RU2790838C2 - Phenyl/pyridyl-n-phenyl/pyridyl derivatives for the treatment of rna viral infection - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to a compound of formula (Ic) or any of its pharmaceutically acceptable salts that can be used to treat and/or prevent RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore virus classification selected from RSV (respiratory syncytial virus) and chikungunya viruses. In the compound of the formula (Ic), the ring

and the ring

both represent a phenylene group, or the ring

is a pyridylene group, and the ring

is a phenylene group; Z” represents –CH₂– or –CO–; R_g is hydrogen and R_h is hydrogen or (C₁–C₄)alkyl; X² represents –CO–NR_k–, where R_k is hydrogen or methyl; –OCH₂–, –CH(OH)–, -NH CO–, –O–, –O–(CH₂)s–O–, where s is 2 or 3, –CO–, –SO₂–, 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, such as triazole, imidazole, tetrazole or oxadiazole, –NH–SO₂–, –NH– or –SO₂–NH–; n is 0, 1, 2 or 3, m and m’ are independently equal to 0, 1 or 2; Y² is hydrogen, halogen, hydroxyl group, (C₁–C₄)alkoxy, etc.; R is (C₁–C₄)alkyl, (C₃-C₆)cycloalkyl, halogen; R’ represents (C₁–C₄)alkyl, optionally interrupted by –SO₂– or –SO–, (C₃-C₆)cycloalkyl or trifluoromethyl group. The invention also relates to the use of a compound of the formula (Ic) for the treatment and/or prevention of the above-mentioned RNA viral infections.

EFFECT: invention also relates to a pharmaceutical composition containing the specified compound and a synthesis method for the production of a compound of the formula (Ic).

9 cl, 5 tbl, 7 ex

Description

The present invention relates to compounds useful in the prevention and/or treatment of RNA viral infection and most preferably RNA viral infection caused by RNA viruses belonging to group IV or V of the Baltimore classification of viruses.

The present invention further relates to certain novel compounds particularly useful in the prevention and/or treatment of an RNA viral infection, and most preferably an RNA viral infection caused by RNA viruses belonging to group IV or V of the Baltimore classification of viruses.

It further relates to pharmaceutical compositions containing said novel compounds and to chemical synthesis methods for their production.

PRIOR ART

Viruses are one of the main pathogens worldwide. In general, viruses are defined as small non-living infectious agents that replicate only inside living cells because they do not have a fully autonomous replication mechanism. In general, despite the variety of shape and size, they consist of a viral particle (known as a "virion") formed from a protein shell that includes at least one nucleic acid molecule and optionally, depending on the type of virus, one or more proteins or nucleoproteins.

Due to the fact that viruses do not have a completely autonomous replication mechanism, they require the mechanism and metabolism of the affected cell or host organism to replicate and produce their numerous copies.

It is generally accepted that the life cycle of viruses, although their replication cycle varies greatly from one species to another, includes six main stages: attachment, entry, deenvelopment, replication, assembly, and release.

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

Of these mechanisms, not only the multiplication of the viral genome is involved in the replication step, but also the synthesis of the messenger RNA of the virus, the viral protein, and the modulation of the transcription or translation mechanism of the host. However, it is also clear that this stage of replication is largely characterized by the type of genome (single-stranded, double-stranded, RNA, DNA…). For example, most DNA viruses are assembled in the nucleus, while most RNA viruses develop only in the cytoplasm. There is also a growing body of evidence that single-stranded RNA viruses, such as the influenza virus, use the splicing and maturation mechanism of the host RNA.

In accordance with and taking into account the importance of this type of genome at the stage of replication, the Baltimore classification of viruses was developed. Based on this classification, viruses are divided into families (or "groups") depending on the type of genome. The present classification of viruses according to 2018 data contains seven different groups:

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

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

- Group III: double-stranded RNA viruses (lncRNA);

- Group IV: (+)-stranded RNA viruses or positive stranded RNA viruses ((+)ssRNA);

- Group V: (-) stranded RNA viruses or negative stranded RNA viruses ((-) sRNA);

- Group VI: single-stranded RNA viruses with intermediate DNA (onRNA-RT);

- Group VII: double-stranded DNA viruses having RNA intermediates (lncRNA-RT).

According to this classification, viruses belonging to group VI are not strictly RNA viruses. For the same reasons, viruses belonging to group VII are not strictly DNA viruses. One well-studied example of virus families belonging to group VI is the Retroviridae family (retroviruses), which includes the human immunodeficiency virus (HIV). One well-studied example of a group VII virus family is the Hepadnaviridae family, which includes hepatitis B virus (HBV).

As a typical example of group IV viruses, Picornaviruses (which is a family of viruses including well-known viruses such as hepatitis A virus, enteroviruses, rhinoviruses, poliovirus and foot-and-mouth disease virus), SARS virus (SARS virus), hepatitis C virus, yellow fever virus and rubella virus. The family Togaviridae also belongs to group IV, and alphaviruses, including chikungunya virus, are a known genus of this family. Flaviridae is also a group IV family that includes a known mosquito-borne virus, i.e. Dengue virus.

As a representative of the viruses belonging to group V, you can specify the Filoviridae family of viruses, including Ebola virus, the Paramyxoviridae family, including respiratory syncytial virus (RSV), the Rhabdoviridae family, the Orthomyxoviridae family, including influenza A virus, influenza B virus and influenza virus C.

Groups within virus families that are specifically contemplated within the scope of the present invention include RNA viruses, especially single-stranded RNA viruses, and more particularly RNA viruses belonging to group IV and group V of the Baltimore classification of viruses.

There are several treatments for diseases caused by RNA viral infections, in particular single-stranded RNA viruses and more specifically RNA viral infections from viruses belonging to group IV and V of the Baltimore classification of viruses. Treatment is focused on relieving symptoms. Thus, there is still a need to identify new antiviral drugs for the treatment of RNA viral infections, such as infections caused by RNA viruses from groups IV and V, in particular small molecular weight chemical molecules.

DEFINITIONS

As used herein, the term "patient" refers to either an animal, such as a valuable animal intended for breeding, companionship or conservation purposes, or preferably a human or child affected or potentially affected by one or more diseases or conditions. described in this document.

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

The identification of those patients who require treatment for the diseases and conditions described herein is entirely within the skill and knowledge of those skilled in the art. A veterinarian or physician skilled in the art can readily identify patients in need of such treatment through clinical tests, physical examination, medical/family history, or biological or diagnostic tests.

As used herein, the term “treatment” or “therapy” as used herein means reversing, alleviating, inhibiting the progression of, or preventing a disease resulting from an RNA viral infection, and more particularly an infection with group IV or V RNA viruses, or one or more of the symptoms. such a disease.

As used herein, the term "effective amount" refers to an amount of a compound of the present invention effective to prevent, reduce, eliminate, treat, or control the symptoms of the diseases and conditions described herein, i.e., RNA viral infection, and more specifically RNA- viral infection from group IV or V. The term "control" is intended to refer to all processes that can slow, interrupt, stop or stop the progression of the diseases and conditions described herein, but does not necessarily indicate the complete elimination of all symptoms of the disease and condition, and also provides for the inclusion of preventive treatment.

The term "effective amount" includes both "prophylactically effective amount" and "therapeutically effective amount".

As used herein, the term "prevention" means reducing the risk of onset or delaying the onset of a given phenomenon, namely, in the present invention, a disease resulting from an RNA viral infection, and more specifically, infection with RNA viruses from group IV or V.

As used herein, the term "prevention" also includes "reducing the likelihood of occurrence" or "reducing the likelihood of reoccurrence".

The term "prophylactically effective amount" refers to the concentration of a compound of this invention effective in inhibiting, preventing, reducing the likelihood of a disease caused by RNA viruses, and more specifically an RNA virus from Baltimore Group IV or V, or in preventing an RNA virus. infection and in particular infection with an RNA virus from group IV or V, or in the prevention of delayed onset of the disease caused by RNA viruses and more specifically RNA virus from group IV or V, when administered prior to infection, i. before, during and/or shortly after the period of contact with an RNA virus and in particular an RNA virus from group IV or V.

Similarly, the term "therapeutically effective amount" refers to a concentration of a compound effective in the treatment of an RNA viral infection, such as resulting in a reduction in RNA viral infection after examination if administered after the onset of infection.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, excipients, compositions, or dosage forms that, within sound medical judgment, are suitable for contact with human and animal tissues without causing undue toxicity, irritation, allergic reactions, or other problematic complications, commensurate with a rational benefit/risk ratio.

As used herein, the term "viral infection or associated condition" refers to a state of infection associated with a virus, more specifically said virus has an RNA genome, and in particular with an RNA virus belonging to group IV or V of the Baltimore classification of viruses. Viruses can be further classified into individual families, orders, and genera.

For reference, the contents of the “Baltimore classification” publication cited herein additionally refer to the virus taxonomy references contained in the 2017 database of the International Committee of Taxonomy of Viruses (ICTV), released online electronically on March 12 2018 at http://ictvonline.org/virusTaxonomy.asp. This taxonomy is included in its entirety in this document.

In particular, the invention contemplates alphaviruses belonging to group IV RNA viruses and to the family Togaviridae, which can be defined as positive stranded single-stranded RNA viruses or (+)snRNA viruses. In accordance with the 2017 taxonomy of viruses, their order is defined as "not assigned". The family Togaviridae includes the genera Alphavirus and Rubivirus.

Examples of alphaviruses contemplated by the invention include: Barma Forest Virus, Chikungunya Virus, Mayaro Virus, O'Nong Nyong Virus, Ross River Virus, Semlinki Forest Virus, Una Virus, Eastern Equine Encephalomyelitis Virus, Tonate Virus, Venezuelan Equine Encephalomyelitis Virus, and Western equine encephalomyelitis.

Most preferably, the alphavirus infection or alphavirus related condition according to the invention is a chikungunya virus infection or a chikungunya related condition.

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 of the Baltimore classification of viruses. Chikungunya is a mosquito-borne viral disease first described during an outbreak in southern Tanzania in 1952. CHIKV is a positive-stranded, single-stranded, enveloped RNA virus with a genome length of approximately 12 kb. The CHIKV genome is organized as follows: 5'-cap-nsPl-nsP2-nsP3-nsP4-(crosslink region)-C-E3-E2-6k-El-poly(A)-3', and the first four proteins in it (nsPl -4) are non-structural proteins, while the structural proteins are the capsid (C) and the envelope proteins (E). There are no differences between individual serotypes among CHIKV isolated in Africa, Asia and the Indian Ocean islands. Based on a phylogenetic analysis based on the El gene sequences, CHIKV can be grouped into three genotypes (lines): Asian, east/central/south African (ECSA), and West African. The Asian genotype differs from the ECSA and West African genotypes by -5% and -15% nucleotides, respectively. African genotypes (ECSA versus West African) were divergent by -15%. Amino acid identity between the three genotypes ranged from 95.2 to 99.8%.

Chikungunya virus can cause outbreaks with severe disease.

Chikungunya is a viral disease transmitted to humans by infected mosquitoes. Large outbreaks of chikungunya have involved both species of Ae. aegypti and Ae. albopictus. If ae. aegypti is limited to the tropics and subtropics, Ae. albopictus is also found in regions with moderate and even cold temperatures. Over the past decades, Ae. albopictus spread from Asia and populated areas of Africa, Europe and America.

The incubation period after infection with the chikungunya virus lasts an average of 2-4 days, after which symptoms of the disease appear. These symptoms include fever and severe joint pain. Other symptoms include muscle pain, headache, nausea, back pain, general weakness, myalgia, and rash. Severe clinical manifestations of chikungunya infection may also occur, for example, hemorrhagic fever, conjunctivitis, photophobia, hepatitis, stomatitis. Neurological manifestations such as encephalitis, febrile seizures, meningeal symptoms, and acute encephalopathy have also been described.

Joint pain often causes weakness and can vary in duration.

The proximity of mosquito breeding sites to human settlements is a significant risk factor for chikungunya.

The chikungunya virus is distributed mainly in Africa, India and Southeast Asia. Over the past decades, mosquitoes carrying the chikungunya virus have spread to Europe and America. In 2007, transmission was first reported in a localized outbreak in northeast Italy. Since then, outbreaks have been reported in France and Croatia.

The invention also contemplates Dengue viruses, which are represented by different serotypes and belong to group IV RNA viruses and to the Flaviviridae family and can be defined as single-stranded positive-stranded RNA viruses or (+)snRNA viruses. More specifically, Dengue virus is a (+)ssRNA virus belonging to group IV of the Baltimore classification of viruses. It is a member of the Flavivirus genus, which belongs to the Flaviviridae family. Other viruses belonging to the Flaviviridae family are hepatitis C virus and yellow fever virus.

The invention also specifically addresses viruses of the order Mononegavirales. The order Mononegavirales includes viruses belonging to group V of the Baltimore classification of viruses. As of 2018, this order mainly includes the following virus families: Bornaviridae, Mymonaviridae, Filoviridae, Nyamiviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae and Sunviridae.

Human respiratory syncytial virus (HRSV) is a syncytial virus that causes respiratory tract infections. It is the main causative agent of lower respiratory tract infections and causes clinic visits in infancy and childhood. The HRSV virus, in particular, is considered by the invention and belongs to the group V RNA viruses. More specifically, the RSV virus is a (-) sRNA virus belonging to group V of the Baltimore classification of viruses. It is a pneumovirus that is part of the Paramyxoviridae family, which belongs to the order Mononegavirales. Other viruses of the order Mononegavirales specifically contemplated by the invention include: measles virus, mumps virus, Nipah virus, rabies virus and human parainfluenza virus (which includes HPIV-1, HPIV-2, HPIV-3 and HPIV-4). It should be noted that the subfamily Paramyxovirinae has traditionally been included in the family Paramyxoviridae with reference to the taxonomy of the order Mononegavirales, updated in 2016.

The genera of viruses specifically considered within the family Paramyxoviridae include: the genus Aquaparamyxovirus, Avulavirus, Ferlavirus, Henipavirus, Morbillivirus, Respirovirus, and Rubulavirus.

The invention also specifically addresses viruses of the Orthomyxoviridae family. According to the 2017 taxonomy of viruses, the family Orthomyxoviridae is in the order "not assigned". Virus genera specifically considered within the Orthomyxoviridae family include: Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus, Gammainfluenzavirus, Isavirus, Quaranjavirus, and Thogotovirus.

In particular, the invention can be considered influenza A virus, influenza B virus, influenza C virus, which belong to the group V RNA viruses and the family Orthomyxoviridae, and can be defined as single-stranded RNA viruses with a negative polarity strand or (-) sRNA viruses. The order Orthomyxoviridae also includes isavirus and togotovirus.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have unexpectedly found that aryl-N-aryl compounds are endowed with 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 of viruses. Groups IV and V include (+)ssRNA viruses and (-)ssRNA viruses, respectively; which are also called single-stranded positive-stranded RNA viruses and single-stranded negative-stranded RNA viruses.

For reference, the contents of the "Baltimore Classification of Viruses" are reviewed in light of the classification and nomenclature of viruses described in the 10th Virus Taxonomy Report dated 2017.

This document discloses a compound of formula (I)

(I),

(I)

Where:

и кольцо

независимо означают фениленовую или пиридиленовую группу,ring

and ring

are independently a phenylene or pyridylene group,

находится в мета- или пара-положении на кольце

, в частности в мета-положении, по отношению к группе -NH-,where is the group

is in the meta or para position on the ring

, in particular in the meta position, in relation to the -NH- group,

X ¹ represents an alkenylene group, in particular an ethenylene group, a -NH-CO- group, a -CO-NH- group, a -CR _a R _b O- group,

Y ¹ is an aryl group selected from a 2-pyridyl group or a pyrimidinyl group, where one of the nitrogen atoms of the pyrimidinyl group is ortho to X ¹ ,

or alternatively X ¹ -Y ¹ is a group (A) of the formula

(A),

(A)

X ² represents a -CO-NH- group, an -NH-CO-NH- group, an -OCH ₂ - group, an -NH-CO- group, or a -SO ₂ -NH- group,

n is 0, 1, 2 or 3,

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

Y ² represents a hydrogen atom, a hydroxyl group or a -CR ¹ R ² R ³ group, where R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom or a (C ₁ -C ₄ )alkyl group, this means that not more than one of R ¹ , R ² and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C _{The 8} ) cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ ) alkyl groups, a halogen atom, or a (C ₁ -C ₄ ) alkoxy group, and said (C ₃ -C ₈ ) cycloalkyl group is optionally interrupted by an oxygen atom at said R ¹ and/or R ² ,

R and R' independently represent a halogen atom, a (C ₁ -C ₄ )alkyl group, a (C ₃ -C ₆ )cycloalkyl group, a (C ₁ -C ₅ )alkoxy group, a -SO ₂ -NR _a R _b group, a -SO ₃ H, -OH group, -O-SO _2- OR _c group or -OP(=O)-(OR _c )(OR _d ) group,

R _a , R _b , R _c and R _d independently represent a hydrogen atom or a (C ₁ -C ₄ )alkyl group,

with the proviso that when X ¹ is a -CR _a R _b O- group, Y ¹ may further be a 3-pyridyl, 4-pyridyl or phenyl group optionally substituted with one or two substituents selected from a halogen atom, (C ₁ -C ₄ )alkyl group, cyano group, (C ₁ -C ₅ )alkoxy group, trifluoromethyl group, trifluoromethoxy group, -SO ₂ -NR _a R _b group, -SO ₃ H group, -OH group, -O-SO ₂ group -OR _c or groups -OP(=O)-(OR _c )(OR _d ),

or any of its pharmaceutically acceptable salts

for use in the treatment and/or prevention of an RNA viral infection caused by a Baltimore Group IV or V RNA virus, and in particular chikungunya virus infection, dengue virus infection, influenza virus infection, or RSV virus infection, or virus-related condition.

According to a first aspect, the present invention relates to a compound of formula (Ic)

Where

, кольцо

, X², n и Y² являются такими, как определено выше для формулы (I),Y ¹ , R, R', R _a , R _b , m, m', ring

, ring

, X ² , n and Y ² are as defined above for formula (I),

or to any of its pharmaceutically acceptable salts.

находится в мета- или пара-положении и предпочтительно в мета-положении на кольце

по отношению к группе -NH-,Still according to said first aspect, the present invention further relates to compounds of formula (Ic) wherein the group

is in the meta or para position and preferably in the meta position on the ring

with respect to the -NH- group,

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

Y ¹ represents a pyridyl or phenyl group optionally substituted with one or two substituents selected from a halogen atom, a (C ₁ -C ₄ )alkyl group and a cyano group, a (C ₁ -C ₅ )alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SO group ₂ -NR _a R _b , -SO ₃ H groups, -OH groups, -O-SO ₂ -OR _c groups or -OP(=O)-(OR _c )(OR _d ) groups,

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

or to any of their pharmaceutically acceptable salts.

In accordance with a second aspect, the present invention relates to compounds of formula (Ic) as defined above, for use in the treatment and/or prevention of an RNA viral infection caused by RNA viruses belonging to group IV or V of the Baltimore classification of viruses, and in particularly chikungunya virus infection, dengue virus infection, influenza virus infection, or RSV virus infection, or a condition associated with a virus.

According to a third aspect, the present invention relates to a compound of formula (Ic):

(Ic),

(Ic),

Where:

и кольцо

независимо означают фениленовую или пиридиленовую группу,ring

and ring

are independently a phenylene or pyridylene group,

Z” represents a -CH ₂ - group or a -CO- group,

R _g and R _h independently represent a hydrogen atom or a (C ₁ -C ₄ )alkyl group,

X ² represents

a -CO-NR _k - group, where R _k represents a hydrogen atom or a methyl group,

group -NH-CO-NH-,

group -OCH ₂ -,

group -CH(OH)-,

group –NH-CO-

group -O-,

group -O-(CH ₂ ) _s -O-, where s is 2 or 3,

group -CO-,

group -SO ₂ -,

a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms such as triazole, imidazole, tetrazole or oxadiazole,

-NH-SO ₂ -,

group -NH-

or

-SO ₂ -NH- group,

n is 0, 1, 2 or 3,

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

Y ² represents

hydrogen atom,

halogen atom,

hydroxyl group,

(C ₁ -C ₄ ) alkoxy group,

, где R_f представляет собой (C₁-C₄)алкильную группу, цианогруппу,

, where R _f represents a (C ₁ -C ₄ )alkyl group, cyano group,

,group

,

, где R_q и R'_q независимо представляют собой атом водорода или метильную группу,group

, where R _q and R' _q independently represent a hydrogen atom or a methyl group,

a morpholinyl group optionally substituted with a (C ₁ -C ₄ )alkyl group,

piperazinyl group,

piperidinyl group,

or

a -CR ¹ R ² R ³ group in which R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom or a (C ₁ -C ₄ )alkyl group optionally substituted with a trifluoromethyl group and/or optionally substituted with a hydroxyl group, it is understood that no more than one of R ₁ , R ₂ and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C ₈ )cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ )alkyl groups, a halogen atom, hydroxy or (C ₁ -C ₄ )alkoxy group, and said (C ₃ -C ₈ )cycloalkyl group is optionally interrupted by one or two oxygen atoms on the specified R ¹ and/or R ² ,

R and R' are independently

(C ₁ -C ₄ )alkyl group, optionally interrupted by -SO ₂ - or -SO- group,

(C ₃ -C ₆ ) cycloalkyl group,

trifluoromethyl group

halogen atom,

(C ₁ -C ₅ ) alkoxy group,

group -SO ₂ -NR _a R _b ,

group -SO ₃ H,

group -OH-,

group -O-SO ₂ -OR _c ,

group -OP(=O)-(OR _c )(OR _d ),

R _a , R _b , R _c and R _d independently represent a hydrogen atom or a (C ₁ -C ₄ )alkyl group,

or to any of its pharmaceutically acceptable salts.

представляет собой группу A формулы

(A) или группу B формулы

(B).In other words,

is a group A of formula

(A) or group B of the formula

(B).

According to a fourth aspect, the present invention provides a compound of formula (Ic) as defined above, or any of its pharmaceutically acceptable salts, and any of compounds (19)-(31) and (91)-(181), as defined herein below, for use as a drug.

According to a fifth aspect, the present invention provides a compound of formula (Ic) as defined above for use in the treatment and/or prevention of an RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore classification of viruses, and in particularly chikungunya virus infection, dengue virus infection, influenza virus infection, or RSV virus infection, or a condition associated with a virus.

Compounds (I) and (Ic) above are particularly useful in the treatment and/or prevention of a viral infection or related condition, in particular an RNA viral infection caused by RNA viruses belonging to group IV or V of the Baltimore classification of viruses, and most preferably chikungunya virus infection, dengue virus infection, influenza virus infection, or RSV virus infection, or a condition associated with a virus.

The above compounds are even more specifically useful in the treatment and/or prevention of a chikungunya virus infection, or an RSV viral infection, or a virus-related condition, most notably an RSV viral infection.

In this document, further aspects of the present invention will be described below, such as the use of the new compounds of formula (Ic) as a drug, pharmaceutical compositions, and a method of synthesis.

According to a particular embodiment of the invention, the object of this document is to describe a compound of formula (I) as defined above, wherein the alkenylene group is an (E)-alkenylene group,

m and m' are independently 0 or 1,

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

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

or any 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 Baltimore Group IV or V, and in particular chikungunya virus infection, Dengue virus infection, influenza virus infection or RSV virus infection, or the condition associated with the virus.

According to a further embodiment, the present invention relates to a compound of formula (I):

(I),

(I)

Where:

и кольцо

независимо означают фениленовую или пиридиленовую группу,ring

and ring

are independently a phenylene or pyridylene group,

находится в мета- или пара-положении на кольце

по отношению к группе -NH-,where is the group

is in the meta or para position on the ring

with respect to the -NH- group,

X ¹ represents an alkenylene group, a -NH-CO- group, a -CO-NH- group, a -CR _a R _b O- group,

Y ¹ is an aryl group selected from a 2-pyridyl group and a pyrimidinyl group, where one of the nitrogen atoms of the pyrimidinyl group is ortho to X ¹ ,

or alternatively X ¹ -Y ¹ is a group (A) of the formula

X ² represents a -CO-NH- group, an -NH-CO-NH- group, an -OCH ₂ - group, an -NH-CO- group, or a -SO ₂ -NH- group,

n is 0, 1, 2 or 3,

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

Y ² represents a hydrogen atom, a hydroxyl group or a -CR ¹ R ² R ³ group, where R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom or a (C ₁ -C ₄ )alkyl group, this means that not more than one of R ¹ , R ² and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C _{The 8} ) cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ ) alkyl groups, a halogen atom, or a (C ₁ -C ₄ ) alkoxy group, and said (C ₃ -C ₈ ) cycloalkyl group is optionally interrupted by an oxygen atom at said R ¹ and/or R ² ,

R and R' independently represent a halogen atom, a (C ₁ -C ₄ )alkyl group, a (C ₃ -C ₆ )cycloalkyl group, a (C ₁ -C ₅ )alkoxy group, a -SO ₂ -NR _a R _b group, a -SO ₃ H, -OH group, -O-SO _2- OR _c group or -OP(=O)-(OR _c )(OR _d ) group,

R _a , R _b , R _c and R _d independently represent a hydrogen atom or a (C ₁ -C ₄ )alkyl group,

with the proviso that when X ¹ is a -CR _a R _b O- group, Y ¹ may further be a 3-pyridyl, 4-pyridyl or phenyl group optionally substituted with one or two substituents selected from a halogen atom, (C ₁ -C ₄ )alkyl group, cyano group, (C ₁ -C ₅ )alkoxy group, trifluoromethyl group, trifluoromethoxy group, -SO ₂ -NR _a R _b group, -SO ₃ H group, -OH group, -O-SO ₂ group -OR _c or groups -OP(=O)-(OR _c )(OR _d ),

and provided that when Y¹-X¹ is a 2-pyridylethenylene group, X² is a -CO-NH- group, and Y² is a -CR group¹R²R³, where R¹, R² and R³ independently represent a hydrogen atom or (C₁-C₄) an alkyl group, and m' is different from 0,

or any 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 of viruses.

In accordance with a specific embodiment of the invention, a further object of the present invention is the compound of formula (Ic)

Where

, X², n и Y² являются такими, как определено выше,R, R', m, m', ring

, X ² , n and Y ² are as defined above,

or any 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 Baltimore Group IV or V, and in particular chikungunya virus infection, Dengue virus infection, influenza virus infection or RSV virus infection, or the condition associated with the virus.

Still in accordance with said specific embodiment, the present invention further relates to compounds of formula (Ic) as defined above, wherein

m is 0, m' is 0 or 1,

X ² represents a -CO-NH- group or a -SO ₂ -NH- group,

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

or any 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 Baltimore Group IV or V, and in particular chikungunya virus infection, Dengue virus infection, influenza virus infection or RSV virus infection, or the condition associated with the virus.

In accordance with a specific embodiment, the present invention relates to a compound of formula (Ic) as defined above, where

и кольцо

оба представляют собой фениленовую группу, или кольцо

представляет собой пиридиленовую группу и кольцо

представляет собой фениленовую группу,ring

and ring

both are a phenylene group, or a ring

is a pyridylene group and a ring

is a phenylene group,

or to any of its pharmaceutically acceptable salts.

In another embodiment, the present invention provides a compound of formula (Ic) as defined above, wherein

m and m' are independently 0 or 1,

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

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

or to any of its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to a compound of formula (Ic), where

R _g is a hydrogen atom and R _h is a hydrogen atom or a (C ₁ -C ₄ )alkyl group such as a methyl group,

or to any of its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to a compound of formula (Ic), where

X ² represents

a -CO-NR _k - group, where R _k represents a hydrogen atom or a methyl group,

group -NH-CO-

group -O-,

group -CO-,

group -CH(OH)-,

group -SO ₂ -,

group -NH-,

a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms such as triazole, imidazole, tetrazole or oxadiazole,

-NH-SO ₂ -,

or

-SO ₂ -NH- group,

or to any of its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to a compound of formula (Ic), where

Y ² represents

hydrogen atom,

halogen atom,

, где R_f представляет собой (C₁-C₄)алкильную группу, цианогруппу,

, where R _f represents a (C ₁ -C ₄ )alkyl group, cyano group,

, где R_q и R'_q независимо представляют собой атом водорода или метильную группу,group

, where R _q and R' _q independently represent a hydrogen atom or a methyl group,

a morpholinyl group optionally substituted with a (C ₁ -C ₄ )alkyl group,

,group

,

(C ₁ -C ₄ )alkoxy group

or

a -CR ¹ R ² R ³ group, where R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom, or a (C ₁ -C ₄ )alkyl group optionally substituted with a trifluoromethyl group, optionally substituted with a hydroxyl group, meaning that not more than one of R ¹ , R ² and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C ₈ ) cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ ) alkyl groups, a halogen atom, hydroxy or (C ₁ -C ₄ ) alkoxy group, and said (C ₃ -C ₈ ) cycloalkyl group is optionally interrupted by one or two atoms oxygen on the specified R ¹ and/or R ² ,

or to any of its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to a compound of formula (Ic), where

R and R' are independently

(C ₁ -C ₄ )alkyl group, optionally interrupted by -SO ₂ - or -SO- group,

(C ₃ -C ₆ ) cycloalkyl group,

a trifluoromethyl group, or

halogen atom,

or to any of its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to a compound of formula (Ic), where

и кольцо

оба представляют собой фениленовую группу, или кольцо

представляет собой пиридиленовую группу и кольцо

представляет собой фениленовую группу,ring

and ring

both are a phenylene group, or a ring

is a pyridylene group and a ring

is a phenylene group,

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

X ² represents

group -CO-NH-,

group -CO-N(CH ₃ )-,

group -NH-CO-,

group -O- or

group -CO-,

group -NH-SO ₂ -,

group -CH(OH)-,

group -SO ₂ -,

divalent triazole,

divalent imidazole,

divalent tetrazole,

divalent oxadiazole,

group -NH-,

Y ² represents

hydrogen,

a morpholinyl group optionally substituted with a (C ₁ -C ₄ )alkyl group,

,group

,

, где R_q и R'_q независимо представляют собой атом водорода или метильную группу,group

, where R _q and R' _q independently represent a hydrogen atom or a methyl group,

, где R_f представляет собой (C₁-C₄)алкильную группу, цианогруппу,

, where R _f represents a (C ₁ -C ₄ )alkyl group, cyano group,

(C ₁ -C ₄ )alkoxy group

or

a -CR ¹ R ² R ³ group, where R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom, or a (C ₁ -C ₄ )alkyl group optionally substituted with a trifluoromethyl group, optionally substituted with a hydroxyl group, meaning that not more than one of R ¹ , R ² and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C ₈ ) cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ ) alkyl groups, a halogen atom, hydroxy or (C ₁ -C ₄ ) alkoxy group, and said (C ₃ -C ₈ ) cycloalkyl group is optionally interrupted by one or two atoms oxygen on the specified R ¹ and/or R ² ,

And

R and R' are independently

(C ₁ -C ₄ )alkyl group,

(C ₃ -C ₆ )cycloalkyl group such as cyclopropyl,

a trifluoromethyl group, or

halogen atom,

or to any of its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to a compound of formula (Ic), where

и кольцо

оба представляют собой фениленовую группу,ring

and ring

both are a phenylene group,

m is 0, n is 1,

X ² represents

a group -CO-NH- or

group -O-,

Y ² represents

group -CR ¹ R ² R ³ where R ¹ , R ² and R ³ independently represent a hydrogen atom or a (C ₁ -C ₄ )alkyl group, it is understood that no more than one of R ¹ , R ² and R ³ represents a hydrogen atom, for example an isopropyl group, or R ¹ and R ² together with the carbon atom (C ₃ -C ₈ ) that carries them form a cycloalkyl group, such as cyclopropyl,

And

R' represents

a (C ₁ -C ₄ )alkyl group such as a tert-butyl group, or

(C ₃ -C ₆ )cycloalkyl group such as cyclopropyl,

or to any of its pharmaceutically acceptable salts.

, кольца

, X¹, X², n, Y¹, Y² друг с другом составляет часть настоящего изобретения.Any combination of the above embodiments for R, R', m, m', ring

, rings

, X ¹ , X ² , n, Y ¹ , Y ² with each other is part of the present invention.

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

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

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

- (23) N-isopentyl-3-((4-((tetrahydropyrimidine-2(1H)-ylidene)carbamoyl)phenyl)amino)benzamide,

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

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

- (26) N-(2-cyclobutylethyl)-3-((4-((tetrahydropyrimidine-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-diazinan-2 -ylidene]benzamide,

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

- (93) 4-({2-chloro-3-[(1,4-dioxan-2-yl)methoxy]phenyl}amino)-3-cyclopropyl-N-[(2E)-4-oxo-1, 3-diazinan-2-ylidene]benzamide,

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

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

- (96) 3-cyclopropyl-N-(1,3-diazinan-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-diazinan-2-ylidene]benzamide,

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

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

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

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

- (102) 3-cyclopropyl-N-(1,3-diazinan-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-diazinan-2-ylidene)benzamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

- (118) 3-cyclopropyl-N-(1,3-diazinan-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-diazinan-2 -ylidene)benzamide,

- (120) 3-cyclopropyl-N-[(2E)-4-oxo-1,3-diazinan-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-diazinan-2-ylidene]benzamide,

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

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

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

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

- (126) 3-cyclopropyl-N-(1,3-diazinan-2-ylidene)-4-[(3-{[2-(oxan-4-yl)ethyl]carbamoyl}phenyl)amino]benzamide,

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

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

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

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

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

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

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

- (134) 3-cyclopropyl-4-({3-[(oxan-3-yl)methoxy]phenyl}amino)-N-[(2E)-4-oxo-1,3-diazinan-2-ylidene] benzamide,

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

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

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

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

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

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

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

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

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

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

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

- (146) 3-cyclopropyl-4-({3-[(oxan-4-yl)methoxy]phenyl}amino)-N-[(2E)-4-oxo-1,3-diazinan-2-ylidene] benzamide,

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

- (148) 4-{[3-(3-cyclohexylpropanamido)-4-fluorophenyl]amino}-N-(1,3-diazinan-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 -diazinan-2-ylidene)benzamide,

- (150) 3-cyclopropyl-4-({3-[2-(1,4-dioxan-2-yl)ethoxy]phenyl}amino)-N-[(2E)-4-oxo-1,3- diazinan-2-ylidene]benzamide,

- (151) 3-cyclopropyl-4-({3-[(oxan-2-yl)methoxy]phenyl}amino)-N-[(2E)-4-oxo-1,3-diazinan-2-ylidene] benzamide,

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

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

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

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

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

- (157) 3-cyclopropyl-N-(1,3-diazinan-2-ylidene)-4-({3-[(oxan-4-yl)carbamoyl]phenyl}amino)benzamide,

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

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

- (160) 3-cyclopropyl-N-(1,3-diazinan-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-dioxan-2-yl)methoxy]phenyl}amino)-N-[(2E)-4-oxo-1,3-diazinan- 2-ylidene]benzamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

- (180) N-(1,3-diazinan-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-diazinan-2-ylidene]benzamide

and their pharmaceutically acceptable salts.

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

In accordance with another aspect, the object of the present invention relates to compounds (19)-(31) and (91)-(181) or any of their pharmaceutically acceptable salts for use as a drug.

According to another aspect, an object of the present invention relates to a compound of formula (Ic) as defined above, or any of its pharmaceutically acceptable salts, and any of compounds (19)-(31) and (91)-(181) or any of its pharmaceutically acceptable salts for use as an agent for the prevention, inhibition or treatment of an RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore classification of viruses.

Compounds (27), (28), (91)-(166) or any of their pharmaceutically acceptable salts may be particularly useful in preventing, inhibiting or treating RSV infection.

Compounds (22), (23), (24), (26), (27) and (28) or any of their pharmaceutically acceptable salts may be particularly useful in the prevention, inhibition or treatment of chikungunya infection.

The compounds of the invention may exist in the form of free bases or addition salts with pharmaceutically acceptable acids.

"Its pharmaceutically acceptable salt" refers to salts formed from acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as salts, formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenesulfonic acid acid and polygalacturonic acid.

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

The compounds of formula (Ic) and any of the compounds (19)-(31) and (91)-(181) or any of their pharmaceutically acceptable salts may form solvates or hydrates, and the invention includes all such solvates and hydrates.

The compounds of formula (Ic) may also be present in tautomeric forms and form part of the invention. The terms "hydrates" and "solvates" simply mean that the compounds (Ic) according to the invention may be in the form of a hydrate or solvate, ie combined or associated with one or more water or solvent molecules. Such compounds have only one chemical characteristic that can be applied to all organic compounds of this type.

In the context of the present invention, the term:

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

- "(C ₁ -C _x )alkyl" as used herein, respectively, refers to C ₁ -C _x normal, secondary or tertiary saturated hydrocarbon, for example (C ₁ -C ₆ )alkyl. Examples are, without limitation, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,

- "alkenylene" means a divalent (C ₁ -C _x )alkyl group containing a double bond, and more specifically an ethenylene group, also known as vinylene or 1,2-ethenediyl,

- "(C ₃ -C ₆ )cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon. Examples are, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

- "(C ₁ -C _x )alkoxy" as used herein refers to an O-(C ₁ -C _x )alkyl moiety in which alkyl is as defined above, eg (C ₁ -C ₆ )alkoxy. Examples are, without limitation, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy, pentoxy,

- "aryl" as used herein refers to a monocyclic aromatic group containing 6 carbon atoms and containing from 0 to 2 heteroatoms such as nitrogen, oxygen or sulfur atoms, and in particular a nitrogen atom. As examples of aryl groups, phenyl, pyridine, pyrimidine, pyridazine, pyrazine and the like can be mentioned without limitation. In the context of the present invention, aryl is preferably phenyl, pyridazine, pyrazine, pyridine such as 2-pyridine or 3-pyridine, and pyrimidine. Aryl is even more preferably phenyl and pyridine such as 2-pyridine or 3-pyridine.

- "divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms", when used herein, means a divalent ring consisting of an aromatic ring containing 5 chains and 1, 2, 3 or 4 heteroatoms selected from atoms nitrogen and oxygen. In one embodiment of the invention, it contains at least 1 heteroatom and preferably at least one nitrogen atom. In another embodiment of the invention, it contains at least 2 heteroatoms and preferably at least one nitrogen atom. According to a further embodiment of the invention, it contains 2, 3 or 4 nitrogen atoms, preferably 3 nitrogen atoms. In accordance with another additional embodiment, it contains one nitrogen atom and one oxygen atom, or two nitrogen atoms and one oxygen atom. Examples are, without limitation, divalent triazoles such as 1,2,3- or 1,2,4-triazoles, oxadiazoles such as 1,2,4-oxadiazole or 1,2,3-oxadiazole, and divalent diazoles such as divalent diazole; and divalent imidazole. In accordance with a preferred embodiment of the invention, such a divalent 5-membered heteroaromatic ring containing 2 or 3 heteroatoms is a divalent triazole.

Compounds of formula (Ic) may contain one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, are within the scope of the present invention.

Compounds of the present invention can be obtained by traditional methods of organic synthesis, practiced by experts in this field of technology. The general reaction sequences depicted below represent a general method suitable for preparing the compounds of the present invention and are not intended to limit the scope or usefulness of the invention.

Compounds of general formula (I) and (Ic) can be prepared according to Scheme 1 below.

Scheme 1.

, кольцо

, X¹, X², n, Y¹, Y² являются такими, как определено выше, а X представляет собой атом хлора, атом иода или атом брома.The synthesis is based on a coupling reaction in which the starting compound is a haloaromatic compound of formula (III), where R, R', m, m', ring

, ring

, X ¹ , X ² , n, Y ¹ , Y ² are as defined above, and X represents a chlorine atom, an iodine atom or a bromine atom.

находится в мета- или пара-положении на кольце

по отношению к группе -NH-.According to one embodiment of the invention, technique (A1) can advantageously be used when the group

is in the meta or para position on the ring

with respect to the -NH- group.

According to synthetic route (A1), the compound of formula (III) can be placed in a protic solvent such as t-butanol. The compound of formula (II) can then be added, for example in a molar ratio ranging from 1 to 1.5 with respect to the compound of formula (III), in the presence of an inorganic base such as Cs ₂ CO ₃ or K ₂ CO ₃ , for example, in a molar ratio ranging from 1 to 5 also with respect to a compound of formula (III), in the presence of a diphosphine such as Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos (2- dicyclohexylphosphino-2',4',6'-triisopropyldiphenyl), or rac-BINAP (rac-(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)), in particular in an amount ranging from 2 mol% to 15 mol% relative to the total amount of the compound of formula (III), and in the presence of an organometallic catalyst such as Pd(OAc) ₂ , or Pd ₂ dba ₃ , or BrettPhos Pd G3, in an amount in the range from 2 mol% to 25 mol % relative to the total amount of the compound of formula (III). The reaction mixture can then be heated at a temperature in the range from 80 to 130°C, for example at 90°C, and stirred for a time in the range from 15 to 25 hours, for example for 20 hours, in an inert gas atmosphere and, for example , argon. The reaction mixture can be concentrated under reduced pressure and the residue can be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give a compound of formula (I) and (Ic).

находится в орто-положении на кольце

по отношению к группе -NH-.According to one embodiment of the invention, technique (A2) can advantageously be used when the group

is in ortho position on the ring

with respect to the -NH- group.

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

The starting compounds of formula (II), (III) are available or can be obtained in accordance with methods known to those skilled in the art.

Accordingly, this document further describes a synthetic process for the production of novel compounds of formula (I) and (Ic) as defined above, comprising at least the step of coupling a compound of formula (II)

(II)

(II)

with a compound of formula (III)

(III),

(III)

, кольцо

, X², Y² являются такими, как определено выше, а X представляет собой атом хлора, атом иода или атом брома, в присутствии неорганического основания и лиганда и в присутствии металлорганического катализатора с получением соединения формулы (I) и (Ic).where X ¹ , Y ¹ , R, R', m, m', ring

, ring

, X ² , Y ² are as defined above, and X is a chlorine atom, an iodine atom or a bromine atom, in the presence of an inorganic base and a ligand, and in the presence of an organometallic catalyst to give a compound of formula (I) and (Ic).

Compounds of general formula (Ic) can be prepared according to Scheme 1' below.

Scheme 1'.

More specifically, the present invention relates to a synthetic process for the production of compounds of formula (Ic) as defined above, comprising at least the step of coupling a compound of formula (IIc)

with a compound of formula (IIIc)

, кольцо

, X², Y², R_h, R_g и Z” являются такими, как определено выше, а X представляет собой атом хлора, атом иода или атом брома, в присутствии неорганического основания и лиганда и в присутствии металлорганического катализатора с получением соединения формулы (Ic).where R, R', m, m', ring

, ring

, X ² , Y ² , R _h , R _g and Z" are as defined above, and X represents a chlorine atom, an iodine atom or a bromine atom, in the presence of an inorganic base and a ligand and in the presence of an organometallic catalyst to obtain a compound of the formula (Ic).

More specifically, compounds of formula (IIc) when used to prepare compounds of formula (Ic) with Z'' =CH ₂ can be obtained in accordance with scheme 4 below.

Scheme 4.

Intermediates of formulas (IIc) and (IVc) are suitable for the preparation of compounds of formula (Ic) according to the invention.

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

According to synthetic route (E), a compound of formula (IVc) and 10% Pd/C in a ratio ranging from 2% to 10% relative to the amount of benzamide can be placed in a protic solvent such as ethanol. The reaction mixture can then be stirred at room temperature for a time ranging from 5 to 20 hours, such as 16 hours, under an H ₂ atmosphere. The reaction mixture can then be filtered and the filtrate can be concentrated under reduced pressure to give a compound of formula (IIc).

According to one embodiment of the invention, when Z'' is a -CO- group, another synthetic route can be followed to obtain compounds of formula (Ic), as shown in Scheme X below.

Scheme X.

The synthesis begins with a coupling reaction of a haloaromatic compound of formula (IIIc) with an aniline derivative (Vc), where R, R', Ra, m, m', X ¹ , X ² , n, Y ¹ , Y ² , Z, Z', Z'' are as defined above, and X represents a chlorine atom, an iodine atom or a bromine atom, following the procedure (A1) or (A2).

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

According to procedure (L), a compound of formula (VIIc) and carbonyldiimidazole (CDI) in a ratio ranging from 1.0 to 3 equivalents, eg 1.2 equivalents, can be placed in an anhydrous polar solvent such as N,N-dimethylformamide. Then the reaction mixture can be stirred at room temperature for a time ranging from 1 to 3 hours, for example for 1 hour. The amine derivative Y ¹ -NH ₂ can then be added, for example in a molar ratio ranging from 1 to 2.5 with respect to the compound (VIIc) in the presence of an organic base such as triethylamine or N,N-diisopropylethylamine, for example in a molar ratio in the range from 2 to 5 also in relation to the compound (VIIc). Then the reaction mixture can be heated at a temperature in the range from 50 to 9°C, for example at 75°C, and stirred for a time ranging from 1 to 24 hours, for example for 16 hours. The reaction mixture can be quenched by adding saturated sodium bicarbonate aqueous solution and extracting the mixture with an organic solvent such as ethyl acetate. The combined organic phases can then be dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a compound of formula (Ic).

The chemical structures and spectroscopic data of some compounds of formula (Ic) according to the invention are illustrated respectively in the following table I and table II.

Table II

Etc. Characteristics 19 ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 7.44 - 7.37 (m, 2H), 7.30 - 7.26 (m, 2H), 6.97 ( d, J = 8.7 Hz, 2H), 6.07 (s, 1H), 3.42 (t, J = 5.8 Hz, 4H), 2.95 - 2.90 (m, 2H), 2.06 - 1.94 (m, 2H), 2.03 - 1.95 (m, 4H), 1.58 - 1.39 (m, 5H), 1.03 - 0.94 (m, 2H).
[M+H] ⁺ =470.3 20 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.78 (s, 2H), 8.57 (s, 1H), 8.42 (t, J = 5.7 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H) , 7.58 (s, 1H), 7.37 - 7.32 (m, 2H), 7.28 - 7.23 (m, 1H), 7.02 (d, J = 8.7 Hz, 2H), 3.35 - 3.25 (m, 4H), 3.17 (d , J = 6.3 Hz, 2H), 2.15 (dt, J = 14.7, 7.2 Hz, 1H), 1.86 - 1.78 (m, 2H), 1.72 - 1.45 (m, 6H), 1.32 - 1.19 (m, 2H).
[M+H] ⁺ =420.4 21 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.78 (s, 2H), 8.60 (s, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 7.40 - 7.33 ( m, 2H), 7.30 - 7.23 (m, 1H), 7.03 (d, J = 8.6 Hz, 2H), 4.48 (d, J = 5.7 Hz, 2H), 4.20 (d, J = 5.7 Hz, 2H), 3.44 (d, J = 5.9 Hz, 2H), 3.35 - 3.27 (m, 4H), 1.84 - 1.78 (m, 2H), 1.26 (s, 2H).
[M+H] ⁺ =422.3 22 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.77 (s, 2H), 8.55 (s, 1H), 8.37 (t, J = 5.6 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H) , 7.59 (s, 1H), 7.37 - 7.29 (m, 2H), 7.27 - 7.21 (m, 1H), 7.02 (d, J = 8.7 Hz, 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).
¹³ C JAMR (75 MHz, D ₆ -DMSO) δ 175.0, 166.6, 159.1, 145.8, 143.1, 136, 131.1, 130.4, 129.6, 120.5, 119.7, 119.4, 116.9, 115.1, 38.6, 37.9, 35.9, 32.7, 25.2.2.2.2.2.2.2.2 , 20.5
[M+H] ⁺ =434.0 23 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.78 (s, 2H), 8.56 (s, 1H), 8.36 (t, J = 5.5 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H) , 7.58 (s, 1H), 7.35 - 7.30 (m, 2H), 7.28 - 7.21 (m, 1H), 7.02 (d, J = 8.7 Hz, 2H), 3.30 - 3.23 (m, 6H), 1.88 - 1.76 (m, 2H), 1.61 (dq, J = 13.3, 6.7 Hz, 1H), 1.41 (dd, J = 14.4, 6.9 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). 24 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.77 (s, 2H), 8.55 (s, 1H), 8.34 (t, J = 5.4 Hz, 1H), 7.92 (d, J = 8.7 Hz, 2H) , 7.57 (s, 1H), 7.33 - 7.28 (m, 2H), 7.28 - 7.20 (m, 1H), 7.01 (d, J = 8.7 Hz, 2H), 3.30 - 3.22 (m, 6H), 1.83 - 1.80 (m, 2H), 1.76 - 1.59 (m, 5H), 1.41 (dd, J = 14.3, 6.8 Hz, 2H), 1.32 - 1.12 (m, 4H), 0.94 - 0.84 (m, 2H).
[M+H] ⁺ = 448.4 25 ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (d, J = 8.5 Hz, 2H), 7.52 (s, 1H), 7.33 - 7.24 (m, 2H), 7.03 (d, J = 8.6 Hz, 2H) , 6.27 (s, 1H), 6.07 (s, 1H), 3.54 (dd, J = 12.9, 6.7 Hz, 2H), 3.33 (t, J = 5.7 Hz, 4H), 1.99 - 1.89 (m, 2H), 1.52 (q, J = 6.9 Hz, 2H), 0.79 - 0.64 (m, 1H), 0.49 (q, J = 5.4 Hz, 2H), 0.11 (q, J = 4.9 Hz, 2H).
[M+H] ⁺ = 406.4 26 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.78 (s, 2H), 8.56 (s, 1H), 8.33 (t, J = 5.5 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H) , 7.58 (s, 1H), 7.37 - 7.28 (m, 2H), 7.27 - 7.21 (m, 1H), 7.02 (d, J = 8.7 Hz, 2H), 3.29 - 3.27 (m, 4H), 3.16 (dd , J = 13.2, 6.5 Hz, 2H), 2.37 - 2.22 (m, 1H), 2.10 - 1.97 (m, 2H), 1.88 - 1.76 (m, 4H), 1.65 - 1.58 (m, 4H).
[M+H] ⁺ =420.4 27 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.83 (s, 2H), 8.32 (t, J = 5.5 Hz, 1H), 7.88 (d, J = 1.3 Hz, 1H), 7.77 (dd, J = 8.3, 1.7 Hz, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.34 - 7.27 (m, 2H), 7.16 - 7.10 (m, 2H), 3.32 - 3.20 (m, 6H), 2.24 (s, 3H), 1.88 - 1.79 (m, 2H), 1.61 (dt, J = 13.3, 6.7 Hz, 1H), 1.40 (dd, J = 14.4, 7.0 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H).
[M+H] ⁺ = 422.4 28 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.80 (s, 1H), 8.33 (t, J = 5.6 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.77 (dd, J = 8.4, 1.7 Hz, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 7.32 - 7.28 (m, 2H), 7.15 - 7.10 (m, 2H), 3.32 - 3.19 (m, 6H), 2.23 (s, 3H), 1.84 - 1.77 (m, 5H), 1.64 - 1.45 (m, 6H), 1.09 - 1.04 (m, 2H).
[M+H] ⁺ = 448.4 29 ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (d, J = 7.9 Hz, 2H), 7.53 (s, 1H), 7.46 - 7.19 (m, 2H), 6.94 (d, J = 8.1 Hz, 2H) , 6.18 (s, 1H), 3.41 (s, 4H), 2.91 (t, J = 7.0 Hz, 2H), 1.98 (s, 2H), 1.61 - 1.47 (m, 1H), 1.34 - 1.24 (m, 2H ), 0.81 (d, J = 6.4 Hz, 6H).
[M+H] ⁺ = 444.3 thirty ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.78 (s, 2H), 8.57 (s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H) , 7.57 (s, 1H), 7.33 (d, J = 5.0 Hz, 2H), 7.30-7.25 (m, 1H), 7.02 (d, J = 8.7 Hz, 2H), 4.06 - 3.94 (m, 1H), 3.31-3.27 (d, J = 4.9 Hz, 4H), 1.88 - 1.78 (m, 1H), 1.59 - 1.51 (m, 1H), 1.50-1.40 (m, 1H), 1.37-1.28 (m, 2H), 1.12 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H).
[M+H] ⁺ = 408.4 31 ¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.81 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.81 (d, J = 9.9 Hz, 1H), 7.50 (t, J = 5.4 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.18-7.14 (m, 3H), 3.51-3.39 (m, 1H), 3.32-3.28 (m , 4H), 2.78-2.72 (m, 2H), 2.23 (s, 3H), 1.88-1.78 (m, 2H), 1.70-1.60 (m, 2H), 1.57-1.33 (m, 6H).
[M+H] ⁺ = 484.4 91 ¹ H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.18 (s, 1H), 7.87 (d, J = 5.3 Hz, 2H), 7.47 (s, 1H), 7.32 (td, J = 7.9, 3.6 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H), 7.03 (t, J = 8.6 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 4.63 - 4.18 (m , 1H), 3.92 (s, 2H), 3.57 - 3.51 (m, 3H), 3.36 (dd, J = 16.4, 9.8 Hz, 2H), 3.22 - 2.94 (m, 1H), 2.62 (t, J = 7.0 Hz, 2H), 1.90 (s, 1H), 1.31 - 1.19 (m, 3H), 0.96 (d, J = 8.2 Hz, 2H), 0.64 (d, J = 4.0 Hz, 2H)
[M+H] ⁺ =510.0 92 ¹ H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.18 (s, 1H), 7.87 (d, J = 5.8 Hz, 2H), 7.48 (s, 1H), 7.32 (td, J = 7.7, 2.9 Hz, 1H), 7.22 - 7.15 (m, 1H), 7.01 (dd, J = 9.0, 2.5 Hz, 1H), 6.90 (d, J = 6.1 Hz, 1H), 4.46 - 4.27 (m, 1H), 3.96 - 3.69 (m, 1H), 3.55 (t, J = 6.9 Hz, 4H), 3.15 (s, 1.5H), 2.99 - 2.80 (m, 1H), 2.62 (t, J = 7.0 Hz , 2.5H), 1.89 (ddd, J = 13.8, 8.6, 5.5 Hz, 1H), 1.18 - 0.98 (m, 3H), 0.95 (d, J = 8.1 Hz, 2H), 0.64 (d, J = 4.7 Hz, 2H)
[M+H] ⁺ =510.0 93 ¹ H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.18 (s, 1H), 7.86 (d, J = 10.6 Hz, 2H), 7.31 (s, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.07 (qd, J = 10.6 , 4.9 Hz, 2H), 3.95 - 3.83 (m, 2H), 3.78 (d, J = 2.7 Hz, 1H), 3.72 - 3.60 (m, 2H), 3.59 - 3.43 (m, 4H), 2.62 (t, J = 7.0 Hz, 2H), 1.88 (ddd, J = 13.7, 8.3, 5.4 Hz, 1H), 1.01 - 0.92 (m, 2H), 0.63 (q, J = 5.5 Hz, 2H)
[M+H] ⁺ =498.9 94 ¹ H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.21 (s, 1H), 9.48 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.90 (dd, J = 8.2, 1.9 Hz, 1H), 7.18 - 7.10 (m, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.62 (t, J = 2.1 Hz, 1H), 6.59 - 6.54 (m, 1H) , 6.53 - 6.48 (m, 1H), 3.56 (t, J = 7.1 Hz, 2H), 3.06 - 2.97 (m, 2H), 2.63 (t, J = 7.1 Hz, 2H), 1.62 - 1.47 (m, 3H ), 1.39 (s, 9H), 0.80 (d, J = 6.4 Hz, 6H)
[M+H] ⁺ =514.0 95 ¹ H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.18 (s, 1H), 7.87 (d, J = 5.9 Hz, 2H), 7.48 (s, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 3.67 (s, 4H), 3.56 (d, J = 5.7 Hz, 4H), 3.20 (d, J = 5.1 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 1.89 (t, J = 5.2 Hz, 1H), 0.95 ( d, J = 8.4 Hz, 2H), 0.64 (d, J = 4.5 Hz, 2H)
[M+H] ⁺ = 495.9 96 ¹ H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.20 (t, J = 5.7 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.17 (t, J = 7.7 Hz, 1H ), 7.09 (d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 3.29 - 3.21 (m , 6H), 2.15 (s, 3H), 1.87 (ddd, J = 13.8, 8.4, 5.5 Hz, 1H), 1.81 (q, J = 5.8 Hz, 2H), 1.65 (dp, J = 13.4, 6.6 Hz, 1H), 1.41 (q, J = 7.0 Hz, 2H), 0.96 - 0.92 (m, 2H), 0.91 (d, J = 6.6 Hz, 6H), 0.59 - 0.55 (m, 2H)
[M+H] ⁺ = 462.4 97 ¹ H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.15 (s, 1H), 7.85 - 7.77 (m, 2H), 7.67 (s, 1H), 7.15 (t, J = 8.4 Hz , 2H), 6.70 (d, J = 7.9 Hz, 1H), 6.67 (t, J = 2.1 Hz, 1H), 6.47 (dd, J = 8.1, 2.1 Hz, 1H), 3.90 (t, J = 6.5 Hz , 2H), 3.54 (t, J = 7.0 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 1.94 (ddd, J = 13.7, 8.4, 5.5 Hz, 1H), 1.69 (t, J = 14.5 Hz, 7H), 1.34 - 1.08 (m, 6H), 1.02 - 0.81 (m, 4H), 0.61 (q, J = 5.8 Hz, 2H)
¹³ C JAMR (151 MHz, DMSO) Δ 160.0, 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, 33.3.3.3, 30.5, 26.6, 26.5, 26.3, 26.3, 26.3, 11.5, 7.6
[M+H] ⁺ = 489.1 98 ¹ H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.21 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 8.2, 1.8 Hz, 1H), 7.29 (s, 1H), 7.18 (s, 3H), 7.13 (d, J = 8.2 Hz, 1H), 6.90 - 6.82 (m, 1H), 4.06 (dq, J = 13.3, 6.6 Hz, 1H), 3.56 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.41 (s, 9H), 1.14 (d, J = 6.6Hz, 6H)
¹³ C JAMR (151 MHz, DMSO) δ 177.4, 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, 30.9,, 30.9. 30.5, 22.8
[M+H] ⁺ =450.1 99 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 8.52 (s, 1H), 7.78 - 7.66 (m, 3H), 7.49 - 7.45 (m, 1H), 7.28 - 7.22 (m, 2H), 7.17 - 7.11 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.30 - 3.24 (m, 4H), 1.97 - 1.88 (m, 1H), 1.81 (d, J = 5.1 Hz , 2H), 1.34 (s, 3H), 0.95 - 0.88 (m, 2H), 0.73 - 0.67 (m, 2H), 0.60 - 0.53 (m, 4H)
[M+H] ⁺ = 432.2 100 ¹ H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.20 (s, 1H), 9.70 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.91 (dd, J = 8.3, 1.9 Hz, 1H), 7.66 (dd, J = 7.9, 1.5 Hz, 1H), 7.27 (t, J = 8.3 Hz, 2H), 6.98 (d , J = 7.7 Hz, 1H), 6.81 - 6.75 (m, 1H), 4.18 - 4.05 (m, 1H), 3.56 (t, J = 6.9 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H) , 1.42 (s, 9H), 1.18 (d, J = 6.6 Hz, 6H)
[M+H] ⁺ =450.3 101 ¹ H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.02 (d, J = 8.4 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.68 (d, J = 1.8 Hz, 1H ), 7.52 - 7.49 (m, 1H), 7.31 - 7.25 (m, 2H), 7.17 - 7.12 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.29 - 3.24 (m, 4H), 1.97 - 1.89 (m, 1H), 1.85 - 1.76 (m, 2H), 1.57 - 1.41 (m, 2H), 1.11 (d, J = 6.8 Hz, 3H), 0.96 - 0.89 (m, 2H), 0.85 (t, J = 7.5 Hz, 3H), 0.60 - 0.53 (m, 2H)
[M+H] ⁺ = 434.3 102 ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2H), 8.11 (d, J = 7.8 Hz, 1H), 7.80 - 7.67 (m, 3H), 7.54 - 7.49 (m, 1H), 7.32 - 7.26 (m, 2H), 7.16 (dt, J = 6.3, 2.5 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.08 (dq, J = 13.2, 6.6 Hz, 1H), 3.28 ( t, J = 4.6 Hz, 4H), 1.95 (tt, J = 8.4, 5.4 Hz, 1H), 1.82 (t, J = 5.6 Hz, 2H), 1.15 (d, J = 6.6 Hz, 6H), 0.98 - 0.89 (m, 2H), 0.62 - 0.54 (m, 2H)
¹³ C JAMR (151 MHz, DMSO) δ 175.1, 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, 38.5.8.8, 20.4, 11.6, 11.6. 7.8
[M+H] ⁺ =450.1 103 ¹ H NMR (500 MHz, DMSO-d6) δ ppm 9.75–8.45 (m, 2 H), 7.71 (dd, J = 8.51, 2.20 Hz, 1 H), 7.67 (d, J = 1.92 Hz, 1 H) , 7.31 - 7.18 (m, 1 H), 7.17 - 7.12 (m, 1 H), 7.09 (d, J = 8.51 Hz, 1 H), 7.04 - 6.95 (m, 1 H), 6.93 - 6.74 (m, 1 H), 5.21 - 4.88 (m, 1 H), 4.62 - 4.32 (m, 1 H), 3.49 - 3.33 (m, 4 H), 1.95 (tt, J = 8.27, 5.32 Hz, 1 H), 1.90 - 1.77 (m, 2 H), 1.58 - 1.42 (m, 2 H), 1.02 - 0.90 (m, 2 H), 0.73 - 1.71 (m, 15 H), 0.64 (br s, 2 H)
[M+H] ⁺ = 489.4 104 ¹ H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2H), 8.33 (d, J = 5.1 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.29 - 7.20 (m, 2H), 3.30 - 3.27 (m, 4H), 3.27 - 3.20 (m, 2H), 1.87 - 1.78 (m, 2H), 1.60 (dt, J = 13.3, 6.7 Hz, 1H), 1.40 (q, J = 7.0 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H)
[M+H] ⁺ = 476.2 105 ¹ H NMR (400 MHz, DMSO-d6) δ 8.81 - 8.74 (m, 2H), 8.32 (t, J = 5.6 Hz, 1H), 7.79 - 7.67 (m, 3H), 7.52 - 7.49 (m, 1H) , 7.32 - 7.25 (m, 2H), 7.18 - 7.13 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.29 - 3.25 (m, 4H), 3.24 - 3.16 (m, 2H), 1.99 - 1.90 (m, 1H), 1.86 - 1.77 (m, 2H), 1.59 - 1.44 (m, 3H), 1.22 - 1.13 (m, 2H), 0.96 - 0.89 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H), 0.60 - 0.54 (m, 2H)
[M+H] ⁺ = 462.4 106 ¹ H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 2H), 8.23 (s, 1H), 7.88 - 7.83 (m, 2H), 7.77 (dd, J = 8.0, 1.5 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 3.27 (d, J = 8.0 Hz, 6H), 1.82 (p, J = 5.7 Hz, 2H), 1.77 (td, J = 8.4, 4.3 Hz, 1H), 1.62 - 1.50 (m, 5H), 1.46 (d, J = 13.4 Hz, 2H), 1.18 - 1.11 (m, 2H), 1.09 - 0.99 (m, 4H), 0.98 - 0.92 (m, 2H), 0.75 - 0.66 (m, 2H), 0.61 - 0.57 (m, 2H)
[M+H] ⁺ = 523.3 107 ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2H), 8.32 (t, J = 5.6 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.70 (d, J = 1.9 Hz, 1H ), 7.51 (d, J = 1.9 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.16 (dt, J = 5.9, 2.7 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.29 (s, 4H), 3.26 - 3.16 (m, 2H), 1.99 - 1.90 (m, 1H), 1.88 - 1.76 (m, 2H), 1.59 - 1.43 (m, 3H), 1.35 - 1.22 (m, 2H) , 1.22 - 1.13 (m, 2H), 0.98 - 0.90 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H), 0.62 - 0.55 (m, 2H)
[M+H] ⁺ = 476.4 108 ¹ H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.82 (dd, J = 8.3, 1.6 Hz, 1H), 7.78 (s, 1H ), 7.71 (d, J = 1.3 Hz, 1H), 7.53 (s, 1H), 7.29 (d, J = 6.6 Hz, 2H), 7.17 (dt, J = 6.4, 2.1 Hz, 1H), 7.11 (d , J = 8.4 Hz, 1H), 4.08 (dq, J = 13.5, 6.7 Hz, 1H), 3.39 - 3.33 (m, 4H), 3.14 (s, 3H), 1.94 (dh, J = 23.7, 5.5 Hz, 3H), 1.15 (d, J = 6.6 Hz, 6H), 0.99 - 0.90 (m, 2H), 0.58 (q, J = 5.5 Hz, 2H)
[M+H] ⁺ = 434.1 109 ¹ H NMR (400 MHz, DMSO-d6) δ 8.81 - 8.71 (m, 3H), 7.82 (s, 1H), 7.77 (dd, J = 1.8, 8.5 Hz, 1H), 7.70 (d, J = 1.8 Hz , 1H), 7.57 - 7.50 (m, 1H), 7.37 - 7.28 (m, 2H), 7.23 - 7.17 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.91 - 4.76 (m, 1H ), 3.30 - 3.26 (m, 4H), 1.99 - 1.91 (m, 1H), 1.87 - 1.78 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H), 0.97 - 0.90 (m, 2H), 0.62 - 0.55 (m, 2H)
[M+H] ⁺ = 474.2 110 ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2H), 7.93 (d, J = 8.6 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.69 (d, J = 2.0 Hz, 1H ), 7.53 - 7.50 (m, 1H), 7.33 - 7.25 (m, 2H), 7.16 (td, J = 2.4, 6.5 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 3.80 - 3.70 ( m, 1H), 3.31 - 3.24 (m, 4H), 1.99 - 1.90 (m, 1H), 1.86 - 1.77 (m, 2H), 1.57 - 1.40 (m, 4H), 0.97 - 0.90 (m, 2H), 0.85 (t, J = 7.4 Hz, 6H), 0.61 - 0.54 (m, 2H)
[M+H] ⁺ = 448.2 111 ¹ H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 2H), 8.54 (t, J = 5.6 Hz, 1H), 8.46 (s, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.22 - 8.13 (m, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.12 (dd, J = 5.3, 1.3 Hz, 1H), 4.03 (q, J = 7.1 Hz , 0H), 3.31 - 3.22 (m, 6H), 1.83 (t, J = 5.5 Hz, 2H), 1.77 - 1.58 (m, 5H), 1.42 (q, J = 6.9 Hz, 2H), 1.35 - 1.26 ( m, 1H), 1.23 - 1.10 (m, 3H), 0.90 (q, J = 10.5, 9.3 Hz, 2H)
[M+H] ⁺ = 517.2 112 ¹ H NMR (500 MHz, DMSO-d6) d ppm 8.79 (br. s, 2 H), 7.87 (s, 1 H), 7.77 (dd, J = 8.23, 1.65 Hz, 1 H), 7.67 (d, J = 1.92 Hz, 1 H), 7.22 (t, J = 8.10 Hz, 1 H), 7.18 - 7.12 (m, 1 H), 7.16 (t, J = 74.60 Hz, 1 H), 6.85 (dd, J = 8.23, 1.92 Hz, 1 H), 6.74 (t, J = 2.20 Hz, 1 H), 6.57 (dd, J = 7.96, 2.20 Hz, 1 H), 3.30 - 3.25 (m, 4 H), 1.98 - 1.90 (m, 1 H), 1.81 (quin, J = 5.76 Hz, 2 H), 0.97 - 0.90 (m, 2 H), 0.64 - 0.53 (m, 2 H)
[M+H] ⁺ = 401.3 113 ¹ H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 2H), 8.28 (t, J = 5.6 Hz, 1H), 7.76 (dd, J = 8.4, 1.8 Hz, 1H), 7.73 (s, 1H ), 7.69 (d, J = 1.7 Hz, 1H), 7.50 (s, 1H), 7.31 - 7.26 (m, 2H), 7.17 - 7.13 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H) , 3.26 (dd, J = 12.7, 6.3 Hz, 6H), 1.94 (ddd, J = 13.7, 8.4, 5.4 Hz, 1H), 1.81 (p, J = 5.8 Hz, 2H), 1.60 (dp, J = 13.4 , 6.6 Hz, 1H), 1.40 (q, J = 7.0 Hz, 2H), 0.95 - 0.91 (m, 2H), 0.89 (d, J = 6.6 Hz, 6H), 0.60 - 0.54 (m, 2H)
[M+H] ⁺ = 448.4 114 ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2H), 8.33 (d, J = 4.2 Hz, 1H), 7.84 - 7.64 (m, 3H), 7.56 - 7.46 (m, 1H), 7.34 - 7.23 (m, 2H), 7.16 (td, J = 2.3, 6.7 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.31 - 3.25 (m, 4H), 2.88 - 2.78 (m, 1H ), 2.00 - 1.89 (m, 1H), 1.82 (quin, J = 5.7 Hz, 2H), 0.98 - 0.90 (m, 2H), 0.73 - 0.63 (m, 2H), 0.61 - 0.51 (m, 4H)
[M+H] ⁺ = 418.2 115 ¹ H NMR (300 MHz, DMSO) δ 8.85 (bs, 1H), 7.75 (dd, J = 8.4, 1.8 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.63 (bs, 1H), 7.16 - 7.10 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H), 6.62 (bs, 1H), 6.44 (d, J = 7.9 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H ), 3.33 - 3.29 (m, 4H), 1.99 - 1.90 (m, 1H), 1.87 - 1.80 (m, 2H), 1.72 - 1.61 (m, 7H), 1.32 - 1.14 (m, 6H), 0.99 - 0.92 (m, 2H), 0.62 - 0.57 (m, 2H)
[M+H] ⁺ =475.5 116 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.17 (s, 1H), 9.73 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H ), 7.71 (s, 1H), 7.53 (s, 1H), 7.20 - 7.08 (m, 3H), 6.80 (d, J = 7.9 Hz, 1H), 3.54 (t, J = 7.0 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.59 (s, 1H), 1.95 (td, J = 8.4, 4.2 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H), 0.99 - 0.88 (m, 2H), 0.60 (q, J = 5.5 Hz, 2H)
[M+H] ⁺ =434.0 117 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 8.08 (d, J = 7.9 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.52 - 7.49 (m, 1H), 7.31 - 7.24 (m, 2H), 7.15 (td, J = 2.4, 6.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.80 - 3.66 (m, 1H), 3.30 - 3.24 (m, 4H ), 1.98 - 1.89 (m, 1H), 1.86 - 1.76 (m, 4H), 1.76 - 1.68 (m, 2H), 1.65 - 1.55 (m, 1H), 1.37 - 1.22 (m, 4H), 1.18 - 1.05 (m, 1H), 0.97 - 0.89 (m, 2H), 0.61 - 0.53 (m, 2H)
[M+H] ⁺ =460.2 118 ¹ H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 2H), 7.76 (dd, J = 7.2, 2.7 Hz, 2H), 7.68 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H ), 7.08 (dd, J = 20.6, 7.7 Hz, 2H), 6.93 (s, 1H), 6.77 (s, 1H), 3.43 (s, 1H), 3.28 (d, J = 4.9 Hz, 4H), 3.21 (s, 1H), 2.89 (s, 3H), 1.94 (s, 1H), 1.85 - 1.78 (m, 2H), 1.57 (s, 1H), 1.41 (d, J = 35.6 Hz, 3H), 0.92 ( d, J = 7.1 Hz, 4H), 0.71 (s, 3H), 0.57 (q, J = 5.6 Hz, 2H)
[M+H] ⁺ = 462.2 119 ^1H NMR (300 MHz, _CDCl3 ) δ 8.04 (d, J = 6.8 Hz, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.57 (t, J = 2.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.23 (dd, J = 8.0, 1.2 Hz, 1H), 6.61 (s, 1H), 3.44 (t, J = 5.8 Hz, 4H), 2.67 (d, J = 6.8 Hz, 2H), 2.00 (q, J = 5.7 Hz, 2H), 1.82 - 1.61 (m, 6H), 1.29 - 1.16 (m, 4H), 1.05 - 0.98 (m , 4H), 0.85 - 0.78 (m, 2H)
[M+H] ⁺ = 498.5 120 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.16 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.60 (t, J = 1.8 Hz, 1H), 7.38 (dt, J = 7.6, 1.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.28 - 7.21 (m , 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.08 (dp, J = 13.7, 6.9 Hz, 1H), 3.54 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.0 Hz , 2H), 1.96 (tt, J = 8.4, 5.6 Hz, 1H), 1.16 (d, J = 6.6 Hz, 6H), 1.02 - 0.92 (m, 2H), 0.67 - 0.58 (m, 2H)
¹³ C JAMR (151 MHz, DMSO) Δ 170.2, 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, 30.5.8.8, 11.6, 7.6, 7.6
[M+H] ⁺ = 434.2 121 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.16 (s, 1H), 8.55 (s, 1H), 7.87 - 7.78 (m, 3H), 7.59 - 7.53 (m, 1H) , 7.31 (q, J = 7.4 Hz, 2H), 7.23 (dt, J = 7.0, 2.1 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 3.54 (t, J = 7.1 Hz, 2H) , 2.62 (t, J = 7.0 Hz, 2H), 1.95 (ddd, J = 13.7, 8.3, 5.4 Hz, 1H), 1.36 (s, 3H), 1.01 - 0.91 (m, 2H), 0.77 - 0.66 (m , 2H), 0.60 (dd, J = 6.2, 1.7 Hz, 4H)
[M+H] ⁺ = 446.3 122 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.15 (s, 1H), 9.29 (s, 1H), 7.87 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H ), 7.34 (s, 1H), 7.21 - 7.12 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 3.53 (s, 2H), 2.71 - 2.67 (m, 1H), 2.62 (d, J = 6.9 Hz, 2H), 1.93 (s, 1H), 1.59 (s, 1H), 1.15 (d, J = 6.8 Hz, 6H), 1.01 (d, J = 8.3 Hz, 2H), 0.85 (d, J = 7.9 Hz, 2H), 0.65 (d, J = 5.0 Hz, 2H), 0.35 (d, J = 3.9 Hz, 2H)
[M+H] ⁺ = 474.1 123 ¹ H NMR (400 MHz, DMSO-d6) δ 8.83 - 8.74 (m, 2H), 7.76 (dd, J = 1.8, 8.4 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.62 (s, 1H) , 7.45 - 7.42 (m, 1H), 7.29 - 7.21 (m, 2H), 7.14 (td, J = 2.0, 7.2 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.30 - 3.24 (m , 4H), 1.98 - 1.89 (m, 1H), 1.86 - 1.77 (m, 2H), 1.36 (s, 9H), 0.97 - 0.90 (m, 2H), 0.61 - 0.54 (m, 2H)
[M+H] ⁺ = 434.3 124 ¹ H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.73 (m, 2H), 7.76 (dd, J = 1.9, 8.3 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.20 - 7.11 (m, 2H), 6.71 (dd, J = 1.7, 7.8 Hz, 1H), 6.66 (t, J = 2.2 Hz, 1H), 6.51 (dd, J = 2.3, 7.8 Hz, 1H), 4.67 (q, J = 8.9 Hz, 2H), 3.29 - 3.23 (m, 4H), 1.98 - 1.88 (m, 1H), 1.85 - 1.77 (m, 2H), 0.97 - 0.89 (m, 2H), 0.60 - 0.53 (m, 2H)
[M+H] ⁺ = 433.2 125 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (m, 2H), 7.76 (dd, J = 1.9, 8.4 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.62 (s, 1H ), 7.18 - 7.10 (m, 2H), 6.69 (dd, J = 1.3, 8.0 Hz, 1H), 6.64 (t, J = 2.3 Hz, 1H), 6.51 - 6.19 (m, 2H), 4.24 (dt, J = 3.6, 14.7 Hz, 2H), 3.30 - 3.24 (m, 4H), 1.98 - 1.89 (m, 1H), 1.81 (quin, J = 5.6 Hz, 2H), 0.97 - 0.90 (m, 2H), 0.60 - 0.53 (m, 2H)
[M+H] ⁺ = 415.2 126 ¹ H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 2H), 8.31 (t, J = 5.6 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.69 (d, J = 1.9 Hz, 1H ), 7.53 - 7.48 (m, 1H), 7.28 (s, 2H), 7.16 (dt, J = 6.6, 2.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.82 (dd, J = 11.2, 3.0 Hz, 2H), 3.30 - 3.21 (m, 8H), 1.94 (tt, J = 8.4, 5.4 Hz, 1H), 1.82 (p, J = 5.7 Hz, 2H), 1.64 - 1.57 (m, 2H ), 1.53 (ddt, J = 10.5, 7.2, 3.8 Hz, 1H), 1.45 (q, J = 6.9 Hz, 2H), 1.15 (qd, J = 12.1, 4.4 Hz, 2H), 0.97 - 0.89 (m, 2H), 0.63 - 0.54 (m, 2H)
[M+H] ⁺ =490.2 127 ¹ H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.71 (m, 2H), 7.75 (dd, J = 2.0, 8.4 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.54 (s , 1H), 7.16 - 7.05 (m, 2H), 6.65 - 6.57 (m, 2H), 6.40 (dd, J = 1.7, 8.3 Hz, 1H), 3.72 (d, J = 6.4 Hz, 2H), 3.30 - 3.25 (m, 4H), 1.98 - 1.89 (m, 1H), 1.86 - 1.60 (m, 8H), 1.32 - 1.12 (m, 3H), 1.09 - 0.90 (m, 4H), 0.60 - 0.53 (m, 2H )
[M+H] ⁺ = 447.3 128 ¹ H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.75 (s, 2H), 7.72 (s, 1H), 7.67 (dd, J = 8.4, 1.7 Hz, 1H), 7.13 (t , J = 7.8 Hz, 1H), 7.08 (d, J = 7.0 Hz, 2H), 6.96 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.29 - 3.22 (m , 4H), 2.33 (t, J = 7.6 Hz, 2H), 2.01 (s, 3H), 1.87 (ddd, J = 13.6, 8.3, 5.4 Hz, 1H), 1.80 (p, J = 5.6 Hz, 2H) , 1.59 (dt, J = 13.1, 6.8 Hz, 1H), 1.51 (q, J = 7.1 Hz, 2H), 0.96 - 0.93 (m, 2H), 0.91 (d, J = 6.5 Hz, 6H), 0.59 - 0.54(m, 2H)
[M+H] ⁺ = 462.4 129 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.76 (dd,J = 8.4, 2.0 Hz, 1H), 7.68 (d,J = 1.9 Hz, 1H), 7.56 (s, 1H ), 7.16 - 7.03 (m, 2H), 6.67 - 6.58 (m, 1H), 6.51 (t, J = 2.2 Hz, 1H), 6.32 (dd, J = 8.1, 2.4 Hz, 1H), 4.61 (p, J = 7.3 Hz, 1H), 3.28 (d, J = 8.7 Hz, 4H), 2.43 - 2.30 (m, 3H), 2.09 - 1.89 (m, 2H), 1.87 - 1.70 (m, 3H), 1.63 (q , J = 9.2, 8.3 Hz, 1H), 1.00 - 0.88 (m, 2H), 0.64 - 0.50 (m, 2H)
[M+H] ⁺ =405.3 130 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H ), 7.17 - 7.05 (m, 2H), 6.67 - 6.54 (m, 2H), 6.41 (dd, J = 7.9, 2.3 Hz, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.29 (d, J = 4.5 Hz, 4H), 1.99 - 1.88 (m, 1H), 1.88 - 1.77 (m, 2H), 1.77 - 1.55 (m, 7H), 1.51 - 1.39 (m, 1H), 1.27 - 1.09 (m, 3H), 0.99 - 0.84 (m, 4H), 0.61 - 0.52 (m, 2H)
[M+H] ⁺ = 461.3 131 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.33 - 7.29 (m, 2H), 8.79 (s, 2H) , 8.36 (t, J = 5.8 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.22 - 7.15 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.34 - 3.24 (m, 4H ), 3.07 (t, J = 7.0, 5.8 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.89 - 1.79 (m, 3H), 1.00 - 0.92 (m, 2H), 0.90 (d, J = 6.7 Hz, 6H), 0.62 - 0.57 (m, 2H)
[M+H] ⁺ = 434.4 132 ¹ H NMR (300 MHz, DMSO) δ 8.79 (s, 2H), 7.76 (dd, J = 8.3, 1.7 Hz, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 7.17 - 7.05 (m , 2H), 6.63 (d, J = 8.1 Hz, 1H), 6.60 (s, 1H), 6.41 (dd, J = 8.2, 1.7 Hz, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.29 (t, J = 4.9 Hz, 4H), 2.00 - 1.89 (m, 1H), 1.84 - 1.79 (m, 2H), 1.75 - 1.64 (m, 2H), 1.62 - 1.53 (m, 1H), 1.29 (dd , J = 15.4, 7.3 Hz, 2H), 0.95 (q, J = 5.6 Hz, 2H), 0.90 (d, J = 5.2 Hz, 6H), 0.57 (q, J = 5.6 Hz, 2H)
^13C NMR (151 MHz, DMSO) δ 160.0, 145.7, 144.7, 131.7, 130.1, 127.2, 126.9, 116.9, 110.5, 106.7, 104.3, 67.9, 38.5, 35.2, 27.7, 28.5, 2
[M+H] ⁺ =435.5 133 ¹ H NMR (400 MHz, DMSO-d6) δ 8.97 (t, J = 5.8 Hz, 1H), 8.77 (br. s., 2H), 7.82 (s, 1H), 7.77 (dd, J = 1.8, 8.4 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.54 (s, 1H), 7.32 (d, J = 4.8 Hz, 2H), 7.24 - 7.16 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.30 - 3.24 (m, 4H), 1.99 - 1.89 (m, 1H), 1.86 - 1.77 (m, 2H), 0.96 - 0.89 (m, 2H ), 0.61 - 0.54 (m, 2H)
[M+H] ⁺ =460.2 134 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.15 (s, 1H), 7.85 - 7.76 (m, 2H), 7.68 (s, 1H), 7.15 (t, J = 8.0 Hz , 2H), 6.75 - 6.70 (m, 1H), 6.68 (t, J = 2.2 Hz, 1H), 6.49 (dd, J = 7.9, 2.2 Hz, 1H), 3.92 - 3.69 (m, 4H), 3.54 ( t, J = 7.0 Hz, 2H), 3.41 - 3.32 (m, 1H), 3.26 (dd, J = 11.1, 9.1 Hz, 1H), 2.61 (t, J = 7.0 Hz, 2H), 2.02 - 1.88 (m , 2H), 1.83 (d, J = 8.3 Hz, 1H), 1.65 - 1.44 (m, 2H), 1.44 - 1.27 (m, 1H), 1.02 - 0.92 (m, 2H), 0.66 - 0.57 (m, 2H )
[M+H] ⁺ = 463.3 135 ^1H NMR (300 MHz, _CDCl3 ) δ 8.04 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.71 (d, J = 8.0 Hz , 1H), 6.64 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 6.41 (s, 1H), 3.48 (t, J = 5.8 Hz, 4H), 2.08 - 1.99 (m, 5H), 1.78 - 1.68 (m, 1H), 1.01 (q, J = 5.7 Hz, 2H), 0.85 (q, J = 5.7 Hz, 2H)
[M+H] ⁺ = 364.3 136 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.79 - 7.74 (m, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.13 - 7.05 (m, 2H), 7.03 - 6.99 (m, 1H), 6.85 (d, J = 7.9 Hz, 1H), 3.90 (d, J = 11.9 Hz, 1H), 3.59 (d, J = 8.1 Hz, 1H), 3.42 - 3.32 (m, 2H), 3.30 - 3.24 (m, 4H), 1.98 - 1.89 (m, 1H), 1.85 - 1.76 (m, 2H), 1.58 - 1.48 (m, 2H), 0.97 - 0.88 (m, 2H), 0.68 - 0.61 (m, 1H), 0.60 - 0.54 (m, 2H), 0.05 (q, J = 3.9 Hz, 1H)
[M+H] ⁺ = 444.2 137 ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99 - 7.94 (m, 2H), 7.31 (t, J = 8.1 Hz, 1H), 7.23 (s, 1H), 7.06 (dd, J = 7.9, 1.9 Hz, 1H), 6.99 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.39 (s, 1H), 3.42 (t, J = 5.6 Hz, 4H), 1.99 (q, J = 5.6 Hz, 2H), 1.82 - 1.72 (m, 1H), 0.98 (q, J = 5.9 Hz, 2H), 0.76 (q, J = 5.9 Hz, 2H)
[M+H] ⁺ = 419.3 138 ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.28 (d, J = 5.6 Hz, 1H), 8.08 (dd, J = 8.4, 2.0 Hz, 1H), 8.04 - 7.99 (m, 2H), 7.78 (d, J = 2.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 5.6, 2.5 Hz, 1H), 6.73 (s, 1H), 3.53 - 3.43 (m, 6H), 2.09 - 1.99 (m, 2H), 1.74 (ddd, J = 30.4, 16.7, 7.1 Hz, 8H), 1.54 (dd, J = 14.5, 6.9 Hz, 2H), 1.27 - 1.20 (m, 4H), 1.03 - 1.00 (m, 2H), 0.86 - 0.78 (m, 2H)
[M+H] ⁺ = 489.6 139 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H ), 7.17 - 7.07 (m, 2H), 6.70 - 6.57 (m, 2H), 6.42 (dd, J = 8.0, 2.3 Hz, 1H), 4.05 - 3.97 (m, 2H), 3.72 - 3.57 (m, 3H ), 3.31-3.23 (m, 4H), 1.99 - 1.89 (m, 1H), 1.82 (t, J = 5.9 Hz, 2H), 1.11 (d, J = 6.1 Hz, 6H), 0.98 - 0.89 (m, 2H), 0.60 - 0.53 (m, 2H)
[M+H] ⁺ = 437.3 140 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.55 (s, 1H ), 7.17 - 6.95 (m, 2H), 6.70 - 6.51 (m, 2H), 6.41 (dd, J = 8.0, 2.4 Hz, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.31-3.25 ( m, 4H), 2.03 - 1.87 (m, 1H), 1.87 - 1.76 (m, 2H), 1.74 - 1.55 (m, 7H), 1.39 (q, J = 7.3 Hz, 2H), 1.28 - 1.03 (m, 6H), 0.98 - 0.77 (m, 4H), 0.60 - 0.52 (m, 2H)
[M+H] ⁺ = 489.4 141 ^1H NMR (300 MHz, _CDCl3 ) δ 8.00 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 7.7 Hz , 1H), 7.03 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 3.50 (t, J = 5.7 Hz, 4H), 2.30 (s, 3H), 2.10 - 1.99 (m, 2H), 1.79 - 1.68 (m, 1H), 1.01 (q, J = 5.5 Hz, 2H), 0.80 (q, J = 5.5 Hz, 2H)
[M+H] ⁺ = 449.3 142 ^1H NMR (300 MHz, _CDCl3 ) δ 8.02 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 6.8 Hz, 1H), 6.54 (s, 1H), 3.46 (t, J = 5.8 Hz, 4H), 3.00 - 2.92 (m, 2H) , 2.08 - 1.98 (m, 2H), 1.81 - 1.64 (m, 6H), 1.34 - 1.20 (m, 6H), 1.04 - 0.96 (m, 4H), 0.80 (q, J = 5.6 Hz, 2H)
[M+H] ⁺ =360.3 143 ¹ H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 2H), 8.17 (s, 1H), 7.79 (dd, J = 8.3, 1.8 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H ), 7.44 (t, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.25 (dd, J = 8.1, 2.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.15 (d , J = 8.3 Hz, 1H), 3.30 - 3.26 (m, 4H), 3.21 - 3.17 (m, 2H), 1.93 (ddd, J = 13.6, 8.4, 5.2 Hz, 1H), 1.82 (q, J = 5.8 Hz, 2H), 1.65 - 1.50 (m, 7H), 1.21 - 1.05 (m, 6H), 0.94 - 0.89 (m, 2H), 0.84 - 0.73 (m, 2H), 0.63 - 0.56 (m, 2H)
[M+H] ⁺ = 523.3 144 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.12 (t , J = 8.1 Hz, 2H), 6.66 (dd, J = 7.6, 2.0 Hz, 1H), 6.43 (t, J = 2.3 Hz, 1H), 6.23 (dd, J = 8.1, 2.4 Hz, 1H), 5.28 - 5.14 (m, 1H), 4.87 (dd, J = 7.2, 6.1 Hz, 2H), 4.54 (dd, J = 7.3, 5.0 Hz, 2H), 3.30 - 3.26 (m, 4H), 1.98 - 1.89 (m , 1H), 1.86 - 1.77 (m, 2H), 0.98 - 0.90 (m, 2H), 0.61 - 0.53 (m, 2H)
[M+H] ⁺ = 407.2 145 ¹ H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.16 (s, 1H), 8.36 (d, J = 4.2 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 1.1 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.24 (dt, J = 6.2, 2.5 Hz, 1H), 7.12 (d, J = 8.3 Hz , 1H), 3.54 (t, J = 7.0 Hz, 2H), 2.83 (tt, J = 8.1, 4.0 Hz, 1H), 2.62 (t, J = 7.0 Hz, 2H), 1.96 (tt, J = 8.4, 5.4 Hz, 1H), 1.01 - 0.90 (m, 2H), 0.68 (td, J = 7.1, 4.7 Hz, 2H), 0.62 (dd, J = 5.4, 1.9 Hz, 2H), 0.56 (dd, J = 3.6 , 2.6Hz, 2H)
[M+H] ⁺ = 432.3 146 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.16 (s, 1H), 7.86 - 7.75 (m, 2H), 7.69 (s, 1H), 7.15 (t, J = 8.5 Hz , 2H), 6.75 - 6.66 (m, 2H), 6.49 (dd, J = 8.2, 1.9 Hz, 1H), 3.88 (dd, J = 11.1, 3.5 Hz, 2H), 3.79 (d, J = 6.4 Hz, 2H), 3.54 (t, J = 7.0 Hz, 2H), 3.32 (t, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.04 - 1.89 (m, 2H), 1.67 (d, J = 11.5 Hz, 2H), 1.32 (qd, J = 12.3, 4.4 Hz, 2H), 1.02 - 0.92 (m, 2H), 0.61 (q, J = 5.4 Hz, 2H)
[M+H] ⁺ =463.0 147 ^1H NMR (300 MHz, _CDCl3 ) δ 9.62 (s, 1H), 8.03 (dd, J = 8.5, 1.9 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 7.8, 1.2 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.09 (t, J = 5.3 Hz, 1H), 3.48 - 3.41 (m, 6H), 2.04 - 1.96 (m, 2H), 1.93 - 1.82 (m, 1H), 1.76 - 1.61 (m , 1H), 1.50 (dd, J = 14.7, 7.1 Hz, 2H), 1.07 (q, J = 5.8 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H), 0.76 (q, J = 5.8 Hz , 2H)
[M+H] ⁺ = 448.4 148 ¹ H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.79 (s, 2H), 8.28 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 10.2 Hz, 1H), 7.75 (d, J = 4.6 Hz, 1H), 7.67 (s, 1H), 7.22 - 7.15 (m, 1H), 7.15 - 7.11 (m, 1H), 6.92 - 6.86 (m, 1H), 3.29 (s, 4H), 2.37 (t, J = 7.7 Hz, 2H), 2.04 - 1.98 (m, 1H), 1.85 - 1.78 (m, 2H), 1.72 - 1.59 (m, 5H), 1.49 - 1.43 (m, 2H) , 1.20 - 1.11 (m, 3H), 0.92 - 0.85 (m, 2H)
[M+H] ⁺ = 534.2 149 ^1H NMR (300 MHz, _CDCl3 ) δ 9.75 (s, 1H), 8.09 (s, 1H), 8.07 (d, J = 9.4 Hz, 1H), 7.96 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 9.4 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 4.63 (t, J = 7.3 Hz, 2H), 3.51 (t, J = 5.8 Hz, 4H), 2.12 - 2.01 (m, 4H), 1.80 - 1.60 (m, 7H), 1.31 - 1.17 (m, 6H), 1.08 - 1.01 (m, 2H), 0.94-0.84 (dd, J = 9.7, 5.9 Hz, 4H)
[M+H] ⁺ =527.5 150 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.16 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.70 (s, 1H ), 7.17 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.2 Hz, 1H), 6.68 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.72 (t, J = 11.0 Hz, 2H), 3.63 (d, J = 11.0 Hz, 2H), 3.57 - 3.51 (m, 3H), 3.49 - 3.42 (m, 1H), 3.27 - 3.18 (m, 1H), 2.61 (t, J = 7.1 Hz, 2H), 1.95 (s, 1H), 1.76 (s, 2H), 0.97 (d, J = 8.2 Hz, 2H), 0.61 (d, J = 4.3 Hz, 2H)
[M+H] ⁺ =479.0 151 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.16 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H ), 7.18 - 7.12 (m, 2H), 6.71 (d, J = 7.8 Hz, 1H), 6.68 (s, 1H), 6.48 (d, J = 10.4 Hz, 1H), 3.87 (d, J = 6.2 Hz , 3H), 3.59 (s, 1H), 3.54 (t, J = 7.1 Hz, 2H), 3.39 (s, 1H), 2.61 (t, J = 7.0 Hz, 2H), 1.95 (s, 1H), 1.81 (s, 1H), 1.64 (d, J = 11.9 Hz, 1H), 1.49 (s, 3H), 1.37 - 1.24 (m, 1H), 1.00 - 0.94 (m, 2H), 0.61 (d, J = 3.8 Hz, 2H)
[M+H] ⁺ = 463.1 152 ¹ H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2H), 8.75 (d, J = 6.7 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.71 (d, J = 1.9 Hz, 1H ), 7.57 - 7.51 (m, 1H), 7.35 - 7.31 (m, 2H), 7.24 - 7.18 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.32 - 4.20 (m, 1H), 3.30 (s, 4H), 3.02 - 2.88 (m, 2H), 2.84 - 2.70 (m, 2H), 2.01 - 1.90 (m, 1H), 1.88 - 1.77 (m, 2H), 1.00 - 0.90 (m, 2H ), 0.64 - 0.54 (m, 2H)
[M+H] ⁺ = 468.2 153 ^1H NMR (300 MHz, _CDCl3 ) δ 7.98 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.36 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.20 (t, J = 8.3 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.65 (s, 1H), 3.42 - 3.39 (m, 4H) , 2.42 - 2.30 (m, 2H), 2.27 (s, 3H), 2.02 - 1.94 (m, 2H), 1.75 - 1.57 (m, 8H), 1.30 - 1.14 (m, 5H)
[M+H] ⁺ =462.5 154 ¹ H NMR (400 MHz, DMSO-d6) δ 8.83 - 8.74 (m, 2H), 7.91 (s, 1H), 7.78 (dd, J = 1.9, 8.4 Hz, 1H), 7.68 (d, J = 1.8 Hz , 1H), 7.51 - 7.44 (m, 1H), 7.40 - 7.28 (m, 2H), 7.26 - 7.19 (m, 1H), 7.14 (d, J = 8.3 Hz, 1H), 3.30 - 3.24 (m, 4H ), 2.24 (s, 2H), 2.01 - 1.90 (m, 1H), 1.86 - 1.76 (m, 2H), 1.16 (s, 6H), 0.97 - 0.83 (m, 2H), 0.62 - 0.52 (m, 2H )
[M+H] ⁺ =432.0 155 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 8.42 (d, J = 6.6 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.69 (d, J = 1.8 Hz, 1H ), 7.54 - 7.51 (m, 1H), 7.34 - 7.26 (m, 2H), 7.19 - 7.14 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.47 - 4.39 (m, 1H), 3.88 - 3.79 (m, 2H), 3.74 - 3.66 (m, 1H), 3.56 (dd, J = 4.5, 8.9 Hz, 1H), 3.30 - 3.25 (m, 4H), 2.16 - 2.08 (m, 1H), 1.97 - 1.87 (m, 2H), 1.86 - 1.77 (m, 2H), 0.96 - 0.90 (m, 2H), 0.61 - 0.54 (m, 2H)
[M+H] ⁺ = 448.2 156 ^1H NMR (300 MHz, _CDCl3 ) δ 7.97 (s, 1H), 7.91 (dd, J = 8.5, 1.9 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.17 (t, J = 8.2 Hz, 1H), 6.68 - 6.60 (m, 2H), 6.55 - 6.47 (m, 1H), 5.59 (s, 1H), 3.89 (t, J = 6.6 Hz, 2H), 3.40 - 3.34 (m, 4H ), 2.28 (s, 3H), 1.96 (dt, J = 11.6, 6.6 Hz, 2H), 1.83 - 1.61 (m, 8H), 1.38 - 1.13 (m, 7H) 157 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 8.21 (d, J = 7.9 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.69 (d, J = 1.8 Hz, 1H ), 7.54 - 7.50 (m, 1H), 7.33 - 7.25 (m, 2H), 7.16 (td, J = 2.8, 5.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.04 - 3.93 ( m, 1H), 3.90 - 3.83 (m, 2H), 3.41 - 3.33 (m, 2H), 3.30 - 3.24 (m, 4H), 1.98 - 1.89 (m, 1H), 1.85 - 1.77 (m, 2H), 1.77 - 1.68 (m, 2H), 1.56 (dq, J = 4.4, 12.0 Hz, 2H), 0.96 - 0.89 (m, 2H), 0.60 - 0.54 (m, 2H)
[M+H] ⁺ = 462.2 158 ¹ H NMR (400 MHz, DMSO-d6) δ 8.83 - 8.73 (m, 2H), 7.81 - 7.76 (m, 2H), 7.69 (d, J = 1.9 Hz, 1H), 7.28 (t, J = 7.8 Hz , 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.09 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 6.99 (t, J = 1.9 Hz, 1H), 6.82 (dt, J = 7.5, 1.3 Hz, 1H), 3.72 - 3.35 (m, 8H), 3.30 - 3.24 (m, 4H), 2.00 - 1.90 (m, 1H), 1.87 - 1.77 (m, 2H), 0.98 - 0.89 (m, 2H), 0.64 - 0.54 (m, 2H)
[M+H] ⁺ = 448.3 159 ^1H NMR (300 MHz, _CDCl3 ) δ 9.52 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.45 (t, J = 6.1 Hz, 1H), 3.73 - 3.64 (m, 2H), 3.40 (t, J = 5.7 Hz, 4H), 2.56 - 2.37 (m, 2H), 2.05 - 1.93 (m, 2H), 1.92 - 1.83 (m, 1H), 1.05 (q, J = 5.8 Hz, 2H), 0.74 (q, J = 5.8 Hz, 2H)
[M+H] ⁺ = 474.3 160 ^1H NMR (300 MHz, _CDCl3 ) δ 10.22 (s, 2H), 8.14 (s, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 7.98 (bs, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 8.4, 1.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 4.84 (t, J = 5.5 Hz, 2H), 3.99 (t, J = 5.5 Hz, 2H), 3.54 (t, J = 5.7 Hz, 4H), 3.38 (s, 3H), 2.11 - 2.05 ( m, 2H), 1.80 - 1.70 (m, 1H), 1.11 - 1.02 (m, 2H), 0.93 - 0.88 (dt, J = 10.0, 5.0 Hz, 2H)
[M+H] ⁺ = 461.4 161 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.16 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.70 (s, 1H ), 7.16 (t, J = 7.9 Hz, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.68 (s, 1H), 6.49 (d, J = 10.4 Hz, 1H), 3.92 (d, J = 6.0 Hz, 2H), 3.88 - 3.73 (m, 3H), 3.70 - 3.58 (m, 2H), 3.57 - 3.45 (m, 3H), 3.39 (t, J = 10.4 Hz, 1H), 2.61 (t, J = 7.0 Hz, 2H), 1.98 - 1.90 (m, 1H), 1.00 - 0.92 (m, 2H), 0.61 (q, J = 5.5 Hz, 2H)
[M+H] ⁺ =465.0 162 ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2H), 7.90 (s, 1H), 7.79 (dd, J = 8.3, 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H ), 7.57 (t, J = 1.9 Hz, 1H), 7.43 - 7.31 (m, 2H), 7.24 (ddd, J = 7.6, 2.4, 1.5 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H) , 3.29 (s, 4H), 2.62 (td, J = 5.7, 3.6 Hz, 1H), 2.46 (d, J = 6.0 Hz, 1H), 2.09 (d, J = 3.6 Hz, 1H), 2.01 - 1.91 ( m, 1H), 1.82 (p, J = 5.8 Hz, 2H), 1.26 (d, J = 5.5 Hz, 3H), 0.97 - 0.89 (m, 2H), 0.63 - 0.55 (m, 2H)
[M+H] ⁺ = 417.8 163 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (m, 2H), 7.79 - 7.73 (m, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H ), 7.11 (d, J = 8.4 Hz, 1H), 7.10 - 7.04 (m, 1H), 6.98 (m, 1H), 6.81 (d, J = 7.7 Hz, 1H), 3.30 - 3.24 (m, 4H) , 2.94 (br. s., 6H), 1.94 (m, 1H), 1.81 (m, 2H), 0.97 - 0.90 (m, 2H), 0.60 - 0.53 (m, 2H)
[M+H] ⁺ = 406.3 164 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.17 (s, 1H), 7.91 (s, 1H), 7.86 - 7.77 (m, 2H), 7.32 (t, J = 7.8 Hz , 1H), 7.21 - 7.13 (m, 2H), 7.08 (s, 1H), 6.89 (d, J = 7.4 Hz, 1H), 3.75 - 3.34 (m, 10H), 2.62 (t, J = 7.0 Hz, 2H), 2.02 - 1.90 (m, 1H), 1.02 - 0.92 (m, 2H), 0.63 (q, J = 5.1 Hz, 2H)
[M+H] ⁺ =462.0 165 ^1H NMR (300 MHz, _CDCl3 ) δ 8.08 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.7 Hz , 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.45 (s, 1H), 3.50 (t, J = 5.7 Hz, 4H), 2.30 (s , 3H), 2.10 - 2.01 (m, 2H), 1.80 - 1.72 (m, 1H), 1.66 (dd, J = 8.2, 5.7 Hz, 2H), 1.40 (dd, J = 8.3, 5.7 Hz, 2H), 1.03 (q, J = 6.0 Hz, 2H), 0.83 (q, J = 6.0 Hz, 2H)
[M+H] ⁺ = 457.3 166 ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, J = 7.0 Hz, 2H), 7.55 (s, 1H), 7.40 - 7.30 (m, 3H), 7.21 (d, J = 9.1 Hz, 1H) , 6.79 (s, 1H), 6.42 (s, 1H), 5.23 (dt, J = 13.1, 6.4 Hz, 1H), 5.01 (t, J = 6.4 Hz, 2H), 4.62 (t, J = 6.5 Hz, 2H), 3.39 (t, J = 5.7 Hz, 4H), 2.03 - 1.91 (m, 2H), 1.75 (ddd, J = 13.7, 8.2, 5.4 Hz, 1H), 0.97 (q, J = 5.6 Hz, 2H ), 0.73 (q, J = 5.6 Hz, 2H)
[M+H] ⁺ = 434.3 167 ¹ H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.74 (m, 2H), 7.80 - 7.74 (m, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.29 - 7.23 (m, 1H) , 7.12 (d, J = 8.1 Hz, 1H), 7.08 (dd, J = 1.3, 8.1 Hz, 1H), 6.96 (t, J = 1.9 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H) , 3.65 - 3.33 (m, 4H), 3.30 - 3.24 (m, 4H), 2.36 - 2.22 (m, 4H), 2.18 (s, 3H), 1.98 - 1.89 (m, 1H), 1.86 - 1.77 (m, 2H), 0.96 - 0.89 (m, 2H), 0.61 - 0.54 (m, 2H)
[M+H] ⁺ = 461.3 168 ¹ H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.21 (s, 1H), 8.67 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H ), 8.18 (dd, J = 8.8, 2.0 Hz, 1H), 7.70 (s, 1H), 7.60 (dt, J = 6.9, 1.8 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 3.56 (td, J = 7.1, 2.7 Hz, 2H), 3.53 - 3.49 (m, 1H), 2.63 (t, J = 7.0 Hz, 2H), 1.37 (s, 3H), 1.24 (d, J = 6.8 Hz, 6H), 0.76 - 0.71 (m, 2H), 0.64 - 0.58 (m, 2H)
[M+H] ⁺ =512.2 169 ¹ H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.76 (s, 2H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H ), 7.45 (s, 1H), 7.20 (s, 1H), 7.05 (dd, J = 8.3, 4.1 Hz, 2H), 6.82 (dd, J = 8.2, 2.0 Hz, 1H), 3.29 - 3.24 (m, 4H), 2.31 (t, J = 7.6 Hz, 2H), 2.12 (s, 3H), 1.92 (ddd, J = 13.7, 8.4, 5.4 Hz, 1H), 1.81 (p, J = 5.5 Hz, 2H), 1.57 (dt, J = 13.0, 6.5 Hz, 1H), 1.49 (q, J = 7.1 Hz, 2H), 0.95 - 0.91 (m, 2H), 0.90 (d, J = 6.5 Hz, 6H), 0.58 - 0.51 (m, 2H)
[M+H] ⁺ = 462.4 170 ¹ H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.12 (t, J = 5.6 Hz, 1H), 7.73 (dd, J = 8.4, 1.8 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.55 (s, 1H), 7.08 (dd, J = 8.6, 2.8 Hz, 2H), 7.04 - 6.99 (m, 2H), 3.29 - 3.25 (m, 4H), 3.21 (q, J = 6.5 Hz, 2H), 2.23 (s, 3H), 1.91 (ddd, J = 13.6, 8.3, 5.4 Hz, 1H), 1.81 (p, J = 5.8 Hz, 2H), 1.62 (dp, J = 13.3 , 6.7 Hz, 1H), 1.38 (q, J = 7.0 Hz, 2H), 0.96 - 0.91 (m, 2H), 0.89 (d, J = 6.6 Hz, 6H), 0.59 - 0.52 (m, 2H)
[M+H] ⁺ = 462.4 171 ^1H NMR (300 MHz, _CDCl3 ) δ 10.18 (s, 2H), 8.15 (dd, J = 8.7, 2.0 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.70 (bs, 1H) , 7.54 - 7.49 (m, 2H), 7.47 - 7.41 (m, 1H), 7.29 (d, J = 6.2 Hz, 1H), 6.84 (s, 1H), 4.59 (t, J = 5.1 Hz, 2H), 3.97 (t, J = 5.1 Hz, 2H), 3.54 (t, J = 5.7 Hz, 4H), 3.28 (s, 3H), 2.13 - 2.02 (m, 2H), 1.84 - 1.72 (m, 1H), 1.09 - 1.02 (m, 2H), 0.89 - 0.84 (m, 2H)
[M+H] ⁺ = 461.4 172 ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 7.51 - 7.46 (m, 1H), 7.37 (d, J = 4.3 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 3.50 (t, J = 5.7 Hz, 4H), 2.10 - 2.02 ( m, 2H), 1.70 - 1.67 (m, 1H), 1.63 (dd, J = 8.4, 5.9 Hz, 2H), 1.41 (dd, J = 8.4, 5.9 Hz, 2H), 1.02 (q, J = 5.3 Hz , 2H), 0.81 (q, J = 5.3 Hz, 2H)
[M+H] ⁺ = 443.3 173 ¹ H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.22 (s, 1H), 8.73 (s, 1H), 8.67 (s, 1H), 8.49 (d, J = 2.1 Hz, 1H ), 8.18 (dd, J = 8.8, 2.1 Hz, 1H), 7.68 (s, 1H), 7.61 - 7.57 (m, 1H), 7.47 - 7.41 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 3.56 (td, J = 7.0, 2.8 Hz, 2H), 2.63 (t, J = 7.1 Hz, 2H), 1.37 (s, 3H), 1.32 (s, 9H), 0.76 - 0.72 (m, 2H ), 0.63 - 0.59 (m, 2H)
[M+H] ⁺ =526.3 174 ¹ H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.22 (s, 1H), 8.63 (s, 1H), 8.61 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H ), 8.09 (dd, J = 8.5, 2.0 Hz, 1H), 7.57 (t, J = 1.8 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H ), 7.30 - 7.20 (m, 2H), 3.59 - 3.53 (m, 2H), 3.19 (p, J = 6.7 Hz, 1H), 2.63 (t, J = 7.1 Hz, 2H), 1.36 (s, 3H) , 1.17 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 0.75 - 0.70 (m, 2H), 0.62 - 0.57 (m, 2H)
[M+H] ⁺ = 496.2 175 ¹ H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.21 (s, 1H), 7.95 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H ), 7.32 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 9.2 Hz, 2H), 7.06 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.76 (s, 1H ), 3.67 - 3.35 (m, 10H), 2.62 (t, J = 7.0 Hz, 2H), 2.26 (s, 3H)
[M+H] ⁺ =436.0 176 ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.96 (d, J = 7.9 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.69 (d, J = 1.8 Hz, 1H ), 7.54 - 7.50 (m, 1H), 7.33 7.25 (m, 2H), 7.16 (td, J = 2.2, 7.1 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.68 (t, J = 5.8 Hz, 1H), 3.99 (td, J = 6.8, 13.8 Hz, 1H), 3.44 (td, J = 5.6, 10.8 Hz, 1H), 3.35 - 3.32 (m, 1H), 3.30 - 3.25 (m, 4H), 1.98 - 1.89 (m, 1H), 1.86 - 1.77 (m, 2H), 1.11 (d, J = 6.6 Hz, 3H), 0.96 - 0.89 (m, 2H), 0.60 - 0.54 (m, 2H)
[M+H] ⁺ = 436.2 177 Mixture of cis and trans isomers
trans isomer: ¹ H NMR (500 MHz, DMSO-d6) δ ppm 0.50 - 0.65 (m, 2 H), 0.88 - 0.97 (m, 2 H), 1.81 (quin, J = 5.7 Hz, 2 H), 1.90 - 2.01 (m, 1 H), 2.13 (ddd, J = 12.6, 8.0, 4.7 Hz, 2 H), 2.20 - 2.30 (m, 2 H), 3.24 - 3.29 (m, 4 H), 4.23 - 4.34 (m, 1 H), 4.36 - 4.46 (m, 1 H), 4.99 (d, J = 5.2 Hz, 1 H), 7.09 (d, J = 8.2 Hz, 1 H), 7.13 - 7.20 (m, 1 H), 7.25 - 7.34 (m, 2 H), 7.48 - 7.55 (m, 1 H), 7.69 (d, J = 1.6 Hz, 1 H), 7.71 - 7.80 (m, 2 H), 8.48 (d, J = 7.1 Hz, 1 H), 8.77 (s, 2 H).
cis-isomer: ¹ H NMR (500 MHz, DMSO-d6) δ ppm 0.50 - 0.65 (m, 2 H), 0.88 - 0.97 (m, 2 H), 1.81 (quin, J = 5.7 Hz, 2 H), 1.84 - 1.92 (m, 2 H), 1.90 - 2.01 (m, 1 H), 2.51 - 2.56 (m, 2 H), 3.24 - 3.29 (m, 4 H), 3.79 - 3.92 (m, 2 H), 5.07 (d, J = 5.5 Hz, 1 H), 7.09 (d, J = 8.2 Hz, 1 H), 7.13 - 7.20 (m, 1 H), 7.25 - 7.34 (m, 2 H), 7.48 - 7.55 ( m, 1 H), 7.69 (d, J = 1.6 Hz, 1 H), 7.71 - 7.80 (m, 2 H), 8.46 (d, J = 7.4 Hz, 1 H), 8.77 (s, 2 H)
[M+H] ⁺ = 448.2 178 ¹ H NMR (500 MHz, DMSO-d6) δ ppm 0.51 - 0.64 (m, 2 H), 0.87 - 0.99 (m, 2 H), 1.81 (br t, J = 5.6 Hz, 2 H), 1.94 (tt , J = 8.4, 5.2 Hz, 1 H), 2.57 - 2.77 (m, 4 H), 3.19 - 3.61 (m, 4 H), 3.23 - 3.30 (m, 4 H), 6.78 (d, J = 7.7 Hz , 1 H), 6.95 (t, J = 1.8 Hz, 1 H), 7.07 (dt, J = 8.2, 1.1 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.26 (t, J = 7.8 Hz, 1 H), 7.67 (d, J = 1.9 Hz, 1 H), 7.73 - 7.80 (m, 2 H), 8.73 - 8.81 (m, 2 H)
[M+H] ⁺ = 447.3 179 ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.50 - 0.62 (m, 2 H), 0.86 - 0.98 (m, 2 H), 1.07 - 1.38 (m, 3 H), 1.60 - 2.86 (m, 8 H), 2.88 - 3.07 (m, 2 H), 3.24 - 3.30 (m, 4 H), 3.74 (br dd, J = 11.4, 5.9 Hz, 2 H), 6.40 (br d, J = 7.9 Hz, 1 H), 6.59 (br d, J = 2.0 Hz, 1 H), 6.62 (br d, J = 7.9 Hz, 1 H), 7.04 - 7.19 (m, 2 H), 7.55 (s, 1 H), 7.67 (d, J = 1.5 Hz, 1 H), 7.75 (dd, J = 8.3, 1.5 Hz, 1 H), 8.77 (br s, 2 H)
[M+H] ⁺ = 448.3 180 ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (bs, 1H), 7.94 - 7.87 (m, 2H), 7.51 (bs, 1H), 7.32 - 7.27 (m, 2H), 7.23 - 7.15 (m, 2H ), 3.67 - 3.61 (m, 4H), 3.54 (q, J = 5.7 Hz, 2H), 3.31 (t, J = 5.6 Hz, 4H), 2.52 (t, J = 6.0 Hz, 2H), 2.46 (bs , 4H), 2.28 (s, 3H), 1.98 - 1.88 (m, 2H), 1.77 (quint, J = 6.0 Hz, 2H)
[M+H] ⁺ = 479.4 181 ¹ H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.23 (s, 1H), 8.67 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H ), 8.17 (dd, J = 8.8, 2.1 Hz, 1H), 7.96 (s, 0H), 7.72 (s, 1H), 7.64 - 7.56 (m, 1H), 7.45 (dd, J = 4.9, 1.8 Hz, 2H), 7.25 - 7.22 (m, 1H), 3.56 (td, J = 7.1, 2.8 Hz, 2H), 3.29 (s, 3H), 2.63 (t, J = 7.1 Hz, 2H), 1.36 (s, 3H ), 0.75 - 0.71 (m, 2H), 0.63 - 0.58 (m, 2H)
[M+H] ⁺ = 484.2

The following examples are given by way of illustration 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 structures of the obtained products were confirmed by NMR spectra.

EXAMPLES

Example 1: compound (22) in table I

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

¹ H NMR (300 MHz, d ₆ -DMSO) δ 11.39 (s, 1H), 8.76 (d, J = 4.8 Hz, 2H), 8.34 (d, J = 8.8 Hz, 2H), 8.16 (d, J = 8.8 Hz, 2H), 7.30 (t, J = 4.8 Hz, 1H).

Following route (E), 4-nitro-N-(pyrimidin-2-yl)benzamide (1 g, 4.1 mmol, 1 eq.) and 10% Pd/C (2.2 g) were placed in EtOH ( 20.5 ml). The reaction mixture was stirred at room temperature for 16 hours under H ₂ atmosphere. 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 silica gel column chromatography to give 4-amino-N-(tetrahydropyrimidin-2(1H)-ylidene)benzamide (580 mg, 65%).

¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.77 (s, 2H), 7.75 (d, J = 8.5 Hz, 2H), 6.48 (d, J = 8.5 Hz, 2H), 5.50 (s, 2H) , 3.28 (t, J = 5.7 Hz, 4H), 1.86–1.76 (m, 2H).

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

^1H NMR (300 MHz, _CDCl3 ) δ 7.89 (t, J = 1.7 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.30 (t , J = 7.9 Hz, 1H), 6.07 (s, 1H), 3.46 (dd, J = 7.4, 5.9 Hz, 2H), 1.90 - 1.76 (m, 3H), 1.67 - 1.52 (m, 6H), 1.20 - 1.09 (m, 2H).

Following route (A1), the reaction mixture of 3-bromo-N-(2-cyclopentylethyl)benzamide (296 mg, 1.0 mmol, 1 eq.), 4-amino-N-(tetrahydropyrimidin-2(1H)-ylidene )benzamide (218 mg, 1.0 mmol, 1 eq.), Pd ₂ (dba) ₃ (92 mg, 0.1 mmol, 10 mol%), XPhos (95 mg, 0.2 mmol, 20 mol%) and K ₂ CO ₃ (553 mg, 4.0 mmol, 4 eq.) in t-BuOH (4 ml) was heated in a microwave reactor at 120°C for 60 minutes. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give N-(2-cyclopentylethyl)-3-({4-[(tetrahydropyrimidin-2(1H)-ylidene)carbamoyl]phenyl}amino)benzamide (22) (240 mg, 55%.

¹ H NMR (300 MHz, d ₆ -DMSO) δ 8.77 (s, 2H), 8.55 (s, 1H), 8.37 (t, J = 5.6 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H) , 7.59 (s, 1H), 7.37 - 7.29 (m, 2H), 7.27 - 7.21 (m, 1H), 7.02 (d, J = 8.7 Hz, 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).

¹³ C JAMR (75 MHz, D ₆ -DMSO) δ 175.0, 166.6, 159.1, 145.8, 143.1, 136, 131.1, 130.4, 129.6, 120.5, 119.7, 119.4, 116.9, 115.1, 38.6, 37.9, 35.9, 32.7, 25.2.2.2.2.2.2.2.2 , 20.5

[M+H] ⁺ =434.0

Example 2 Compound (97) in Table I

3-Bromophenol (701 mg, 3.97 mmol, 1.2 eq.) was taken up in N,N-dimethylformamide (4 ml) with Cs ₂ CO ₃ (1.3 g, 3.97 mmol, 1.2 eq. ). After adding (3-bromopropyl)cyclohexane (715 mg, 3.31 mmol, 1 eq.), the reaction mixture was stirred at room temperature for 16 hours under an inert argon atmosphere. A saturated NaHCO ₃ aqueous solution was added to the reaction mixture, 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 silica gel column chromatography to give 1-bromo-3-(3-cyclohexylpropoxy)benzene (882 mg, 90%).

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

According to procedure (A1), the reaction mixture of 1-bromo-3-(3-cyclohexylpropoxy)benzene (547 mg, 1.84 mmol, 1.1 eq.), methyl 4-amino-3-cyclopropyl-benzoate (320 mg, 1.67 mmol, 1 eq.), BrettPhos Pd G3 (31.9 mg, 33.5 µmol, 2 mol%) and Cs ₂ CO ₃ (818 mg, 2.51 mmol, 1.5 eq.) in anhydrous DMF (8 ml) was degassed with N ₂ and heated at 80°C for 75 minutes in an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with a pad of EtOAc. Then, a saturated aqueous sodium chloride solution was added to the filtrate, and the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give methyl 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoate (1.35 g, 80%).

¹ H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.66 (dd, J = 8.5, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.24 - 7.14 (m , 2H), 6.76 (d, J = 7.9 Hz, 1H), 6.73 (t, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.1, 2.2 Hz, 1H), 3.92 (t, J = 6.5 Hz , 2H), 3.78 (s, 3H), 1.94 (ddd, J = 13.8, 8.3, 5.4 Hz, 1H), 1.75 - 1.58 (m, 7H), 1.35 - 1.08 (m, 6H), 1.04 - 0.94 (m , 2H), 0.88 (q, J = 10.0, 9.3 Hz, 2H), 0.65–0.56 (m, 2H).

Following procedure (K), methyl 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoate (575 mg, 1.34 mmol, 1 eq) was taken up in methanol (10 ml) and added 2 M NaOH aqueous solution (4.7 ml, 9.4 mmol, 7 eq.). The reaction mixture was heated at 80°C and stirred for 3 hours. It was concentrated under reduced pressure and after addition of 2 M aqueous HCl solution (7 ml, 14 mmol, 10.5 eq.) was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (540 mg, 97%).

¹ H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.76 (s, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H ), 7.18 (t, J = 8.6 Hz, 2H), 6.74 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 6.53 (dd, J = 8.1, 2.1 Hz, 1H ), 3.91 (t, J = 6.5 Hz, 2H), 1.94 (ddd, J = 13.6, 8.4, 5.4 Hz, 1H), 1.75 - 1.58 (m, 7H), 1.35 - 1.09 (m, 6H), 0.98 ( dd, J = 4.0, 2.0 Hz, 2H), 0.88 (q, J = 10.1, 9.3 Hz, 2H), 0.65 - 0.56 (m, 2H).

According to procedure (L) a reaction mixture of 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (100 mg, 241 µmol, 1 eq.) and CDI (47.0 mg, 290 µmol , 1.2 eq.) in anhydrous DMF (1.0 ml) was stirred at room temperature for 1 hour. The mixture was then added to a solution of beta-alacleatinin hydrochloride (72.2 mg, 483 µmol, 2 eq.) and diisopropylethylamine (DIPEA) (126 µl, 724 µmol, 3 eq.) in anhydrous DMF (1.0 ml), and the resulting as a result, the mixture was heated at 75°C and stirred for 16 hours. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. Then the combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-[(2E)-4-oxo-1,3-diazinan-2- ylidene]benzamide (97) (75.0 mg, 62%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 10.78 (s, 1H), 10.15 (s, 1H), 7.85 - 7.77 (m, 2H), 7.67 (s, 1H), 7.15 (t, J = 8.4 Hz, 2H), 6.70 (d, J = 7.9 Hz, 1H), 6.67 (t, J = 2.1 Hz, 1H), 6.47 (dd, J = 8.1, 2.1 Hz, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.54 (t, J = 7.0 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 1.94 (ddd, J = 13.7, 8.4, 5.5 Hz, 1H), 1.69 (t, J = 14.5 Hz, 7H), 1.34 - 1.08 (m, 6H), 1.02 - 0.81 (m, 4H), 0.61 (q, J = 5.8 Hz, 2H).

¹³ C NMR (151 MHz, d ₆ -DMSO) δ 160.0, 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, 33.6, 2 , 26.3, 11.5, 7.6

[M+H] ⁺ = 489.1

Example 3 Compound (98) in Table I

1-1H- 1,2,3-triazolopyridinium-3-oxide-hexafluorophosphate (HATU) (3.78 g, 9.95 mmol, 1 eq.) and DIPEA (2.60 ml, 114.9 mmol, 1.5 eq.) and then stirred the reaction mixture at room temperature overnight. The reaction mixture was quenched with 1 M aqueous hydrochloric acid and extracted with EtOAc. Then the combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-N-isopropylbenzamide (1.88 g, 76%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 8.34 (d, J = 7.4 Hz, 1H), 8.03 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.43 (t, J = 7.9 Hz, 1H), 4.17 - 4.00 (m, J = 6.7 Hz, 1H), 1.17 (d, J = 6.6 Hz, 6H).

According to path (A1), the reaction mixture of 3-bromo-N-isopropylbenzamide (197 mg, 0.796 mmol, 1.1 eq.), methyl 4-amino-3-tert-butyl benzoate (150 mg, 0.724 mmol, 1 eq.), Pd(OAc) ₂ (4.9 mg, 0.022 µmol, 3 mol%), rac-BINAP (9.0 mg, 0.015 mmol, 2 mol%) and K ₂ CO ₃ (300 mg, 2 ,17 mmol, 3 eq.) in anhydrous toluene (3 ml) was degassed with N ₂ and heated at 110° C. for 75 minutes under an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with a pad of EtOAc. Then, a saturated aqueous sodium chloride solution was added to the filtrate, and the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give methyl 3-tert-butyl 4-{[3-(isopropylcarbamoyl)phenyl]amino}benzoate (163 mg, 60%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 8.09 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.3, 1.9 Hz, 1H) , 7.39 (s, 1H), 7.33 - 7.22 (m, 3H), 7.17 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 4.07 (dq, J = 13.4, 6.6 Hz, 1H), 3.83 (s, 3H), 1.42 (s, 9H), 1.15 (d, J = 6.6 Hz, 6H).

According to procedure (K), methyl 3-tert-butyl-4-{[3-(isopropylcarbamoyl)phenyl]amino}benzoate (160 mg, 0.434 mmol, 1 eq) was taken up in methanol (2 mL) and 2 M aqueous NaOH solution (1.3 ml, 2.61 mmol, 6 eq.). The reaction mixture was heated at 80°C and stirred for 3 hours. It was then concentrated under reduced pressure and, after addition of 2 M 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 (142 mg, 90%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 12.64 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 8.02 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H) , 7.35 (s, 1H), 7.27 - 7.19 (m, 3H), 7.16 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 6.5 Hz, 1H), 4.14 - 3.99 (m, 1H), 1.42 (s, 9H), 1.15 (d, J = 6.6 Hz, 6H).

According to procedure (L), a reaction mixture of 3-tert-butyl-4-{[3-(isopropylcarbamoyl)phenyl]amino}benzoic acid (65.0 mg, 180 µmol, 1 eq.) and CDI (35.0 mg , 216 μmol, 1.2 eq.) in anhydrous DMF (1.0 ml) was stirred at room temperature for 1 hour. The mixture was then added to a solution of beta-alacleatinin hydrochloride (53.8 mg, 359 µmol, 2 eq.) and DIPEA (93.9 µl, 539 µmol, 3 eq.) in anhydrous DMF (1.0 ml) and the resulting the mixture was heated at 75°C and stirred for 16 hours. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. Then the combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-tert-butyl-4-{[3-(isopropylcarbamoyl)phenyl]amino}-N-[(2E)-4-oxo-1,3-diazinan-2- ylidene]benzamide (98) (37.0 mg, 45%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 10.83 (s, 1H), 10.21 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H) , 7.90 (dd, J = 8.2, 1.8 Hz, 1H), 7.29 (s, 1H), 7.18 (s, 3H), 7.13 (d, J = 8.2 Hz, 1H), 6.90 - 6.82 (m, 1H), 4.06 (dq, J = 13.3, 6.6 Hz, 1H), 3.56 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.41 (s, 9H), 1.14 (d, J = 6.6 Hz, 6H).

¹³ C JAMR (151 MHz, D ₆ -DMSO) δ 177.4, 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, 35.22.2, 35.2 , 30.9, 30.5, 22.8

[M+H] ⁺ =450.1

Example 4 Compound (102) in Table I

Following route (A1), the reaction mixture of 3-bromo-N-isopropylbenzamide (135 mg, 0.547 mmol, 1.1 eq.), methyl 4-amino-3-cyclopropyl benzoate (100 mg, 0.497 mmol, 1 eq. .), BrettPhos Pd G3 (23.7 mg, 24.8 μmol, 5 mol%) and Cs ₂ CO ₃ (243 mg, 0.745 mmol, 1.5 eq.) in anhydrous DMF (2 ml) were degassed with N ₂ and heated at 80°C for 75 minutes in an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with a pad of EtOAc. Then, a saturated aqueous sodium chloride solution was added to the filtrate, and the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give methyl 3-cyclopropyl-4-{[3-(isopropylcarbamoyl)phenyl]amino}benzoate (131 mg, 71%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 8.17 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.67 (dd, J = 8.8, 1.9 Hz, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.47 (dt, J = 7.6, 1.3 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.31 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 4.09 (dq, J = 13.3, 6.6 Hz, 1H), 3.79 (s, 3H), 1.96 (tt, J = 8.3, 5.6 Hz, 1H), 1.16 (d , J = 6.6 Hz, 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 (130 mg, 0.350 mmol, 1 eq.) was taken up in methanol (2 mL) and 2 M aq. NaOH solution (0.88 ml, 1.75 mmol, 5 eq.). The reaction mixture was heated at 80°C and stirred for 3 hours. It was then concentrated under reduced pressure and, after addition of 2 M 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 (115 mg, 92%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 12.38 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.69 - 7.61 (m, 2H), 7.54 ( d, J = 2.0 Hz, 1H), 7.44 (dt, J = 7.6, 1.3 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.29 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H ), 7.12 (d, J = 8.5 Hz, 1H), 4.09 (dq, J = 13.2, 6.6 Hz, 1H), 1.96 (tt, J = 8.3, 5.4 Hz, 1H), 1.16 (d, J = 6.6 Hz , 6H), 1.03 - 0.92 (m, 2H), 0.68 - 0.57 (m, 2H).

According to procedure (L), a reaction mixture of 3-cyclopropyl-4-{[3-(isopropylcarbamoyl)phenyl]amino}benzoic acid (82.0 mg, 230 µmol, 1 eq.) and CDI (44.8 mg, 276 μmol, 1.2 eq.) in anhydrous DMF (1.0 ml) 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 (65.7 mg, 460 µmol, 2 eq.) and DIPEA (120 µl, 691 µmol, 3 eq.) in anhydrous DMF (1 0 ml), and the resulting mixture was heated at 75°C and stirred for 16 hours. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. Then the combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography followed by preparative HPLC (high performance liquid chromatography) to obtain 3-cyclopropyl-N-(1,3-diazinan-2-ylidene)-4-{[3-(isopropylcarbamoyl)phenyl] amino}benzamide (102) (17.8 mg, 18%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 10.79 (s, 1H), 10.16 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.60 (t, J = 1.8 Hz, 1H), 7.38 (dt, J = 7.6, 1.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.28 - 7.21 ( m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.08 (dp, J = 13.7, 6.9 Hz, 1H), 3.54 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 1.96 (tt, J = 8.4, 5.6 Hz, 1H), 1.16 (d, J = 6.6 Hz, 6H), 1.02 - 0.92 (m, 2H), 0.67 - 0.58 (m, 2H).

¹³ C JAMR (151 MHz, D ₆ -DMSO) Δ 170.2, 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, 36.8.8, 30.5, 22.8, 11.6, 11.6 , 7.6

[M+H] ⁺ = 434.2

Example 5 Compound (120) in Table I

According to procedure (L), a reaction mixture of 3-cyclopropyl-4-{[3-(isopropylcarbamoyl)phenyl]amino}benzoic acid (50.0 mg, 148 µmol, 1 eq.) and CDI (28.8 mg, 177 μmol, 1.2 eq.) in anhydrous DMF (1.0 ml) was stirred at room temperature for 1 hour. The mixture was then added to a solution of beta-alacleatinin hydrochloride (44.2 mg, 296 µmol, 2 eq.) and DIPEA (77.2 µl, 443 µmol, 3 eq.) in anhydrous DMF (1.0 ml), and obtained in as a result, the mixture was heated at 75°C and stirred for 16 hours. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. Then the combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-cyclopropyl-4-{[3-(isopropylcarbamoyl)phenyl]amino}-N-[(2E)-4-oxo-1,3-diazinan-2-ylidene] benzamide (120) (30.0 mg, 45%).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 8.79 (s, 2H), 8.12 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.68 (s, 1H) , 7.54 (s, 1H), 7.31 (s, 2H), 7.18 (s, 1H), 7.10 (d, J = 8.3 Hz, 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 = 6.6 Hz, 6H), 0.95 (d, J = 7.4 Hz, 2H), 0.59 (d, J = 4.2 Hz, 2H ).

¹³ C JAMR (151 MHz, D ₆ -DMSO) δ 175.1, 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, 41.3.3.5, 22.8, 20.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4 , 11.6, 7.8

[M+H] ⁺ =420.3

Pharmacological data

Example 6: Chikungunya virus

The compounds of the invention have been subjected to pharmacological tests demonstrating their usefulness as active substances in therapy and in particular in the prevention, inhibition or treatment of chikungunya virus infection.

MATERIAL AND METHODS

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

The ability of compounds to inhibit viral replication was evaluated in an experiment in which infected cells were treated with compounds of formula (Ic) at a concentration of 1 μm. Ribavirin was used as a positive control for chikungunya virus inhibition. In parallel, the toxicity of the compounds was assessed.

• Cell amplification

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

• Compound preparation

100 μl of the cell suspension was dispensed into a ViewPlate-96 Black imaging plate (6005182, PerkinElmer) and a clear 96-well cell culture plate (655180, Greiner bio-one). After incubation for 24 h at 37° C. at 5% CO ₂ the compounds were added at the appropriate concentration.

• Screening at 1 µM

An intermediate dilution was prepared with DMSO (D8418, Sigma) at a concentration of 2 mM in a 96-well microplate with a V-shaped bottom of the wells from the stock solution:

Mix 1 µl of 50 mM stock library in 25 µl of DMSO (dimethyl sulfoxide).

Mix 2 µl of 25 mM stock library in 25 µl of DMSO.

• Determination of IC ₅₀ values

An intermediate dilution was prepared with DMSO (D8418, Sigma) at a concentration of 25 mM in a 96-well microplate with a V-shaped bottom of the wells from the stock solution:

Mix 2 µl of 50 mM stock library in 2 µl of DMSO.

Perform a serial dilution in 2 μl of DMSO 13 times until reaching 0.0015 mm. Continue as described in Table III:

Table III

Concentration (mM) Volume DMSO 100% (µl) Solution volume A 12.5 2 2 µl 50 mM solution B 6.25 2 2 µl solution A C 3.125 2 2 µl solution B D 1.56 2 2 µl solution C E 0.78 2 2 µl solution D F 0.39 2 2 µl solution E G 0.195 2 2 µl solution F H 0.0976 2 2 µl solution G I 0.0488 2 2 µl H solution J 0.0244 2 2 µl solution I K 0.0122 2 2 µl solution J L 0.0061 2 2 µl K solution M 0.0030 2 2 µl solution L N 0.0015 2 2 µl solution M

For both screening and IC ₅₀ determination, 1 μl of each solution was added to 1 ml wells of a Masterblock 96-well master plate (Greiner bio-one, 780261) containing 1 ml of DMEM medium. As a positive control, 5 μl of 80 mM ribavirin solution (R9644, Sigma) was added to 1 ml of DMEM medium. On the other hand, DMSO was used as a negative control.

• Infection

Cells were infected with 30 µl of the Réunion outbreak-isolated CHIKV strain (LR2006-OPY1) modified by the insertion of the green fluorescent protein (GFP) gene at 5' (CHIK 5'LR) (Tsetsarkin K, Higgs S, McGee CE, De Lamballerie X, Charrel RN, Vanlandingham DL Infectious Clones of Chikungunya Virus (La Réunion-Isolate - Ref-SKU: 001N-EVA249 (PMID: 17187566), available at the following address: https://www.european-virus-archive. com/nucleic-acid/chikv-lr-5gfp-infectious-clone) for Vector Competence Studies Vector Borne Zoonotic Dis 2006; 6(4)). This modified virus was used to infect cells at a MOI of 0.1. The LR2006-OPY1 CHIKV strain (CHIKV-LR) was obtained from the World Reference and Research Center for Arboviruses, University of Texas Medical School, Galveston, Texas, USA. This strain was originally isolated from the blood serum of a French patient with fever who returned from Reunion Island.

• Cell lysis

After 22 h at 37° C. under 5% CO ₂ , the medium was removed and the cells were washed as described above. 60 µl of RIPA buffer solution (50 mM Tris-HCl pH 8, 100 mM NaCl, 1 mM MgCl₂, 1% Triton X-100) was added to the cells and incubated for at least 20 min, after which the fluorescence signal was read. To normalize the fluorescent signal by the amount of protein, Pierce 660 nm protein quantification reagent (22660, Thermo scientific) was used.

The CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) (G3581, Promega) was used to test for compound toxicity. Added 20 μl of MTS solution and after one hour read the optical density at 492 nm.

results

- Performed the first round of experiments, in which the results are expressed as a percentage of inhibition, which was calculated as follows in the following stages:

1. Fluorescence intensity (FI)/optical density 660 nm (A660) = A

This ratio makes it possible to correlate the infection (virus with GFP) with the amount of protein.

2. A' = A - background noise on the plate with uninfected cells,

3. B = fluorescence intensity (FI)/absorbance 660 nm (A660) of plates with infected but untreated cells,

4. The ratio C=A'/B is then converted to percent infection after treatment compared to the untreated sample and subsequently to percent infection. For example, a value of 100 in Table IV below means that after processing, the signal characteristic of GFP fluorescence is eliminated, which corresponds to the absence of infection.

5. C' = 100 - C

This value corresponds to the percentage of inhibition.

The following table IV includes the indicated C' value for some compounds, calculated as described above, representing the average of 2 experiments, and the corresponding standard deviation.

Some values were originally higher than 100. In these cases, the value was reduced to 100. This means that some molecules also affect cell viability. In other words, the value of A may be lower than the background noise.

In addition, for each indicator, the test was performed using ribavirin as a control. The value of the percentage of inhibition was checked taking into account 100%.

Table IV

Etc.
Etc. CHIKV inhibition, % Mean (n=2) Standard deviation (n=2) 22 94 5 23 98 0 24 100 0 26 97 0 27 96 1 28 97 0

- Performed the second round of experiments with results in the form of IC ₅₀ values.

IC ₅₀ values range from 0.1 nM to 1 μM, in particular from 0.5 to 500 nM, and even more specifically from 1 to 400 nM, for example from 1 to 200 nM. For example, compounds 22, 23 and 24 have IC ₅₀ values ranging from 100 to 400 nM.

Conclusion

Based on the results described above, it can be concluded that the compounds of formula (Ic) are suitable chemical compounds for the treatment and/or prevention of RNA viral infections caused by group IV RNA viruses, more specifically alphavirus infections, and most specifically chikungunya viral infections.

Example 7: RSV virus

The compounds of the invention have been subjected to pharmacological tests demonstrating their usefulness as active ingredients in therapy and in particular in the prevention, inhibition or treatment of RSV viral infection.

MATERIAL AND METHODS

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

HEp-2 cells were maintained in Eagle's Minimal Essential Medium (EMEM) balanced with Earle's salts (BSS) to contain 2 mM L-glutamine, 10% fetal bovine serum, 100 U/mL penicillin, and 100 µg/ml streptomycin. For screening purposes, cells were grown to 90% confluency, trypsinized, and isolated. The trypsin was neutralized with the cell culture medium and the cells were centrifuged at 150 xg for 5 minutes, after which the supernatant was discarded and the cell pellet was resuspended in assay medium (EMEM balanced with Earle's salts (BSS) such that it contained 2 mM L-glutamine, 2% fetal bovine serum, 100 U/ml penicillin and 100 µg/ml streptomycin). Cells were seeded in clear bottom white cell culture plates at a density of 1.5×10 ⁴ cells/well in 50 μl and 4×10 ³ cells/well in 25 μl for 96-well plates and 384-well plates, respectively. Only analytical medium was added to the control column for medium/background determination. Tablets with cells were placed in a humidified chamber and incubated overnight at 37°C/5% CO ₂ . After overnight incubation, the confluence and healthy appearance of the cells were checked.

The concentration of test substances was adjusted to 10 times the test concentration at a maximum DMSO concentration of 10% (maximum final analytical concentration is 1% DMSO) and added to cell plates in volumes of 10 µl for 96-well plates and 5 µl for 384-well plates. In the wells for cell control and virus control was added only the solvent of the test substance. Virus or assay media was added to cytotoxicity test wells and media/background control wells immediately after test substances at an MOI of 0.5, 40, or 20 µl for 96-well and 384-well plates, respectively. To prepare the virus suspension, the original frozen cultures of RSV A2 were thawed and diluted to the required concentration in plaque-forming units in the assay medium on ice.

Cell plates were additionally incubated inside a humidified chamber for an incubation period of 72 h at 37°C/5%CO ₂ . After this incubation period, the cells were observed under a microscope to check for the characteristic cytopathic effect of the virus in the virus control wells and healthy cells in the cell control wells. After bringing the plates to room temperature, 20/40 μl of Viral ToxGlo reagent (Promega) was added to each well of 384/96-well plates. The plates were incubated at room temperature protected from light on a plate rack for 20 minutes, after which the luminescence was measured on a spectrophotometer (Biotek Synergy HTX).

RSV inhibition was calculated as percent inhibition of the cytopathic effect relative to virus control wells, and cytotoxicity was calculated as percent surviving cells relative to cell control wells. This made it possible to calculate EC ₅₀ values for each test substance in case of identification of viral inhibition or response to a cytotoxic dose. EC ₅₀ values have been established ranging from 0.001 μM to 2.5 μM, and more specifically for compounds 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 166.

Table V

Etc. EC ₅₀ (nM) 27 365 28 308 91 2 92 2 93 13 94 17 95 19 96 20 97 25 98 33 99 34 100 37 101 40 102 41 103 44 104 50 105 62 106 67 107 68 108 77 109 79 110 80 111 86 112 97 113 102 114 110 115 110 116 122 117 125 118 126 119 130 120 136 121 139 122 141 123 147 124 150 125 151 126 165 127 172 128 209 129 223 130 234 131 246 132 259 133 261 134 265 135 286 136 298 137 304 138 310 139 340 140 368 141 370 142 387 143 398 144 413 145 421 146 439 147 460 148 463 149 494 150 512 151 525 152 593 153 704 154 917 155 949 156 966 157 1030 158 1032 159 1103 161 1308 162 1374 163 1472 164 1504 165 1756 166 2739

Conclusion

Based on the results described above, it can be concluded that the compounds of formula (Ic) are suitable chemical compounds for the treatment and/or prevention of RNA viral infections caused by group V RNA viruses, more specifically pneumovirus infections and most specifically RSV viral infections.

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

Pharmaceutical compositions of the invention may contain one or more compounds of the invention in any form described herein.

Another additional object of the present invention is the use of at least one compound of formula (Ic) as defined above and compounds (19)-(31) and (91)-(181) as defined above, or one of their pharmaceutically acceptable salts according to the present invention for the preparation of a medicament for the prevention or treatment of an RNA viral infection in a subject caused by an RNA virus from group IV or group V according to the Baltimore classification of viruses, and, for example, chikungunya infection, dengue infection, flu infections or RSV infections.

Thus, the present invention relates to one compound of formula (Ic) as defined above, and to compounds (19)-(31) and (91)-(181) or one of their acceptable salts as an agent for inhibiting, preventing or treatment of an RNA virus infection, and most preferably an infection caused by a group IV or V RNA virus, and for example chikungunya infection, dengue infection, influenza infection or RSV infection.

In accordance with a specific embodiment of the invention, the treatment is continuous or intermittent.

"Continuous treatment" means long-term treatment, which can be carried out with different frequency of administration of the drug, for example, once a day, daily, once every three days, once a week, or once every two weeks, or once a month.

According to one embodiment of the invention, the compound of formula (Ic), or any of its pharmaceutically acceptable salts, is administered at a dose ranging from 0.1 to 1000 mg, in particular ranging from 0.1 to 10 mg, or, for example, ranging from 10 to 200 mg, or, for example, varying from 200 to 1000 mg.

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

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

The compounds can be administered according to any route of administration such as, for example, intramuscular, intravenous, intranasal or oral route, etc.

The compounds of the present invention may, where appropriate, be administered as prodrugs, such as esters, of the compounds to which the invention relates. "Prodrug" means a compound that can be converted in vivo through metabolism (eg, hydrolysis, reduction or oxidation) to a compound of the present invention. For example, an ester prodrug of a compound of the present invention can be converted to the parent molecule via in vivo hydrolysis. Suitable esters of the compounds of the present invention are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis-β-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyl tartrates , methanesulfonates, ethanesulfonates, benzenesulfonates, para-toluenesulfonates, cyclohexylsulfonates and quinates. Examples of ester prodrugs are as described in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, references to the compounds of the present invention are also intended to include any forms of prodrugs or metabolites.

The composition of the invention may further 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 disclosed in particular in Ullmann's Encyclopedia of Industrial Chemistry, 6 ^th Ed. (various editors, 1989-1998, Marcel Dekker) and Pharmaceutical Dosage Forms and Drug Delivery Systems (ANSEL et al., 1994, WILLIAMS & WILKINS).

The above excipients are selected according to the dosage form and the desired route of administration.

In accordance with another embodiment of the invention, pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (for example, in the form of powders, ointments or drops), transbuccal, for example, in in the form of an oral or nasal spray, etc. depending on the severity of the infection to be treated.

Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection and infusion techniques. Preferably the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions can be prepared according to methods 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 diluent or solvent suitable for parenteral administration, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as the solvent or suspension medium.

The compositions of this invention can be administered by any route, including, without limitation, oral, parenteral, sublingual, transdermal, vaginal, rectal, transmucosal, topical, intranasal via inhalation, buccal or intranasal administration, or combinations thereof. Parenteral administration includes, without limitation, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal and intraarticular administration. The compositions of this invention can also be administered in the form of an implant allowing slow release of the compositions, as well as by slow controlled IV (intravenous) infusion.

For example, the compound of formula (Ic) may be presented in any pharmaceutical form suitable for enteral or parenteral administration, in combination with appropriate excipients, for example, in the form of uncoated or coated tablets, hard gelatin capsules, soft shell capsules, and others. capsules, suppositories, or in drinkable form, such as suspensions, syrups, or in the form of injectable solutions or suspensions, in doses providing a daily administration of from 0.1 to 1000 mg of the active substance.

In a specific embodiment, the compound of formula (Ic) according to the invention is administered orally.

The oral route of administration is particularly preferred in the aspect of prophylaxis or treatment according to the invention.

Claims (128)

1. Compound of formula (Ic):

(Ic), Where: ring

and ring

both are a phenylene group or a ring

is a pyridylene group, and the ring

is a phenylene group, Z” represents a –CH ₂ – group or a –CO– group, R _g is a hydrogen atom and R _h is a hydrogen atom or a (C ₁ -C ₄ )alkyl group such as a methyl group, X ² represents a –CO–NR _k – group, where R _k is a hydrogen atom or a methyl group, group -OCH ₂ -, group –CH(OH)–, -NH-CO– group, group –O–, group –O–(CH ₂ ) _s –O–, where s is 2 or 3, group -CO-, group -SO ₂ -, a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms such as triazole, imidazole, tetrazole or oxadiazole, -NH-SO ₂ -, -NH- group or group -SO ₂ -NH-, n is 0, 1, 2 or 3, m and m' are independently 0, 1 or 2, Y ² represents hydrogen atom, halogen atom, hydroxyl group, (C ₁ -C ₄ ) alkoxy group,

, where R _f is a (C ₁ -C ₄ )alkyl group, cyano group, group

, group

, where R _q and R' _q independently represent a hydrogen atom or a methyl group, a morpholinyl group optionally substituted with a (C ₁ -C ₄ )alkyl group, piperazinyl group, piperidinyl group or a -CR ¹ R ² R ³ group, where R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom, or a (C ₁ -C ₄ )alkyl group optionally substituted with a trifluoromethyl group and/or optionally substituted with a hydroxyl group, when this implies that no more than one of R ¹ , R ² and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C ₈ )cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ )alkyl groups, a halogen atom or hydroxy group and said (C ₃ -C ₈ )cycloalkyl group is optionally interrupted by one or two oxygen atoms on said R ¹ and/or ^R2 , R represents a (C ₁ -C ₄ )alkyl group, (C ₃ -C ₆ )cycloalkyl group or a halogen atom, R' is a (C ₁ -C ₄ )alkyl group optionally interrupted by a -SO ₂ - group or -SO - group, a (C ₃ -C ₆ )cycloalkyl group or a trifluoromethyl group, or any of its pharmaceutically acceptable salts. 2. The compound of formula (Ic) according to claim 1, where X ² represents a –CO–NR _k – group, where R _k is a hydrogen atom or a methyl group, -NH-CO– group, group –O–, group -CO-, group –CH(OH)–, group -SO ₂ -, group -NH-, a divalent 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms such as triazole, imidazole, tetrazole or oxadiazole, -NH-SO ₂ - or group -SO ₂ -NH-, or any of its pharmaceutically acceptable salts. 3. The compound of formula (Ic) according to claim 1 or 2, where Y ² represents hydrogen atom, halogen atom,

, where R _f is a (C ₁ -C ₄ )alkyl group, cyano group, group

, where R _q and R' _q independently represent a hydrogen atom or a methyl group, a morpholinyl group optionally substituted with a (C ₁ -C ₄ )alkyl group, group

, (C ₁ –C ₄ ) alkoxy group or a -CR ¹ R ² R ³ group, where R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom, or a (C ₁ -C ₄ )alkyl group optionally substituted with a trifluoromethyl group, optionally substituted with a hydroxyl group, meaning that not more than one of R ¹ , R ² and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C ₈ ) the cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ ) alkyl groups, a halogen or hydroxy atom and said (C ₃ -C ₈ ) cycloalkyl group is optionally interrupted by one or two oxygen atoms on said R ¹ and/or R ² , or any of its pharmaceutically acceptable salts. 4. The compound of formula (Ic) according to any one of paragraphs. 1–3 where the ring

and ring

both are a phenylene group or a ring

is a pyridylene group and a ring

is a phenylene group, m is 0 or 1, n is 0 or 1, X ² represents group –CO–NH–, group –CO-N(CH ₃ )–, -NH-CO- group, group –O– or group -CO-, group –NH–SO ₂ –, group –CH(OH)–, group -SO ₂ -, divalent triazole, divalent imidazole, divalent tetrazole, divalent oxadiazole, -NH- group Y ² represents hydrogen atom, a morpholinyl group optionally substituted with a (C ₁ -C ₄ )alkyl group, group

, group

, where R _q and R' _q independently represent a hydrogen atom or a methyl group,

, where R _f is a (C ₁ -C ₄ )alkyl group, cyano group, (C ₁ –C ₄ ) alkoxy group or a -CR ¹ R ² R ³ group, where R ¹ , R ² and R ³ independently represent a hydrogen atom, a fluorine atom, or a (C ₁ -C ₄ )alkyl group optionally substituted with a trifluoromethyl group, optionally substituted with a hydroxyl group, meaning that not more than one of R ¹ , R ² and R ³ represents a hydrogen atom, or R ¹ and R ² together with the carbon atom bearing them (C ₃ -C ₈ ) cycloalkyl group, where the specified (C ₃ -C ₈ ) the cycloalkyl group is optionally substituted with one or two (C ₁ -C ₄ ) alkyl groups, a halogen or hydroxy atom and said (C ₃ -C ₈ ) cycloalkyl group is optionally interrupted by one or two oxygen atoms on said R ¹ and/or R ² , And R represents a (C ₁ -C ₄ )alkyl group, a (C ₃ -C ₆ )cycloalkyl group such as cyclopropyl, or a halogen atom, R' represents a (C ₁ -C ₄ )alkyl group, a (C ₃ -C ₆ )cycloalkyl group such as cyclopropyl, or a trifluoromethyl group, or any of its pharmaceutically acceptable salts. 5. The compound of formula (Ic) according to any one of paragraphs. 1–4, where ring

and ring

both are a phenylene group, m is 0, n is 1, X ² represents group –CO–NH– or group –O–, Y ² represents group -CR ¹ R ² R ³ where R ¹ , R ² and R ³ independently represent a hydrogen atom or a (C ₁ -C ₄ )alkyl group, it is understood that no more than one of R ¹ , R ² and R ³ represents a hydrogen atom, for example, an isopropyl group, or R ¹ and R ² form together with the carbon atom (C ₃ -C ₈ ) that carries them, a cycloalkyl group, such as cyclopropyl, And R' represents (C ₁ -C ₄ )alkyl group such as tert-butyl group, or (C ₃ -C ₆ )cycloalkyl group such as cyclopropyl, or any of its pharmaceutically acceptable salts. 6. The compound of formula (Ic) according to claim 1, selected from

or any of its pharmaceutically acceptable salts. 7. The use of compounds of formula (Ic) according to any one of paragraphs. 1-5 or any of its pharmaceutically acceptable salts or any of compounds (19)-(31) and (91)-(181) as defined in paragraph 6 or any of its pharmaceutically acceptable salts for treatment and/or prevention of RNA virus infection caused by an RNA virus belonging to group IV or V of the Baltimore classification of viruses, selected from RSV (respiratory syncytial virus) and chikungunya viruses. 8. Pharmaceutical composition for the treatment and/or prevention of an RNA viral infection caused by an RNA virus belonging to group IV or V of the Baltimore virus classification, selected from RSV and chikungunya viruses, containing at least one compound as defined in any of pp. 1-5, or any of its pharmaceutically acceptable salts, or at least any of compounds (19)-(31) and (91)-(181) as defined in paragraph 6, or any of its pharmaceutically acceptable salts, and also at least one pharmaceutically acceptable excipient. 9. Method of synthesis for the production of compounds of formula (Ic), as defined in any of paragraphs. 1-5, or any of its pharmaceutically acceptable salts, or a compound as defined in paragraph 6, or any of its pharmaceutically acceptable salts, comprising at least the step of coupling a compound of formula (IIc)

with a compound of formula (IIIc)

where R, R', m, m', ring

, ring

, X ² , Y ² , R _h , R _g and Z" are as defined in paragraph 1, X represents a chlorine atom, an iodine atom or a bromine atom, in the presence of an inorganic base and diphosphine and in the presence of an organometallic catalyst to obtain a compound of formula (Ic), as defined in any of paragraphs. 1-5, or any of its pharmaceutically acceptable salts, or compounds as defined in paragraph 6, or any of its pharmaceutically acceptable salts.