alaninine hydrochloride (72.2mg,483 μmol,2 equiv) and DIPEA (126 μ L,724 μmol,3 equiv) in anhydrous DMF (1.0mL) and the resulting mixture was heated at 75 ℃ and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with saturated aqueous brine solution over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4- { [3- (3-cyclohexylpropoxy) phenyl group]Amino } -3-cyclopropyl-N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide (97) (75.0mg, 62%).

¹H NMR(400MHz,d₆-DMSO)δ10.78(s,1H),10.15(s,1H),7.85-7.77(m,2H),7.67(s,1H),7.15(t,J＝8.4Hz,2H),6.70(d,J＝7.9Hz,1H),6.67(t,J＝2.1Hz,1H),6.47(dd,J＝8.1,2.1Hz,1H),3.90(t,J＝6.5Hz,2H),3.54(t,J＝7.0Hz,2H),2.61(t,J＝7.0Hz,2H),1.94(ddd,J＝13.7,8.4,5.5Hz,1H),1.69(t,J＝14.5Hz,7H),1.34-1.08(m,6H),1.02-0.81(m,4H),0.61(q,J＝5.8Hz,2H)。

¹³C NMR(151MHz,d₆-DMSO)δ160.0,157.6,146.3,144.8,131.0,130.2,128.0,115.7,111.4,107.5,105.4,68.0,37.2,36.8,33.7,33.3,30.5,26.6,26.5,26.3,11.5,7.6

[M+H]⁺＝489.1

Example 3Compound in Table I (98)

To a solution of 3-bromobenzoic acid (2.00g,9.95mmol,1 eq) and isopropylamine (940 μ L,10.9mmol,1.1 eq) in anhydrous DMF (10mL) were added HATU (3.78g,9.95mmol,1 eq) and DIPEA (2.60mL,114.9mmol,1.5 eq), and the reaction mixture was then stirred at room temperature overnight. The reaction was quenched with 1M aqueous hydrochloric acid and extracted with EtOAc. The combined organic layers were then MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-bromo-N-isopropylbenzamide (1.88g, 76%).

¹H NMR(400MHz,d₆-DMSO)δ8.34(d,J＝7.4Hz,1H),8.03(s,1H),7.85(d,J＝7.8Hz,1H),7.75-7.68(m,1H),7.43(t,J＝7.9Hz,1H),4.17-4.00(m,J＝6.7Hz,1H),1.17(d,J＝6.6Hz,6H)。

According to scheme (A1), 3-bromo-N-isopropylbenzamide (197mg,0.796mmol,1.1 equiv.), 4-amino-3-tert-butyl-benzoic acid methyl ester (150mg,0.724mmol,1 equiv.), Pd (OAc)₂(4.9mg,0.022mmol,3 mol%), rac-BINAP (9.0mg,0.015mmol,2 mol%) and K₂CO₃(300mg,2.17mmol,3 equiv.) of the reaction mixture in dry toluene (3mL) with N₂Degassed and heated at 110 ℃ for 75 minutes under an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the pad was washed with EtOAc. Saturated aqueous brine was then added to the filtrate, and the mixture was extracted with EtOAc. The combined organic phases were passed over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-tert-butyl-4- { [3- (isopropylcarbamoyl) phenyl]Amino } benzoic acid methyl ester163mg,60％)。

¹H NMR(400MHz,d₆-DMSO)δ8.09(d,J＝7.8Hz,1H),8.01(d,J＝2.0Hz,1H),7.74(dd,J＝8.3,1.9Hz,1H),7.39(s,1H),7.33-7.22(m,3H),7.17(d,J＝8.4Hz,1H),6.98(d,J＝7.6Hz,1H),4.07(dq,J＝13.4,6.6Hz,1H),3.83(s,3H),1.42(s,9H),1.15(d,J＝6.6Hz,6H)。

Methyl 3-tert-butyl-4- { [3- (isopropylcarbamoyl) phenyl ] amino } benzoate (160mg,0.434mmol,1 eq) was placed in methanol (2mL) according to procedure (K) and 2M aqueous NaOH (1.3mL,2.61mmol,6 eq) was added. The reaction mixture was heated at 80 ℃ and stirred for 3 hours. It was then concentrated under reduced pressure and, after addition of 2M aqueous HCl (10 eq), extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-tert-butyl-4- { [3- (isopropylcarbamoyl) phenyl ] amino } benzoic acid (142mg, 90%).

¹H NMR(400MHz,d₆-DMSO)δ12.64(s,1H),8.07(d,J＝7.7Hz,1H),8.02(s,1H),7.73(d,J＝8.4Hz,1H),7.35(s,1H),7.27-7.19(m,3H),7.16(d,J＝8.2Hz,1H),6.94(d,J＝6.5Hz,1H),4.14-3.99(m,1H),1.42(s,9H),1.15(d,J＝6.6Hz,6H)。

According to procedure (L), 3-tert-butyl-4- { [3- (isopropylcarbamoyl) phenyl]A reaction mixture of amino } benzoic acid (65.0mg, 180. mu. mol,1 equiv.) and CDI (35.0mg, 216. mu. mol,1.2 equiv.) in anhydrous DMF (1.0mL) was stirred at room temperature for 1 hour. The mixture was then added to a solution of β -alaninine hydrochloride (53.8mg,359 μmol,2 equiv) and DIPEA (93.9 μ L,539 μmol,3 equiv) in anhydrous DMF (1.0mL) and the resulting mixture was heated and stirred at 75 ℃ for 16 h. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with saturated aqueous brine solution over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-tert-butyl-4- { [3- (isopropylcarbamoyl) phenyl]Amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide (98) (37.0mg, 45%).

¹H NMR(400MHz,d₆-DMSO)δ10.83(s,1H),10.21(s,1H),8.27(d,J＝1.8Hz,1H),8.04(d,J＝7.8Hz,1H),7.90(dd,J＝8.2,1.8Hz,1H),7.29(s,1H),7.18(s,3H),7.13(d,J＝8.2Hz,1H),6.90-6.82(m,1H),4.06(dq,J＝13.3,6.6Hz,1H),3.56(t,J＝7.0Hz,2H),2.63(t,J＝7.0Hz,2H),1.41(s,9H),1.14(d,J＝6.6Hz,6H)。

¹³C NMR(151MHz,d₆-DMSO)δ177.4,170.2,166.1,157.8,147.1,145.0,144.0,136.5,133.5,129.1,128.7,128.1,126.6,118.5,117.3,115.5,41.3,36.8,35.2,30.9,30.5,22.8

[M+H]⁺＝450.1

Example 4Compound (102) in Table I

According to scheme (A1), 3-bromo-N-isopropylbenzamide (135mg,0.547mmol,1.1 equiv.), 4-amino-3-cyclopropyl-benzoic acid methyl ester (100mg,0.497mmol,1 equiv.), Brettphos Pd G3(23.7mg, 24.8. mu. mol,5 mol%) and Cs₂CO₃(243mg,0.745mmol,1.5 equiv.) of the reaction mixture in anhydrous DMF (2mL) with N₂Degassed and heated at 80 ℃ for 75 minutes under an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the pad was washed with EtOAc. Saturated aqueous brine was then added to the filtrate, and the mixture was extracted with EtOAc. The combined organic phases were passed over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-cyclopropyl-4- { [3- (isopropylcarbamoyl) phenyl group]Amino } benzoic acid methyl ester (131mg, 71%).

¹H NMR(400MHz,d₆-DMSO)δ8.17(d,J＝7.8Hz,1H),8.01(s,1H),7.67(dd,J＝8.8,1.9Hz,2H),7.55(d,J＝2.0Hz,1H),7.47(dt,J＝7.6,1.3Hz,1H),7.38(t,J＝7.8Hz,1H),7.31(ddd,J＝7.9,2.1,1.1Hz,1H),7.12(d,J＝8.5Hz,1H),4.09(dq,J＝13.3,6.6Hz,1H),3.79(s,3H),1.96(tt,J＝8.3,5.6Hz,1H),1.16(d,J＝6.6Hz,6H),1.04-0.95(m,2H),0.65-0.57(m,2H)。

According to procedure (K), methyl 3-cyclopropyl-4- { [3- (isopropylcarbamoyl) phenyl ] amino } benzoate (130mg,0.350mmol,1 eq) was placed in methanol (2mL) and 2M aqueous NaOH (0.88mL,1.75mmol,5 eq) was added. The reaction mixture was heated at 80 ℃ and stirred for 3 hours. It was then concentrated under reduced pressure and, after addition of 2M aqueous HCl (10 eq), extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-cyclopropyl-4- { [3- (isopropylcarbamoyl) phenyl ] amino } benzoic acid (115mg, 92%).

¹H NMR(400MHz,d₆-DMSO)δ12.38(s,1H),8.16(d,J＝7.8Hz,1H),7.96(s,1H),7.69-7.61(m,2H),7.54(d,J＝2.0Hz,1H),7.44(dt,J＝7.6,1.3Hz,1H),7.37(t,J＝7.7Hz,1H),7.29(ddd,J＝7.9,2.1,1.1Hz,1H),7.12(d,J＝8.5Hz,1H),4.09(dq,J＝13.2,6.6Hz,1H),1.96(tt,J＝8.3,5.4Hz,1H),1.16(d,J＝6.6Hz,6H),1.03-0.92(m,2H),0.68-0.57(m,2H)。

According to procedure (L), 3-cyclopropyl-4- { [3- (isopropylcarbamoyl) phenyl]A reaction mixture of amino } benzoic acid (82.0mg, 230. mu. mol,1 equiv.) and CDI (44.8mg, 276. mu. mol,1.2 equiv.) in anhydrous DMF (1.0mL) was stirred at room temperature for 1 hour. The mixture was then added to a solution of 1,4,5, 6-tetrahydropyrimidin-2-amine hydrochloride (65.7mg,460 μmol,2 equiv.) and DIPEA (120 μ L,691 μmol,3 equiv.) in anhydrous DMF (1.0mL) and the resulting mixture was heated at 75 ℃ and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with saturated aqueous brine solution over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel followed by preparative HPLC to give 3-cyclopropyl-N- (1, 3-diazine-2-ylidene) -4- { [3- (isopropylcarbamoyl) phenyl]Amino } benzamide (102) (17.8mg, 18%).

¹H NMR(400MHz,d₆-DMSO)δ10.79(s,1H),10.16(s,1H),8.14(d,J＝7.8Hz,1H),7.87(s,1H),7.82(d,J＝8.1Hz,2H),7.60(t,J＝1.8Hz,1H),7.38(dt,J＝7.6,1.4Hz,1H),7.33(t,J＝7.7Hz,1H),7.28-7.21(m,1H),7.12(d,J＝8.3Hz,1H),4.08(dp,J＝13.7,6.9Hz,1H),3.54(t,J＝7.0Hz,2H),2.62(t,J＝7.0Hz,2H),1.96(tt,J＝8.4,5.6Hz,1H),1.16(d,J＝6.6Hz,6H),1.02-0.92(m,2H),0.67-0.58(m,2H)。

¹³C NMR(151MHz,d₆-DMSO)δ170.2,165.9,157.6,146.3,143.6,136.5,131.0,129.2,128.0,128.0,121.6,119.9,118.4,115.4,41.4,36.8,30.5,22.8,11.6,7.6

[M+H]⁺＝434.2

Example 5Compound in Table I (120)

According to procedure (L), 3-cyclopropyl-4- { [3- (isopropylcarbamoyl) phenyl]A reaction mixture of amino } benzoic acid (50.0mg, 148. mu. mol,1 equiv.) and CDI (28.8mg, 177. mu. mol,1.2 equiv.) in anhydrous DMF (1.0mL) was stirred at room temperature for 1 hour. The mixture was then added to a solution of β -alaninine hydrochloride (44.2mg,296 μmol,2 equiv) and DIPEA (77.2 μ L,443 μmol,3 equiv) in anhydrous DMF (1.0mL) and the resulting mixture was heated and stirred at 75 ℃ for 16 h. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, and extracted with EtOAc. The combined organic layers were then washed with saturated aqueous brine solution over MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-cyclopropyl-4- { [3- (isopropylcarbamoyl) phenyl group]Amino } -N- [ (2E) -4-oxo-1, 3-diazine-2-ylidene]Benzamide (120) (30.0mg, 45%).

¹H NMR(400MHz,d₆-DMSO)δ8.79(s,2H),8.12(d,J＝7.6Hz,1H),7.75(d,J＝7.6Hz,2H),7.68(s,1H),7.54(s,1H),7.31(s,2H),7.18(s,1H),7.10(d,J＝8.3Hz,1H),4.14-4.02(m,1H),3.29(s,4H),2.00-1.91(m,1H),1.83(s,2H),1.15(d,J＝6.6Hz,6H),0.95(d,J＝7.4Hz,2H),0.59(d,J＝4.2Hz,2H)。

¹³C NMR(151MHz,d₆-DMSO)δ175.1,166.1,159.2,144.6,144.5,136.5,132.6,131.8,129.2,127.3,127.0,120.4,119.0,117.3,116.7,41.3,38.5,22.8,20.4,11.6,7.8

[M+H]⁺＝420.3

Pharmacological data

Example 6 chikungunya Virus

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

Materials and methods

Inhibition of chikungunya virus (CHIKV) production in the infected HEK293T cell line.

The ability of compounds to inhibit viral replication was assessed using an experiment in which infected cells were treated with 1 μ M of a compound of formula (Ic). As a positive control for inhibition of buckling, ribavirin was used. Toxicity of the compounds was evaluated in parallel.

Amplification of cells

Human embryonic kidney cells 293T (HEK293T, CRL-11268) were maintained in Dulbecco's modified eagle's medium (DMEM, 31966-. After removal of the medium, the cells were treated with Ca-free media²⁺And Mg²⁺The salt solution washes to remove all traces of serum. After aspirating the wash solution, the cells were dissociated with a 0.25% trypsin-EDTA solution and incubated in an incubator at 37 ℃ for at least 30 s. The concentration of the cell suspension was determined by an automatic cell counter (EVE, NanoEntek) and adjusted to 0.33X 10 with DMEM medium supplemented with 10% FBS, if necessary⁶Individual cells/mL.

Preparation of the Compounds

100 μ L of the cell suspension was dispensed into a Viewplate-96 Black (6005182, Perkinelmer) and a clear 96-well cell culture plate (655180, Greiner bio-one). At 5% CO₂After incubation at 37 ℃ for 24h, compounds were added at the appropriate concentrations.

Screening at 1. mu.M

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

mu.L of a 50mM stock pool was mixed in 25. mu.L of DMSO.

Mix 2. mu.L of 25mM stock pool in 25. mu.L DMSO.

₅₀Determination of IC value

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

mu.L of a 50mM stock pool was mixed in 2. mu.L of DMSO.

Serial dilutions were performed 13 times in 2 μ L DMSO to reach 0.0015 mM. Performed as follows in table III:

TABLE III

About IC₅₀To 1mL of Masterblock 96 well containing 1mL of DMEM medium (Greiner bio-one, 780261). As a positive control, 5. mu.L of 80mM ribavirin solution (R9644, Sigma) was added to 1mL DMEM. On the other hand, DMSO was used as a negative control.

Infection with

Infection of cells with 30. mu.L of CHIKV strain (LR2006-OPY1) (CHIK 5 'LR) having a burst of GFP-modified La Rionen at 5' (Tstsarkin K, Higgs, McGee CE, De Lamballerie X, Charrel RN, Vanlandingham DL. Infectious Clones of Chikungunya Virus (La Rionen interference) was performedRef-SKU:001N-EVA249(PMID:17187566) Https:// www.european-virus-architectural, com/nucleic-acid/chikv-lr-5gfp-in defects-clone) for Vector compatibility students, Vector born nonomatic Dis.2006; 6(4)). The modified virus was used to infect cells at MOI 0.1. LR2006-OPY1 strain of CHIKV (CHIKV-LR) was obtained from World Reference Center for deboviruses at the University of Texas Medical Branch, Galveston, TX. This strain was originally isolated from serum of febrile french patients returned from La reunion Island.

Cell lysis

At 5% CO₂After 22h at 37 ℃ the medium was removed and the cells were plated as aboveAnd (4) washing. mu.L of RIPA buffer (50mM Tris-HCl pH8,100mM NaCl,1mM MgCl2, 1% Triton X-100) was added to the cells and incubated for at least 20min before reading the fluorescence signal. Pierce 660nm Protein Assay Reagent (22660, Thermo scientific) was used to normalize the fluorescence signal by Protein amount.

Mixing CellTiterOne Solution Cell promotion Assay (MTS) (G3581, Promega) was used to examine the toxicity of compounds. We added 20. mu.L of MTS solution and read the absorbance at 492nm after 1 hour.

Results

Has already carried outFirst round of experimentWherein the results are expressed as a percentage inhibition, which is calculated by the following steps:

1. fluorescence Intensity (FI)/absorbance 660nm (A660) ═ A

This ratio allows to consider the infection (GFP virus) as protein amount.

Background noise of a' ═ a-uninfected plates,

B-Fluorescence Intensity (FI)/absorbance 660nm (a660) of infected but untreated plates,

c ═ a'/B, which was then converted to percent infection after treatment relative to untreated samples and subsequently expressed as percent infection. For example, a value of 100 in table IV below means that after treatment, the signal due to GFP fluorescence is eliminated, which is associated with the absence of infection.

5.C’＝100-C

This value corresponds to the percentage of inhibition.

Table IV below covers the C' values (calculated as above using the mean of 2 experiments) and the corresponding standard deviations for some compounds.

Some values are initially above 100. In these cases, the value has been reduced to 100. This means that some molecules also have an effect on the viability of the cells. In other words, the a value may be lower than the background noise.

In addition, for each measurement, tests were performed with ribavirin as a control. The value of the percentage inhibition was checked to give 100%.

TABLE IV

Has already carried outSecond round of experimentThe results are given as IC₅₀The value is obtained.

IC₅₀Values are in the range between 0.1nM and 1. mu.M, especially between 0.5 and 500nM, and even more especially between 1-400nM, for example between 1-200 nM. For example, compounds 22, 23 and 24 have IC's in the range between 100-400nM₅₀The value is obtained.

Conclusion

Based on the previous results, it can be concluded that the compound of formula (Ic) is a suitable chemical compound for the treatment and/or prevention of RNA viral infections, more specifically alphavirus infections and most particularly chikungunya virus infections, caused by RNA viruses of group IV.

Example 7 RSV Virus

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

Materials and methods

Protocol for screening antiviral compounds for RSV inhibition and cytotoxicity Using Viral ToxGlo assay

HEp-2 cells were maintained in Eagle's Minimal Essential Medium (EMEM) containing Earle's BSS, which was adjusted to contain 2mM L-glutamine, 10% fetal bovine serum, 100U/ml penicillin and 100. mu.g/ml streptomycin. For the purposes of the screening assay, they were grown to 90% confluence, treated with trypsin and recovered. Trypsin was neutralized with cell culture medium and cells were centrifuged at 150x g for 5 minutes, then the supernatant was discarded and the cell pellet resuspendedFloat in assay medium (EMEM containing Earle's BSS adjusted to contain 2mM L-glutamine, 2% fetal bovine serum and 100U/ml penicillin and 100. mu.g/ml streptomycin). For 96-well and 384-well plates, 1.5 × 10 in 50 μ l each⁴Density of individual cells/well and 4 × 10 in 25 μ l³Density of individual cells/well cells were seeded into white clear-bottom cell culture plates. For the medium/background control column, only assay medium was added. The cell plate was placed in a humidity controlled chamber and incubated at 37 deg.C/5% CO₂Incubate overnight. After overnight incubation, cells were examined for confluency and healthy appearance.

The assay was prepared at 10-fold the assay concentration of 10% of the maximum DMSO concentration (final assay concentration was maximum 1% DMSO) and added to the cell plates in volumes of 10 μ Ι (for 96-well plates) and 5 μ Ι (for 384-well plates). For cell control and virus control wells, only the test solvent was added. Virus or assay medium was added to the cytotoxicity test wells and the media/cell control wells, respectively, at 40 or 20 μ l for 96 and 384 well plates, at an MOI of 0.5 immediately after the test. Viral suspensions were prepared by thawing frozen stocks of RSV a2 and diluting to the desired plaque forming unit concentration in assay medium on ice.

Cell plates were plated in humidity controlled chamber at 37 ℃/5% CO₂Further incubation was carried out for 72 h. After the incubation period, the cells were observed under a microscope to check for characteristic cytopathic effects in the virus control wells and healthy cells in the cell control wells. After the plates were brought to room temperature, 20/40 μ l Viral ToxGlo (Promega) was added to each well of the 384/96 well cell plate. The plates were incubated on a plate shaker for 20 minutes at room temperature in the dark, and the luminescence was then measured on a spectrophotometer (Biotek Synergy HTX).

RSV inhibition was calculated as a percentage of inhibition of cytopathic effects relative to viral controls and cytotoxicity was calculated as a percentage of cell survival relative to cell control wells. This allowed the EC to be calculated for each test₅₀Values wherein a viral inhibitory or cytotoxic dose response is identified. EC in the range between 0.001. mu.M to 2.5. mu.M was found₅₀Values, and more particularly to chemical compoundingEC of articles 27, 28, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 161, 162, 163, 164, 165, and 166₅₀The value is obtained.

TABLE V

Conclusion

Based on the foregoing results, it can be concluded that the compound of formula (Ic) is a suitable chemical compound for the treatment and/or prevention of RNA viral infections, more specifically pneumoviral infections and most particularly RSV viral infections, caused by RNA viruses of group V.

The present invention further relates to a pharmaceutical composition comprising at least one novel compound as defined above or any one of its pharmaceutically acceptable salts, or at least any one of the compounds (19) to (31) and (91) to (181) as defined above or any one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

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

Yet another object of the invention consists of: use of at least one compound of formula (Ic) as defined above, and one of compounds (19) to (31) and (91) to (181) as defined above, or one of its pharmaceutically acceptable salts according to the invention, for the preparation of a medicament for the prevention or treatment of an RNA virus infection caused by an RNA virus from group IV or group V according to the Baltimore classification, and for example a chikungunya infection, a dengue infection, an influenza infection or an RSV infection in a subject.

The present invention therefore relates to one compound of formula (Ic) as defined above and one of compounds (19) to (31) and (91) to (181) or one of their acceptable salts as a medicament for the inhibition, prevention or treatment of RNA viral infections, and most preferably RNA viral infections from group IV or V, and for example chikungunya infections, dengue infections, influenza infections or RSV infections.

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

By "continuous treatment" is meant a long-term treatment that can be achieved at various frequencies of administration, such as 1 time per day, 1 time per 3 days, 1 time per week, or 1 time per 2 weeks or 1 time per month.

According to one embodiment, any of the compounds of formula (Ic) or a pharmaceutically acceptable salt thereof is administered in a specific dose which varies between 0.1-1000mg, especially between 0.1-10mg, or for example between 10-200mg, or for example between 200-1000 mg.

Another object of the present invention relates to a therapeutic method for the treatment and/or prevention of an RNA viral infection in a subject, and most preferably an RNA viral infection caused by a virus belonging to group IV or V of the Baltimore classification, comprising administering a therapeutically effective amount of a compound of formula (Ic), compounds (19) to (31) and (91) to (181) or one of their acceptable salts, as defined above.

In a specific embodiment, the present invention provides a compound of formula (Ic) according to the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically active derivative thereof or the use of the method according to the present invention, wherein the compound of formula (Ic) is to be administered in combination with a co-agent (co-agent) useful for the treatment of said RNA viral infection, and most preferably said RNA viral infection from group IV or V, and for example a chikungunya infection, a dengue infection, an influenza infection or a RSV infection.

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

Where appropriate, the compounds of the invention may be administered as prodrugs (such as esters) of the compounds to which the invention relates. "prodrug" refers to a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis, reduction, or oxidation) to a compound of the invention. For example, ester prodrugs of the compounds of the present invention may be converted to the parent molecule by hydrolysis in vivo. Suitable esters of the compounds of the invention are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-di- β -hydroxynaphthoates, glycocholates, isethionates, di-p-toluoyl tartrate, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and quinic acid esters. Examples of ester prodrugs are those described by f.j.leinweber, Drug metab.res, 1987,18, 379. As used herein, reference to a compound of the invention is also intended to include any prodrug or metabolite form.

The compositions of the present invention may also include one or more additives such as diluents, excipients, stabilizers, and preservatives. Such additives are well known to those skilled in the art and are described in particular in "Ullmann's Encyclopedia of Industrial Chemistry, 6 th edition" (Multi-edition, 1989-.

The aforementioned excipients are selected according to the dosage form and the desired mode of administration.

According to another embodiment, the pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracerebroventricularly, intravaginally, intraperitoneally, topically (topically) (e.g., by powder, ointment, or drops), buccally, as an oral or nasal spray, and the like, depending on the severity of the infection to be treated.

The compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted depot. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be formulated according to the 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. Acceptable 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.

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

For example, the compounds of formula (Ic) may be present in any pharmaceutical form suitable for enteral or parenteral administration, accompanied by suitable excipients, for example in the form of plain or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories or drinkings such as suspensions, syrups or injectable solutions or suspensions, in dosages such that 0.1 to 1000mg of active substance can be administered per day.

In a particular embodiment, the compounds of formula (Ic) according to the invention are administered orally.

The oral route of administration is particularly preferred in the prevention or treatment of the present invention.

96页详细技术资料下载

上一篇：一种医用注射器针头装配设备

下一篇：用于治疗RNA病毒感染的苯基/吡啶基-N-苯基/吡啶基衍生物

phenyl/pyridyl-N-phenyl/pyridyl derivatives for the treatment of RNA viral infections

相关技术

网友询问留言